Aspirin and clopidogrel after recent ischemic stroke or transient ischemic attack

Long-term treatment with antiplatelet agents is an important strategy for the secondary prevention of ischemic stroke and other major atherothrombotic events.¹ In 1996, the Clopidogrel Versus Aspirin in Patients at Risk for Ischemic Events (CAPRIE) study showed that clopidogrel (Plavix) was better than acetylsalicylic acid (aspirin) for reducing the combined risk of ischemic stroke, myocardial infarction (MI), and vascular death in a broad population of patients with symptomatic atherosclerosis (recent ischemic stroke, recent MI, or established peripheral arterial disease).² Posthoc analyses of this trial showed an increased advantage of clopidogrel over aspirin in a range of high-risk cohorts, including in patients who had diabetes,³ a prior history of ischemic stroke or MI,⁴ had undergone cardiac surgery,⁵ and had hypercholesterolemia.⁶

Clopidogrel added to customary treatment including aspirin was shown to provide an early and sustained incremental benefit with a clinically acceptable risk of bleeding in patients with atherothrombotic disease affecting the coronary arteries. In the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial, patients who received clopidogrel (initiated as a 300-mg loading dose and continued at 75 mg/day for up to 12 months) experienced a 20% relative reduction in the combined risk of stroke, MI, or cardiovascular death, compared with placebo (P = .009).⁷ These findings supported the evaluation of the efficacy and safety of adding aspirin to clopidogrel in high-risk patients with symptomatic cerebrovascular disease, which we did in the Management of Atherothrombosis with Clopidogrel in High-risk patients (MATCH) Trial.

Methods

MATCH was a randomized, double-blind, placebo-controlled trial that included patients with recent ischemic stroke or transient ischemic attack (TIA) who were at high risk for atherothrombotic recurrence.⁸ To be included in the study, patients had to have had a recent ischemic stroke or TIA and at least 1 of the following vascular risk factors: diabetes, symptomatic peripheral arterial disease, stable or unstable angina, prior MI, or previous ischemic stroke. All patients received 75 mg/day of clopidogrel as part of standard therapy, and they were randomly assigned to receive either 75 mg/day of aspirin or placebo. The planned duration of treatment and follow-up was 18 months for all patients. The primary efficacy analysis (intention-to-treat) compared the combined risk of ischemic stroke, MI, vascular death, or rehospitalization for acute ischemia in the 2 treatment groups.

Results

The MATCH study included 7599 patients with a mean age of 66 years at randomization. The mean time from qualifying event to randomization was 26.5 days. The qualifying event was ischemic stroke in 79% of patients and TIA in 21%, and the baseline demographic characteristics indicated a high-risk population, with the most common risk factors being hypertension (78%), di­abetes (68%), and hypercholesterolemia (56%). In addition, 19% of patients had experienced a prior TIA, and 26% had experienced a previous ische­mic stroke. Among those who qualified on the basis of recent is­ch­e­mic stroke, 53% had small-vessel occlusion (lacunar stroke).

The primary end point occurred in 15.7% of patients in the aspirin group and 16.7% of the patients in the placebo group, corresponding to a 6.4% relative risk reduction (RRR) and a 1% absolute risk reduction in favor of adding aspirin to clopidogrel (Figure 1). The on-treatment analysis was consistent with the intention-to-treat analysis, with an RRR of 9.5%. For each component of the primary end point, there was a reduction in pa­tients in the aspirin group compared with those in the placebo group. When the incidence of the primary end point was analyzed in a range of prespecified patient subpopulations, there was a reduction with aspirin and clopidogrel in most subgroups (Figure 2). There was a trend toward an in­creased benefit of adding aspirin to clopidogrel as the time between the qualifying event and randomization to therapy decreased.

The trend toward benefit with aspirin added to clopidogrel was offset by an increased incidence of bleeding. Compared with placebo, aspirin increased the risk of life-threatening bleeding from 1.30% to 2.5% (P < .001) and the rate of ma&shy;jor bleeding from 0.58% to 1.94% (P < .001). There was no increase in fatal bleeding, however, when as&shy;pirin was added to clopidogrel. The majority of the increase in life-threatening bleeding with aspirin was the result of gastrointestinal or intracranial hemorrhage, consistent with the effect of aspirin in the CAPRIE study.⁹ There was no difference in the cumulative rate of in&shy;tracranial hemorrhage over the first 3 months of treatment, suggesting the possibility of a favorable benefit-to-risk ratio in the acute period after an ischemic stroke or TIA.

