• Mukul Sharma, Lesly A Pearce, Oscar R Benavente, David C Anderson, Stuart J Connolly, Santiago Palacio, Christopher S Coffey, and Robert G Hart.
• From the Divisions of Neurology (M.S., R.G.H.) and Cardiology (S.J.C.), Department of Medicine, McMaster University/Population Health Research Institute, Hamilton, Ontario, Canada; Biostatistics Consultant, Minot, ND (L.A.P.); Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (O.R.B.); Department of Neurology, University of Minnesota, Minneapolis (D.C.A.); Department of Neurology, University of Texas Health Science Center, San Antonio (S.P.); and Department of Biostatistics, University of Iowa, Iowa City (C.S.C.). Mike.Sharma@phri.ca.
• Stroke. 2014 Oct 1;45(10):2989-94.

Background And PurposeThe Secondary Prevention of Small Subcortical Stroke trial (SPS3) recruited participants meeting clinical and radiological criteria for symptomatic lacunes. Individuals randomized to dual antiplatelet therapy with clopidogrel and aspirin had an unanticipated increase in all-cause mortality compared with those assigned to aspirin. We investigated the factors associated with mortality in this well-characterized population.MethodsWe identified independent predictors of mortality among baseline demographic and clinical factors by Cox regression analysis in participants of the SPS3 trial. Separately, we examined the effect on mortality of nonfatal bleeding during the trial.ResultsDuring a mean follow-up of 3.6 years, the mortality rate was 1.78% per year for the 3020 participants (mean age, 63 years). Significant independent predictors of mortality at study entry were age, diabetes mellitus, history of hypertension, systolic blood pressure (hazard ratio [HR], 1.3 per 20 mm Hg increase), serum hemoglobin<13 g/dL (HR, 1.6), renal function (HR, 1.3 per estimated glomerular filtration rate decrease of 20 mL/min), and body mass index (HR, 1.8 per 10 kg/m2 decrease). Participants with ischemic heart disease (P=0.01 for interaction) and normotensive/prehypertensive participants (P=0.03 for interaction) were at increased risk if assigned to dual antiplatelet therapy. Nonfatal major hemorrhage increased mortality in both treatment arms (HR, 4.5; 95% confidence interval, 3.1-6.6; P<0.001).ConclusionsUnexpected interactions between assigned antiplatelet therapy and each of ischemic heart disease and normal/prehypertensive status accounted for increased mortality among patients with recent lacunar stroke given dual antiplatelet therapy. Despite extensive exploratory analyses, the mechanisms underlying these interactions are uncertain.Clinical Trial Registration Urlhttp://www.SPS3ClinicalTrials.gov. Unique identifier: NCT00059306.© 2014 American Heart Association, Inc.

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