Associations of Imaging Markers of Small Vessel Disease and 'Brain Frailty' with Clinical Outcome in Patients with Acute Lacunar Stroke: A Secondary Analysis of the Efficacy of Nitric Oxide in Stroke (ENOS) Trial

Abstract

Background: Cerebral small vessel disease (SVD) is a common cause of lacunar stroke, cognitive impairment and dementia. We assessed the association of baseline imaging markers of SVD and 'brain frailty' with functional and cognitive outcomes after acute stroke, including lacunar stroke, in the Efficacy of Nitric Oxide in Stroke (ENOS) trial. Methods: ENOS randomised 4011 patients with acute stroke (<48 hours of onset) to transdermal GTN or no GTN for 7 days. The primary outcome was functional outcome (modified Rankin Scale, mRS) at day 90. Stroke syndrome was classified using the Oxfordshire Community Stroke Project classification. Brain imaging was adjudicated masked to clinical information and treatment, and assessed for SVD (leukoaraiosis, old lacunar infarcts/lacunes, atrophy) and 'brain frailty' (leukoaraiosis, atrophy, old vascular lesions). Ordered categorical data were analysed using ordinal logistic regression with adjustment for prognostic variables. Findings: In all participants, and in 1397/4011 (34.8%) participants with lacunar syndromes (LACS), baseline imaging features of SVD and 'brain frailty' on CT were common and independently associated with unfavourable shifts in mRS at day 90 in all participants (SVD score: OR 1.15, 95% CI 1.07-1.24; 'brain frailty' score: OR 1.25, 95% CI 1.17-1.34) and in those with LACS (SVD score: OR 1.30, 95% CI 1.15-1.47; 'brain frailty' score: OR 1.28, 95% CI 1.14-1.44). 'Brain frailty' was associated with worse cognitive scores at 90 days in all and in LACS participants. GTN did not influence three-month outcomes in participants with LACS. Interpretation: Baseline imaging features of SVD and 'brain frailty' were common in lacunar stroke and all stroke, predicted worse prognosis after all acute stroke with a stronger effect in lacunar stroke, and may aid future clinical decision-making. Whether the vascular or neurodegenerative features are more associated with cognitive impairment requires further testing. Trial Registration Number: ISRCTN99414122 Funding Statement: BUPA Foundation and the Medical Research Council. Declaration of Interests: NS reports grants from NIHR HTA (11_129_109) during the conduct of the study. PMB reports grants from British Heart Foundation, grants from NIHR Health Technology Appraisal Prog, during the conduct of the study; other from Platelet Solutions Ltd, personal fees from Diamedica, personal fees from Nestle, personal fees from Phagenesis Ltd, personal fees from ReNeuron, personal fees from Athersys, personal fees from Covidien outside the submitted work. JMW reports grants from Medical Research Council, grants from Fondation Leducq, grants from EU Horizon 2020 during the conduct of the study. JPA, AA, JLB, EB, LAC, AMC, VC, HKC, RAD, JG, PK and SS have nothing to disclose. Ethics Approval Statement: ENOS was approved by ethics committees/competent authorities in all participating countries.