4-Key Findings From Caprie

Clopidogrel:Clopidogrel:Key Findings from Key Findings from

CAPRIECAPRIE

Slide 1 SD3325 7/15/98

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Patients with a wide spectrum of atherosclerotic disease Patients with a wide spectrum of atherosclerotic disease are at risk of all major atherothrombotic eventsare at risk of all major atherothrombotic events

Atherothrombotic process is similar regardless of clinical Atherothrombotic process is similar regardless of clinical manifestation of underlying atherosclerosismanifestation of underlying atherosclerosis

Clopidogrel was expected to benefit the entire spectrum Clopidogrel was expected to benefit the entire spectrum of atherosclerotic patientsof atherosclerotic patients

Clopidogrel was hypothesized to provide approximately Clopidogrel was hypothesized to provide approximately 10% additional relative risk reduction vs. aspirin10% additional relative risk reduction vs. aspirin

Rationale for CAPRIERationale for CAPRIE

CAPRIE Steering Committee. Lancet 1996;348:1329-1339.CAPRIE Steering Committee. Lancet 1996;348:1329-1339.

SD3325 07/15/98 3

Main finding:Main finding: From a meta-analysis of 142 trials, including moreFrom a meta-analysis of 142 trials, including more

than 73,000 high-risk patients, platelet aggregation inhibitors than 73,000 high-risk patients, platelet aggregation inhibitors reduced the risk of the composite outcome of ischemic stroke, reduced the risk of the composite outcome of ischemic stroke, MI, or vascular death by 25%MI, or vascular death by 25%

The odds reduction was consistent:The odds reduction was consistent: Over a wide range of clinical manifestations (ischemic Over a wide range of clinical manifestations (ischemic

cerebrovascular, coronary, and atherosclerotic peripheral cerebrovascular, coronary, and atherosclerotic peripheral arterial disease)arterial disease)

Across subsets of patients at varying risks withinAcross subsets of patients at varying risks withinspecific clinical disordersspecific clinical disorders

Rationale for CAPRIE:Rationale for CAPRIE:Antiplatelet Trialists’ CollaborationAntiplatelet Trialists’ Collaboration

Antiplatelet Trialists’ Collaboration. BMJ 1994;308:81-106.Antiplatelet Trialists’ Collaboration. BMJ 1994;308:81-106.

SD3325 07/15/98 4

Clopidogrel: An ADP Receptor AntagonistClopidogrel: An ADP Receptor Antagonist

ClopidogrelClopidogrel

, H2SO4

S

H

Cl

N

COOCH3

SD3325 07/15/98 5

• Acts by selective inhibition of ADP binding to its platelet Acts by selective inhibition of ADP binding to its platelet receptor and prevents subsequent platelet aggregationreceptor and prevents subsequent platelet aggregation

Clopidogrel Mechanism of ActionClopidogrel Mechanism of ActionADPADP

ADPADP

Fibrinogen Binding SiteFibrinogen Binding Site

ClopidogrelClopidogrelClopidogrelClopidogrel

Fibrinogen Binding ReducedFibrinogen Binding Reduced

FibrinogenFibrinogen

PlateletPlatelet

Herbert. Exp Opin Invest Drugs 1994;3:449-455.Herbert. Exp Opin Invest Drugs 1994;3:449-455.

SD3325 07/15/98 6

CAPRIE Study: MethodologyCAPRIE Study: MethodologyStudy designStudy design Multicenter, prospective, randomized, blindedMulticenter, prospective, randomized, blinded

Study populationStudy population 19,185 patients with atherosclerotic19,185 patients with atheroscleroticvascular diseasevascular disease

Qualifying conditionsQualifying conditions Ischemic stroke (Ischemic stroke (1 week and 1 week and 6 months)6 months)Myocardial infarction (MI) (Myocardial infarction (MI) (35 days)35 days)Established peripheral arterial diseaseEstablished peripheral arterial disease

