Slide 1

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 2

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 3

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 4

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 5

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 6

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 7

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 8

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 9

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 10

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 11

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 12

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 13

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 14

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 15

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 16

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 17

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 18

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 19

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 20

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 21

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 22

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 23

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 24

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 25

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 26

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 27

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 28

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 29

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 30

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 31

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 32

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 33

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 34

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 35

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 36

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 37

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 38

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 39

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 40

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 41

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 42

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 43

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 44

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 45

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 46

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 47

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 48

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 49

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 50

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 51

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 52

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 53

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 54

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 55

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 56

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 57

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 58

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 59

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 60

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 61

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 62

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 63

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 64

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 65

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 66

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 67

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 68

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 69

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 70

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 71

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 72

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 73

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 74

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 75

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 76

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 77

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 78

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 79

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 80

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 81

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 82

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 83

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 84

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 85

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 86

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 87

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 88

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 89

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 90

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 91

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 92

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 93

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 94

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 95

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 96

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU


Slide 97

Women and
Coronary Artery Disease
(CAD)
Prof. Roland KASSAB
Head of Division of Cardiology, HDF
Metropolitan Palace Hotel, Beirut
1st May 2010

Women and CAD










Epidemiology
Cardiovascular risk factors
Risk stratification
Diagnosis
Prognosis and treatment outcome
JUPITER: meta-analysis of Women
PCI and CABG
Hormone replacement therapy
Concluions

PROGNOSTIC VALUE : BNP

Epidemiology
Statistics on Women and
Cardiovascular Disease
 Comparisons to Men
 Age Differences Among Women
 Racial and Ethnic Group
Differences

CVD and Other Major Causes of Death
for Women in the United States: 2004
500,000
400,000
300,000
200,000
100,000
0
Total CVD

CHD

Cancer

Source: Adapted from American Heart Association 2008

Stroke

Asthma +
COPD

Congestive Heart Failure: Gender
Differences


Compared to men, women with heart failure
are:






Older
More likely to have hypertension
More likely to have diabetes
More likely to have diastolic dysfunction







Knowledge of diastolic dysfunction
prognosis and treatment is limited
Trials of congestive heart failure treatments
have included mainly men
Source: Stromberg 2003

Cardiovascular Disease Mortality:
U.S. Males and Females 1980-2004
550,000

500,000
Men
Women

450,000

400,000
1980

1985

1990

1995

Source: Adapted from American Heart Association 2008

2000

2004

Annual Numbers of U.S. Adults Diagnosed with
Myocardial Infarction and Fatal CHD
by Age and Sex Categories: 1987-2004
300,000

200,000
Men
Women

100,000

0
35-44

45-64

65-74

Age in Years
Source: Adapted from American Heart Association 2008

75+

Acute MI Mortality by Age and
Sex
30
25
Men

20
Death During
Hospitalization
(%)

Women

15
10
5
0
<50

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age

Source: Adapted from Vaccarino 1999

Racial and Ethnic Groups




Cardiovascular disease is the leading
cause of death for African Americans,
Latinos, Asian Americans, Pacific
Islanders, and American Indians
African American women are at the
highest risk for death from heart
disease among all racial, ethnic,
and gender groups

Source: American Heart Association 2004

Age-adjusted Death Rates for Leading
Causes of Death in White and Black/African
American Women: U.S. 2004
150
100
Per
100,000
Population

Black/African
American Women
White Women

50
0
CHD

Stroke

Lung
Cancer

Source: Adapted from American Heart Association 2008

Breast
Cancer

Summary 1




Among U.S. women, cardiovascular disease
is the leading cause of death
Among U.S. women, cardiovascular disease
is the leading cause of death for whites,
African Americans, Latinas, Asian
Americans, Pacific Islanders, and American
Indians
Source: American Heart Association 2008

Summary 2




Mortality from CVD has decreased more
for men in the past 20 years than for
women
Over 10,000 women under age 45 suffer
an acute myocardial infarction every year

Source: American Heart Association 2008

Are All Statins Born Alike ?

