Time Course of Evolution of Disability and Cause‐Specific Mortality After Ischemic Stroke: Implications for Trial Design

Background Outcome in stroke trials is often based on a 3‐month modified Rankin scale (mRS). How 3‐month mRS relates to longer‐term outcomes will depend on late recovery, delayed stroke‐related deaths, recurrent strokes, and nonstroke deaths. We evaluated 3‐month mRS and death/disability at 1 and 5 years in a population‐based cohort study. Methods and Results In 3‐month survivors of ischemic stroke (Oxford Vascular Study; 2002‐2014), we related 3‐month mRS to disability (defined as mRS >2) at 1 and 5 years and/or death rates (age/sex adjusted). Accrual of disability and index‐stroke‐related and nonstroke deaths in each poststroke year was categorized according to 3‐month mRS. Among 1606 patients with acute ischemic stroke, 181 died within 3 months, but 126 index‐stroke‐related deaths and 320 other deaths occurred during the subsequent 4866 patient‐years of follow‐up up to 5 years. Although 69/126 (54.8%) post‐3‐month index‐stroke‐related deaths occurred after 1 year, mRS>2 at 1 year strongly predicted these deaths (adjusted hazard ratio=21.94, 95%CI 7.88‐61.09, P<0.0001). Consequently, a 3‐month mRS >2 was a strong independent predictor of death at both 1 year (adjusted hazard ratio=6.67, 95%CI 4.16‐10.69, P<0.0001) and 5 years (adjusted hazard ratio=2.93, 95%CI 2.38‐3.60, P<0.0001). Although mRS improved by ≥1 point from 3 months to 1 year in 317/1266 (25.0%) patients with 3‐month mRS ≥1, improvement in mRS after 1 year was limited (improvement by ≥1 point: 91/858 [10.6%]; improvement to mRS ≤2: 13/353 [3.7%]). Conclusions Our results reaffirm use of the 3‐month mRS outcome in stroke trials. Although later recovery does occur, extending follow‐up to 1 year would capture most long‐term stroke‐related disability. However, administrative mortality follow‐up beyond 1 year has the potential to demonstrate translation of early disability gains into additional reductions in long‐term mortality without much erosion by non‐stroke‐related deaths.

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