Patients taking aspirin plus extended-release dipyridamole (ASA-ERDP) had a similar risk for recurrent stroke as those taking clopidogrel, and therapy with telmisartan, an angiotensin-receptor blocker, did not significantly lower risk for recurrent stroke, according to results of the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial, published in two separate reports in the September 18 New England Journal of Medicine.
Comparison of Antiplatelet Regimens
A total of 20,332 patients who had had a recent ischemic stroke participated in the PRoFESS trial. Investigators randomized patients to a fixed combination of low-dose ASA (25 mg) and ERDP (200 mg) twice daily or to clopidogrel (75 mg) once daily. Patients were followed for 2.5 years—at time of discharge or at one week after discharge, and then at one, three, and six months, as well as every six months thereafter.
Ralph L. Sacco, MD, Professor and Chairman in the Department of Neurology at the University of Miami School of Medicine, and colleagues noted that “the trial did not meet the predefined criteria for noninferiority but showed similar rates of recurrent stroke with ASA-ERDP and with clopidogrel.”
Nine percent of patients receiving ASA-ERDP and 8.8% of those taking clopidogrel had recurrent stroke. The secondary outcome of stroke, myocardial infarction, or death from vascular causes occurred in 13.1% of patients in each treatment group. More hemorrhagic events, including intracranial hemorrhage, occurred in patients receiving ASA-ERDP than in those receiving clopidogrel.
According to the researchers, there was “no evidence that either of the two treatments was superior to the other in the prevention of recurrent stroke.”
Antihypertensive Therapy
Participants in the PRoFESS trial were also randomized to receive telmisartan (80 mg once daily) or placebo, in addition to medications for blood pressure control prescribed at the discretion of the investigators.
“We showed that the addition of angiotensin-receptor blocker therapy to the use of other antihypertensive drugs soon after a stroke and continuing for a mean of 2.5 years did not significantly reduce the risk of subsequent stroke, major cardiovascular events, or new-onset diabetes,” said Salim Yusuf, MB, BS, DPhil, and colleagues in the second PRoFESS report. There was little early benefit until after the first six months of treatment, which suggests that longer-term treatment may confer an advantage with telmisartan.
During the follow-up period, mean blood pressure was 3.8/2.0 mm Hg lower in the telmisartan group than in the placebo group, while recurrent stroke occurred in 8.7% of patients in the telmisartan group and 9.2% of those in the placebo group. “The results of our analysis were unaltered after accounting for the modest reduction in blood pressure in the telmisartan group,” said Dr. Yusuf, Professor in the Department of Medicine, Joint Member in the Department of Clinical Epidemiology and Biostatistics, and Director of the Population Health Research Institute at McMaster University in Hamilton, Ontario, and coauthors. “This finding raises the question of whether agents that block the renin-angiotensin system offer additional benefit independent of their effects on blood pressure.”
According to the researchers, new-onset diabetes occurred in 1.7% of the telmisartan group and 2.1% of the placebo group. In addition, 13.5% of the telmisartan group and 14.4% of the placebo group experienced major cardiovascular events.
Making Treatment Decisions
“Despite some evidence from previous trials that inhibition of the renin-angiotensin system may help prevent strokes even independently of the blood-pressure–lowering effect, this aspect of the trial, much like the antiplatelet comparison, was persuasively null,” commented David M. Kent, MD, and David E. Thaler, MD, PhD, in an accompanying editorial.
“Although the inconsistency among trial results should make us examine the trials for differences in design or populations that might support explanatory hand-waving, it is also reasonable to conclude from these comparisons that efficacy should not be the sole, or perhaps even the major, determinant of treatment decisions for antiplatelet therapy after stroke,” they said. For example, ASA-ERDP may be difficult for some patients to tolerate; headache is a common side effect, and combination treatment must be taken twice daily. In addition, more serious hemorrhagic complications were observed in patients taking ASA-ERDP, compared with those taking clopidogrel, in the PRoFESS trial. Finally, “ASA costs pennies per day, whereas low-dose ASA-ERDP and clopidogrel cost greater than 100 times that.”
—Karen L. Spittler