The first evaluation of clopidogrel after stroke or transient ischemic attack was the Clopidogrel versus Aspirin in Patients at Risk of Recurrent Ischaemic Events (CAPRIE) study. A total of 19,185 patients with recent stroke/transient ischemic attack, recent myocardial infarction, or peripheral arterial disease were randomly assigned to receive aspirin at 325 mg/day or clopidogrel at 75mg/day; 6,431 patients were in the cerebrovascular disease (stroke/transient ischemic attack) cohort. At follow-up (mean: 1.91 years), a statistically significant benefit was seen for clopidogrel over aspirin in the composite endpoint of ischemic stroke, acute myocardial infarction, or vascular death among all patients (annual incidence rates for composite outcome: clopidogrel, 5.32%; aspirin, 5.83%; absolute risk reduction 0.51%; relative risk reduction 8.7%; P=0.043). The CAPRIE cohort data does show that much of the difference favoring clopidogrel over aspirin was derived from the peripheral artery disease group (relative risk reduction 3.8%; P=0.0028). In the stroke/transient ischemic attack cohort, comparative risk reduction for the composite endpoint was reduced and not statistically significant (relative risk reduction 7.3%; P=0.26).16
The Management of Atherosclerosis with Clopidogrel in High-Risk Patients (MATCH) study was an evaluation of clopidogrel versus clopidogrel plus aspirin in the prevention of secondary stroke. Seven thousand five hundred ninety-nine patients with a history of stroke or transient ischemic attack and other vascular risk factors were randomly assigned to clopidogrel alone or clopidogrel plus aspirin. After a mean follow-up of 18 months, the clopidogrel plus aspirin combination group demonstrated only an insignificant benefit in the composite outcome of rehospitalization for an ischemic event, ischemic stroke, acute myocardial infarction, or vascular death (clopidogrel plus aspirin 15.70%; clopidogrel monotherapy 16.73%; relative risk reduction 6.4%; P=0.244).13 In addition, the clopidogrel plus aspirin combination produced an increased absolute incidence of life-threatening bleeding episodes versus clopidogrel alone (2.6% versus 1.3%) that was greater than the absolute reduction in efficacy outcome events. Therefore, the combination of clopidogrel plus aspirin is not recommended for secondary event prevention after stroke or transient ischemic attack.17,18
In the recently reported Clopidogrel for High Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study, patients with documented coronary disease, cerebrovascular disease, or peripheral artery disease were administered either clopidogrel (75 mg/day) plus aspirin (75–162 mg/day) or aspirin alone.19 The study also included patients with multiple atherosclerotic risk factors but without documented arterial disease.
There was no significant difference between treatment arms regarding the primary composite endpoint of myocardial infarction, stroke, or cardiovascular death. Prespecified subgroup analyses showed a 1% absolute decrease in the incidence of the primary endpoint in patients with documented vascular disease (P=0.046) and an increase of 1.1% in the asymptomatic patients with multiple vascular risk factors (P=0.20) among those patients randomized to combination therapy. Severe bleeding (defined as fatal bleeding, intracranial hemorrhage, or bleeding causing hemodynamic compromise) occurred in 1.7% of patients in the combination therapy arm and 1.3% in the aspirin arm (P=0.09). Moderate bleeding, defined as that necessitating transfusion but not meeting the criteria for severe bleeding, occurred in 2.1% of patients in the combination therapy arm and 1.3% in the aspirin arm (P<0.001). The investigators concluded that clopidogrel plus aspirin provided no significant advantage over aspirin alone in reducing incidence of the primary combined endpoint.
Extended-release dipyridamole in combination with aspirin was evaluated in the European Stroke Prevention Study-2 (ESPS-2). The combination was compared with aspirin alone and with dipyridamole alone, as well as with placebo, in 6,602 patients with a history of stroke or transient ischemic attack. Extended-release dipyridamole and aspirin monotherapy showed similar efficacy in reducing the risk of stroke (relative risk reduction versus placebo: aspirin 18%, P=0.013; extended-release dipyridamole 16%, P=0.039). The extended-release dipyridamole plus aspirin combination, however, showed evidence of additive benefit; the relative risk reduction for stroke with extended-release dipyridamole plus aspirin was 23% versus aspirin alone (P=0.006) and 25% versus extended-release dipyridamole alone (P=0.002). Compared with placebo, the extended-release dipyridamole plus aspirin combination was associated with relative risk reductions of 37% (P<0.001) for stroke and 24% (P<0.001) for stroke or death. This combination reduced the relative risk of stroke over aspirin alone by 23%.20