The Relative Safety and Efficacy of Clopidogrel in Women and Men: A Sex-Specific Meta-Analysis

1
The Relative Safety and Efficacy of Clopidogrel
in Women and Men A Sex-Specific Meta-Analysis

• Jeffrey S. Berger, Deepak L. Bhatt, Christopher
  P. Cannon, Zhengming Chen, J.B. Jones, Shamir R.
  Mehta,
• Marc S. Sabatine, Steven R. Steinhubl,
• Eric J. Topol, Peter B. Berger
• Duke Clinical Research Institute, Durham, North
  Carolina
• Geisinger Clinic, Danville, Pennsylvania

Berger JS, et al. Presented AHA 2007
Abstact Circulation 2007116 Suppl IIII-483.
2
Platelets and Cardiovascular Disease

• Platelets play a major role in the pathogenesis
  of atherosclerosis and coronary thrombosis
• Platelets are an important link between
  inflammation, thrombosis, and atherogenesis

ADP TxA2
Thrombin
Platelet
Collagen
vWF
Inflammation
3
Mechanisms of Action Oral Antiplatelet Agents
ADP
dipyridamole
phosphodiesterase
ADP
ADP
GP IIb/IIIa Inhibitors
cAMP
collagenthrombinTXA2
Activation
COX
TXA2
ADPadenosine diphosphate, TXA2thromboxane A2,
COXcyclooxygenase. Adapted from Schafer AI. Am J
Med. 1996101199-209.
4
Anti-platelet Therapies and SexAspirin
CV Events Women 0.88 (.79-0.99) Men 0.86
(0.78-0.94)

• Stroke
• Women 0.83 (.70-0.97)
• Men 1.13 (0.96-1.33)
• MI
• Women 1.01 (.64-1.21)
• Men 0.68 (0.54-0.86)

Berger JS et al. JAMA 2006295306-13
5
Anti-platelet Therapies and SexGlycoprotein
IIb/IIIa Inhibitors

Prevalence Event rate Odds Ratio P int F
emale 35 11.1 1.15 Male 65
11.3 0.81 lt0.0001
Boersma et al. Lancet 2002359189-99
6
ClopidogrelWhat Do We Know?

• 5 randomized trials of clopidogrel vs. placebo
• CURE, CREDO, CLARITY, COMMIT, CHARISMA
• Benefit from 2o prevention in the treatment of
  pts with CVD
• Maree et al Circulation 20072196-207
• Clopidogrel resistance or hyporesponsiveness
• Not yet proven to be clinically relevant
• Some (though not all) studies suggest a greater
  frequency of hyporesponsiveness in females
• Ivandic et al Clin Chemistry 200652383-8

7
Objective

• To better understand the impact of sex on the
  clinical response to clopidogrel

8
Methods

• Performed a sex-specific meta-analysis of
  clopidogrel for the prevention of CV events
• Comprehensive search of MEDLINE and EMBASE in May
  2007
• Search algorithm clopidogrel, myocardial
  infarction, stroke, angina, PCI, CV disease,
  randomized controlled trial
• Experts questioned bibliographies of relevant
  studies searched for other relevant studies
  monitored major scientific meetings

9
Inclusion Criteria

• Studies had to be
• Prospective
• Randomized controlled trials
• Clopidogrel vs. placebo
• Report clinical outcomes

10
Outcomes

• Cardiovascular Events
• Non-fatal MI
• Non-fatal Stroke
• Cardiovascular Mortality
• Each Individual Endpoint
• All-cause Mortality
• Major Bleeding

11
Statistical Analysis

• The principal investigator of each trial provided
  the data stratified by sex
• Performed with Comprehensive meta-analysis
  software (Biostat Englewood, NJ)
• Q statistic calculated to assess heterogeneity
  between trials outcomes between women and men
• Odds ratio (OR) (Mantel-Haenszel and Peto
  methods) were used
• OR of individual trials pooled using random
  effects model by combining the OR and 95
  confidence interval (CI) for each study

