Results of the PRoFESS Trial: Use Any Antiplatelet Agent and Get Back to the Basics

Abstract & Commentary

By Dara G. Jamieson, MD, Associate Professor of Clinical Neurology, Weill-Cornell Medical College. Dr. Jamieson reports that she is a retained consultant for Boehringer Ingelheim, Merck, and Ortho-McNeil; and is on the speaker's bureau for Boehringer Ingelheim and Merck.

Synopsis: Aspirin plus extended-release dipyridamole and clopidogrel are both appropriate options to decrease disability from recurrent stroke; however, telmisartan does not lower risk of suffering a second stroke.

Sources: Sacco RL, Diener HC, Yusuf S, et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med 2008;359:1238-1251; Yusuf S, Diener HC, Sacco RL, et al. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med 2008;359:1225-1237; Kent DM, Thaler DE. Stroke prevention — insights from incoherence. N Engl J Med 2008;359:1287-1289; Diener HC, Sacco RL, Yusuf S, et al. Effects of aspirin plus extended-release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischemic stroke in the PRoFESS trial: a double-blind, active and placebo-controlled study. Lancet Neurol 2008;7:875-884; Hankey GJ, Eikelboom JW. What do the results of the PRoFESS trial teach us? Lancet Neurol 2008;7:860-862.

Antiplatelet therapy is appropriate for recurrent stroke risk reduction in patients with non-cardioembolic ischemic stroke; current options include aspirin and two branded products (clopidogrel and the combination of aspirin plus extended-release dipyridamole [ASA-ERDP]). The Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial is a double-blind, 2-by-2 factorial trial, in which patients with a recent ischemic stroke were randomized to receive 25 mg of aspirin plus 200 mg of ASA-ERDP twice daily or 75 mg of clopidogrel daily. The primary outcome was first recurrence of stroke; the secondary outcome was a composite of stroke, myocardial infarction, or death from vascular causes. A total of 20,332 patients were followed for a mean of 2.5 years. Premature discontinuation of the study drug was significantly more frequent among patients receiving ASA-ERDP (29.1%) than among those receiving clopidogrel (22.6%). Recurrent stroke occurred in 916 patients (9.0%) receiving ASA-ERDP and in 898 patients (8.8%) receiving clopidogrel (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11). Major hemorrhagic events, including intracranial hemorrhage, were more common in ASA-ERDP recipients (4.1%) than in clopidogrel recipients (3.6%) (hazard ratio, 1.15; 95% CI, 1.00 to 1.32). The net risk of recurrent stroke or major hemorrhagic event was similar in the ASA-ERDP (11.7%) and clopidogrel (11.4%) groups (hazard ratio, 1.03; 95% CI, 0.95 to 1.11). There was no difference in the incidence of composite vascular events between patients on ASA-ERDP or clopidogrel.

Inhibition of the renin-angiotensin system reduces the rate of secondary vascular events, but the cerebrovascular benefit of an angiotensin II receptor blocker (ARB) initiated early after an ischemic stroke is uncertain. The patients of PRoFESS also were randomized to the ARB telmisartan (80 mg daily) or placebo. A total of 880 patients (8.7%) in the telmisartan group and 934 patients (9.2%) in the placebo group had a subsequent stroke (hazard ratio in the telmisartan group, 0.95; 95% CI, 0.86 to 1.04; p=0.23). The mean blood pressure was 3.8/2.0 mm Hg lower in the telmisartan group than in the placebo group. Therapy with telmisartan did not significantly lower the rate of recurrent stroke, composite vascular events, or diabetes.

The putative neuroprotective effects of antiplatelet compounds and telmisartan also were investigated in the PRoFESS trial. The predefined endpoints for the substudy evaluating disability and cognitive function after recurrent stroke were the modified Rankin scale and Barthel index at 3 months, and cognitive function, assessed with the mini-mental state examination score at 4 weeks after randomization and at the penultimate visit. There were no significant differences in the proportion of patients with cognitive impairment or dementia among the treatment groups. This substudy concluded that disability due to recurrent stroke and cognitive decline were not different between the two antiplatelet regimens and were not affected by the preventive use of telmisartan.

Commentary

The results of the PRoFESS study were surprising based on expectations from older clinical trials. Prior to this head-to-head comparison, the indirect comparison of the results of other clinical trials such as the Second European Stroke Prevention Study (ESPS-2), Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE), and Aspirin and clopidogrel compared with clopidogrel alone after recent ischemic stroke or transient ischemic attack in high-risk patients (MATCH) indicated the superiority of ASA-ERDP over clopidogrel in the prevention of recurrent ischemic stroke. Trials of clopidogrel plus aspirin showed a greater risk of life-threatening bleeding as compared with monotherapy; however, earlier trials of ASA-ERDP showed no increased risk of life-threatening bleeding as compared with aspirin alone. The major concern with treatment with ASA-ERDP was the transient headache in up to one-third of patients at initiation of treatment.

PRoFESS did not indicate the expected clinical superiority of ASA-ERDP, and the discontinuation rate of the medication due to headache was lower than expected. The conclusion of the trial was that net risk of recurrent stroke or major hemorrhagic event was similar with the two antiplatelet agents and that there was no evidence that either of the two treatments was superior to the other in the prevention of recurrent stroke. The increased risk of intracranial bleeding among patients treated with ASA-ERDP emphasizes the risk of treatment with dual antiplatelet treatment, including aspirin plus clopidogrel, despite lack of such evidence for ASA-ERDP prior to PRoFESS.

The results of PRoFESS indicate that we have a choice of antiplatelet agents of overlapping efficacy; other factors in the choice include cost and tolerability. In the next few years we may have even more choices if prasugrel, a new thienopyridine with greater antiplatelet potency but more hemorrhagic risk, becomes available for recurrent ischemic stroke risk reduction.

The editorial by Kent and Thaler accompanying the New England Journal of Medicine publication used a zen approach to interpret the results, concluding "For stroke prevention, use an antiplatelet drug. Treat hypertension." Treatment with any antiplatelet agent decreases the recurrent stroke rate by 9%, three years after the prior non-cardioembolic stroke. Antiplatelet treatment must be accompanied by aggressive life style adjustment and management of medical risk factors, especially hypertension. In addition, by the time recurrent ischemic stroke risk reduction is considered, the patient may already have permanent neurological disability. We need better implementation of the lifestyles and medical treatments that we know will prevent the first ischemic stroke. Then we can effectively prevent ischemic stroke recurrence.