Cardiovascular Risk Factors in
Women


Unmodifiable





Age
Family History

Modifiable









Diabetes
Dysplipidemia
Hypertension
Obesity
Poor Diet
Sedentary Lifestyle
Cigarette Smoking

Source: ATP III 2002, Mosca 2007

Approximate and Cumulative LDL
Cholesterol Reduction Achievable By
Dietary Modification
Dietary Component

Dietary Change

Major
Saturated fat
Dietary cholesterol
Weight reduction
Other LDL-lowering options
Viscous fiber
Plant/sterol
stanol esters
Cumulative estimate

Approximate
LDL Reduction

<7% of calories
<200 mg/day
Lose 10 lbs

8-10%
3-5%
5-8%

5-10 g/day
2g/day

3-5%
6-15%

Source: Adapted from ATP III 2002

20-30%

Treatable Risk Factors: The Epidemiology of
Cholesterol Levels and Subfractions






Low HDL more important in women than men
 For every 1 mg/dL increase in HDL 3% decrease
in CHD risk for women and 2% decrease in CHD
risk for men
Total cholesterol/HDL ratio very predictive of CHD
risk in women
Triglyceride elevation associated with greater
atherogenic significance in women than in men
Source: Maron 2000

Treatable Risk Factors: Cholesterol
Level and Subfractions






LDL>160 mg/dL associated with 3.3-fold
elevation in risk for women less than 65 years
old
LDL pattern of small, dense particles (more
atherogenic) present in 25% of population,
but less frequently seen in women
Menopausal transition associated with
increasing proportion of this subfraction
Source: Keil 2000, Carr 2000, Hokanson 1996

Relative Risk of Various Factors for
CHD for Women and Men
2.4

Relative Risk

2.5

1.9

2
1.5

1.5 1.5

1.8
1.6

1.4

1.3

1.4
Men
Women

1.1
1

0.5

0
HTN
Source: MMWR 1992

CHOL

DM

Obesity

Smoking

Relative Risk of Cardiovascular Events
According to Baseline Levels of hs-CRP
in Healthy Postmenopausal Women
5

4.4

4
Relative
Risk

3

2.1

2
1

2.1

1

0
Median = 0.06
mg/dl

Median = 0.19
mg/dl

Median = 2.1
mg/dl

Quartile of Plasma Levels

Source: Ridker 2000

Median = 4.4
mg/dl

P for trend < 0.001

Fibrinogen Levels and CHD Risk in
Women

Odds Rate for CHD
Event*

3.5
2.98

3
2.5

2.19

2

1.7

1.5
1

1

0.5
0

Source: Eriksson 1999

P for trend <0.0001
 2.8

>2.8,  3.1

>3.1,  3.6

>3.6

Fibrinogen, g/L

*Adjusted for age, smoking, BMI, systolic blood pressure, total
cholesterol, HDL, triglycerides, and educational level

Relative Risk of Cardiovascular Events
According to Baseline Levels of
Homocysteine in Healthy Postmenopausal
Women
2

2
1.5
1

Relative Risk

1

1.1

1.1

0.5
0

P for trend = 0.02 (not significant)
1
Median = 8.2
μ mol/liter

2
Median = 10.3
μ mol/liter

3
Median = 12.1
μ mol/liter

Quartile of Plasma Levels
Source: Ridker 2000

4
Median = 15.7
μmol/liter

Psychosocial Stressors in Women
with CHD: The Stockholm Female
Coronary Risk Study




Among women who were married or
cohabitating with a male partner, marital
stress was associated with nearly 3-fold
increased risk of recurrent CHD events
Living alone and work stress did not
significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Depression and CHD: Results from
the Women’s Health Initiative Study


Depression is an independent
predictor of CHD death among
women with no history of CHD

