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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 - PowerPoint PPT Presentation
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The Relative Safety and Efficacy of The Relative Safety and Efficacy of Clopidogrel in Women and Men: Clopidogrel in Women and Men:
A Sex-Specific Meta-Analysis A Sex-Specific Meta-Analysis
Jeffrey S. Berger, Deepak L. Bhatt, Christopher P. Cannon, Jeffrey S. Berger, Deepak L. Bhatt, Christopher P. Cannon, Zhengming Chen, J.B. Jones, Shamir R. Mehta, Zhengming Chen, J.B. Jones, Shamir R. Mehta,
Marc S. Sabatine, Steven R. Steinhubl, Marc S. Sabatine, Steven R. Steinhubl,
Eric J. Topol, Peter B. BergerEric J. Topol, Peter B. Berger
Duke Clinical Research Institute, Durham, North CarolinaDuke Clinical Research Institute, Durham, North Carolina
Geisinger Clinic, Danville, PennsylvaniaGeisinger Clinic, Danville, Pennsylvania
Berger JS, et al. Presented AHA 2007; Abstact Circulation 2007;116 Suppl II;II-483.Berger JS, et al. Presented AHA 2007; Abstact Circulation 2007;116 Suppl II;II-483.
Platelets and Cardiovascular Disease
Platelets play a major Platelets play a major role in the pathogenesis role in the pathogenesis of atherosclerosis and of atherosclerosis and coronary thrombosis coronary thrombosis
Platelets are an Platelets are an important link between important link between inflammation, inflammation, thrombosis, and thrombosis, and atherogenesisatherogenesis
Platelet
ADPTxA2
Thrombin
Collagen
vWFInflammation
ADP=adenosine diphosphate, TXAADP=adenosine diphosphate, TXA22=thromboxane A=thromboxane A22, COX=cyclooxygenase., COX=cyclooxygenase.
Adapted from Schafer AI. Am J Med. 1996;101:199-209.Adapted from Schafer AI. Am J Med. 1996;101:199-209.
collagenthrombin
TXA2
ADPADP
TXATXA22
ADP phosphodiesterasephosphodiesterase
ADPADP
(fibrinogen(fibrinogenreceptors)receptors)
GP IIb/IIIaGP IIb/IIIaActivation
COX
clopidogrel
ticlopidine
aspirin
dipyridamole
cAMP
Mechanisms of Action Mechanisms of Action Oral Antiplatelet AgentsOral Antiplatelet Agents
GP IIb/IIIa Inhibitors
Anti-platelet Therapies and SexAnti-platelet Therapies and SexAspirinAspirin
StrokeStrokeWomen 0.83 (.70-0.97)Women 0.83 (.70-0.97)Men 1.13 (0.96-1.33)Men 1.13 (0.96-1.33)
MIMIWomen 1.01 (.64-1.21)Women 1.01 (.64-1.21)Men 0.68 (0.54-0.86)Men 0.68 (0.54-0.86)
Berger JS et al. JAMA Berger JS et al. JAMA 2006;295:306-132006;295:306-13
CV EventsCV Events Women 0.88 (.79-0.99)Women 0.88 (.79-0.99)Men 0.86 (0.78-0.94)Men 0.86 (0.78-0.94)
Anti-platelet Therapies and SexAnti-platelet Therapies and SexGlycoprotein IIb/IIIa InhibitorsGlycoprotein IIb/IIIa Inhibitors
Boersma et al. Lancet 2002;359:189-99Boersma et al. Lancet 2002;359:189-99
PrevalencePrevalence Event rateEvent rate Odds RatioOdds Ratio PPintint
FemaleFemale 35% 35% 11.1%11.1% 1.151.15MaleMale 65% 65% 11.3%11.3% 0.810.81 <0.0001<0.0001
ClopidogrelClopidogrelWhat Do We Know?What Do We Know?
