NEW ORLEANS – The combination of aspirin and clopidogrel proved no more effective than aspirin alone for secondary stroke prevention, and dual therapy significantly boosted the major hemorrhage rate and patient mortality in a randomized, multicenter trial with more than 3,000 patients.
The poor performance of this dual antiplatelet combination in this large study, called the Secondary Prevention of Small Subcortical Strokes (SPS3) trial, leaves the secondary stroke prevention guideline published last year by the American Heart Association and American Stroke Association unchanged in its recommendation of three antiplatelet drug options for patients with a history of stroke or transient ischemic attack: aspirin, aspirin plus dipyridamole, or clopidogrel (Stroke 2011;42:227-76), Dr. Oscar R. Benavente said at the International Stroke Conference.
The new trial results "do not support the use of combination therapy for secondary stroke prevention in patients with lacunar strokes," said Dr. Benavente, the study’s co-principal investigator and research director of the Stroke and Cerebrovascular Disease Program at the Vancouver Coastal Health Research Institute.
The SPS3 study enrolled 3,020 patients within 180 days of a small, subcortical, lacunar stroke at 81 sites in eight countries during 2003-2011. The trial excluded patients with cortical stroke, cardioembolic disease, or carotid stenosis. More than half of the enrolled patients received care at U.S. centers. Their average age was 63 years, about two-thirds were men, and they entered the study an average of 76 days following their index stroke.
The study randomized 1,503 patients to treatment with 325 mg of aspirin daily, and 1,517 patients to the same aspirin dosage plus 75 mg of clopidogrel (Plavix) daily.
The study’s data and safety monitoring board stopped this portion of the trial early last July, after an average follow-up of 3.5 years, because of safety and futility. (The study continues with a concurrent randomization that is comparing the efficacy of usual and "intensive" blood pressure control.) The antiplatelet randomization stopped because the results showed a "surprising," statistically significant increased rate of all-cause mortality and major hemorrhages in patients treated with dual antiplatelet therapy, Dr. Benavente said.
All-cause mortality occurred at a rate of 1.4%/patient-year in the aspirin-only group, and a rate of 2.1%/patient-year in the dual-therapy arm, a 50% relative risk difference. A breakdown of the causes of death showed a statistically significant difference for only one subgroup, "probable vascular" death, which was threefold higher in the aspirin plus clopidogrel patients than in those on aspirin only. The causes of death will require more analysis to better understand the danger posed by the dual-drug regimen, Dr. Benavente said at the meeting, which was sponsored by the American Heart Association.
Major hemorrhages occurred in 1.1% of the aspirin-only patients and in 2.1% of those on the dual regimen. When separated by type of hemorrhage, the only significant difference between the two treatment groups was in the incidence of non–central nervous system hemorrhages, a category that mostly consisted of gastrointestinal bleeds, he said.
The two regimens showed no significant difference for the study’s primary efficacy outcome, the incidence of ischemic and hemorrhagic strokes, which occurred at 2.7%/patient-year among those on aspirin only and 2.5%/patient-year in those on both drugs. The rates of ischemic strokes only, hemorrhagic strokes only, major vascular events, and myocardial infarctions also showed no significant differences between the two treatment arms.
SPS3 did not include a patient group treated only with clopidogrel because previous, large studies had already compared clopidogrel alone with aspirin alone, and with aspirin plus dipyridamole. The results of those studies "have not clearly established that [clopidogrel] is superior to or even equivalent to" aspirin, aspirin plus dipyridamole, and ticlopidine (Ticlid), said last year’s treatment recommendations from the American Heart Association and American Stroke Association.
The SPS3 study was sponsored by the National Institute of Neurological Disorders and Stroke. Dr. Benavente said that he has received research support from Sanofi-Aventis and Bristol-Myers Squibb.