Study drugsStudy drugs Clopidogrel 75 mg once dailyClopidogrel 75 mg once dailyAspirin 325 mg once dailyAspirin 325 mg once daily

Primary end pointPrimary end point MI, ischemic stroke, or vascular deathMI, ischemic stroke, or vascular death

Treatment durationTreatment duration Up to 3 years (mean 1.6 years)Up to 3 years (mean 1.6 years)

Investigational sitesInvestigational sites 384 in 16 countries384 in 16 countriesCAPRIE Steering Committee. Lancet 1996;348:1329-1339.CAPRIE Steering Committee. Lancet 1996;348:1329-1339.

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Qualifying conditions (one of the following):Qualifying conditions (one of the following): Recent ischemic stroke (IS): 1 week to 6 monthsRecent ischemic stroke (IS): 1 week to 6 months Recent myocardial infarction (MI): within 35 daysRecent myocardial infarction (MI): within 35 days Established peripheral arterial disease (PAD): current Established peripheral arterial disease (PAD): current

intermittent claudication or prior arterial interventionintermittent claudication or prior arterial intervention

Patients with prior atherothrombotic events or atherosclerotic Patients with prior atherothrombotic events or atherosclerotic disease in more than one arterial bed were includeddisease in more than one arterial bed were included

Patients with known intolerance to aspirin or a history of Patients with known intolerance to aspirin or a history of bleeding and peptic ulcers were excludedbleeding and peptic ulcers were excluded

CAPRIE Study: Patient PopulationCAPRIE Study: Patient Population


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Primary analysis:Primary analysis: Ischemic stroke, myocardial infarction (MI), or vascular Ischemic stroke, myocardial infarction (MI), or vascular

deathdeath

Secondary analysis:Secondary analysis: Ischemic stroke, MI, amputation, orIschemic stroke, MI, amputation, or

vascular deathvascular death Vascular deathVascular death Any stroke, MI, or death from any causeAny stroke, MI, or death from any cause Death from any causeDeath from any cause

CAPRIE Study: Outcome Event ClustersCAPRIE Study: Outcome Event Clusters


SD3325 07/15/98 9

Baseline Patient Characteristics in CAPRIE: Baseline Patient Characteristics in CAPRIE: Risk FactorsRisk Factors


Clopidogrel, n=9599Clopidogrel, n=9599Aspirin, n=9586Aspirin, n=9586

Risk FactorsRisk Factors

Per

cent

Per

cent

Diabetes MellitusDiabetes Mellitus HypertensionHypertension HypercholesterolemiaHypercholesterolemia Cigarette Smoker Cigarette Smoker (Current)(Current)

0

20

40

60

SD3325 07/15/98 10

Baseline Patient Characteristics in CAPRIE:Baseline Patient Characteristics in CAPRIE:History of Ischemic EventsHistory of Ischemic Events

*Excluding qualifying condition*Excluding qualifying conditionCAPRIE Steering Committee. Lancet 1996;348:1329-1339.CAPRIE Steering Committee. Lancet 1996;348:1329-1339.

History of Ischemic EventsHistory of Ischemic Events

30

Per

cent

Per

cent

Ischemic Ischemic Stroke*Stroke*

Angina Angina (Stable)(Stable)

Angina Angina (Unstable)(Unstable)