Source: Wassertheil-Smoller 2004

Risk Stratification:


High Risk



Diabetes mellitus
Documented atherosclerotic disease









Established coronary heart disease
Peripheral arterial disease
Cerebrovascular disease
Abdominal aortic aneurysm

Includes many patients with chronic kidney disease,
especially ESRD
10-year Framingham global risk > 20%, or high risk
based on another population-adapted global risk
assessment tool

Source: Mosca 2007

Risk Stratification:


At Risk:
 > 1 major risk factors for CVD, including:













Cigarette smoking
Hypertension
Dyslipidemia
Family history of premature CVD (CVD at < 55 years in a male
relative, or < 65 years in a female relative)
Obesity, especially central obesity
Physical inactivity
Poor diet

Metabolic syndrome
Evidence of subclinical coronary artery disease (eg
coronary calcification), or poor exercise capacity on
treadmill test or abnormal heart rate recovery after
stopping exercise

Source: Mosca 2007

Definition of Metabolic
Syndrome in Women








Abdominal obesity - waist circumference >
35 in.
High triglycerides ≥ 150mg/dL
Low HDL cholesterol < 50mg/dL
Elevated BP ≥ 130/85mm Hg
Fasting glucose ≥ 100mg/dL

Source: AHA/NHLBI 2005

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Source: http://www.nhlbi.nih.gov/about/framingham/riskabs.htm

Diagnosis of Coronary Artery
Disease in Women






Chest pain is experienced by most women with CHD, but
non-chest pain presentations are more common in women
than men
Other Presenting Symptoms
 Upper abdominal pain, fullness, burning sensation
 Shortness of breath
 Nausea
 Neck, back, jaw pain

Associations
 Precipitated by exertion
 Precipitated by emotional distress
Source: Charney 2002, Goldberg 1998

Testing for Ischemic Heart Disease
in Women and Factors to Consider
Technique

Assessment

Angiography

Coronary
anatomy
Coronary CT
Coronary
calcification,
and anatomy
Echocardiography Regional wall
motion
Nuclear Cardiology Regional blood
flow
Source: Charney 2002, Greenland 2007

Issues in Women
Less focal disease
Less well-validated
than other techniques

Reader expertise
variable
Attenuation issues

Drawbacks of Diagnostic Imaging in
Women






Low exercise capacity – likelihood of reaching
adequate pressure rate product
 Solution: Pharmacologic stress testing
Breast attenuation artifact – higher false positive
imaging studies
 Solution: Gated acquisition; attenuation
correction for nuclear imaging
 Solution: Echocardiography
Lower pretest probability of CAD – higher false
positive rate
 Solution: Integrate clinical variables, risk
factors, into decision-making process
Source: Duvernoy, personal communication

Value of the Exercise ECG in
Women
80
70

77
70

68
61

60
50
Men
Women

40
30
20
10
0
Source: Kwok 1999

Sensitivity

Specificity

Value of Stress Echocardiography
Compared to Stress ECG in
Women
100
90
80
70
60
% 50
40
30
20
10
0

81

77

81

80
56

64

*

**

Echo
ECG

*P < 0.004 vs. Echo
**Old P < 0.005 vs. Echo

Sensitivity
Source: Marwick 1995

Specificity

Accuracy

CHD: Differences in Presentation
and Findings in Women Compared to
Men
 Lower

prevalence of MI
 More severe CHF
 More severe angina
 Less angiographic CAD
 More ostial lesions
 More microvascular dysfunction?
 Abnormal vasomotor tone?
 More endothelial dysfunction?
Source: Jacobs 2003

Women and CHD:
What Test to Order When








For women at high or intermediate risk of coronary
artery disease, consider treadmill echocardiogarphy or
nuclear perfusion imaging
For women unable to exercise, consider dobutamine
stress echocardiography or adenosine or dipyridamole
nuclear imaging
In high risk women with typical symptoms of coronary
artery disease, consider coronary angiography
For high risk women, consider cardiac catheterization
if symptoms persist despite negative non-invasive
imaging

