Clopidogrel versus aspirin in patients at risk of ischaemic events - CAPRIE

Description:

Clopidogrel versus aspirin in patients with cerebral, peripheral, or coronary disease.

Hypothesis:

To assess the relative efficacy and safety of clopidogrel and aspirin in reducing the risk of ischemic events.

Study Design

Study Design:

Patients Screened: Not given
Patients Enrolled: 19,185
Mean Follow Up: 1.91 years
Mean Patient Age: 62.5
Female: 28

Patient Populations:

Ischemic stroke: Focal neurologic deficit likely to be of atherothrombotic origin; Onset ≥ 1 week and ≤ 6 months before randomization; Neurological signs persisting ≥ 1 week from stroke onset; CT or MRI ruling out hemorrhage or non-relevant disease.
Myocardial infarction with onset ≤ 35 days before randomization. Two of the following: Characteristic ischemic pain for ≥ 20 min; elevation of CK, CK-MB, LDH, or AST to twice upper limit of normal; development of new Q waves in two adjacent ECG leads or new dominant R wave in V1.

Peripheral vascular disease: Intermittent claudication and ankle/arm systolic BP ratio ≤ 0.85 in either leg at rest; or history of intermittent claudication with previous leg amputation, reconstructive surgery, or peripheral angioplasty.

Exclusions:

Age < 21 years
Severe cerebral deficit likely to lead to patient being bedridden or demented
Carotid endarterectomy after qualifying stroke
Qualifying stroke induced by carotid endarterectomy or angiography
Patient unlikely to be discharged alive after qualifying event
Comorbidity likely to limit life expectancy to less than 3 years
Uncontrolled hypertension
Scheduled for major surgery
Contraindications to study drugs: renal or hepatic insufficiency; hemostatic disorder or systemic bleeding; thrombocytopenia or neutropenia; drug-induced hematologic or hepatic abnormalities; abnormal WBC, differential, or platelet count; anticipated requirement for long-term anticoagulants or antiplatelet agents; history of aspirin sensitivity.
Women of childbearing age not using reliable contraception
Currently receiving investigational drug
Previous enrollment in other clopidogrel studies
Geographic or other factors making study participation impractical.

Primary Endpoints:

First occurrence of an event in the outcome cluster of ischaemic stroke, myocardial infarction, or vascular death

Secondary Endpoints:

Ischaemic stroke, myocardial infarction, vascular death, or amputation.
Vascular death only.

Drug/Procedures Used:

Clopidogrel, 75 mg po qd, versus aspirin 325 mg po qd.

Concomitant Medications:

Use of anticoagulants or antiplatelet drugs was discontinued before randomization and thrombolytic treatment should not have been received within the previous 48 hours.

Principal Findings:

There were 1960 first events included in the primary endpoint. By intention-to-treat, there were 939 events in the clopidogrel group during 17 636 patient-years at risk, an average rate per year of 5.32 percent. There were 1021 events in the aspirin group during 17 519 patient-years at risk, an average rate per year of 5.83 percent. These rates reflect a statistically significant (p = 0.043) relative-risk reduction of 8.7% (95% Cl, 0.3 to 16.5) in favor of clopidogrel.

For patients with stroke, the average event rate per year in the clopidogrel group was 7.15 percent compared with 7.71 percent in the aspirin group, a relative-risk reduction of 7.3 percent (-5.7 to 18.7) in favor of clopidogrel (p=0.26).

For patients with myocardial infarction, the average event rate per year was 5.03 percent in the clopidogrel group compared with 4.84 percent in the aspirin group; a relative-risk increase of 3.7 percent (22.1 to -12.0) associated with clopidogrel (p=0.66).

For patients with peripheral arterial disease, the average event rate per year in the clopidogrel group was 3.71 percent compared with 4.86 percent in the aspirin group; a relative-risk reduction of 23.8 percent (8.9 to 36.2) in favor of clopidogrel (p=0.0028).

Previous history of vascular events and vascular risk factors show that there was an overlap in the three clinical subgroups. For example, 12 percent of the stroke subgroup and 8 percent peripheral arterial disease reported a history of myocardial infarction. Two percent of the younger myocardial infarction subgroup reported previous stroke and 6 percent peripheral arterial disease. Six percent of the peripheral arterial disease group had experienced a previous stroke and 21 percent a previous myocardial infarction.

To help interpret the apparently discrepant finding in the myocardial infarction subgroup, an additional analysis, not specified in the protocol, was considered relevant because aspirin has similar benefits in preventing major ischaemic events in patients with acute myocardial infarction and in those with a remote history of myocardial infarction. There were 2144 patients in the stroke and peripheral arterial disease groups who had a distant past history of myocardial infarction. When this cohort was combined with the 6302 patients who presented with myocardial infarction as the qualifying event, the overall relative-risk reduction was 7.4 percent (-5.2 to 18.6) in favor of clopidogrel.

There were no major differences in terms of safety. Reported adverse experiences in the clopidogrel and aspirin groups judged to be severe included rash (0.26% vs 0.10%), diarrhoea (0.23% vs 0.11%), upper gastrointestinal discomfort (0.97% vs 1.22%), intracranial haemorrhage (0.33% vs 0.47%), and gastrointestinal haemorrhage (0.52% vs 0.72%), respectively.

There were ten (0.10%) patients in the clopidogrel group with significant reductions in neutrophils (< 1.2 x 10(9)/L) and 16 (0.17%) in the aspirin group.

Interpretation:

Long-term administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischaemic stroke, myocardial infarction, or vascular death. The overall safety profile of clopidogrel is at least as good as that of medium-dose aspirin.

References:

1. Lancet. 1996;348(9038):1329-39. Final results

Clinical Topics: Invasive Cardiovascular Angiography and Intervention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Interventions and Vascular Medicine

Keywords: Intermittent Claudication, Myocardial Infarction, Stroke, Platelet Aggregation Inhibitors, Risk Reduction Behavior, Peripheral Arterial Disease, Ticlopidine, Pain, Electrocardiography, Angioplasty, Leg, Intracranial Hemorrhages, Neutrophils, Hemorrhage, Exanthema


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