Intermittent Intermittent Claudication*Claudication*

TIA/RINDTIA/RIND MI*MI*0

10

20

Clopidogrel, n=9599Clopidogrel, n=9599

Aspirin, n=9586Aspirin, n=9586

SD3325 07/15/98 11

CAPRIE Study:CAPRIE Study:Specific Features of MI and PAD SubgroupsSpecific Features of MI and PAD SubgroupsMI subgroup (MI subgroup (nn = 6,302)= 6,302) ClopidogrelClopidogrel AspirinAspirinTime to randomization, days*Time to randomization, days* 17.5 17.5 ++ 10.110.1 17.7 17.7 ++ 10.310.3MI location:MI location: Anterior/lateralAnterior/lateral 34%34% 34%34% Inferior/posteriorInferior/posterior 57%57% 57%57% Other/indeterminateOther/indeterminate 8%8% 9%9%PAD subgroup (PAD subgroup (nn = 6,452) = 6,452)Duration of disease, years*Duration of disease, years* 4.1 4.1 ++ 4.74.7 4.2 4.2 ++ 4.94.9Basis of eligibility:Basis of eligibility: Arterial interventionArterial intervention 62%62% 64%64% Current claudicationCurrent claudication 38%38% 36%36%Ankle/arm BP ratio*Ankle/arm BP ratio* ‡‡ 0.56 0.56 ++ 0.150.15 0.57 0.57 ++ 0.160.16*Mean *Mean ++ SD. SD. ‡‡Current claudicants only.Current claudicants only.

Data on file (CAPRIE Report No. 602-6-110, p. 86).Data on file (CAPRIE Report No. 602-6-110, p. 86).

SD3325 07/15/98 12

CAPRIE Study:CAPRIE Study:Specific Features of Stroke SubgroupSpecific Features of Stroke Subgroup

Stroke Subgroup (Stroke Subgroup (nn = 6,431)= 6,431) ClopidogrelClopidogrel AspirinAspirinTime to randomization, days*Time to randomization, days* 53.3 53.3 ++ 47.647.6 ++52.7 52.7 47.347.3Stroke typeStroke type AtherothromboticAtherothrombotic 60%60% 58%58% LacunarLacunar 39%39% 41%41% RetinalRetinal 1%1% 1%1%Stroke severityStroke severity MildMild 22%22% 23%23% ModerateModerate 56%56% 55%55% SevereSevere 22%22% 22%22%

*Mean *Mean ++ SD. SD.

Data on file (CAPRIE Report No. 602-6-110, p. 86).Data on file (CAPRIE Report No. 602-6-110, p. 86).

SD3325 07/15/98 13

CAPRIE Study DisciplineCAPRIE Study Discipline

MeasureMeasureClopidogrelClopidogrel((nn = 9,599)= 9,599)

AspirinAspirin((nn = 9,586)= 9,586)

No study drugNo study drug 46 (0.5%)46 (0.5%) 40 (0.4%)40 (0.4%)

Early permanent studyEarly permanent studydrug discontinuationdrug discontinuation

2,041 (21.3%)2,041 (21.3%) 2,018 (21.1%)2,018 (21.1%)

Study drug complianceStudy drug compliance 90.6%90.6% 90.7%90.7%

Code breaksCode breaks 11 (0.1%)11 (0.1%) 10 (0.1%)10 (0.1%)

Lost to follow-upLost to follow-up 22 (0.2%)22 (0.2%) 20 (0.2%)20 (0.2%)CAPRIE Steering Committee. Lancet 1996;348:1329-1339.CAPRIE Steering Committee. Lancet 1996;348:1329-1339.

SD3325 07/15/98 14

CAPRIE Study: Primary AnalysisCAPRIE Study: Primary Analysis

ClopidogrelClopidogrel 405405

TreatmentTreatmentGroupGroup

Non-Non-fatalfatal

3333

FatalFatal

Ischemic Ischemic StrokeStroke

226226

Non-Non-fatalfatal

4949

FatalFatal

MIMI

226226

OtherOtherVascularVascular

DeathDeath

939939

TotalTotalFirstFirst

EventsEvents

5.32%5.32%

EventEventRate / YrRate / Yr

AspirinAspirin 430430 3232 270270 6363 226226 10211021 5.83%5.83%

Relative Risk Reduction: 8.7% (Relative Risk Reduction: 8.7% (pp = 0.043) = 0.043)(95% Confidence Interval: 0.3%, 16.5%)(95% Confidence Interval: 0.3%, 16.5%)