• 5 randomized trials of clopidogrel vs. placebo5 randomized trials of clopidogrel vs. placebo• CURE, CREDO, CLARITY, COMMIT, CHARISMACURE, CREDO, CLARITY, COMMIT, CHARISMA• Benefit from 2Benefit from 2oo prevention in the treatment of pts with CVD prevention in the treatment of pts with CVD
Maree et al Circulation 2007;2196-207Maree et al Circulation 2007;2196-207
• Clopidogrel “resistance” or “hyporesponsiveness”Clopidogrel “resistance” or “hyporesponsiveness”• Not yet proven to be clinically relevantNot yet proven to be clinically relevant• Some (though not all) studies suggest a greater frequency of Some (though not all) studies suggest a greater frequency of
hyporesponsiveness in femaleshyporesponsiveness in females
Ivandic et al Clin Chemistry 2006;52:383-8Ivandic et al Clin Chemistry 2006;52:383-8
ObjectiveObjective
To better understand the impact of To better understand the impact of sex on the clinical response to sex on the clinical response to
clopidogrelclopidogrel
MethodsMethods• Performed a sex-specific meta-analysis of clopidogrel for Performed a sex-specific meta-analysis of clopidogrel for
the prevention of CV events the prevention of CV events
• Comprehensive search of MEDLINE and EMBASE in May Comprehensive search of MEDLINE and EMBASE in May 20072007
• Search algorithm: Search algorithm: clopidogrel, myocardial infarction, clopidogrel, myocardial infarction, stroke, angina, PCI, CV disease, randomized controlled stroke, angina, PCI, CV disease, randomized controlled trialtrial
• Experts questioned; bibliographies of relevant studies Experts questioned; bibliographies of relevant studies searched for other relevant studies; monitored major searched for other relevant studies; monitored major scientific meetingsscientific meetings
Inclusion CriteriaInclusion Criteria
Studies had to be:Studies had to be:
• Prospective Prospective
• Randomized controlled trialsRandomized controlled trials
• Clopidogrel vs. placeboClopidogrel vs. placebo
• Report clinical outcomesReport clinical outcomes
OutcomesOutcomes
• Cardiovascular Events Cardiovascular Events
•Non-fatal MINon-fatal MI
•Non-fatal StrokeNon-fatal Stroke
•Cardiovascular Mortality Cardiovascular Mortality
• Each Individual EndpointEach Individual Endpoint
• All-cause Mortality All-cause Mortality • Major BleedingMajor Bleeding
Statistical AnalysisStatistical Analysis
• The principal investigator of each trial provided the data The principal investigator of each trial provided the data stratified by sexstratified by sex
• Performed with Comprehensive meta-analysis softwarePerformed with Comprehensive meta-analysis software (Biostat; Englewood, NJ)(Biostat; Englewood, NJ)
• Q statistic calculated to assess heterogeneity between Q statistic calculated to assess heterogeneity between trials & outcomes between women and mentrials & outcomes between women and men
• Odds ratio (OR) (Mantel-Haenszel and Peto methods) Odds ratio (OR) (Mantel-Haenszel and Peto methods) were usedwere used
• OR of individual trials pooled using random effects model OR of individual trials pooled using random effects model by combining the OR and 95% confidence interval (CI) for by combining the OR and 95% confidence interval (CI) for each studyeach study
Studies Included in the Meta-AnalysisStudies Included in the Meta-Analysis
TrialTrial NN Pt PopulationPt Population FemaleFemale F/UF/U
CURECURE 12,56212,562 Non-STE ACSNon-STE ACS 39%39% 12 mo 12 mo
(median 9 (median 9 mo)mo)
CREDOCREDO 2,1162,116 Planned PCIPlanned PCI 29%29% 12 mo12 mo
