PDF: PRoFESS
(2008)Objective
Aspirin–dipyridamole versus clopidogrel for prevention of recurrent stroke in patients with recent noncardioembolic ischemic stroke.
Study Summary
Intervention
Aspirin 25 mg + extended-release dipyridamole 200 mg twice daily vs. clopidogrel 75 mg daily. Follow-up visits occurred within 1 week post-discharge, then at 1, 3, 6 months, and every 6 months thereafter. Mean follow-up: 2.5 years.
Study Design
Arms: Array
Outcome
• Stroke, MI, or CV death — 13.1% vs. 13.1%; HR 0.99 (95% CI 0.92–1.07)
• MI — 1.7% vs. 1.9%; HR 0.90 (95% CI 0.73–1.10)
• CV mortality — 4.3% vs. 4.5%; HR 0.94 (95% CI 0.82–1.07)
• All-cause mortality — 7.3% vs. 7.4%; HR 0.97 (95% CI 0.87–1.07)
• CHF — 1.4% vs. 1.8%; HR 0.78 (95% CI 0.62–0.96)
• Major hemorrhage — 4.1% vs. 3.6%; HR 1.15 (95% CI 1.00–1.32)
• Intracranial hemorrhage — 1.4% vs. 1.0%; HR 1.42 (95% CI 1.11–1.83); p=0.006
• Discontinuation due to adverse event — 16.4% vs. 10.6% (mostly headache: 5.9% vs. 0.9%)
• Premature discontinuation (any reason) — 29.1% vs. 22.6%; p<0.001
Bottom Line
The trial showed similar rates of recurrent stroke between aspirin plus extended-release dipyridamole and clopidogrel, but did not meet criteria for noninferiority. There was increased hemorrhagic stroke risk with the combination therapy.
Major Points
- Large randomized trial comparing aspirin plus extended-release dipyridamole versus clopidogrel for secondary stroke prevention
- Primary outcome of recurrent stroke occurred in 9.0% vs 8.8% (HR 1.01, 95% CI 0.92-1.11)
- Trial failed to meet prespecified noninferiority criteria despite similar stroke rates
- Increased major hemorrhagic events with aspirin-dipyridamole (4.1% vs 3.6%)
- Significantly more intracranial hemorrhage with combination therapy (1.4% vs 1.0%)
- Higher discontinuation rates due to adverse events with aspirin-dipyridamole (16.4% vs 10.6%)
- Identical rates of composite vascular outcome (stroke, MI, vascular death): 13.1% in both groups
Study Design
- Study Type
- Randomized, double-blind, 2-by-2 factorial trial
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 20332
- Follow-up
- Mean 2.5 years (range 1.5-4.4 years)
- Centers
- 695
- Countries
- 35 countries including United States, Canada, Europe, Asia, Latin America, South Africa, Australia
Primary Outcome
Definition: First recurrence of stroke of any type
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 898/10,151 (8.8%) | 916/10,181 (9.0%) | 1.01 (0.92-1.11) | Not significant |
Limitations & Criticisms
- Failed to meet prespecified noninferiority criteria despite similar stroke rates
- Higher bleeding risk with aspirin-dipyridamole combination
- High discontinuation rates due to adverse events in combination arm
- Study underpowered for noninferiority testing given equivalent efficacies
- Conservative noninferiority margin of 7.5% may have been too strict
- Headache and other side effects more common with combination therapy
Citation
Sacco RL, Diener HC, Yusuf S, et al. Aspirin and Extended-Release Dipyridamole versus Clopidogrel for Recurrent Stroke. N Engl J Med 2008;359:1238-51.