Small subcortical strokes (S3) are an important stroke subtype that account for about 25% of all ischemic strokes. In Hispanic Americans, S3 are the most frequent stroke subtype and occur at a relatively young age. S3 are usually due to cerebral small artery disease, a common substrate for vascular dementia. Over two million survivors of S3 are at high risk for recurrent stroke and for vascular dementia; millions more suffer subclinical S3 and cognitive decline caused by cerebral small artery disease. Secondary Prevention of Small Subcortical Strokes (SPS3) consists of two randomized, multicenter clinical trials that follow a 3 year NINDS-sponsored pilot study. It will enroll 2500 participants (20% of whom will be Hispanic Americans) with symptomatic, MRI-defined $3 without carotid stenosis or major cardiac sources of embolism at 35 clinical sites. Patients will be assigned, in a factorial design, to two interventions: 1. Antiplatelet Intervention 325 mg/d vs aspirin 325 mg/d plus clopidogrel 75 mg/d. 2. Blood Pressure Intervention: systolic blood pressure targets of 130 to 149 mmHg vs <130 mmHg. The antiplatelet comparison will be double-blinded, while the blood pressure intervention will open-label with blinded assessment and verification of cognition and clinical events. Follow-up will be every three months for a mean of 3 years. Main outcomes are: 1. recurrent stroke (ischemic and hemorrhagic) 2. cognitive decline 3. major vascular events Key hypotheses are: 1. Combination antiplatelet therapy is more efficacious than aspirin alone for prevention of stroke recurrence and for reduction in cognitive decline. 2. Intensive blood pressure control is associated with fewer recurrent strokes and reduction in cognitive decline. 3. The absolute reduction in stroke and cognitive decline by combined antiplatelet therapy and (separately) by intensive blood pressure lowering is greater for Hispanic Americans vs. non Hispanic white participants. No previous randomized trials have focused specifically on secondary prevention after S3, on optimal target levels of blood pressure control after stroke and their relationship to cognitive decline, or on prevention of stroke and dementia in Hispanic Americans. The results of SPS3 will likely lead to important reduction in the burden of serious neurological disease (stroke and vascular dementia) for millions of people with S3, and particularly for Hispanic Americans.
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