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
2009 Lipid Guidelines
 Care Gap
 Secondary Prevention
 Primary Prevention and Risk Assessment
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
Statin therapy associated with low risk
Review of placebo-controlled statin monotherapy* trials; N = 74,102
Outcome
Statin
(%)
Placebo
(%)
RD
P value
Statin better
Myalgias
15.4
18.7
2.7
0.37
CK elevations
0.9
0.4
0.2
0.64
Rhabdomyolysis
0.2
0.1
0.4
0.13
Hepatotoxicity
1.4
1.1
4.2
<0.01
AE discontinuation
5.6
6.1
-0.5
0.80
*Atorvastatin, fluvastatin, lovastatin, pravastatin,
rosuvastatin, simvastatin
CK = creatine kinase
AE = adverse events
Placebo better
-30
-15
0
15
30
Risk difference per 1000 patients (RD)
(95% CI)
Kashani A et al. Circulation. 2006;114:2788-97.
2009 Lipid Guidelines
 Care Gap
 Secondary Prevention
 Primary Prevention and Risk Assessment
Primary Endpoint
CV Death or Non-fatal MI or Non-fatal Stroke
35
Placebo
n = 732 (29.3%)
30
Per cent
Rosuvastatin
n = 692 (27.5%)
25
20
15
Hazard ratio = 0.92
95% CI 0.83 to 1.02
p = 0.12
10
5
0
No. at risk
Placebo
Rosuvastatin
0
6
2497
2514
2315
2345
12
18
24
30
Months of follow-up
2156
2207
2003
2068
1851
1932
1431
1484
36
811
855
Kjekshus J et al,
N Engl J Med 2007;357
GISSI-HF – Co-Primary Endpoints
(i) All cause mortality and (ii) All cause mortality or hospitalizations
for cardiovascular reasons
Placebo
(n=2289)
n (%)
HR*
CI
p
value
657 (29)
644 (28)
1.00
[95.5% CI
0.90-1.12]
0.94
1305 (57)
1283 (56)
1.01
[99% CI
0.91-1.11]
0.90
Rosuvastatin
(n=2285)
n (%)
Primary Endpoints
All-cause mortality
All-cause mortality or
CV hospitalisations
HR – Hazard Ratio; CI – Confidence Interval
*adjusted HR
GISSI-HF Investigators. Lancet 2008; doi:10.1016/S01.40-6736(08)61240-4
4D study in diabetic hemodialysis
patients: no benefit of statin therapy
60
Placebo
50
p=0.37
40
Atorvastatin
Cumulative
incidence of 30
primary
endpoint
20
(%)
10
0
0
1
2
3
4
5
6
Time (years)
No. at risk:
Placebo
636
532
383
252
136
51
19
Atorvastatin
619
515
378
252
136
58
29
4D=Die Deutsche Diabetes Dialyse Studie
Wanner C et al. N Engl J Med 2005; 353: 238–248
AURORA: primary endpoint
Kaplan-Meier estimate of time to
first major CV event
40
Placebo
35
30
Cumulative
incidence of
primary
endpoint
(%)
Rosuvastatin
25
20
15
10
HR=0.96 (95% CI 0.84–1.11)
P=0.59
5
0
0
No. at risk:
Rosuvastatin
Placebo
1390
1384
1
3
4
2
Years from randomization
1152
1163
962
952
826
809
551
534
5
148
153
2009 Lipid Guidelines
 Care Gap
 Secondary Prevention
 Primary Prevention and Risk Assessment
What does the Framingham Risk Score not include?
Genetic risk
Impaired glucose (non-diabetic)
Abdominal obesity
Ethnic origin
Socioeconomic status
Measures of psychosocial stress
Diet
Level of exercise
Alcohol consumption
Novel biomarkers
Atherosclerosis imaging
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
80
90
50
Attained age (years)
≥2 Major RFs
1 Major RF
*Optimal RF defined as total cholesterol <4.65 mmol/L
BP <120/80 mmHg, nonsmoker, nondiabetic
≥1 Elevated RF
≥1 Not optimal RF
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
Stakeholders in the Elaboration
of Canadian Lipid Guidelines
 C-Change: Canadian Cardiovascular Harmonization of National
Guidelines Endeavor.
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














Canadian Association of Cardiac Rehabilitation
Canadian Cardiovascular Society
Canadian College of Family Physicians
Canadian Council for Tobacco Control
Canadian Council of Cardiovascular Nurses
Canadian Diabetes Association
Canadian Hypertension Society
Canadian Medical Association
Canadian Obesity Network
Canadian Pharmacist Association
Canadian Society for Exercise Physiology
Canadian Stroke Network
Canadian Working Group on Dyslipidemias
Obesity Canada
Public Health Agency of Canada
Royal College of Physicians and Surgeons of Canada
Canadian Institutes of Health Research (CIHR)
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
Screening
•
•
•
•
•
•
•
•
•
C
Men over 40 and postmenopausal women
Anyone with atherosclerosis regardless of age
Anyone with diabetes regardless of age
Family history of premature CVD
Arterial hypertension (Check metabolic disorder, dyslipidemia)
Inflammatory diseases (lupus, rheumatoid arthritis, psoriasis)
Children of patients with severe dyslipidemia
HIV infection with HAART therapy
Clinical hyperlipidemias (xanthomas,
xanthelasmas, premature arcus corneus)
• Erectile dysfunction
• Chronic renal disease
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.
Metabolic Syndrome
•
•
•
•
•
C
Association of several metabolic abnormalities
Uniform classification remains elusive
International Diabetes Federation classification
Higher long-term risk than FRS estimates
Measuring hsCRP may help stratify risk
• “ We recommend that clinical judgement be used to
move up an FRS-determined score category based on his
or her “load” of metabolic risk factors or the severity of
the metabolic syndrome”
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
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