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Posted by on May 16, 2008 in Neurology, Pharma

Large Stroke Trial a Bust for Boehringer Ingelheim

Large Stroke Trial a Bust for Boehringer Ingelheim

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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 1.075the margin chosen for noninferioritythe 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.

bmartin (1127 Posts)

A native East Tennessean, Barbara Martin is a formerly practicing, board-certified neurologist who received her BS (psychology, summa cum laude) and MD from Duke University before completing her postgraduate training (internship, residency, fellowship) at the Hospital of the University of Pennsylvania in Philadelphia. She has worked in academia, private practice, medical publishing, drug market research, and continuing medical education (CME). For the last 3 years, she has worked in a freelance capacity as a medical writer, analyst, and consultant. Follow Dr. Barbara Martin on and Twitter.