Utrecht, the Netherlands - The long-awaited results of a new study confirm that aspirin given with dipyridamole is considerably more effective than aspirin alone for the secondary prevention of stroke [1].

The findings from the European/Australasian Stroke Prevention in Reversible Ischemia Trial (ESPRIT) are reported in the May 20, 2006 issue of the Lancet.

In an accompanying commentary [2], neurologist Dr Bo Norrving (University Hospital, Lund, Sweden) says: "The trial was done by a skilled team of trialists and conforms to stringent trial criteria. Dual dipyridamole and aspirin therapy joins the podium of well-established interventions to be applied in routine clinical practice in secondary stroke prevention."

The researchers explain that although an earlier trial, the second European Stroke Prevention Study (ESPS 2), showed that dipyridamole added to aspirin reduced the risk of subsequent stroke more than aspirin alone, the results were much debated. This was partly because four earlier but smaller studies of the same treatment comparison showed no such benefit, they note. "The need for another confirmatory trial to resolve the uncertainties has been widely recognized," Norrving says in his commentary.

Both the researchers and the editorialist note that two previous large trials—CHARISMA and MATCH—showed no benefit of dual therapy with clopidogrel and aspirin in secondary stroke prevention.

In ESPRIT, patients who had had a transient ischemic attack (TIA) or minor stroke of presumed arterial origin within the past six months were assigned to aspirin (30-325 mg daily) with (n=1363) or without (n=1376) dipyridamole 200 mg twice daily. The primary outcome was a composite of death from all vascular causes, nonfatal stroke, nonfatal myocardial infarction, or major bleeding complication, whichever happened first.

The researchers note that treatment was not blinded but say that this is unlikely to have introduced bias, because the members of the auditing committee who classified the outcome events were unaware of the allocated therapy. Although Norrving agrees on the latter point, he says the question of whether the design could have prejudiced findings "is legitimate."

Primary outcome events occurred in 173 (13%) of patients on aspirin and dipyridamole, compared with 216 (16%) of those taking aspirin alone (hazard ratio 0.80; absolute risk reduction 1% per year).

The trialists also added the ESPRIT data to a meta-analysis of previous trials of aspirin plus dipyridamole (including the ESPS 2 data), which resulted in an overall risk ratio for the composite of vascular death, stroke, or MI of 0.82 compared with aspirin alone.

"The combined results of ESPS 2 and ESPRIT are consistent and provide robust evidence for the larger efficacy of the combination therapy," they state.

In ESPRIT, there were no firm restrictions in the dose of aspirin used; any amount between 30 mg and 325 mg daily was allowed. This strategy "is an indication of variation in clinical practice and allows broader generalizability of our findings," the researchers comment.

Also, the study was not designed to look at any particular preparation, and it allowed the use of both the fixed-dose combination and aspirin and dipyridamole prescribed separately. (A combined aspirin-25-mg/dipyridamole-200-mg product to be taken twice daily is marketed by Boehringer Ingelheim in certain countries.)

"Our study showed that both the combination product and the two antithrombotics separately are equally effective," one of the investigators, Dr Patricia Halkes (University Medical Center Utrecht, the Netherlands), told heartwire.

The researchers also point out that a large number of patients—about a third of the study population—discontinued treatment because of side effects, mainly headache, which is a well-known adverse effect of dipyridamole. Similar figures were seen in the ESPS 2 trial.

Halkes said complaints of headache were usually immediate, within the first few months of therapy. "It may help if doctors titrate therapy, perhaps starting at 200 mg of dipyridamole a day for the first week," she says. However, she acknowledges that this strategy "requires further study."

Another limitation is that two thirds of the patients in ESPRIT were randomized one to six months after the event, but stroke recurrence "is especially high in the first few weeks after the event," the researchers note.