Clopidogrel + aspirin doesn't reduce bleeding, death after lacunar strokes
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Small subcortical brain infarcts, commonly known as lacunar strokes, constitute about 25 percent of ischemic strokes (J Neurol Neurosurg Psychiatry 2002;72:211-216). Although lacunar strokes occasionally result from mechanisms of brain ischemia such as cardiogenic embolism or carotid artery stenosis, most result from intrinsic disease of the small penetrating arteries, according to the study authors, but this underlying disorder is the most frequent cause of covert brain infarcts and vascular cognitive impairment (Neurology 1999;53:337-343).
However, the Secondary Prevention of Small Subcortical Strokes (SPS3) investigators, who conducted this study, said the secondary prevention of lacunar stroke as detected by the use of MRI has not been the focus of a randomized trial.
Aspirin has been the standard therapy for patients with lacunar infarcts. While aspirin plus clopidogrel, or dual-antiplatelet therapy, has reduced strokes in those with atrial fibrillation and acute coronary syndromes, it also has been associated with increased bleeds (Am J Cardiol 2009;103:1107-1112).
Thus, the SPS3 trial tested two randomized interventions, in a two-by-two factorial design, in patients with recent symptomatic, MRI-confirmed lacunar stroke: clopidogrel and aspirin versus aspirin alone and two target levels of systolic blood pressure.
The antiplatelet component of the trial was terminated at the recommendation of the data and safety monitoring committee because of lack of efficacy combined with evidence of harm.
Oscar R. Benavente, MD, of the division of neurology at the Brain Research Center at the University of British Columbia in Vancouver, British Columbia, and colleagues conducted a double-blind, multicenter trial involving 3,020 patients with recent symptomatic lacunar infarcts identified by MRI.
They randomly assigned patients to receive 75 mg of clopidogrel or placebo daily; patients in both groups received 325 mg of aspirin daily. The primary outcome was any recurrent stroke, including ischemic stroke and intracranial hemorrhage.
The participants had a mean age of 63 years, and 63 percent were men. After a mean follow-up of 3.4 years, the risk of recurrent stroke was not significantly reduced with dual-antiplatelet therapy (125 strokes; rate, 2.5 percent per year) as compared with aspirin alone (138 strokes, 2.7 percent per year), nor was the risk of recurrent ischemic stroke or disabling or fatal stroke.
The investigators also reported that the risk of major hemorrhage was almost doubled with dual-antiplatelet therapy (105 hemorrhages, 2.1 percent per year), as compared with aspirin alone (56, 1.1 percent per year).
Among classifiable recurrent ischemic strokes, 71 percent were lacunar strokes. All-cause mortality was increased among patients assigned to receive dual-antiplatelet therapy (77 deaths in the group receiving aspirin alone vs. 113 in the group receiving dual-antiplatelet therapy); this difference was not accounted for by fatal hemorrhages (nine in the group receiving dual-antiplatelet therapy vs. four in the group receiving aspirin alone).
“The SPS3 trial documents the lack of benefit of dual-antiplatelet therapy in a specific, well-defined subtype of ischemic stroke that results primarily from cerebral small-artery disease,” wrote the study authors.
However, they added that the results must be interpreted in the context of the other component of the trial, which involved vigorous management of blood pressure. “The rate of recurrent stroke among patients taking aspirin alone (2.7 percent per year) was substantially lower than anticipated,” Benavente et al wrote. “The use of statins by the majority of the study participants and the good blood pressure control achieved probably contributed to the low observed rate in our trial, which was similar to the rates in other recent trials testing antiplatelet therapies for the prevention of recurrent stroke.”
Also, because dual-antiplatelet therapy was associated with a trend toward a reduction in recurrent strokes attributed to atherosclerosis but not recurrent lacunar strokes, they suggested a hypothesis that "the role of platelets is different in different types of ischemic cerebrovascular disease."
This study was supported by a grant from the National Institute of Neurological Disorders and Stroke and by Sanofi-Aventis and Bristol-Myers Squibb, which donated the clopidogrel and matching placebo used in the study.