Impact of Cerebral Small Vessel Disease on Functional Decline: Bleeding With Antithrombotic Therapy 2 Study.

Abstract

To what extent cerebral small vessel disease (SVD) contributes to functional disability remains unclear. We investigated the longitudinal effect of SVD burden on functional decline. In this investigator-initiated, prospective, multicenter, and observational study, patients receiving oral antithrombotic therapy for cerebrovascular or cardiovascular diseases were enrolled from 52 hospitals across Japan (2016-2019) and followed for 24 months. SVD score (range, 0-4) was calculated on baseline magnetic resonance imaging obtained under prespecified conditions. The outcomes were an increase in modified Rankin Scale (mRS) score from baseline to end of follow-up (ΔmRS score ≥1). Logistic regression evaluated the association between ΔmRS score ≥1 and SVD score, adjusting for age, sex, premorbid mRS, vascular risk factors, antithrombotic therapy, magnetic resonance imaging field strength, and bleeding or ischemic events during follow-up. Bleeding and ischemic events were treated as time-dependent covariates. Causal mediation analyses using a 4-way decomposition separated the effects of SVD score ≥3 on ΔmRS score ≥1 into direct and indirect effects (mediated by major bleeding or ischemic events). Of 5378 patients enrolled, 613 were excluded mainly due to the lack of clinical or imaging data. Finally, 4765 patients were analyzed (1573 women; median age, 73 years); ΔmRS score ≥1 was observed in 13.2% of patients with SVD score 0, 16.1% with 1, 20.7% with 2, 28.1% with 3, and 28.2% with 4. SVD score of 3 (adjusted odds ratio, 1.65 [95% CI, 1.27-2.15]) and SVD score of 4 (1.62 [95% CI, 1.19-2.19]) were associated with ΔmRS score ≥1 compared with SVD score of 0. Causal mediation analysis indicated that 73.05% of the total effect of SVD score ≥3 on ΔmRS score ≥1 was attributed to the controlled direct effect (coefficient, 0.497 [95% CI, 0.26-0.73]). SVD burden was associated with functional decline beyond significant bleeding or ischemic events.