Source: Anderson 2007, Klocke 2003, Douglas 2008, Duvernoy 2005

Women and CHD:
What Test to Order When




A stepwise approach beginning with conventional
exercise testing may be considered for women who:
 Are at low or intermediate risk for coronary artery
disease
 Are able to exercise
 Have an electrocardiogram that can be interpreted
during stress testing
An image-enhanced test may be more predictive in
women than conventional electrocardiogram stress
testing, and may also be more cost effective in women at
intermediate risk for CHD

Source: Anderson 2007, Klocke 2003, Douglas 2008,Mieres 2005

PROGNOSTIC VALUE : pro-BNP

Cardiovascular Disease in
Women : Prognosis and
Treatment Outcomes

Women Received Less Interventions
to Prevent and Treat Heart Disease








Less cholesterol screening
Less lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin
during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators
compared to men with the same recognized
indications
Sources: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005, Chou 2007, Hernandez 2007, Cho 2008

Prognosis After MI
 38% of women die within first year
 Compared to 25% of men
 35% of women will have second MI within
6 years
 Compared to 18% of men

Source: Wenger 2004

Prognosis






Women < 65 yrs have 2 X mortality rate after MI
compared to men of same age
After MI, women have significantly higher rates of:
 Depression
 Physical disability

After CABG, women have significantly higher rates of:
 Hospital readmission
 Reduced mental health and physical functioning
Source: Vaccarino 1999, Ades 2002, Lauzon 2003, Vaccarino 2003

Undertreatment of MI in Women


Compared with men:
 Less emergent thrombolysis
 Less acute catheterization and
angioplasty
 Less acute surgical revascularization
 Less use of heparin, beta-blockers, and
aspirin

Source: Chandra 1998, Nohria 1998

Benefits of ASA in Women with
Established CAD
10
9
8
7
6
Mortality
at 3 Years 5
Follow-Up (%) 4
3
2
1
0

9.1

5.1

5.1

2.7 *
* P = 0.002 **P
= 0.0001

Aspirin
Source: Adapted from Harpaz 1996

**

CVD
Mortality
All Cause
Mortality

No Aspirin

Addition of Clopidogrel to Aspirin
and Fibrinolytic Therapy for MI with
ST-Segment Elevation in Women
30
24.7

25
% with
Antiographic
Reocclusion,
Death, or
Recurrent MI
Before
Angiography

20

16.9

15
10
5
0
Clopidogrel

Source: Sabatine 2005

Placebo

P < 0.05; reduction
in odds = 38%

*P <0.05
compared
with white
men

Relative Risk

Adjusted Odds for Use of Implantable
Cardioverter-Defibrillator According
to Guidelines by Race and Sex
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

*

White Men

Source: Adapted from Hernandez 2007

Black Men

*

*

White
Women

Black
Women

Gender Gap in Dyslipidemia
Treatment






Significantly more men than women have
annual cholesterol measurements

Significantly more men than women
receive effective lipid-lowering therapy
African Americans receive less lipidlowering treatment compared to whites

Source: O’Meara 2004, Hendrix 2005, Chou 2007, Cho 2008

Meta-Analysis of 11 Clinical Trials of
Statin Therapy Including 15,917
Women with Known CHD
0

CHD Events

Non-Fatal MI

CHD Mortality

-5
-10
-15

%
-20
Reduction
-25

-21
-26

-30
-35
-40
Source: Grady 2003.

-36

Relative Risk
(Cox regression analysis)

Simvastatin and Gender Risk
for CHD and Mortality
1.2

1.12

1
0.8
0.6

0.66*

0.65* 0.66*

0.4

Women
Men

0.2
0

Total Death

Source: Scandinavian Simvastatin Survival Study Group 1994

Major Coronary
Event

*P <0.05

Heart Protection Study: Major
Findings






Randomized, placebo-controlled trial of over
20,000 patients at risk for CVD
Statin treatment reduced the risk of heart
attacks and strokes by at least one third, as
well as reducing the need for arterial
surgery, angioplasty and amputations.

