Transcript Ezetimibe / Simvastatin Combination

The 2009 Canadian Lipid Guidelines
Milan Gupta, MD
Department of Medicine, McMaster University
Division of Cardiology, William Osler Health Centre
Division of Cardiology / CV Surgery, University of Toronto
Disclosures
Honoraria
Abbott, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol
Myers Squibb, Eli Lilly, GlaxoSmithKline, IMI, Merck, Merck
Schering, Novartis, Pfizer, Roche, sanofi-aventis, Servier, Solvay
Research
AstraZeneca, Bristol Myers Squibb, GSK, IMI, Pfizer, sanofi-aventis
Equity
None
Burden of Cardiovascular Disease
CVD causes 1 in 3 deaths in Canada
Other 17%
Neuro-degenerative 2%
Psychiatric 5%
Heart 34%
Diabetes 3%
Accidents 4%
Respiratory 8%
Statistics Canada
Genest J et al. Can J Cardiol 2009;25(10):567–79.
Cancer 27%
20% with CHD Present with No Traditional Risk
Factors; An Additional 43% Present with Only One
4 Risk
Factors (< 1%)
Risk factors
• Smoking
• HTN
• Cholesterol
• DM
3 Risk
Factors
No Risk
Factor
8.9%
19.4%
2 Risk
Factors
27.8%
62.4%
43.0%
1 Risk
Factor
Khot UN et al. JAMA 2003;290:898–904.
Relationship Between Proportional Reduction in
Events and Optimal LDL-C Reduction at 1 Year
A prospective meta-analysis of data from 90,056 individuals from 14 trials of statins1
A 1 mmol/L (39 mg/dL) reduction in LDL-C was associated with a…
40
30
20
10
0
-10
50
Proportional reduction in
event rate (%SE)
Proportional reduction in
event rate (%SE)
50
23% reduction in
major coronary events
0.5
1.0
(19) (38)
1.5
(58)
Reduction in
LDL-C mmol/L (mg/dL)
2.0
(77)
21% reduction in
major vascular events
40
30
20
10
0
-10
0.5
(19)
1.0
(38)
1.5
(58)
Reduction in
LDL-C mmol/L (mg/dL)
Adapted from Baigent C, et al, Cholesterol Treatment Trialists’ (CTT) Collaborators. Lancet 2005;366:1267–1278.
2.0
(77)
2006 CCS Dyslipidemia Guidelines
Risk level
High*
Moderate‡§
Low‡§
Recommendations
10-year CAD risk
>20%
and
Treatment targets†:
Primary: LDL-C <2.0 mmol/L
Secondary: TC:HDL-C <4.0
10%-19%
and
Treat when:
LDL-C ≥3.5 mmol/L or
TC:HDL-C ≥5.0
<10%
and
Treat when:
LDL-C ≥5.0 mmol/L or
TC:HDL-C ≥6.0
High risk
patients should
lower LDL-C by
at least 50%
Low-Moderate risk,
patients should
lower LDL-C by at
least 40%
May initiate treatment at lower or higher levels if family history or other investigations indicate elevated or reduced
risk. Optimal apo B < 1.2 g/L low risk, <1.05 g/L intermediate risk, < 0.85 g/L in high risk patients.
*
McPherson R, Frohlich J, Fodor G, Genest J. Canadian Cardiovascular Society position statement –
Recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease.
Can J Cardiol 2006;22(11):913-927.