SD3325 07/15/98 15

CAPRIE Study: MI ParadoxCAPRIE Study: MI ParadoxRelative Risk Reduction* byRelative Risk Reduction* by

Qualifying Entry CriteriaQualifying Entry Criteria11

*Cluster of IS, MI, or vascular death. *Cluster of IS, MI, or vascular death. 11CAPRIE Steering Committee. Lancet 1996;348:1329-1339.CAPRIE Steering Committee. Lancet 1996;348:1329-1339.22Easton. Neurology 1998;50(suppl 4):A157. Easton. Neurology 1998;50(suppl 4):A157. 33Gent. Circulation. 1997;96(suppl):I-467.Gent. Circulation. 1997;96(suppl):I-467.

IS IS n=6431n=6431

MI MI n=6302n=6302

PADPAD n=6452n=6452

Total Total n=19185n=19185

clopidogrel betterclopidogrel better00 1010 202010102020 3030

8.78.7

7.37.3

-3.7-3.7

23.823.8

Relative Risk Reduction ofRelative Risk Reduction ofIndividual End PointsIndividual End Points

IS (fatal or IS (fatal or non-fatal)non-fatal)22

MI (fatal or MI (fatal or non-fatalnon-fatal))33

Vascular Vascular deathdeath11

IS, MI, IS, MI, vascular deathvascular death11

clopidogrel betterclopidogrel better00 1010 202010102020 3030

19.219.2

5.25.2

7.67.6

n=19,185n=19,185

8.78.7

SD3325 07/15/98 16

CAPRIE Study: Efficacy of ClopidogrelCAPRIE Study: Efficacy of Clopidogrel

Time from Randomization (Months)Time from Randomization (Months)

Cum

ulat

ive

Ris

k, %

Cum

ulat

ive

Ris

k, %

00 33 66 99 1212 1515 1818 2121 2424 2727 3030 3333 3636

PlaceboPlacebo11

AspirinAspirin22

ClopidogrelClopidogrel22

11Placebo arm extrapolated from Placebo arm extrapolated from APTC meta-analysis. Antiplatelet APTC meta-analysis. Antiplatelet Trialists’ Collaboration. BMJ 1994; Trialists’ Collaboration. BMJ 1994; 308:81-106, and CAPRIE308:81-106, and CAPRIE22CAPRIE Steering Committee. CAPRIE Steering Committee. Lancet 1996;348:1329-1339.Lancet 1996;348:1329-1339. pp = 0.043. = 0.043.00

44

88

1212

1616

5.85.8

5.35.3

7.77.7

15.215.214.114.1

20.320.3

p p = 0.043, = 0.043, clopidogrel clopidogrel vs. aspirinvs. aspirin

Event Rate Event Rate per Yearper Year

Event Rate Event Rate at 3 Yearsat 3 Years

SD3325 07/15/98 17

Different Measures of EfficacyDifferent Measures of Efficacy

Treatment benefit can be expressed by different Treatment benefit can be expressed by different measures, for example: measures, for example: Relative risk reductionRelative risk reduction Absolute risk reductionAbsolute risk reduction Odds ratioOdds ratio

Number of events prevented (or number needed to Number of events prevented (or number needed to treat*) is a more meaningful expression for medical treat*) is a more meaningful expression for medical decision makersdecision makers

*Laupacis et al. N Engl J Med 1988;318:1728-1733.*Laupacis et al. N Engl J Med 1988;318:1728-1733.