Major CV events were reduced in women
(5082 enrolled) as well as men, and in all
age groups, across all cholesterol levels.
Source: HPS Writing Group, Lancet 2002

Primary Prevention of CHD Events with
Statin Treatment: AFCAPS/TexCAPS
Relative Risk of First Major Coronary Events
0
-5
-10
-15
-20
% -25
-30
-35
-40
-45
-50

Source: Downs 1998

Men
Women
-37
-46

P < 0.001
compared to
placebo

Statins for the Primary Prevention of CVD in Women with
Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women
from Primary Prevention Statin Trials
Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,
Jacques Genest, and Paul M Ridker
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
on behalf of the JUPITER Trial Study Group
Circulation 2010; 121:1069-1077

Background
Statins for patients with CVD is established
• Similar benefit in women, men
• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial
• Prior meta-analyses: non-significant
• RR CHD events 0.87 (0.22-1.68), P=0.17
N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives
1. Pre-specified analysis in JUPITER for efficacy
and safety of rosuvastatin in women and men
with elevated hsCRP and non-elevated LDL
cholesterol
2. Updated meta-analysis of statin therapy for
primary prevention of CVD in women

JUPITER : Trial Objective
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin

To investigate whether rosuvastatin 20 mg vs
placebo decreases major CVD events
in apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are
at increased vascular risk due to enhanced
inflammatory response, with hsCRP > 2 mg/L
Ridker PM et al NEJM 2008;2195

JUPITER : Trial Design
6,801 women > 60 years
11,001 men > 50 years
1,315 sites, 26 countries

Rosuvastatin 20 mg (N=8901)

No Prior CVD or DM
Men >50, Women >60

LDL <130 mg/dL
hsCRP >2 mg/L

4-week
run-in

Placebo (N=8901)

MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker PM et al NEJM 2008;2195

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow
89,863Screened
Screened
89,890

Men > 50 years
Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

4 week
Placebo
Run-In

17,802 Randomized
Randomized
17,802

8,901Assigned
Assigned toto
8,901
Rosuvastatin 20
Rosuvastatin
20mg
mg

Reason for
for Exclusion
Exclusion
Reason

LDL > >
130
mg/dL
52
LDL-C
130
mg/dL
53
hsCRP << 2.0
2.0 mg/L
mg/L
36
hsCRP
37
Withdrew
Consent
54
Withdrew Consent
Diabetes
Diabetes
1 1
Hypothyroid
<1
Hypothyroid
Liver Disease
Disease
<1
Liver
<1
TG >> 500
500 mg/dL
mg/dL
<1
TG
<1
Age
out
of
range
<1
Age out of range
Current Use
Use of
of HRT
HRT
<1
Current
Cancer
<1
Cancer
<1
Poor Compliance/Other
Compliance/Other 33
Poor

8,901 Assigned
Assigned toto
8,901
Placebo
Placebo

8,600Completed
Completed Study
8,857
Study 8,864
Study
8,600 Completed
Completed Study
120
Lost
to
follow-up
120Lost
Lost to
to follow-up
44 Lost to follow-up
37
follow-up

8,901
8,901 Included in Efficacy
and
and Safety
Safety Analyses
Analyses

(%)
(%)

8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses

JUPITER

Baseline Clinical Characteristics
Women
(N = 6801)

Men
(N = 11001)

Age, years (IQR)

68.0 (65.0-73.0)

63.0 (58.0-70.0)

Ethnicity, %
Caucasian
Black
Hispanic

61.7
15.9
18.9

77.1
10.4
8.8

BMI, kg/m2 (IQR)

29.2 (25.7-33.2)

27.9 (25.1-31.2)

