PROFESS Trial Published: Combination Therapy Falls Short of Noninferiority vs Clopidogrel

Susan Jeffrey

August 28, 2008

August 28, 2008 — 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.


"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 Ralph L. Sacco, MD, from the Miller School of Medicine at the University of Miami, in Florida, 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 [MI], 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.

The results are published online as 2 papers August 27 in the New England Journal of Medicine. The findings were previously presented at the 17th European Stroke Conference, in Nice, France, and reported by Medscape Neurology & Neurosurgery at that time.


Factorial Design

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 United States 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 1 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

PROFESS: Primary Outcome for Comparison of Aspirin Plus Extended-Release Dipyridamole vs Clopidogrel

End Point Aspirin + ER-Dipyridamole Clopidogrel Hazard Ratio (95% CI) P
Stroke recurrence, n (%) 915 (9.0) 898 (8.8) 1.01 (0.92 – 1.11) .783

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 2 groups in the frequency of death, any hemorrhagic event (major or minor), or thrombotic thrombocytopenia purpura or neutropenia.

PROFESS: Major Hemorrhagic Events

Event Aspirin + ER-Dipyridamole Clopidogrel Hazard Ratio (95% CI)
Major hemorrhagic events, n (%) 419 (4.1) 365 (3.6) 1.15 (1.00 – 1.32)
ICH 147 (1.4) 103 (1.0) 1.42 (1.11 – 1.83)

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

PROFESS: Benefit/Risk Analysis

End Point Aspirin + ER-Dipyridamole Clopidogrel Hazard Ratio (95% CI) P
Recurrent stroke or major hemorrhagic event, n (%) 1194 (11.7) 1156 (11.4) 1.03 (0.95 – 1.11) .504

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.

Dr. Sacco told Medscape Neurology & Neurosurgery 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 2 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."

Telmisartan vs Placebo

In a separate paper, the PROFESS researchers, with lead author Salim Yusuf, MD, from McMaster University, in Hamilton, Ontario, 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 angiotensin-converting enzyme (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.

PROFESS: Primary and Secondary Outcomes with Telmisartan vs Placebo

End Point Telmisartan Placebo Hazard Ratio (95% CI) P
Recurrent stroke, n (%) 880 (8.7) 934 (9.2) 0.95 (0.86 – 1.04) .23
Major CV events, n (%) 1367 (13.5) 1463 (14.4) 0.94 (0.87 – 1.01) .11
New-onset diabetes (%) 1.7 2.1 0.82 (0.65 – 1.04) .10

Subsequent analyses suggested there may have been an effect by time, Dr. 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," Dr. 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 Hans-Christof Diener, MD, from the University of Duisberg-Essen, in Essen, Germany. Results of that analysis, that at least in the preliminary analysis presented in Nice showed no evidence of any such neuroprotective effects, will be published separately.

The study was funded by Boehringer Ingelheim. In selected countries, the telmisartan comparison was supported by Bayer Schering Pharma and GlaxoSmithKline. Dr. Sacco reports receiving consulting fees from Boehringer Ingelheim, GlaxoSmithKline, and Sanofi-Aventis and lecture fees from Boehringer Ingelheim. Dr. Yusuf reports receiving consulting and lecture fees from Boehringer Ingelheim, Sanofi-Aventis, Bristol-Myers Squibb, AstraZeneca, and GlaxoSmithKline and grant support from Sanofi-Aventis, Bristol-Myers Squibb, and GlaxoSmithKline. Disclosures for other coauthors appear in the papers.

N Engl J Med. Published online August 27, 2008.


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