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Clinical Advisory: Secondary Prevention of Small Subcortical Strokes Trial: NINDS Stops Treatment with Combination Antiplatelet Therapy (Clopidogrel plus Aspirin) Due to Higher Risk of Major Hemorrhage and Death

The National Institute of Neurological Disorders and Stroke (NINDS) has stopped the combination antiplatelet intervention in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial. The SPS3 trial is a randomized, multicenter clinical trial being conducted throughout North America, Latin America and Spain, to learn about preventing a second stroke in patients who had a subcortical stroke and to learn how to prevent cognitive problems after a stroke. A subcortical stroke, also known as lacunar stroke, causes damage to small areas in the brain. The study was designed to test whether a combination of both aspirin and clopidogrel (antiplatelets) would be more effective than taking aspirin alone as a means to prevent a recurrent stroke. Although both drugs are widely prescribed for general stroke prevention, SPS3 is the first test of the two drugs taken in combination to prevent recurrent strokes in patients with prior subcortical stroke. The investigators are also studying blood pressure control after a stroke and trying to determine the best level for stroke prevention.

Recruitment of 3,020 participants was completed on April 2, 2011. Patients with a recent (within 180 days) symptomatic small subcortical stroke, verified by MRI, were randomized simultaneously to both an antiplatelet intervention and to a target level of systolic blood pressure control.

Antiplatelet Intervention — All participants received a daily dose of 325 mg of enteric-coated aspirin and were randomized to also receive either a daily dose of 75 mg of clopidogrel or a matching placebo.

Blood Pressure Intervention — Patients were randomized to maintain a target level of systolic blood pressure control of either <130 mmHg ("intensive") or 130-149 mmHg ("usual"). Physicians work with the participants to achieve these blood pressure levels either through lifestyle changes and/or with the use of medications.

The NINDS acted on the recommendation of the study's Data and Safety Monitoring Board (DSMB) in stopping the antiplatelet component of the study. At the time of the most recent review on June 19, 2011, 6.5% of patients treated with a combination of aspirin and clopidogrel experienced a bleeding event (5.5% major non-CNS hemorrhage) compared with 3.3% of those assigned to aspirin (2.5% major non-CNS hemorrhage)(p<0.001). Patients assigned to combination treatment had more deaths from all causes, 5.8% vs. 4.1% (p=0.04), compared with those receiving aspirin alone. In addition, a futility analysis showed little likelihood of benefit in favor of aspirin plus clopidogrel on recurrent stroke should the study continue to conclusion.

These results support current guidelines that recommend against the use of the combination of clopidogrel plus aspirin for secondary stroke prevention and now extend this advice to those with recent small subcortical strokes, or lacunar infarcts, that have been confirmed by MRI. The SPS3 Steering Committee concurred with the DSMB recommendations and the subsequent NINDS action; investigators have notified patients in the combination antiplatelet treatment arm.

However, the DSMB strongly recommended that the blood pressure intervention component of the trial be continued without modification. All participants are encouraged to continue taking aspirin and blood pressure control medications and to remain active in the trial, which is expected to complete follow-up by April 2012.

Further information about this trial (NCT00059306) can be found at http://www.clinicaltrials.gov.

1. SPS3 Steering Committee. Oscar Benavente MD (Neurology PI), Robert Hart MD (Neurology CoPI) David Anderson MD, Antonio Arauz MD, Marie Benavente RN, BScN, Christopher Coffey PhD (Statistician CoPI), Robin Conwit MD, Robert Cote MD, Bart Demaerschalk MD, Mitchell Elkind MD, Richard Grimm MD, Leslie McClure (Statistician PI), Pablo Pergola MD, Ana Roldan MD, Jeff Szychowski PhD, Robert Talbert Pharm D.

NINDS (http://www.ninds.nih.gov) is the nation's leading funder of research on the brain and nervous system. The NINDS mission is to reduce the burden of neurological disease - a burden borne by every age group, by every segment of society, by people all over the world.

The National Institutes of Health (NIH) - The Nation's Medical Research Agency - includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.