12
Studies Included in the Meta-Analysis
Trial N Pt Population Female F/U
CURE 12,562 Non-STE ACS 39 12 mo (median 9 mo)
CREDO 2,116 Planned PCI 29 12 mo
CLARITY 3,491 STEMI 20 30 days
COMMIT 45,852 STEMI 28 In-hospital or 28 days
CHARISMA 15,603 CVD (or multiple risk factors for CVD) 30 28 mo (median)
13
Men 0.842
lt0.001
Women 0.929 0.074
Heterogeneity Between Women and Men P0.092
14
Men 0.907
0.008
Women 0.986 0.762
Heterogeneity Between Women and Men P0.158
15
Men 0.832
lt0.001
Women 0.807
0.004
Heterogeneity between women and men P0.733
16
Men 0.826
0.010
Women 0.914 0.562
Heterogeneity between women and men P0.552
17
Men 1.220
0.011
Women 1.433
0.002
Heterogeneity between women and men P0.243
18
Subgroup Analyses

• ACS
• Major CV Event
• Women 0.93 (0.85-1.01)
• Men 0.83 (0.74-0.93)
• All-Cause Mortality
• Women 0.99 (0.90-1.09)
• Men 0.89 (0.82-0.97)
• Myocardial Infarction
• Women 0.80 (0.68-0.94)
• Men 0.82 (0.73-0.91)
• Stroke
• Women 0.80 (0.45-1.45)
• Men 0.83 (0.68-1.00)
• Major Bleeding

• Established CVDt
• Major CV Event
• Women 0.93 (0.85-1.01)
• Men 0.84 (0.78-0.92)
• All-Cause Mortality
• Women 0.98 (0.89-1.07)
• Men 0.90 (0.83-0.96)
• Myocardial Infarction
• Women 0.81 (0.70-0.94)
• Men 0.82 (0.74-0.90)
• Stroke
• Women 0.92 (0.67-1.27)
• Men 0.81 (0.69-0.94)
• Major Bleeding

CURE, CLARITY, COMMIT tExcluded pts w/o
established CVD from CHARISMA
19
Limitations

• Meta-analyses have inherent limitations
• Results can be due to chance
• Bias can be introduced by combining trials with
  different designs
• Results ought not be applied to populations
  dissimilar to those in included studies
• Possibility of heterogeneity between trials

20
Conclusions

• Clopidogrel reduced the risk of cardiovascular
  events in both women and men
• While the directionality and proportionality of
  the reductions are roughly similar, the effect in
  women was driven by a reduction of MI
• The reduction of MI, stroke and death by
  clopidogrel in men were all significant
• Clopidogrel increased the risk of major bleeding
  by 43 in women, 21 in men

21
Thank you

• CURE Yusuf S, Zhao F, Mehta SR, et al.
  Clopidogrel in Unstable Angina to Prevent
  Recurrent Events Trial I. Effects of clopidogrel
  in addition to aspirin in patients with acute
  coronary syndromes without ST-segment elevation.
  New England Journal of Medicine.
  2001345494-502.
• CREDO Steinhubl SR, Berger PB, Mann JT, 3rd, et
  al. Early and sustained dual oral antiplatelet
  therapy following percutaneous coronary
  intervention a randomized controlled trial. JAMA
  20022882411-20.
• COMMIT Chen ZM, Jiang LX, Chen YP, et al.
  Addition of clopidogrel to aspirin in 45,852
  patients with acute myocardial infarction
  randomised placebo-controlled trial. Lancet
  20053661607-21.
• CLARITY Sabatine MS, Cannon CP, Gibson CM, et
  al. Addition of clopidogrel to aspirin and
  fibrinolytic therapy for myocardial infarction
  with ST-segment elevation. New England Journal of
  Medicine 20053521179-89.
• CHARISMA Bhatt DL, Fox KA, Hacke W, et al.
  Clopidogrel and aspirin versus aspirin alone for
  the prevention of atherothrombotic events. New
  England Journal of Medicine 20063541706-17.