CHRC High-Risk Registries: VP and GOALL
Patients are Not Reaching LDL Targets
Adapted from Yan A,, et al; Vascular Protection (VP) and Guidelines Oriented Approach to Lioid Lowering (GOALL) Registries
Investigators. Am J Med 2006; 119: 676-683
Estimated 10 Risk of CHD Events in Women
100%
10 Year Risk
Percent
80%
>20%
10-20%
6-10%
<6%
60%
40%
20%
0%
30-39
40-49
50-59
Age (years)
Wilson P, Smith SC, Blumenthal RS et al. JACC 2003;41:1898-906
60-69
70-79
Risk charts in different ethnic groups
Risk of CHD and
stroke relative to
Caucasian
whites
CHD
Stroke
Potential mechanisms
Risk Charts
South
Asians

 or 
body fat and insulin resistancerelated factors
 Smoking, cholesterol
Underestimate
African
American


Greater salt-sensitive HBP & diabetes
paradoxical healthy lipid profile
Substantial obesity/ Social
Good prediction
Mexican
American
 or 
 or 
 obesity rates &  physical activity
May overestimate
Chinese
 or 

cholesterol, Sat. fat
hypertension and intracerebral
haemorrhage
May overestimate
Lifetime Risk
Men
(n = 3564)
70
Women
69
60
70
(n = 4362)
60
50
46
50
Adjusted
cumulative 40
incidence 30
of CVD (%)
20
36
50
50
40
39
30
27
20
10
5
10
8
0
0
50
60
70
≥2 Major RFs
1 Major RF
80
90
50
Attained age (years)
≥1 Elevated RF
≥1 Not optimal RF
*Optimal RF defined as total cholesterol <4.65 mmol/L
BP <120/80 mmHg, nonsmoker, nondiabetic
60
70
80
90
All optimal RFs
Lloyd-Jones DM et al. Circulation. 2006;113:791-8.
Fully Adjusted Relative Risk
hsCRP Adds Prognostic Information Beyond Traditional Risk
Factors in All Major Cohorts Evaluated
3
3
3
3
3
3
3
2
2
2
2
2
2
2
1
1
1
1
1
1
1
0
0
0
0
0
0
0
WHS 2000
PHS 1997
UK 2000
MONICA 2004
ARIC 2004
NHS 2004
Iceland 2004
3
3
3
3
3
3
3
2
2
2
2
2
2
2
1
1
1
1
1
1
1
0
0
0
0
0
0
0
HPFUS 2004
EPIC-N 2005
Strong 2005
< 1 mg/L
Kuopio 2005
CHS 2005
1 to 3 mg/L
PIMA 2005
> 3 mg/L
FHS 2008
JUPITER
Multinational, randomized, double-blind, placebo-controlled trial of
rosuvastatin in the prevention of FIRST major cardiovascular events
among individuals with low LDL and elevated hsCRP
No prior CVD or DM
Men ≥50, Women ≥ 60
LDL <130 mg/dL
(3.36 mmol/L)
hsCRP ≥2 mg/L
Rosuvastatin 20 mg (n=8,901)
4-week
run-in
Placebo (n=8,901)
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. Circulation 2003;108:2292-7.
JUPITER -1° Composite Endpoint of Non-Fatal MI, NonFatal Stroke, UA/Revascularization and CV Death
Cumulative Incidence
0.08
HR 0.56, 95% CI 0.46-0.69
p<0.00001
0.06
Placebo
251/8,901
- 44%
Number Needed to Treat (NNT5) = 25
0.04
Rosuvastatin
142/8,901
0.02
0.00
0
1
Number at Risk
Rosuvastatin
Placebo
8,901
8,901
8,631
8,621
8,412
8,353
2
Follow-up (Years)
6,540
6,508
3,893
3,872
1,958
1,963
3
1,353
1,333
4
983
955
544
534
157
174
Ridker PM et al. N Engl J Med 2008;359:2195-207.