SD3325 07/15/98 18

Number of Events PreventedNumber of Events Prevented

Correlated to:Correlated to: Baseline riskBaseline risk Relative risk reduction (RRR)Relative risk reduction (RRR)

Examples:Examples:Events prevented perEvents prevented per 1,000 patients treated1,000 patients treated

33242455

Baseline riskBaseline risk1%1%8%8%6%6%

RRRRRR30%30%30%30%8%8%

SD3325 07/15/98 19

Efficacy of Clopidogrel: Events Prevented Efficacy of Clopidogrel: Events Prevented (Ischemic Stroke, Myocardial Infarction, Vascular (Ischemic Stroke, Myocardial Infarction, Vascular Death)Death)

Time from Randomization (Months)Time from Randomization (Months)

Eve

nt R

ate/

1,00

0 P

atie

nts/

Yea

rE

vent

Rat

e/1,

000

Pat

ient

s/Y

ear

00 33 66 99 1212 1515 1818 2121 2424 2727 3030 3333 3636

Event Rate per YearEvent Rate per Year

PlaceboPlacebo11

AspirinAspirin22

7.7%7.7%

5.8%5.8%

5.3%5.3%

Based on the APTC Based on the APTC findings,findings,11 in a population in a population similar to CAPRIE, for each similar to CAPRIE, for each 1,000 patients treated per 1,000 patients treated per year, aspirin can be year, aspirin can be expected to prevent 19 expected to prevent 19 events and clopidogrel 24.events and clopidogrel 24.22

1919 2424

00

4040

8080

120120

160160

58587777

5353

11Placebo arm extrapolated from APTC meta-analysis. Placebo arm extrapolated from APTC meta-analysis. Antiplatelet Trialists’ Collaboration. BMJ 1994;308:81-106, and CAPRIEAntiplatelet Trialists’ Collaboration. BMJ 1994;308:81-106, and CAPRIE

22CAPRIE Steering Committee. Lancet 1996;348:1329-1339.CAPRIE Steering Committee. Lancet 1996;348:1329-1339. pp = 0.043. = 0.043.

ClopidogrelClopidogrel22

SD3325 07/15/98 20

CAPRIE Study: CAPRIE Study: Clinical Evidence of Efficacy of ClopidogrelClinical Evidence of Efficacy of Clopidogrel

*(MI, ischemic stroke,and vascular death)*(MI, ischemic stroke,and vascular death)**Based on the**Based on the CAPRIE trial and Antiplatelet CAPRIE trial and Antiplatelet Trialists’ Collaboration meta-analysis, aspirin Trialists’ Collaboration meta-analysis, aspirin can be expected to prevent 19 ischemic can be expected to prevent 19 ischemic events* for every 1,000 patients treated per events* for every 1,000 patients treated per year.year.1,21,2 In contrast, clopidogrel can be expected In contrast, clopidogrel can be expected to prevent 24 ischemic events* for every 1,000 to prevent 24 ischemic events* for every 1,000 patients treated per year, a 26% difference.patients treated per year, a 26% difference.

11CAPRIE Steering Committee. Lancet CAPRIE Steering Committee. Lancet 1996;348:1329-1339. 1996;348:1329-1339. 22Antiplatelet Trialists’ Antiplatelet Trialists’ Collaboration. BMJ 1994; 308:81-106.Collaboration. BMJ 1994; 308:81-106.

Clopidogrel Clopidogrel prevents 26% more prevents 26% more ischemic events* ischemic events*

than aspirin** than aspirin**

25

26%26%

0

5

10

15

20

2419Ev

ents

Pre

vent

ed/Y

ear/1

,000

Pat

ient

sEv

ents

Pre

vent

ed/Y

ear/1

,000

Pat

ient

s

AspirinAspirin1,21,2 Clopidogrel Clopidogrel1,21,2

SD3325 07/15/98 21

Events Prevented byEvents Prevented byCardiovascular PharmacotherapiesCardiovascular Pharmacotherapies

ClopidogrelClopidogrel1,21,2 IS, MI, vascularIS, MI, vasculardeathdeath

2424

TreatmentTreatment End PointEnd Point

Mean No. of EventsMean No. of EventsPrevented per 1,000Prevented per 1,000Patients per YearPatients per YearPopulationPopulation

AtheroscleroticAtherosclerotic

AspirinAspirin1,21,2 IS, MI, vascularIS, MI, vasculardeathdeath

1919AtheroscleroticAtherosclerotic

11CAPRIE Steering Committee. Lancet 1996;348:1329-1339.CAPRIE Steering Committee. Lancet 1996;348:1329-1339.22Antiplatelet Trialists’ Collaboration. BMJ 1994;308:81-106. Antiplatelet Trialists’ Collaboration. BMJ 1994;308:81-106.

