Aspirin + dipyridamole = clopidogrel for recurrent stroke prevention (PROFESS)

Clinical Question

What is the best approach to the prevention of recurrent stroke?

Bottom Line

Aspirin plus dipyridamole is similarly effective to clopidogrel for the prevention of recurrent stroke. The risk of intracerebral hemorrhage is slightly lower with clopidogrel, and headache is more common with aspirin plus dipyridamole. (LOE = 1b)


Sacco RL, Diener HC, Yusuf S, et al, for the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) study group. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med 2008;359(12):1238-1251.  [PMID:18753638]

Study Design

Randomized controlled trial (double-blinded)






Outpatient (any)


Antiplatelet agents such as aspirin, clopidogrel, and aspirin plus extended-release dipyridamole (APERD) all reduce the risk of recurrent stroke. Direct comparisons have shown small benefits of both APERD and clopidogrel over aspirin alone, while aspirin plus clopidogrel is no more effective and increases the risk of bleeding. Researchers recruited 20,332 patients older than 55 years with an ischemic stroke in the previous 90 days; they also enrolled patients aged 50 years to 54 years or within 90 days to 120 days if they also had at least 2 additional vascular risk factors. Patients were randomly assigned to receive aspirin 25 mg plus dipyridamole 200 mg twice daily or clopidogrel 75 mg once daily and were followed up for a mean of 2.5 years. This was a 2x2 factorial design, so patients were also assigned to telmisartan or placebo, but those results are not reported in this article. The mean age of participants was 66 years, 36% were women, and 58% were white. The primary outcome was recurrent stroke as adjudicated by an independent monitoring team. The analysis was by intention to treat, and this was a noninferiority trial (ie, they were trying to prove that APERD was at least as good as clopidogrel, not that it was better). This was the case, as there was no difference between groups in the primary outcome of recurrent stroke (9.0% receiving APERD, 8.8% receiving clopidogrel), in all-cause mortality (7.3% vs 7.4%), or in a composite outcome of stroke, myocardial infarction, or vascular death (13.1% for both groups). Major hemorrhage was slightly more common in the APERD group (4.1% vs 3.6%; P = .05; number needed to treat to harm [NNTH] = 200 over 2.5 years), as was intracranial hemorrhage (1.4% vs 1.0%; NNTH = 250 over 2.5 years). Headache was a more common side effect among patients taking APERD than among those taking clopidogrel (30% vs 7%), and patients taking APERD were more likely to discontinue the study medication than were patients taking clopidogrel (5.9% vs 0.9%; NNTH = 20).