Ridker et al NEJM 2008
JUPITER
Secondary Endpoint – All Cause Mortality
HR 0.80, 95%CI 0.67-0.97
P= 0.02
0.06
Placebo 247 / 8901
0.04
0.03
0.02
Rosuvastatin 198 / 8901
0.00
0.01
Cumulative Incidence
0.05
- 20 %
0
Number at Risk
Rosuvastatin 8,901
Placebo
8,901
1
2
3
4
Follow-up (years)
8,847
8,852
8,787
8,775
6,999
6,987
4,312
4,319
2,268
2,295
1,602
1,614
1,192
1,196
683
684
227
246
Guidelines for the Diagnosis and
Treatment of Dyslipidemia and
Prevention of Cardiovascular
Disease 2009
www.ccs.ca
2009 Canadian Dyslipidemia Guidelines Committee
Jacques Genest, MD
Ruth McPherson, MD, PhD
Jiri Frohlich, MD
Todd Anderson, MD
Norm Campbell, MD
André Carpentier, MD
Patrick Couture, MD
Robert Dufour, MD
George Fodor, MD
Gordon Francis, MD
Steven Grover, MD
Milan Gupta, MD
Robert A. Hegele, MD
David C. Lau, MD
Lawrence Leiter, MD
Gary F. Lewis, MD
Eva Lonn, MD
G.B. John Mancini, MD
Dominic Ng, MD, PhD
Glen J. Pearson, Pharm D
Allan Sniderman, MD
James M. Stone, MD, PhD
Ehud Ur, MD
Criteria Used for Evaluation of Evidence
Recommendation Grade
Class I
Evidence and/or general agreement that a given diagnostic procedure/treatment is beneficial, useful and effective
Class II
I
IIa IIb
III
Conflicting evidence and /or a divergence of opinion about the usefulness /efficacy of the treatment
Class II a Weight of evidence in favor
Class II b Usefulness/efficacy less well established
Class III
Evidence that the treatment is not useful and in some cases may be harmful
Level of Evidence
A
Level A
Data derived from multiple randomized clinical trials (RCT) or meta-analysis
Level B
Data derived from a single RCT or large non-randomized studies
Level C
Consensus of opinion by experts and/or small studies, retrospective studies, registries
C
Who to Screen?
Physicians should screen every 1 to 3 years, with a full
lipid profile and other investigations as indicated:
•
All men ≥ 40 years and all women who are post-menopausal
and/or ≥ 50 years
•
Other adults of any age with CVD risk factors:
Non-modifiable
• family history of
premature CVD
•
Modifiable
• cigarette smoking
• obesity
Metabolic
Other
• diabetes
• hypertension
• atherosclerosis
• clinical
manifestations of
hyperlipidemias
• HIV infection
treated with
HAART therapy
• erectile dysfunction
• chronic renal
disease (eGFR < 60
mL/min/1.73 m2)
• inflammatory
diseases (systemic
lupus, rheumatoid
arthritis, psoriasis,
etc.)
Children of patients with a history of hypercholesterolemia
or chylomicronemia
Genest J et al. Can J Cardiol 2009;25(10):567–79.
Risk Assessment
CV risk assessment remains imperfect
• Framingham Risk Score (CVD)
– FRS has been shown to underestimate the risk of some patients (e.g.,
the young and women, and possibly those with the metabolic
syndrome)
• Reynolds Risk Score (CVD)
– Is an alternative and includes family history and hsCRP
– Web-based version www.reynoldsriskscore.org
We now recommend cardiovascular risk (total CVD) assessment,
not only CAD, as CHEP and CDA do.
Modified FRS for TOTAL CVD
Now Available and Recommended
Available in the 2009 recommendations publication: Genest J et al. Can J Cardiol 2009;25(10):567–79 or
speak to your local AstraZeneca representative for copies.
Recommended Lifestyle Changes
• Smoking cessation, including the use of pharmacological
therapy, as required
• A diet low in sodium and simple sugars, with substitution of
unsaturated fats for saturated and trans fats and increased
consumption of fruits and vegetables
• Caloric restriction to achieve and maintain ideal body weight
• Moderate to vigorous exercise for 30-60 minutes on most, and
preferably all, days of the week
• Psychological stress management
Genest J et al. Can J Cardiol 2009;25:567-79.
High Risk Level
• Documented evidence of atherosclerosis
• Diabetic adults over 45 (men), 50 (women)
• FRS or RRS 10 year risk score > 20%
– Requires intensive lifestyle modification advice
– Requires pharmacological lowering of LDL-C
End-stage renal disease or congestive heart
failure due to systolic dysfunction:
• New studies on statins and heart failure
• Statins may not reduce risk in advanced heart
failure (CORONA, GISSI HF)
A
• Similar results for hemodialysis patients (AURORA,
4D trials): no effect on CVD
Use clinical judgment
A
Target Levels
Risk Level
Initiate treatment if:
Primary
LDL-C
High
Consider treatment in all patients <2 mmol/L
CAD,PVD
Or ↓50% LDL-C
Atherosclerosis
Most Pts with Diabetes
FRS>20%
Class
A I Level A
RRS>20%
Primary
Alternate
ApoB<0.80
Class I Level A
A
Moderate Risk Levels
Major health concern among midlife Canadians
• FRS 10-19% at 10 years
o
o
Family history and high hsCRP modulate risk
Reynolds Risk Score potentially useful
• Requires lifestyle changes
• May require pharmacological therapy
Which Moderate Risk Patients Warrant Treatment?
