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 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 Platelet ADP TxA 2 Thrombin Collagen vWF Inflammation

3. ADP=adenosine diphosphate, TXA 2 =thromboxane A 2, COX=cyclooxygenase. Adapted from Schafer AI. Am J Med. 1996;101:199-209. collagen thrombin TXA 2 ADP TXA 2 ADP phosphodiesterase ADP (fibrinogenreceptors) GP IIb/IIIa Activation COX clopidogrel ticlopidine aspirin dipyridamole cAMP Mechanisms of Action Oral Antiplatelet Agents GP IIb/IIIa Inhibitors

4. Anti-platelet Therapies and Sex Aspirin 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 CV Events Women 0.88 (.79-0.99) Men 0.86 (0.78-0.94)

5. Anti-platelet Therapies and Sex Glycoprotein IIb/IIIa Inhibitors Boersma et al. Lancet 2002;359:189-99 PrevalenceEvent rateOdds RatioP int Female35% 11.1%1.15 Male65% 11.3%0.81<0.0001

6. Clopidogrel What Do We Know? 5 randomized trials of clopidogrel vs. placebo 5 randomized trials of clopidogrel vs. placebo CURE, CREDO, CLARITY, COMMIT, CHARISMA CURE, CREDO, CLARITY, COMMIT, CHARISMA Benefit from 2 o prevention in the treatment of pts with CVD Benefit from 2 o prevention in the treatment of pts with CVD Maree et al Circulation 2007;2196-207 Clopidogrel “resistance” or “hyporesponsiveness” Clopidogrel “resistance” or “hyporesponsiveness” Not yet proven to be clinically relevant Not yet proven to be clinically relevant Some (though not all) studies suggest a greater frequency of hyporesponsiveness in females Some (though not all) studies suggest a greater frequency of hyporesponsiveness in females Ivandic et al Clin Chemistry 2006;52:383-8

7. Objective To better understand the impact of sex on the clinical response to clopidogrel 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 Performed a sex-specific meta-analysis of clopidogrel for the prevention of CV events Comprehensive search of MEDLINE and EMBASE in May 2007 Comprehensive search of MEDLINE and EMBASE in May 2007 Search algorithm: clopidogrel, myocardial infarction, stroke, angina, PCI, CV disease, randomized controlled trial 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 Experts questioned; bibliographies of relevant studies searched for other relevant studies; monitored major scientific meetings

9. Inclusion Criteria Studies had to be: Prospective Prospective Randomized controlled trials Randomized controlled trials Clopidogrel vs. placebo Clopidogrel vs. placebo Report clinical outcomes Report clinical outcomes

10. Outcomes Cardiovascular Events Cardiovascular Events Non-fatal MI Non-fatal MI Non-fatal Stroke Non-fatal Stroke Cardiovascular Mortality Cardiovascular Mortality Each Individual Endpoint Each Individual Endpoint All-cause Mortality All-cause Mortality Major Bleeding Major Bleeding

11. Statistical Analysis The principal investigator of each trial provided the data stratified by sex The principal investigator of each trial provided the data stratified by sex Performed with Comprehensive meta-analysis software (Biostat; Englewood, NJ) Performed with Comprehensive meta-analysis software (Biostat; Englewood, NJ) Q statistic calculated to assess heterogeneity between trials & outcomes between women and men Q statistic calculated to assess heterogeneity between trials & outcomes between women and men Odds ratio (OR) (Mantel-Haenszel and Peto methods) were used 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 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 TrialN Pt Population FemaleF/U CURE12,562 Non-STE ACS 39% 12 mo (median 9 mo) CREDO2,116 Planned PCI 29% 12 mo CLARITY3,491STEMI20% 30 days COMMIT45,852STEMI28% In-hospital or 28 days CHARISMA15,603 CVD (or multiple risk factors for CVD) 30% 28 mo (median)

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

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

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

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

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

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 CVD t 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; t Excluded pts w/o established CVD from CHARISMA

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

20. Conclusions Clopidogrel reduced the risk of cardiovascular events in both women and men 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 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 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 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.