Large Stroke Trial a Bust for Boehringer Ingelheim

In the largest trial ever to assess the prevention of second stroke  (N = 20,332), Boehringer Ingelheim's Aggrenox (aspirin 25 mg/ extended-release dipyridamole 200 mg) twice daily was no more effective than Plavix (clopidogrel 75 mg; sanofi-aventis, BMS) once daily for preventing the primary outcome of ischemic or hemorrhagic stroke in patients with a prior nonembolic, ischemic stroke. The results of the trial were presented Wednesday at the European Stroke Conference in Nice, France, and covered by heartwire.

In the study, abbreviated PROFESS, the standard for the comparative analysis was, first, noninferiority* and then superiority. The rates of the primary endpoint, various secondary endpoints, and hemorrhagic events are tabulated below. Because the upper limit of the 95% confidence interval for the primary endpoint (1.11) exceeded 1.075—the margin chosen for noninferiority—the noninferiority of Aggrenox to Plavix could not be concluded. However, the recurrent strokes rates were not statistically significantly different between the 2 antiplatelet agents.

Endpoint	Aggrenox, %	Plavix, %	Hazard Ratio (95% CI)	Significance
Recurrent stroke	9.0	8.8	1.01 (0.92, 1.11)	P = .783
Ischemic	7.7	7.9	—	—
Hemorrhagic	0.8	0.4	—	—
Other/unknown	0.5	0.5	—	—
Stroke/MI/vascular death	13.1	13.1	0.99 (0.92, 1.07)	P = .829
MI	1.7	1.9	0.90 (0.73, 1.10)	P = .2846
Death	7.3	7.4	0.97 (0.87, 1.07)	P = .5112
New or worsening CHF	1.4	1.8	0.78 (0.62, 0.96)	P = .022
Major hemorrhagic event	4.1	3.6	1.15 (1.00, 1.32)	P = .057
Life-threatening hemorrhagic events	1.3	1.1	—	—
Stroke recurrence or major hemorrhage	11.7	11.4	1.03 (0.95, 1.11)	P = .504
Headache leading to discontinuation	5.9	0.9	—	—

Likewise, the rates of secondary endpoints, with the exception of new or worsening congestive heart failure, were not significantly different between the 2 treatment groups. The rate of a major hemorrhagic event was significantly higher with Aggrenox, but the rates of life-threatening hemorrhagic events were similar with the 2 medications. Headache leading to discontinuation of therapy was also higher (not unexpectedly) with Aggrenox.

In separate analyses, BI's angiotensin-receptor blocker Micardis (telmisartan) was no more effective than placebo for preventing recurrent stroke in the PROFESS population (8.7% vs 9.2%; P = .231), and neuroprotective effects (as measured by functional outcomes) were not significantly higher with either Aggrenox or Micardis.

The presenters, Ralph Sacco, Salim Yusef, and Hans-Christof Diener, did not commit to clinical recommendations, given the study results; however, Yusef acknowledged to an unidentified questioner that Plavix could be considered a first-choice medication for the prevention of second stroke, owing to the higher drop-out rate and higher bleeding risk associated with Aggrenox, reported heartwire.

Props should be given to BI for conducting such a large trial that pitted its twice-daily antiplatelet agent in head-to-head fashion against the once-daily blockbuster Plavix; however, the results do not appear to improve the outlook for increased use of Aggrenox. Sales of the drug approached $260 million in the United States last year, according to the Motley Fool.

PROFESS = Prevention Regimen for Effectively Avoiding Second Strokes.

*The intent in noninferiority trials is to show that a treatment is not worse than an active control by more than a specified margin.

Photo: iStockPhoto.