Hypertension, %

62.7

54.1

Smoker, %

7.6

21.0

Family History, %

12.2

11.1

Metabolic Syndrome, %

46.7

38.7

All values are median (interquartile range) or %
Mora S et al Circulation 2010; 1069

JUPITER

Baseline Blood Levels (median, interquartile range)
Women
(N = 6801)

Men
(N = 11001)

hsCRP, mg/L

4.6

(3.1 - 7.7)

4.1

(2.7 – 6.8)

LDL, mg/dL

109

(96 - 120)

108

(93 - 119)

HDL, mg/dL

54

(46 – 66)

45

(38 – 55)

Triglycerides, mg/L

118

(88 - 163)

118

(84 - 174)

Total Cholesterol, mg/dL

192

(175 - 205)

182

(165 - 195)

Glucose, mg/dL

93

(87 – 101)

95

(88 – 102)

HbA1c, %

5.8

(5.5 – 6.0)

5.6

(5.4 – 5.9)

All values are median (interquartile range).
Mora S et al Circulation 2010; 1069

JUPITER

Effects of rosuvastatin 20 mg on lipids and hsCRP at 12 months
Women
Rosuva
Placebo
hsCRP, mg/L

- 1.8

- 0.6

- 1.7

(- 3.6, - 0.6) (- 2.2, +0.8)

LDL, mg/dL

- 51
(- 65, - 27)

HDL, mg/dL
Triglycerides, mg/L

Total Cholesterol, mg/dL

Men
Rosuva
Placebo

+4
(- 7, +17)

(- 3.4, - 0.4)

- 0.8
(- 2.5, +0.8)

- 49

+3

(- 62, - 29)

(- 9, +15)

+3

+1

+3

+1

(- 2, + 8)

(- 4, + 6)

(- 2, + 8)

(- 3, + 5)

- 17

-1

- 16

+2

(- 44, + 3)

(- 23, +21)

(- 50, +7)

(- 26, +27)

- 51

+4

- 50

+3

(- 68, - 27)

(- 9, +19)

(- 66, - 28)

(- 9, +17)

All values are median (interquartile range) change from baseline to 12 months
Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Women

Rosuva

Placebo

No. (Rate)*

No. (Rate)*

HR

95% CI

39 (0.56)

70 (1.04)

0.54

0.37-0.80
P=0.002

Men

103 (0.88)

181 (1.54)

0.58

P for
heterogeneity

0.80

0.45-0.73
P<0.0001

* Rates are per 100 person-years

Mora S et al Circulation 2010; 1069

JUPITER

Primary Trial Endpoint : Number Needed to Treat (5-years)
Mora S et al Circulation 2010; 1069

Rosuva

Placebo

No. (Rate)

No. (Rate)

NNT*

Women

39 (0.56)

70 (1.04)

36

Men

103 (0.88)

181 (1.54)

22

142 (0.77)

251 (1.36)

All

* Calculated based on the method of Altman and Andersen

25

JUPITER
Components of the Primary Endpoint
Endpoint

Women

Men

P for
Heterogeneity

Primary Endpoint

0.54
0.37 - 0.80

0.58
0.45 - 0.73

0.80

Nonfatal MI

0.56
0.24 - 1.33

0.29
0.16 - 0.54

0.24

Nonfatal Stroke

0.84
0.45 – 1.58

0.33
0.17 – 0.63

0.04

MI, Stroke, CVD Death

0.73
0.48 – 1.13

0.44
0.31 – 0.61

0.06

Revasc/Unstable Angina

0.24
0.11 – 0.51

0.63
0.46 – 0.85

0.01

All-cause Death

0.77
0.55 – 1.06

0.82
0.66 – 1.03

0.74

Mora S et al Circulation 2010; 1069

JUPITER
Adverse Events and Measured Safety Parameters
Event

Women
Rosuva
Placebo

Men
Rosuva
Placebo

Any SAE
Muscle weakness
Myopathy
Rhabdomyolysis
Incident Cancer
Cancer Deaths
Hemorrhagic stroke

