SPS3: Combining clopidogrel with aspirin fails to prevent recurrent strokes

International Stroke Conference 2012

NEW ORLEANS — Adding clopidogrel to aspirin therapy is unlikely to prevent recurrent strokes and may increase the risks for bleeding and death in patients who have small subcortical strokes.

Oscar Benavente, MD, professor of neurology at University of British Columbia in Vancouver, Canada, presented preliminary results of the Secondary Prevention of Small Subcortical Strokes (SPS3) trial. The anticoagulation part of the trial was stopped prematurely in August because of the suggested risk for bleeding and death in patients assigned to combination therapy. A futility analysis revealed that there was a small probability of showing a benefit in favor of combination therapy over aspirin alone if this part of the trial continued to its planned end.

Oscar Benavente Courtesy of the American Heart Association

The randomized, double blind trial enrolled 3,020 patients with small subcortical stroke verified by MRI at 81 sites in the United States, Canada, Mexico, Spain and South America. Patients were randomly assigned within 180 days of symptom onset to daily aspirin 325 mg plus placebo or aspirin 325 mg plus clopidogrel 75 mg (Plavix, Sanofi-Aventis).

Results showed no difference in stroke recurrence between treatment arms. The primary outcome — ischemic and hemorrhagic stroke — occurred at a rate of 2.7% per year in the aspirin alone group vs. 2.5% per year in the aspirin plus clopidogrel group (HR=0.92; 95% CI, 0.73-1.20).

“Major bleeds were increased, which has been seen in other trials of combination [therapy],” Benavente said during a press conference.

Risk for bleeding was nearly twofold in the aspirin plus clopidogrel group (2.1% per year vs. 1.1% per year; HR=2; 95% CI, 1.4-2.7). Most were non-central nervous system hemorrhages and occurred more in the combination therapy group (1.7% per year vs. 0.79% per year; HR=2.2; 95% CI, 1.5-3.1).

“Unexpectedly, total mortality was increased,” Benavente said.

All-cause mortality occurred in the aspirin plus clopidogrel group at a rate of 2.1% per year compared with 1.4% per year with aspirin alone (HR=1.5; 95% CI, 1.1-2.0). Most deaths were related to nonvascular causes.

“Dual antiplatelet therapy was not more efficacious than aspirin alone. These results do not support the use of combination therapy for secondary stroke prevention in patients with lacunar strokes,” Benavente said during the press conference.

American Heart Association/American Stroke Association guidelines for preventing recurrent strokes recommend aspirin or clopidogrel, but not combined therapy.

An SPS3 trial BP intervention continues and results are anticipated in late 2012. – by Katie Kalvaitis

For more information:

• Benavente O. Plenary session III. LB9. Presented at: the American Stroke Association’s International Stroke Conference 2012; Feb. 1-3, 2012; New Orleans.

Disclosure: Dr. Benavente reports research grants from NIH/National Institute of Neurological Disorders and Stroke and research support from Bristol-Myers Squibb and Sanofi-Aventis.

Cardiologists have many reasons to use clopidogrel plus aspirin, particularly for unstable angina, MI and post-stenting. In the stroke world, most of the data have not suggested any benefits for clopidogrel plus aspirin. We know from prior trials that there is an increased risk for bleeding among stroke patients taking clopidogrel plus aspirin. For this study, which looked at small vessel stroke, there is no evidence that we should be using clopidogrel plus aspirin; in fact, there is greater risk both in terms of hemorrhage and mortality. When you have a patient with stroke and are trying to prevent recurrent strokes, you have to think twice about choosing clopidogrel plus aspirin. [This combination] is being looked at for acute stroke. There is a large NIH-funded trial, the POINT trial, which will examine clopidogrel plus aspirin vs. aspirin in the acute phase of a transient ischemic attack or stroke. Maybe like unstable angina there are roles for clopidogrel plus aspirin in the early phases. In this study, for long-term recurrence, the risk for bleeding and risk for death look too great to use [this combination] in the long run.

– Ralph L. Sacco, MD, FAHA, FAAN
Immediate Past President, American Heart Association/American Stroke Association
Chair of Neurology, University of Miami Miller School of Medicine

Disclosure: Dr. Sacco reports no relevant financial disclosures.

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