Microbleeds in the Secondary Prevention of Small Subcortical Strokes Trial: Stroke, Mortality, and Treatment Interactions

Objective: To characterize cerebral microbleeds (CMBs) in lacunar stroke patients in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial and to assess their relationship with recurrent stroke and death, and response to assigned treatment. Methods: SPS3 is a randomized, clinical trial conducted between 2003 and 2011. Patients with recent magnetic resonance imaging (MRI)-documented lacunar infarcts were randomly assigned in a factorial design to target levels of systolic blood pressure (130-149mmHg vs <130mmHg; open label) and to antiplatelet treatment (aspirin/clopidogrel vs aspirin/placebo; double-blinded). The current analysis involves 1,278 trial participants who had a baseline axial T2*-weighted gradient echo MRI sequence allowing for CMB detection. Results: CMBs were present in 30% of 1,278 patients (mean age=63 years). Male gender (odds ratio [OR] = 1.7, 95% confidence interval [CI] = 1.3-2.3), history of hypertension (OR=1.6, 95% CI=1.2-2.3), increased systolic blood pressure (1.2 per 20mmHg, 95% CI=1.1-1.4), nondiabetic status (OR=1.4, 95% CI=1.1-1.9), multiple old lacunar infarcts (OR=1.9, 95% CI=1.5-2.5), and moderate (OR=1.7, 95% CI=1.2-2.3) or severe (OR=4.2, 95% CI=3.05.9) white matter hyperintensities on MRI were independently associated with CMBs. During a mean follow-up of 3.3 years, overall stroke recurrence was 2.5% per patient-year. Patients with CMBs had an adjusted 2-fold increased risk of recurrent stroke (hazard ratio=2.1, 95% CI=1.4-3.1). CMBs were not a risk factor for death. There were no statistically significant interactions between CMBs and treatment assignments. Interpretation: Patients with lacunar stroke and CMBs likely harbor a more advanced form of cerebral small vessel disease in need of efficacious therapeutic strategies.