MI, CHD deathMI, CHD death

ACE inhibitorsACE inhibitors44

(>60 yrs)(>60 yrs)

Acute MI + LVAcute MI + LVdysfunctiondysfunction

MI, vascularMI, vascular 1818

AntihypertensiveAntihypertensivedrugsdrugs33

Fatal or non-fatal stroke,Fatal or non-fatal stroke, 88HypertensionHypertension

deathdeath

33SHEP Cooperative Research Group. JAMA 1991;265:3255-3264.SHEP Cooperative Research Group. JAMA 1991;265:3255-3264.44Pfeffer MA, et al. (SAVE Trial) N Engl J Med 1992;327:669-677.Pfeffer MA, et al. (SAVE Trial) N Engl J Med 1992;327:669-677.

SD3325 07/15/98 22

Impact of Platelet Aggregation Inhibitors:Impact of Platelet Aggregation Inhibitors:Extrapolation to US and EU Atherothrombotic PatientsExtrapolation to US and EU Atherothrombotic Patients

AspirinAspirin ClopidogrelClopidogrel

Even

ts P

reve

nted

/Yea

rEv

ents

Pre

vent

ed/Y

ear

00

100,000100,000

200,000200,000

300,000300,000

400,000400,000

500,000500,000

380,000 480,000

100,000 additional 100,000 additional events (IS, MI, events (IS, MI,

vascular death) vascular death) could be could be

prevented if all prevented if all atherothrombotic atherothrombotic patients in US and patients in US and

EU (20 M) were EU (20 M) were treated per yeartreated per year

100,000100,000

SD3325 07/15/98 23

Adverse Events in the CAPRIE StudyAdverse Events in the CAPRIE Study

% of Patients with Events% of Patients with EventsAspirinAspirin

(325 mg/day)(325 mg/day)ClopidogrelClopidogrel(75 mg/day)(75 mg/day)

Intracranial hemorrhageIntracranial hemorrhage11 0.490.49 0.350.35Gastrointestinal bleedingGastrointestinal bleeding11 2.66*2.66* 1.991.99Gastrointestinal ulcersGastrointestinal ulcers22 1.15*1.15* 0.680.68Indigestion/nausea/vomitingIndigestion/nausea/vomiting11 17.59*17.59* 15.0115.01DiarrheaDiarrhea11 3.363.36 4.46*4.46*RashRash11 4.614.61 6.02*6.02*NeutropeniaNeutropenia11 0.170.17 0.100.10

11CAPRIE Steering Committee. Lancet 1996;348:1329-1339. CAPRIE Steering Committee. Lancet 1996;348:1329-1339. 22Lok. Eur Heart J 1998;19(suppl):P487.Lok. Eur Heart J 1998;19(suppl):P487. **pp<0.05<0.05

SD3325 07/15/98 24

CAPRIE Study: Hemorrhagic EventsCAPRIE Study: Hemorrhagic Events

Trend to more cerebral hemorrhages, fatal or non-fatal, and more Trend to more cerebral hemorrhages, fatal or non-fatal, and more hemorrhagic deaths in aspirin group: 37 versus 51 (0.39% vs. 0.53%)hemorrhagic deaths in aspirin group: 37 versus 51 (0.39% vs. 0.53%)

ClopidogrelClopidogrelAspirinAspirin

300300

005050

100100150150200200250250

Hospitalization for GI Hospitalization for GI Bleeding EventsBleeding Events11

GI Hemorrhages GI Hemorrhages ((pp<0.002)<0.002)22

Num

ber o

f Pat

ient

sN

umbe

r of P

atie

nts

7171(0.74%)(0.74%)

104104(1.08%)(1.08%)

191191 255255

11Bogousslavsky. Cerebrovasc Dis 1998;8(suppl 4):43. Abstract CLI 76.Bogousslavsky. Cerebrovasc Dis 1998;8(suppl 4):43. Abstract CLI 76.22CAPRIE Steering Committee. Lancet 1996;348:1329-1339. CAPRIE Steering Committee. Lancet 1996;348:1329-1339.