Discussion

In reconciling the findings of MATCH with those of positive clopidogrel trials in cardiology, it is important to consider the study drug regimens and the patient populations that were evaluated in the different studies. In the MATCH study, aspirin was compared with placebo in patients receiving clopidogrel as part of standard therapy, whereas in the CURE and Clopidogrel for the Reduction of Events During Observation (CREDO) trials, clopidogrel was compared with placebo in patients receiving aspirin as part of standard therapy.^7,10 In the CAPRIE trial, clopidogrel was shown to have a superior efficacy and bleeding-related safety profile compared with aspirin.² It is perhaps not surprising, therefore, that in the MATCH trial, the addition of a less efficacious therapy to a more efficacious agent resulted in a smaller overall benefit than was observed in the cardiology trials. Another contrast is that the disease profiles of the CURE and CREDO populations were more homogeneous than those in the MATCH trial because most patients included in MATCH had lacunar strokes owing to microangiopathy, which might not be of pure ather&shy;othrombotic origin. Thus, the benefit of dual antiplatelet therapy may be greater in other cerebrovascular populations.

A posthoc analysis has compared cumulative rates for the composite of ischemic stroke, MI, or vascular death for the 2 treatment groups in the MATCH trial with the treatment groups in the CAPRIE ischemic stroke cohort who had the same high-risk criteria that were used to select MATCH patients. The 2 patient groups who received clopidogrel mono&shy;&shy;therapy had highly comparable survival curves and similar cumulative event rates (13.0% in CAPRIE versus 12.7% in MATCH).^2,8 These curves are situated between those for aspirin monotherapy in CAPRIE and aspirin added to clopidogrel in MATCH. These findings should be interpreted with caution, but they are consistent with the hypothesis that the relative efficacies of the 3 antiplatelet regimens are clopidogrel plus aspirin is better than clopidogrel alone, which is better than aspirin alone.

Following the MATCH trial, several additional cerebrovascular patient populations are being evaluated in a range of important ongoing trials. Further data regarding the use of clopidogrel added to aspirin versus aspirin alone are expected to be provided by the Clopidogrel for High Athero&shy;throm&shy;botic Risk and Ischemic Stabili&shy;za&shy;tion, Man&shy;agement, and Avoi&shy;dance (CHARISMA) study, in which a spectrum of patients at risk for athero&shy;thrombotic events is enrolled.¹¹ Cere&shy;bro&shy;vascular patients are a subset of the overall CHARISMA study population and are at lower risk than the patient types that were studied in the MATCH trial. Other studies will also provide new information on the use of clopidogrel added to standard therapy, including aspirin in different stroke settings, such as acute minor ischemic stroke or TIA (Fast Assessment of Stroke and Transient Ischemic Attack to Prevent Early Recurrence [FASTER] trial), lacunar stroke (Secondary Pre&shy;vention of Small Subcortical Strokes [SPS3] trial), or ischemic stroke caused by aortic arch plaques (Aortic Arch Related Cerebral Hazard trial [ARCH]).¹²

Conclusion

The results of our study showed that in high-risk patients with recent ischemic stroke or TIA, the addition of aspirin to clopidogrel therapy was associated with a nonstatistically significant trend toward fewer major vascular events. The risk of life-threatening bleeding, however, was in&shy;creased by the addition of aspirin. Because the MATCH population was not representative of all clinical settings of atherothrombosis in patients with cerebrovascular disease, further trial evidence is required to evaluate the benefit of combination therapy with clopidogrel added to aspirin versus aspirin alone in patients with strokes resulting from other causes. Such trials are ongoing. Early initiation and prolonged use of clopidogrel added to standard therapy including aspirin remains the standard of care for patients with unstable angina and non—Q-wave MI, and for those undergoing percutaneous coronary intervention. An important outstanding issue is whether to use clopidogrel plus aspirin for patients with evidence of coronary atherothrombotic disease who have had a cerebrovascular event. Until more data become available, the decision should be guided by the individual patient’s clinical profile and the judgment of the treating physician.