PRoFESS Trial: Aspirin + Extended-Release Dipyridamole vs Clopidogrel for Recurrent Stroke
In patients with completed non-cardioembolic ischaemic stroke within 90 days, is aspirin 50 mg/day plus extended-release dipyridamole 400 mg/day noninferior to clopidogrel 75 mg/day for preventing recurrent stroke over a mean 2.5-year follow-up? Noninferiority trial with a prespecified hazard-ratio margin of 1.075.
Sacco RL et al. (NEJM 2008;359:1238-1251) · doi:10.1056/NEJMoa0805002 · 20,332 patients
Population
Included
- Ischemic stroke within 90 days before randomization
- Stroke confirmed by clinical features and neuroimaging (symptoms >24 hours, or shorter with imaging evidence of new infarction)
- Age 50 or older (with additional vascular risk factors for those 50–54)
- Independent enough to attend follow-up visits
- Recent ischemic stroke (within <90 days before randomization), defined by symptoms persisting for more than 24 hours or symptoms of a shorter duration but with evidence of a recent brain infarction on a computed tomographic scan or magnetic resonance imaging
- Clinical and neurologic stability before randomization
- An age of 55 years or older
After protocol amendment (broadened entry)
- Younger patients (50 to 54 years of age), or those with less recent strokes (within 90 to 120 days before randomization), were eligible if they also had at least two additional vascular risk factors
Excluded
- Cardioembolic source requiring anticoagulation (e.g., atrial fibrillation, mechanical valve)
- Contraindication to aspirin, dipyridamole, or clopidogrel
- Planned use of any other antiplatelet or anticoagulant during the trial
- Severe disability precluding follow-up
- TIA without infarction (not a qualifying event)
- Contraindications to one of the antiplatelet agents (aspirin, extended-release dipyridamole, or clopidogrel)
- Otherwise unsuitable for randomization
Editorial note (clinical surface, CLAUDE.md §13)
- The PRoFESS publication reports exclusion criteria in summary form; the verbatim list above is the full set stated in the trial report. The curated exclusion summary on this entry (cardioembolic source, planned other antithrombotic, severe disability precluding follow-up) reflects the operational selection consistent with a non-cardioembolic secondary-prevention monotherapy comparison but is broader than the verbatim publication text. Subjects entered a 2x2 factorial design and were concurrently randomized to telmisartan or placebo (antihypertensive comparison reported separately: Yusuf S et al., NEJM 2008).
Source: Sacco RL et al., NEJM 2008;359(12):1238-1251; PMID 18753638· Retrieved 2026-06-09
Primary Outcome (noninferiority)
First recurrent stroke (any type) over mean 2.5-year follow-up — NI margin HR 1.075
Negligible absolute difference
Recurrent stroke at 2.5y
Noninferiority NOT formally established: the upper bound of the 95% CI (1.11) crosses the prespecified NI margin (1.075). Do NOT describe the regimens as "equivalent" or "interchangeable" on PRoFESS evidence alone. ICH was significantly higher with ASA–ERDP (1.4% vs 1.0%, HR 1.42, 95% CI 1.11–1.83); discontinuation 29.1% vs 22.6% (P<0.001), driven mainly by dipyridamole headache.
Study Arms
- Agent
- Aspirin plus extended-release dipyridamole (fixed-dose combination)
- Dose
- 25 mg of aspirin plus 200 mg of extended-release dipyridamole per capsule (total daily 50 mg aspirin + 400 mg ER-dipyridamole)
- Route
- Oral
- Frequency
- Twice daily
- Duration
- Long-term; mean follow-up 2.5 years (range 1.5-4.4)
- Co-interventions
- Double-dummy with matching clopidogrel placebo. Concurrent 2x2 factorial randomization to telmisartan or placebo. Best medical management of vascular risk factors.
Dosing verbatim from Sacco RL et al., NEJM 2008. Headache is a recognized class effect of dipyridamole and drove higher discontinuation in this arm (29.1% vs 22.6% for any cause, P<0.001). Intracranial hemorrhage was significantly higher with this regimen (1.4% vs 1.0%, HR 1.42, 95% CI 1.11-1.83).
- Agent
- Clopidogrel
- Dose
- 75 mg
- Route
- Oral
- Frequency
- Once daily
- Duration
- Long-term; mean follow-up 2.5 years (range 1.5-4.4)
- Co-interventions
- Double-dummy with matching ASA-ERDP placebo (no aspirin background in this arm). Concurrent 2x2 factorial randomization to telmisartan or placebo. Best medical management of vascular risk factors.
Randomized double-blind double-dummy noninferiority design (prespecified hazard-ratio margin 1.075). Recurrent stroke 9.0% (ASA-ERDP) vs 8.8% (clopidogrel), HR 1.01 (95% CI 0.92-1.11); the upper CI bound crossed the margin so noninferiority was not formally established. Source: Sacco RL et al., NEJM 2008.
Safety
Intracranial hemorrhage
1.4%
1%
Intracranial hemorrhage: 147 (1.4%) with ASA–ERDP vs 103 (1.0%) with clopidogrel. HR 1.42 (95% CI 1.11–1.83). Statistically significant excess with the dipyridamole-containing regimen. Source: Sacco RL et al., NEJM 2008, Table 3.
All-cause mortality
7.3%
7.4%
Death from any cause: 739 (7.3%) ASA–ERDP vs 756 (7.4%) clopidogrel. Comparable between arms.
Major hemorrhagic events
4.1%
3.6%
Major hemorrhagic events of any kind: 419 (4.1%) ASA–ERDP vs 365 (3.6%) clopidogrel. HR 1.15 (95% CI 1.00–1.32). Borderline significance; consistent with the directional excess seen in intracranial bleeding.
Trial Design
Type
- Randomized double-blind double-dummy noninferiority trial
- 2×2 factorial (antiplatelet × telmisartan/placebo)
- 695 centers, 35 countries
- 1:1 allocation between ASA–ERDP and clopidogrel
- Noninferiority margin: hazard ratio 1.075
Timeline
Enrolled Sep 2003 – Feb 2008; mean follow-up 2.5 years
N
20,332
Enrollment
20,332 patients (ASA–ERDP 10,181 / clopidogrel 10,151) at 695 centers in 35 countries. Randomized double-blind double-dummy noninferiority trial; 2×2 factorial with telmisartan vs placebo. Enrolled September 2003 to February 2008. Mean follow-up 2.5 years (range 1.5–4.4). NI margin HR 1.075. Trial ran to prespecified 1,715-event count. Sponsor: Boehringer Ingelheim. Published NEJM 2008.
ClinicalTrials.gov
NCT00153062Bedside Pearl
PRoFESS compared aspirin + ER-dipyridamole with clopidogrel as long-term monotherapy after non-cardioembolic ischemic stroke. Recurrent stroke rates were 9.0% vs 8.8% (HR 1.01, 95% CI 0.92–1.11), but the CI crossed the prespecified noninferiority margin of 1.075 so noninferiority was not formally established. Intracranial hemorrhage was higher with ASA–ERDP (1.4% vs 1.0%, HR 1.42) and discontinuation was higher (29.1% vs 22.6%). Choose between the two regimens based on side-effect profile, bleeding risk, and CYP2C19 status, not on a claim of equivalence.
See also