Boston, MA - In the largest secondary stroke-prevention trial to date, the combination of aspirin and extended-release (ER) dipyridamole (Aggrenox, Boehringer Ingelheim) did not meet prespecified criteria for noninferiority vs clopidogrel (Plavix/Iscover, Sanofi-Aventis/Bristol-Myers Squibb), but rates of recurrent stroke, the primary outcome, were similar between the groups [1].

"Therefore, the study does not show that either aspirin plus extended-release dipyridamole or clopidogrel is superior to the other in the prevention of stroke," the investigators, with first author Dr Ralph L Sacco (Miller School of Medicine at the University of Miami, FL), conclude.

"These findings provide additional safety and efficacy data physicians need in making individual treatment decisions for prevention of recurrent stroke or the combined end point of stroke, myocardial infarction, or death from vascular causes in their patients with stroke," they write.

In a factorial design, the trial also examined the effect of early blood-pressure lowering after a stroke using telmisartan (Micardis, Boehringer Ingelheim) vs placebo and found no benefit of the addition of the angiotensin-receptor blocker (ARB) in prevention of stroke recurrence, major cardiovascular events, or diabetes, at least during the 2.5 years of follow-up in this study [2].

The results are published online as two papers August 27, 2008 in the New England Journal of Medicine. The findings were previously presented at the European Stroke Conference 2008, in Nice, France.

The PROFESS trial included 20 332 patients from 695 sites in 35 countries. All had had a noncardioembolic ischemic stroke within the previous 120 days. They were randomized in a factorial design to receive aspirin (25 mg) plus ER dipyridamole (200 mg) twice daily or clopidogrel (75 mg) once daily. Subjects were then again randomized to receive either 80 mg per day of telmisartan or placebo.

Current guidelines in Europe and the US recommend that for antiplatelet therapy after a stroke, aspirin, aspirin plus dipyridamole, and clopidogrel are options for prevention of stroke recurrence, but there is no recommendation for the use of one of these agents over the others. Direct comparison of aspirin alone vs aspirin and dipyridamole in the European and Australian Stroke Prevention in Reversible Ischemia Trial (ESPRIT) and the European Stroke Prevention Study 2 (ESPS2) had shown the combination to be more effective than aspirin alone, without increasing major bleeding. The PROFESS trial aimed to provide information on a direct comparison of the combination vs clopidogrel.

The planned antiplatelet comparison used a sequential analysis of noninferiority first, then superiority, the researchers noted. The margin chosen for noninferiority was 1.075, or a 7.5% noninferiority difference.

In the end, the comparison for the primary outcome of recurrent stroke did not meet this predefined criterion for noninferiority, although the number of recurrent strokes was similar between the groups

The secondary outcome, a composite of stroke, MI, and vascular death, was identical between groups, they note. Other end points, including deaths and MI, were not statistically different between groups, with the exception of new or worsening heart failure, which was significantly less frequent in the combination group.

Major hemorrhagic events were increased with the combination vs clopidogrel; intracranial hemorrhage (ICH), including 128 hemorrhagic strokes counted in the primary outcome, was significantly higher with the combination. There were no significant differences between the two groups in the frequency of death, any hemorrhagic event (major or minor), or thrombotic thrombocytopenia purpura or neutropenia.

Despite the increase in bleeds, the net risk for recurrent stroke or major hemorrhagic event was similar between the groups.

Adverse events leading to permanent discontinuation were increased with the combination (16.4%) vs clopidogrel (10.6%). Headache was more frequent with the combination, leading to permanent discontinuation in 5.9% of the patients on combination therapy vs 0.9% on clopidogrel.

Sacco said that this study provides more evidence that clopidogrel is as effective as ER dipyridamole and aspirin in terms of reducing recurrent stroke.

"How we choose between the two agents is still going to be up to clinicians," he said. "For those patients with more cardiac disease, some of us may choose clopidogrel more often, and for others we still have extended-release dipyridamole as an option."

In a separate paper, the PROFESS researchers, with lead author Dr Salim Yusuf (McMaster University, Hamilton, ON), published results of the telmisartan-placebo comparison.

Previous studies, including the Heart Outcomes Prevention Evaluation (HOPE) and the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), had shown a benefit associated with using an ACE inhibitor initiated late after stroke, with or without a large reduction in blood pressure. In this trial, the PROFESS researchers investigated whether using a blocker of the renin-angiotensin system, telmisartan, initiated early after a stroke, would reduce recurrent stroke.

Despite a mean blood-pressure difference between the groups of 3.8/2.0 mm Hg in favor of telmisartan, there was no difference between groups on the primary end point of recurrent stroke, on secondary outcomes of a composite of major cardiovascular events (death from cardiovascular causes, recurrent stroke, MI, or new or worsening heart failure), or in new-onset diabetes.

Subsequent analyses suggested there may have been an effect by time, Yusuf noted when he presented these results in Nice, and the researchers speculate that the trial may have been too short to see a benefit with treatment. Suboptimal adherence in the treatment group, as well as competing use of other blood-pressure-lowering agents, reduced the blood-pressure differential between the groups, "which hurt our power," he said.

"What we need are longer trials, but large trials, with greater blood-pressure lowering," Yusuf concluded.

A third factorial analysis of the PROFESS data, looking for any neuroprotective effects of dipyridamole, aspirin, or the ARB telmisartan in those patients who did have a recurrent stroke, was also presented at the European Stroke Conference by first author Dr Hans-Christof Diener (University of Duisberg-Essen, Germany). Results of that analysis, that showed no evidence of any such neuroprotective effects, were published separately [3] .

In an editorial accompanying the papers [4], Drs David M Kent and David E Thaler (Tufts University School of Medicine, Boston, MA) point out that if clinical trials were sporting contests, aspirin plus extended-release dipyridamole "was the clear favorite" against clopidogrel going into the PROFESS trial. The combination had shown substantial and consistent benefit in both the ESPS2 and ESPRIT trials, while clopidogrel "had barely bested aspirin" in the CAPRIE trial.

"On the basis of these results, although aspirin remains the most commonly prescribed antiplatelet agent in patients with stroke, and cautious guideline committees have not strongly favored one of these newer agents over the other, low-dose aspirin plus extended-release dipyridamole became the preferred agent for au courant doctors (ourselves included) determined to select the best of all possible evidence-based antiplatelet regimens for secondary stroke prevention," they write.

Indirect comparison of these trials logically suggested that the combination would be superior to clopidogrel, Kent and Thaler note. "However, the results of the PROFESS trial show us once again that the compelling logic of transitive property, so reliable in mathematics, has little authority in the often-illogical world of clinical trials," they write. The trial not only failed to show superiority for the combination but failed even to reach the noninferiority margin, "meaning, by the investigators' own unforgiving rules, that we cannot be fully confident that low-dose aspirin plus extended-release dipyridamole is not inferior to clopidogrel."

In an era of comparative effectiveness, when multiple agents are compared, they write, randomized trials often can't be understood in isolation but must be interpreted in the context of sometimes-complex networks of similar or relevant evidence. However, the reduction of such networks to clinical recommendations is not always straightforward, "since different paths within the network may give inconsistent results, and the network may be incoherent," they point out.

"In the case of PROFESS and the tangle of related trials, enlightenment might be expressed simply, as a haiku: 'For stroke prevention/use an antiplatelet drug/Treat hypertension,' " they conclude.