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Combination Therapy Better After Cerebral Ischemia



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Am Fam Physician. 2006 Oct 15;74(8):1414-1417.

After a transient ischemic attack (TIA) or nondisabling stroke of arterial origin, patients have a 4 to 16 percent annual risk of a major vascular event. Studies using aspirin in dosages ranging from 30 to 300 mg daily indicate that 13 to 22 percent of these events can be avoided. Combinations of aspirin plus clopidogrel (Plavix) have shown no additional benefit, but one large study reported a 22 percent relative risk reduction from a combination of 50 mg aspirin and 200 mg dipyridamole (Persantine). Because this conflicted with results from earlier studies and meta-analyses, the European/Australasian Stroke Prevention in Reversible Ischemia Trial compared aspirin and aspirin plus dipyridamole in the follow-up care of patients with TIA or minor stroke of arterial origin.

The study included 2,739 patients who were referred to participating hospitals between July 1997 and December 2005 within six months of TIA (including transient blindness in one eye) or minor stroke of arterial origin (3 or less on the Rankin scale). Patients with a possible cardiac source of embolism, those with carotid stenosis, and those with coagulation disorders or contraindications to aspirin or dipyridamole were excluded from the study. The patients were randomly assigned to aspirin alone or combination therapy. The dosage of aspirin was decided by the treating physician but had to be between 30 and 325 mg daily. The intake data collected included a full neurologic history and examination, assessment of vascular risk factors, disability score (using the Rankin scale), and electrocardiography and magnetic resonance imaging or computed tomography of the brain. Patients were assessed every six months to record possible new cerebral ischemic events, disability score, hospitalizations, changes in medication, and possible adverse events. The primary outcome measure was any combination of death from all vascular causes, nonfatal stroke, nonfatal myocardial infarction, and major bleeding event. Secondary outcomes included each of these events individually as well as any death.

The 1,363 patients allocated to aspirin plus dipyridamole were comparable to the 1,376 allocated to aspirin alone in all important variables. Two thirds of the participants were men and the average age was 63 years. One third had a history of TIA, and 42 percent were asymptomatic at the beginning of the study. The mean follow-up was 3.5 years, with 66 percent of the combined treatment group and 84 percent of the aspirin-alone group still taking the assigned treatment at five years.

At least one of the primary event outcomes occurred in 173 patients (13 percent) assigned to combination therapy compared with 216 (16 percent) taking aspirin alone. This corresponds to an absolute risk reduction of 1 percent per year or a number needed to treat of 104 to prevent a death from one of the major outcomes. Ischemic events were less common in the combination therapy group, and the hazard ratio for all deaths was 0.88. Major bleeding events were more common in patients treated with aspirin alone (53 versus 35 in the combination group). Conversely, minor bleeding events occurred in 171 patients in the combination therapy group compared with 168 in the aspirin-alone group. Patients taking the combination medication were more likely to discontinue therapy (470 compared with 184 in the aspirin-alone group), with headache being the most common reason given for discontinuation.

The authors added the results of this study to those of an earlier meta-analysis and found that the overall risk ratio for the composite outcome was 0.82 for the combination therapy. They conclude that the combination therapy is more effective than aspirin alone in preventing new serious vascular events in patients following TIA or minor stroke.

The ESPRIT Study Group. . Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet. May 20, 2006;367:1665–73.



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