Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke

Abstract

Background: Recurrent stroke is a frequent, disabling event after ischemic stroke. This study compared the efficacy and safety of two antiplatelet regimens--aspirin plus extended-release dipyridamole (ASA-ERDP) versus clopidogrel.

Methods: In this double-blind, 2-by-2 factorial trial, we randomly assigned patients to receive 25 mg of aspirin plus 200 mg of extended-release dipyridamole twice daily or to receive 75 mg of clopidogrel daily. The primary outcome was first recurrence of stroke. The secondary outcome was a composite of stroke, myocardial infarction, or death from vascular causes. Sequential statistical testing of noninferiority (margin of 1.075), followed by superiority testing, was planned.

Results: A total of 20,332 patients were followed for a mean of 2.5 years. Recurrent stroke occurred in 916 patients (9.0%) receiving ASA-ERDP and in 898 patients (8.8%) receiving clopidogrel (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11). The secondary outcome occurred in 1333 patients (13.1%) in each group (hazard ratio for ASA-ERDP, 0.99; 95% CI, 0.92 to 1.07). There were more major hemorrhagic events among ASA-ERDP recipients (419 [4.1%]) than among clopidogrel recipients (365 [3.6%]) (hazard ratio, 1.15; 95% CI, 1.00 to 1.32), including intracranial hemorrhage (hazard ratio, 1.42; 95% CI, 1.11 to 1.83). The net risk of recurrent stroke or major hemorrhagic event was similar in the two groups (1194 ASA-ERDP recipients [11.7%], vs. 1156 clopidogrel recipients [11.4%]; hazard ratio, 1.03; 95% CI, 0.95 to 1.11).

Conclusions: The trial did not meet the predefined criteria for noninferiority but showed similar rates of recurrent stroke with ASA-ERDP and with clopidogrel. There is no evidence that either of the two treatments was superior to the other in the prevention of recurrent stroke. (ClinicalTrials.gov number, NCT00153062.)

Figure 1. Kaplan–Meier Estimates of the Cumulative Probability of Primary and Secondary Outcomes, According to Treatment Group

The primary outcome of first recurrence of stroke (Panel A) occurred in 916 of 10,181 patients (9.0%) treated with aspirin plus extended-release dipyridamole (ERDP) and in 898 of 10,151 patients (8.8%) treated with clopidogrel (hazard ratio for aspirin–ERDP, 1.01; 95% confidence interval [CI], 0.92 to 1.11). The main secondary outcome of stroke, myocardial infarction (MI), or death from vascular causes (Panel B) occurred in 1333 patients (13.1%) in each of the two groups (hazard ratio for aspirin–ERDP, 0.99; 95% CI, 0.92 to 1.07). The estimated hazard ratios are based on a Cox model with covariates of baseline values of age, use or nonuse of angiotensin-converting–enzyme inhibitors, diabetes status, and score on the modified Rankin scale.

Figure 2. Frequency of Types of Recurrent Stroke among the Study Patients, According to Treatment Group

The mean follow-up period was 2.5 years. Numbers of patients in each stroke category are given to the right of the bar and total numbers are given on top. The hazard ratio for recurrent stroke among patients receiving aspirin plus extended-release dipyridamole (ERDP), as compared with those receiving clopidogrel, was 1.01 (95% confidence interval, 0.92 to 1.11).

Figure 3. Hazard Ratios for the Primary Outcome of First Recurrence of Stroke, According to Prespecified and Post Hoc Baseline Characteristics

The hazard ratios are for recurrent stroke among patients receiving aspirin plus extended-release dipyridamole (ERDP) as compared with those receiving clopidogrel. The sizes of the squares are proportional to the number of events. All tests for interaction between treatment group and subgroup had P values greater than 0.05, except for history of hypertension, for which P = 0.05. See the Supplementary Appendix for the calculation of stroke risk score. Ethnic group was selfreported. ACE denotes angiotensin-converting enzyme, TIA transient ischemic event, and TOAST Trial of Org 10172 in Acute Stroke Treatment.