7.7
8.9
0.07
0
1.4
0.2
0.04

7.4
8.3
0.06
0
1.4
0.2
0.04

7.6
8.1
0.04
0.01
0.2
0.2
0.02

7.9
7.9
0.04
0
0.2
0.3
0.05

GFR (ml/min/1.73m2 at 12 mth)
ALT > 3xULN

64.1
0.04

64.2
0.07

71.0
0.16

70.5
0.10

95
5.9
1.0

99
5.9
1.4

99
5.8
1.2

Fasting glucose (24 mth) 96
HbA1c (% at 24 mth)
5.9
Incident Diabetes*
1.5

All values are medians or rates per 100 person-years
*Physician reported, P for heterogeneity by sex = 0.16

Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

13 154 Women, 240 CVD events
Year

RR

95% CI

Placebo

AFCAPS/TexCAPS

1998

0.67

(0.34-1.31)

21/498

14/499

MEGA

2006

0.73

(0.49-1.10) 56/2718

40/2638

JUPITER

2008

0.54

(0.37-0.80) 70/3375

39/3426

ALL

0.63 (0.49-0.82)

P for heterogeneity 0.56

.1

Mora S et al Circulation 2010; 1069

.5
Favors Statin

1

5
Favors Placebo

Statin

P<0.001
10

Study Limitations
JUPITER median follow-up 1.9 years (max 5)
Limited long-term safety data for rosuvastatin
Low absolute event rates in women <65 years
Meta-analysis: degree of LDL cholesterol lowering differed

Mora S et al Circulation 2010; 1069

Conclusions – JUPITER sex-specific analysis
Among apparently healthy women with elevated hsCRP and
non-elevated LDL cholesterol, rosuvastatin resulted in similar
and significant relative risk reduction in CVD compared with men
Women had lower absolute event rates, especially <65 years old
Women had more benefit for revascularization / unstable angina,
men had more benefit for stroke
Subgroup analysis suggested women with family history of
premature CHD benefit more than those without family history
Higher physician-reported diabetes in women compared with men,
but test for heterogeneity by sex non-significant

Overall safety in women similar to men

Mora S et al Circulation 2010; 1069

JUPITER
Conclusions – Meta-Analysis
For primary prevention of CVD in women,
statin allocation yielded significant relative risk
reduction by one third
This relative risk reduction is similar to prior results
in men for primary prevention and men or women for
secondary prevention
These findings may have guideline implications for
statin therapy in apparently healthy women meeting
JUPITER entry criteria, even without high risk
Framingham scores
Mora S et al Circulation 2010; 1069

Interventional Procedures and
Surgery


Higher complication and death rates






Smaller artery size
More co-existing illnesses (older at presentation)
Higher rates of diabetes
More urgent and emergent presentations
Higher incidence of congestive heart failure in
women from diastolic dysfunction

Source: Jacobs 2003

Coronary Revascularization
in Women Compared to Men






Increased use of PTCA compared to stents,
because of smaller vessel size
Decreased rates of glycoprotein IIb/IIIa
inhibitor use, possibly because of increased
bleeding complications in women
Higher in-hospital mortality for CABG and PCI



Higher rates of vascular complications
Higher transfusion rates

Source: Jacobs 2003

Revascularization Outcomes in
Women: Improvements in
Recent Years




NHLBI registry data shows improved
clinical success rates and lower major
complication rates for women undergoing
PTCA
Retrospective data suggest that women
have lower mortality rates when
undergoing off-pump CABG, compared to
standard CABG

Source: Jacobs 1997, Petro 2000

Sex Differences for In-Hospital
Mortality After CABG: Higher
Mortality in Younger Women
2.5

2.23
1.86

2

1.47

1.5

1.16

1.02

1

Adjusted
Odds
Ratio for
InHospital
Mortality

0.5
0
< 50

5059

6069
Age Group

Source: Adapted from Vaccarino 2002

7079

≥ 80

P for interaction between
sex and age = 0.002.