•LDL-C > 3.5 mmol/L
•TC:HDL ratio > 5.0
•Those with a definite family history of premature CVD*
•Those with multiple features of the metabolic syndrome*
In moderate risk patients not fitting the above criteria, if male >
50 or female >60, consider testing hsCRP
•If hsCRP > 2, consider treatment (Class IIA, Level B)
Subjects should be free of acute illness and the lower of 2
hsCRP values, taken at least 2 weeks apart, should be used.
Genest J et al. Can J Cardiol 2009 Oct;[in press].
Target Levels
Risk Level
Initiate treatment if:
Primary
LDL-C
High
Consider treatment in all patients <2 mmol/L
CAD,PVD
Or ↓50% LDL-C
Atherosclerosis
Most Pts with Diabetes
FRS>20%
Class
A I Level A
RRS>20%
Moderate
(strive towards )
FRS 10-19% LDL-C>3.5 mmol/L
TC/HDL >5.0
hsCRP >2
men 50+, women 60+
Family history and hsCRP modulate risk
Primary
Alternate
ApoB<0.80
Class I Level A
A
<2 mmol/L
Or ↓50% LDL-C
ApoB<0.80
Class A
IIA Level A
AIIA Level A
Class
Low Risk Level
 Framingham Risk Score < 10%
 Pharmacological treatment for severe
genetic dyslipidemia C
 Use clinical judgment, proper timing
 Careful family history for added risk factors
 RRS can re-classify low-risk patients
Risk Assessment and Treatment Targets
Risk
Assessment
HIGH
FRS > 20%
RRS > 20%
Initiate/consider treatment
if any of the following:
•
•
•
•
CAD
PVD
Atherosclerosis
Most Diabetic Patients
Primary Target
LDL-C
Primary Alternate
ApoB
< 2 mmol/L or
↓ LDL-C 50%
ApoB < 0.80
(consider treatment in all patients)
Moderate
FRS 10-19%
•
•
•
•
LDL-C > 3.5 mmol/L
TC/HDL-C > 5.0
hsCRP > 2 mg/L *
Family history
A
A
(strive towards )
LOW
FRS < 10%
• LDL-C > 5.0mmol/L
↓ LDL-C 50%
A
* Only screen for hsCRP in men ≥ 50 and women ≥ 60 if they do NOT already have CVD, diabetes, multiple risk factors, family history or hyperlipidemia
Genest J et al. Can J Cardiol 2009 Oct;[in press].
Residual Risk (When LDL-C at target)
OPTIONAL Secondary Targets in High Risk Patients
Test
Cut-point
TC/HDL-C
>4.0
• Niacin
• Fibrate
Non HDL-C
>3.5 mmol/L
• Niacin
• Fibrate
Apo B/AI
>0.8
Triglycerides
>1.7 mmol/L
hsCRP
>2.0 mg/L
Genest J et al. Can J Cardiol 2009 Oct;[in press].
Intervention
• Niacin
• Ezetimibe
• Fibrate
• Niacin
• Statin
• Ezetimibe
Risk Assessment and Treatment Targets
Risk
Assessment
HIGH
FRS > 20%
RRS > 20%
Initiate/consider treatment
if any of the following:
•
•
•
•
CAD
PVD
Atherosclerosis
Most Diabetic Patients
Primary Target
LDL-C
Primary Alternate
ApoB
< 2 mmol/L or
↓ LDL-C 50%
ApoB < 0.80
(consider treatment in all patients)
Moderate
FRS 10-19%
•
•
•
•
LDL-C > 3.5 mmol/L
TC/HDL-C > 5.0
hsCRP > 2 mg/L *
Family history
A
A
(strive towards )
LOW
FRS < 10%
• LDL-C > 5.0mmol/L
↓ LDL-C 50%
A
* Only screen for hsCRP in men ≥ 50 and women ≥ 60 if they do NOT already have CVD, diabetes, multiple risk factors, family history or hyperlipidemia
Genest J et al. Can J Cardiol 2009 Oct;[in press].