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

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

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

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  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 2007;116 Suppl II;II-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. clopidogrel ticlopidine GP IIb/IIIa (fibrinogen receptors) aspirin Mechanisms of Action Oral Antiplatelet Agents ADP dipyridamole phosphodiesterase ADP ADP GP IIb/IIIa Inhibitors cAMP collagenthrombinTXA2 Activation COX TXA2 ADP=adenosine diphosphate, TXA2=thromboxane A2, COX=cyclooxygenase. Adapted from Schafer AI. Am J Med. 1996;101:199-209.

  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 2006;295:306-13

  5. Anti-platelet Therapies and SexGlycoprotein IIb/IIIa Inhibitors Prevalence Event rate Odds Ratio P int Female 35% 11.1% 1.15 Male 65% 11.3% 0.81 <0.0001 Boersma et al. Lancet 2002;359:189-99

  6. 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 2007;2196-207 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 2006;52:383-8 ClopidogrelWhat Do We Know?

  7. To better understand the impact of sex on the clinical response to clopidogrel Objective

  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

  13. Men 0.842 <0.001 Women 0.929 0.074 Heterogeneity Between Women and Men P=0.092

  14. Men 0.907 0.008 Women 0.986 0.762 Heterogeneity Between Women and Men P=0.158

  15. Men 0.832 <0.001 Women 0.807 0.004 Heterogeneity between women and men P=0.733

  16. Men 0.826 0.010 Women 0.914 0.562 Heterogeneity between women and men P=0.552

  17. Men 1.220 0.011 Women 1.433 0.002 Heterogeneity between women and men P=0.243

  18. 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 Women 1.50 (1.14-1.97) Men 1.18 (0.96-1.44) 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 Women 1.43 (1.14-1.79) Men 1.19 (1.02-1.40) Subgroup Analyses *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. 2001;345:494-502. 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 2002;288:2411-20. 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 2005;366:1607-21. 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 2005;352:1179-89. 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 2006;354:1706-17.

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