CLARITYCLARITY 3,4913,491 STEMISTEMI 20%20% 30 days30 days
COMMITCOMMIT 45,85245,852 STEMISTEMI 28%28% In-hospital or In-hospital or 28 days28 days
CHARISMACHARISMA 15,60315,603 CVD (or multiple CVD (or multiple risk factors for risk factors for
CVD)CVD)
30%30% 28 mo 28 mo (median)(median)
Group byGender
Study name Odds ratio and 95% CI
Odds ratio p-Value
Men CURE_M 0.748 0.000Men CREDO_M 0.715 0.063Men CLARITY_M 0.822 0.136Men COMMIT_M 0.886 0.003Men CHARISMA_M 0.896 0.135Men 0.842 0.000Women CURE_W 0.883 0.191Women CREDO_W 0.674 0.161Women CLARITY_W 0.822 0.378Women COMMIT_W 0.944 0.264Women CHARISMA_W 1.013 0.916Women 0.929 0.074
0.1 0.2 0.5 1 2 5 10
Clopidogrel Placebo
Major Cardiovascular Events
Heterogeneity Between Women and Men P=0.092Heterogeneity Between Women and Men P=0.092
Men 0.842 <0.001Men 0.842 <0.001
Women 0.929 0.074Women 0.929 0.074
Group byGender
Study name Odds ratio and 95% CI
Odds ratio p-Value
Men CURE_M 0.859 0.113Men CREDO_M 0.751 0.475Men CLARITY_M 0.904 0.620Men COMMIT_M 0.899 0.019Men CHARISMA_M 0.994 0.942Men 0.907 0.008Women CURE_W 1.036 0.771Women CREDO_W 0.742 0.558Women CLARITY_W 1.199 0.510Women COMMIT_W 0.972 0.605Women CHARISMA_W 0.986 0.918Women 0.986 0.762
0.1 0.2 0.5 1 2 5 10
Clopidogrel Placebo
All-Cause Mortality
Heterogeneity Between Women and Men P=0.158Heterogeneity Between Women and Men P=0.158
Men 0.907 0.008Men 0.907 0.008
Women 0.986 0.762Women 0.986 0.762
Group byGender
Study name Odds ratio and 95% CI
Odds ratio p-Value
Men CURE_M 0.757 0.003Men CREDO_M 0.797 0.240Men CLARITY_M 0.718 0.059Men COMMIT_M 0.876 0.084Men CHARISMA_M 0.925 0.506Men 0.832 0.000Women CURE_W 0.786 0.057Women CREDO_W 0.704 0.276Women CLARITY_W 0.578 0.130Women COMMIT_W 0.831 0.095Women CHARISMA_W 0.937 0.764Women 0.807 0.004
0.1 0.2 0.5 1 2 5 10
Clopidogrel Placebo
Myocardial Infarction
Heterogeneity between women and men P=0.733Heterogeneity between women and men P=0.733
Women 0.807 0.004Women 0.807 0.004
Men 0.832 <0.001Men 0.832 <0.001
Group byGender
Study name Odds ratio and 95% CI
Odds ratio p-Value
Men CURE_M 0.789 0.248Men CREDO_M 0.586 0.396Men CLARITY_M 0.883 0.727Men COMMIT_M 0.836 0.128Men CHARISMA_M 0.832 0.114Men 0.826 0.010Women CURE_W 0.998 0.995Women CREDO_W 2.893 0.516Women CLARITY_W 0.077 0.014Women COMMIT_W 0.938 0.671Women CHARISMA_W 0.945 0.749Women 0.914 0.562
0.1 0.2 0.5 1 2 5 10
Clopidogrel Placebo
Stroke
Heterogeneity between women and men P=0.552Heterogeneity between women and men P=0.552
Men 0.826 0.010Men 0.826 0.010
Women 0.914 0.562Women 0.914 0.562
Group byGender
Study name Odds ratio and 95% CI
Odds ratio p-Value
Men CURE_M 1.240 0.099Men CREDO_M 1.288 0.189Men CLARITY_M 1.163 0.632Men COMMIT_M 1.051 0.797Men CHARISMA_M 1.286 0.108Men 1.220 0.011Women CURE_W 1.679 0.002Women CREDO_W 1.544 0.166Women CLARITY_W 0.958 0.922Women COMMIT_W 1.307 0.369Women CHARISMA_W 1.175 0.519Women 1.433 0.002
0.1 0.2 0.5 1 2 5 10
Clopidogrel Placebo
Major Bleeding
Heterogeneity between women and men P=0.243Heterogeneity between women and men P=0.243
Women 1.433 0.002Women 1.433 0.002
Men 1.220 0.011Men 1.220 0.011
ACS*ACS*Major CV EventMajor CV Event
Women 0.93 (0.85-1.01)Women 0.93 (0.85-1.01)Men 0.83 (0.74-0.93) Men 0.83 (0.74-0.93)
All-Cause MortalityAll-Cause MortalityWomen 0.99 (0.90-1.09)Women 0.99 (0.90-1.09)Men 0.89 (0.82-0.97)Men 0.89 (0.82-0.97)
Myocardial InfarctionMyocardial InfarctionWomen 0.80 (0.68-0.94)Women 0.80 (0.68-0.94)Men 0.82 (0.73-0.91) Men 0.82 (0.73-0.91)