SD3325 07/15/98 25

� Higher incidence of ulcers in aspirin group: 110 (1.15%) vs. 65 (0.68%) in Higher incidence of ulcers in aspirin group: 110 (1.15%) vs. 65 (0.68%) in clopidogrel group (clopidogrel group (pp<0.05)<0.05)11

� More GI disorders in aspirin group (More GI disorders in aspirin group (pp<0.001)<0.001)22

� Overall incidence of GI events (abdominal pain, dyspepsia, gastritis, Overall incidence of GI events (abdominal pain, dyspepsia, gastritis, constipation): 27.1% for clopidogrel, 29.8% for aspirinconstipation): 27.1% for clopidogrel, 29.8% for aspirin11

Events Events Clopidogrel, % Clopidogrel, % Aspirin, % Aspirin, %

UlcersUlcers11 0.680.68 1.15 1.15

Indigestion,Indigestion,nausea, nausea, 15.0115.01 17.59 17.59vomitingvomiting22

CAPRIE Study: Gastrointestinal TolerabilityCAPRIE Study: Gastrointestinal Tolerability

11Lok. Eur Heart J 1998;19(suppl):P487.Lok. Eur Heart J 1998;19(suppl):P487.22CAPRIE Steering Committee. Lancet 1996;348:1329-1339. CAPRIE Steering Committee. Lancet 1996;348:1329-1339.

SD3325 07/15/98 26

� Incidence of any rash is statistically different (Incidence of any rash is statistically different (pp<0.001)<0.001)

� Few severe rashes in either groupFew severe rashes in either group

� Small number of rashes led to early premature discontinuation:Small number of rashes led to early premature discontinuation:(0.90% for clopidogrel and 0.41% for aspirin)(0.90% for clopidogrel and 0.41% for aspirin)

EventsEvents All, %All, % Severe, %Severe, %ClopidogrelClopidogrel Aspirin Aspirin Clopidogrel Aspirin Clopidogrel Aspirin

Any rashAny rash** 6.026.02 4.61** 4.61** 0.260.26 0.10** 0.10**

Any allergic reactionAny allergic reaction** 0.920.92 1.011.01 0.080.08 0.11 0.11

CAPRIE Study: Skin DisordersCAPRIE Study: Skin Disorders

*The two groups of events are mutually exclusive.*The two groups of events are mutually exclusive.

CAPRIE Steering Committee. Lancet 1996;348:1329-1339.CAPRIE Steering Committee. Lancet 1996;348:1329-1339.****pp<0.05<0.05

SD3325 07/15/98 27

� Incidence of diarrhea is statistically different (Incidence of diarrhea is statistically different (pp<0.001)<0.001)

� Few cases of severe diarrhea in either groupFew cases of severe diarrhea in either group

� Diarrhea rarely led to early permanent discontinuation Diarrhea rarely led to early permanent discontinuation (0.42% for clopidogrel and 0.27% for aspirin)(0.42% for clopidogrel and 0.27% for aspirin)

Events All, %Events All, % Severe, % Severe, % ClopidogrelClopidogrel Aspirin Aspirin Clopidogrel Clopidogrel Aspirin Aspirin

