the relative safety and efficacy of clopidogrel in women and men: a sex-specific meta-analysis

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


Odds ratio p-Value


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


Odds ratio p-Value


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


Odds ratio p-Value


0.1 0.2 0.5 1 2 5 10

Clopidogrel Placebo

Stroke


Men 0.826 0.010Men 0.826 0.010

Women 0.914 0.562Women 0.914 0.562

Group byGender


Odds ratio p-Value


0.1 0.2 0.5 1 2 5 10

Clopidogrel Placebo

Major Bleeding


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.

the relative safety and efficacy of clopidogrel in women and men: a sex-specific meta-analysis

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