CABG Outcomes in Women: A
Vicious Cycle
Perception: Higher postoperative morbidity/mortality
in women
Fewer long-term
benefits for women

Prompt referral for CABG
discouraged in women

Higher operative
risk for women
Women referred at later stages
of disease, w/ more comorbidities
Source: Adapted from Vaccarino 2003

“Hormone Replacement Therapy”
Risk-Benefit Balance: 1960’s-1990’s

Risks

Source: Limacher 2002

Benefits
CHD
Osteoporosis
Vasomotor
Symptoms
GU Symptoms
Skin Preservation

Postmenopausal Estrogen Therapy








Meta-analysis of observational data: 35% CHD risk
reduction in women using hormone therapy
Lipid Effects:
 LDL Cholesterol
 Lipoprotein (a)
 HDL Cholesterol
Metabolic Effects:
 Fasting glucose
 Fasting insulin levels
Fibrinolytic Effects:  tissue plasminogen activator,
 plasminogen-activator inhibitor 1
Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD
Events

15
10
Estrogen-Progestin

5

Placebo

1
0
2
(2763) (2631) (2506)

3
(2392)

4
(1435)

Follow-up, yrs (No. at Risk)
Source: Adapted from Hulley 1998

5
(113)

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute Excess
Risk
 Excess

CHD events: 7/10,000 woman-years

 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 woman-years
 Excess invasive breast cancer: 8/10,000 womanyears

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen
and Progestin Arm: Absolute
Benefits
 Fewer

colorectal cancers: 6/10,000 woman-

years
 Fewer hip fractures: 5/10,000 woman-years

Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone
in Postmenopausal Women Compared to Placebo:
Major Clinical Outcomes

Relative Risk Compared to Placebo
Hip Fracture

0.61

*
0.77

Breast Cancer

0.91

CHD

Total Mortality

1.04
1.08

Colorectal Cancer

1.39

Stroke

0

0.5

Favors Treatment
Source: Adapted from WHI Steering Committee 2004

1

*

1.5

Favors Placebo

* P < .05
2

HT Risk-Benefit Balance: 2004
Risks
DVT/PE
Gallbladder Disease
Breast Cancer
Breast/Bleeding Side
Effects
CHD
Stroke
Dementia
Pancreatitis
?Ovarian Cancer

Source: ACOG Task Force for Hormone Therapy 2004

Benefits
Vasomotor Symptoms
Osteoporosis
Vaginal Atrophy
Colon Cancer
Skin Preservation
Depression

Raloxifene Use for the Heart (RUTH)
Trial: Primary and Secondary CVD
Outcomes
600
500
400

Raloxifene
Placebo

300
200
100
0

*
CHD events

Fatal CHD

Source: Adapted from Barrett Connor 2006

Stroke

Fatal Stroke

* p < .05

Interventions that are not useful/effective
and may be harmful for the prevention
of heart disease



Hormone therapy and selective
estrogen-receptor modulators (SERMs)
should not be used for the primary or
secondary prevention of CVD

Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and
CVD: Summary of Major Randomized Trials
Use of estrogen plus progestin associated with a
small but significant risk of CHD and stroke
 Use of estrogen without progestin associated with
a small but significant risk of stroke
 Use of all hormone preparations should be limited
to short term menopausal symptom relief
 Use of a selective estrogen receptor modulator
(raloxifene) does not affect risk of CHD or stroke,
but is associated with an increased risk of fatal
stroke


Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

Conclusions
♥ Gender differences exist in diagnosis,
treatment, and prognosis of CHD
♥ Knowledge of gender differences is
essential for appropriate therapy
♥ Evidence-based guidelines provide a
new framework for prevention and
treatment of cardiovascular disease in
women

THANK YOU