CAPRIE

Published

Gent M, et al. "A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events". The Lancet. 1996. 348(9038):1329-39.
PubMed • Full text • PDF

Clinical Question

In patients with a recent CV event (stroke or MI), how does clopidogrel compare to aspirin in the secondary prevention of stroke, MI, and CV death?

Bottom Line

Clopidogrel reduces CV outcomes more than aspirin when used as secondary prevention among patients with prior stroke or MI.

Major Points

Prior placebo-controlled studies demonstrated that aspirin and ticlopidine independently reduce risk of stroke, MI, and CV death, with head-to-head studies demonstrating a slight advantage of ticlopidine. CAPRIE sought to evaluate whether clopidogrel, a thienopyridine like ticlopidine, would compare favorably to aspirin using similar outcome measures. In CAPRIE, clopidogrel reduced the risk of CV events by 9% compared to aspirin without an adverse effect on bleeding events.

Guidelines

2014 AHA/ASA Secondary Stroke Prevention Guidelines

• For patients with noncardioembolic ischemic stroke or TIA, the use of antiplatelet agents rather than oral anticoagulation is recommended to reduce the risk of recurrent stroke and other cardiovascular events (Class I; Level of Evidence A).
• Aspirin (50–325 mg/d) monotherapy (Class I; Level of Evidence A) or the combination of aspirin 25 mg and extended-release dipyridamole 200 mg twice daily (Class I; Level of Evidence B) is indicated as initial therapy after TIA or ischemic stroke for prevention of future stroke. (Revised recommendation)
• Clopidogrel (75 mg) monotherapy is a reasonable option for secondary prevention of stroke in place of aspirin or combination aspirin/dipyridamole (Class IIa; Level of Evidence B). This recommendation also applies to patients who are allergic to aspirin.
• The selection of an antiplatelet agent should be individualized on the basis of patient risk factor profiles, cost, tolerance, relative known efficacy of the agents,and other clinical characteristics (Class I; Level of Evidence C).
• The combination of aspirin and clopidogrel might be considered for initiation within 24 hours of a minor ischemic stroke or TIA and for continuation for 90 days (Class IIb; Level of Evidence B). (New recommendation in 2014 Update)
• The combination of aspirin and clopidogrel, when initiated days to years after a minor stroke or TIA and continued for 2 to 3 years, increases the risk of hemorrhage relative to either agent alone and is not recommended for routine long-term secondary prevention after ischemic stroke or TIA (Class III; Level of Evidence A).
• For patients who have an ischemic stroke or TIA while taking aspirin, there is no evidence that increasing the dose of aspirin provides additional benefit. Although alternative antiplatelet agents are often considered, no single agent or combination has been adequately studied in patients who have had an event while receiving aspirin (Class IIb; Level of Evidence C).
• For patients with a history of ischemic stroke or TIA, AF, and CAD, the usefulness of adding antiplatelet therapy to VKA therapy is uncertain for purposes of reducing the risk of ischemic cardiovascular and cerebrovascular events (Class IIb; Level of Evidence C).
• Unstable angina and coronary artery stenting represent special circumstances in which management may warrant DAPT/VKA therapy. (New Recommendation in 2014 Update)

Design

• Multicenter, double-blind, parallel-group, randomized controlled trial
• N=19,185
  • Clopidogrel (n=9,599)
  • Aspirin (n=9,586)
• Enrollment: March 1992 to February 1995
• Mean follow-up: 1.9 years

Population

Inclusion Criteria

• Recent CV event, defined as:
  • Ischemic stroke onset ≥1 week and ≤6 months before randomization, with neurological signs ≥1 week from stroke onset
  • MI onset ≤35 days before randomization with two of: ≥20 min characteristic anginal pain, elevated cardiac enzymes, new Q waves in two contiguous leads or new dominant R wave in V1
  • Symptomatic PAD with intermittent claudication and ankle/arm systolic BP ratio ≤0.85 in either leg at rest or history of claudication leading to limb amputation, reconstructive surgery, or angioplasty without complications

Exclusion Criteria

• Age <21 years
• Severe CNS deficit likely leading to bed-bound or demented state
• Carotid endarterectomy (CEA) after qualifying stroke
• Qualifying stroke induced by CEA or angiography
• Patient unlikely to be discharged after qualifying event
• Severe comorbidity limiting life expectancy to <3 years
• Uncontrolled HTN
• Upcoming major surgery
• Severe renal or hepatic insufficiency
• Bleeding disorder
• Thrombocytopenia, neutropenia, or otherwise abnormal CBC
• Drug-induced hematologic or hepatic disorders
• Anticipated requirement for long-term anticoagulation, or non-study antiplatelet agents including NSAIDs
• Aspirin insensitivity
• Women of childbearing age not using reliable contraception
• Currently receiving study drug
• Previously entered in clopidogrel studies
• Geographic or other factors making study participation impractical

Interventions

• Patients randomized to clopidogrel 75mg daily or aspirin 325mg daily, asked to take one tablet daily with morning meal
• Reassessment with monthly visits for first 4 months, then every 4 months thereafter
• Permanent discontinuation of study drug if ANC <450 x10⁹/L or platelets <80 x10⁹/L

Outcomes

Comparisons are clopidogrel vs. aspirin.

Primary Outcomes

Ischemic stroke, MI, or CV death (event rate/year)

5.32% vs. 5.83% (RR 0.91; 95% CI 0.84-0.97; P=0.043)

Secondary Outcomes

Ischemic stroke, MI, amputation, or CV death (event rate/year)

5.56% vs. 6.01% (P=0.076)

CV death (event rate/year)

1.90% vs. 2.06% (P=0.29)

Any stroke, MI, or death from any cause (event rate/year)

6.43% vs. 6.90% (P=0.081)

Death from any cause (event rate/year)

3.05% vs. 3.11% (P=0.71)

Adverse events

Rash

6.0% vs. 4.6% (P<0.05)

Diarrhea

4.5% vs. 0.23% (P<0.05)

GI complaints

15.0% vs. 17.6% (P<0.05)

GI bleeding

2.0% vs. 2.7% (P<0.05)

Abnormal liver function

3.0% vs. 3.2% (P<0.05)

Any bleeding

9.3% vs. 9.3% (P=NS)

Intracranial bleed

0.35% vs. 0.49% (P=NS)

Discontinuation of drug for reasons other than outcome event

21.3% vs. 21.1% (P=NS)

Criticisms

A common complaint is that composite primary endpoints, as used in CAPRIE, may not be the most statistically rigorous. One counter-argument is that composite outcomes, particularly among cardiovascular trials, are of great importance from a patient perspective; that is, patients are interested in all efficacy endpoints, not just one type of event such as stroke. A second is that it would be prohibitive to enroll or follow a sufficiently large number of patients to identify a statistically meaningful difference in the rate of a single event such as stroke.

Funding

Funded by Sanofi and Bristol-Myers Squibb.