Diarrhea 4.46 3.36* Diarrhea 4.46 3.36* 0.23 0.23 0.11 0.11

CAPRIE Study: DiarrheaCAPRIE Study: Diarrhea


**pp<0.05<0.05

SD3325 07/15/98 28

CAPRIE Study: CAPRIE Study: Validated Cases of Low Neutrophil CountsValidated Cases of Low Neutrophil Counts

NeutropeniaNeutropenia(<1200/mm(<1200/mm33))

CategoryCategoryClopidogrelClopidogrel

(n=9,599)(n=9,599)AspirinAspirin

(n=9,586)(n=9,586)

Severe neutropeniaSevere neutropenia(<450/mm(<450/mm33))

10 (0.10%)10 (0.10%)

5 (0.05%)5 (0.05%)

16 (0.17%)16 (0.17%)

4 (0.04%)4 (0.04%)


SD3325 07/15/98 29

Clopidogrel: Summary 1Clopidogrel: Summary 1 Mechanism of action: ADP receptor antagonist providing effective Mechanism of action: ADP receptor antagonist providing effective

inhibition of platelet aggregationinhibition of platelet aggregation

Clopidogrel is more effective than aspirinClopidogrel is more effective than aspirin11: : Clopidogrel prevents 26% more ischemic events* than Clopidogrel prevents 26% more ischemic events* than

aspirin**aspirin** 19.2% more effective than aspirin in reducing the risk of 19.2% more effective than aspirin in reducing the risk of

myocardial infarction (relative risk reduction 19.2%, myocardial infarction (relative risk reduction 19.2%, pp=0.008)=0.008)33

Favorable effect on each component of the outcome clusterFavorable effect on each component of the outcome cluster

*(MI, ischemic stroke and vascular death) **Based on the CAPRIE trial and Antiplatelet Trialists’ Collaboration meta-analysis, aspirin can *(MI, ischemic stroke and vascular death) **Based on the CAPRIE trial and Antiplatelet Trialists’ Collaboration meta-analysis, aspirin can be expected to prevent 19 ischemic events* for every 1,000 patients treated per year.be expected to prevent 19 ischemic events* for every 1,000 patients treated per year. 1,21,2 In contrast, clopidogrel can be expected to In contrast, clopidogrel can be expected to prevent 24 ischemic events* for every 1,000 patients treated per year, a 26% difference.prevent 24 ischemic events* for every 1,000 patients treated per year, a 26% difference.11CAPRIE Steering Committee. Lancet 1996;348:1329-1339. CAPRIE Steering Committee. Lancet 1996;348:1329-1339. 22Antiplatelet Trialists’ Collaboration. BMJ 1994;308:81-106. Antiplatelet Trialists’ Collaboration. BMJ 1994;308:81-106. 33Gent M. Circulation 1997;96(suppl):I-467.Gent M. Circulation 1997;96(suppl):I-467.

SD3325 07/15/98 30

Clopidogrel: Summary 2Clopidogrel: Summary 2 Favorable safety profileFavorable safety profile11

Less GI bleeding and fewer related hospitalizations vs. Less GI bleeding and fewer related hospitalizations vs. aspirinaspirin22

Better GI safety and improved gastric tolerability vs. Better GI safety and improved gastric tolerability vs. aspirin (325 mg)aspirin (325 mg)

Difference in favor of clopidogrel for GI bleeding is likely to Difference in favor of clopidogrel for GI bleeding is likely to be underestimated in CAPRIE due to study exclusion be underestimated in CAPRIE due to study exclusion criteriacriteria

Convenient dosing: 75 mg once daily with no dose Convenient dosing: 75 mg once daily with no dose adjustments necessaryadjustments necessary

11CAPRIE Steering Committee. LANCET 1996;348:1329-1339.CAPRIE Steering Committee. LANCET 1996;348:1329-1339.22Bogousslavsky. Cerebrovasc Dis 1998;8(suppl 4):43. Abstract CLI 76.Bogousslavsky. Cerebrovasc Dis 1998;8(suppl 4):43. Abstract CLI 76.

4-Key Findings From Caprie

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