StrokeStrokeWomen 0.80 (0.45-1.45)Women 0.80 (0.45-1.45)Men 0.83 (0.68-1.00) Men 0.83 (0.68-1.00)
Major BleedingMajor BleedingWomen 1.50 (1.14-1.97)Women 1.50 (1.14-1.97)Men 1.18 (0.96-1.44) Men 1.18 (0.96-1.44)
Established CVDEstablished CVDtt
Major CV EventMajor CV EventWomen 0.93 (0.85-1.01)Women 0.93 (0.85-1.01)Men 0.84 (0.78-0.92) Men 0.84 (0.78-0.92)
All-Cause MortalityAll-Cause MortalityWomen 0.98 (0.89-1.07)Women 0.98 (0.89-1.07)Men 0.90 (0.83-0.96)Men 0.90 (0.83-0.96)
Myocardial InfarctionMyocardial InfarctionWomen 0.81 (0.70-0.94)Women 0.81 (0.70-0.94)Men 0.82 (0.74-0.90) Men 0.82 (0.74-0.90)
StrokeStrokeWomen 0.92 (0.67-1.27)Women 0.92 (0.67-1.27)Men 0.81 (0.69-0.94) Men 0.81 (0.69-0.94)
Major BleedingMajor BleedingWomen 1.43 (1.14-1.79)Women 1.43 (1.14-1.79)Men 1.19 (1.02-1.40)Men 1.19 (1.02-1.40)
Subgroup AnalysesSubgroup Analyses
**CURE, CLARITY, COMMIT; CURE, CLARITY, COMMIT; ttExcluded pts w/o established CVD from CHARISMAExcluded pts w/o established CVD from CHARISMA
LimitationsLimitations
• Meta-analyses have inherent limitationsMeta-analyses have inherent limitations
• Results can be due to chanceResults can be due to chance
• Bias can be introduced by combining trials Bias can be introduced by combining trials with different designswith different designs
• Results ought not be applied to populations Results ought not be applied to populations dissimilar to those in included studiesdissimilar to those in included studies
• Possibility of heterogeneity between trials Possibility of heterogeneity between trials
ConclusionsConclusions
• Clopidogrel reduced the risk of cardiovascular events Clopidogrel reduced the risk of cardiovascular events in both women and menin both women and men
• While the directionality and proportionality of the While the directionality and proportionality of the reductions are roughly similar, the effect in women reductions are roughly similar, the effect in women was driven by a reduction of MI was driven by a reduction of MI
• The reduction of MI, stroke and death by clopidogrel The reduction of MI, stroke and death by clopidogrel in men were all significantin men were all significant
• Clopidogrel increased the risk of major bleeding by Clopidogrel increased the risk of major bleeding by 43% in women, 21% in men43% in women, 21% in men
Thank you……CURECURE: : Yusuf S, Zhao F, Mehta SR, et al. Clopidogrel in Unstable Angina to 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 Prevent Recurrent Events Trial I. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. New patients with acute coronary syndromes without ST-segment elevation. New England Journal of MedicineEngland Journal of Medicine. . 2001;345:494-502.2001;345:494-502.
CREDOCREDO: : Steinhubl SR, Berger PB, Mann JT, 3rd, et al. Early and sustained Steinhubl SR, Berger PB, Mann JT, 3rd, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;288:2411-20.randomized controlled trial. JAMA 2002;288:2411-20.
COMMITCOMMIT: : Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005;366:1607-21. placebo-controlled trial. Lancet 2005;366:1607-21.
CLARITYCLARITY: : Sabatine MS, Cannon CP, Gibson CM, et al. Addition of Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. New England Journal of Medicine 2005;352:1179-89.segment elevation. New England Journal of Medicine 2005;352:1179-89.
CHARISMACHARISMA: : Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. New versus aspirin alone for the prevention of atherothrombotic events. New England Journal of Medicine 2006;354:1706-17.England Journal of Medicine 2006;354:1706-17.