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

Abstract

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.

Keywords: cerebrovascular disease/stroke; clinical trial design; health economics; longitudinal cohort study; stroke recovery.

Figure 1

Flowchart illustrating the ischemic stroke patients who were alive at baseline and at 3‐month, 1‐year, and 5‐year follow‐up assessments.

Figure 2

Proportions of 3‐month survivors of ischemic stroke, categorized according to 3‐month mRS, who were (A) dead at 1 year; (B) dead at 5 years; (C) disabled (mRS>2) at 5 years, only including those alive at 5 years in the total; and (D) dead/disabled at 5‐years. Bars represent 95% confidence intervals. mRS indicates modified Rankin Scale.

Figure 3

Kaplan‐Meier survival curves after index stroke for 3‐month survivors (3‐month mRS 0‐2 vs 3, 4, 5), for (A) all ischemic strokes, (B) treatable major strokes potentially eligible for thrombolysis/thrombectomy, (C) AF‐related strokes, and (D) lacunar strokes. Because there were few patients with 3‐month mRS>2 for the lacunar group, we compared mRS 0 to 2 vs >2. P‐values from log‐rank test for each group are shown. The numbers shown below each panel are all deaths in each time period (Year 0‐1, 1‐2, and so on), over the total number of individuals at risk for that period. AF indicates atrial fibrillation; mRS, modified Rankin Scale.

Figure 4

Proportions of 3‐month ischemic stroke survivors, categorized according to pre‐3‐month mRS, representing (A) cumulative deaths at the end of each poststroke year, (B) new deaths at the end of each poststroke year from causes related and unrelated to the index stroke, and (C) only from non‐stroke‐related causes, for poststroke years 1 through 5. Only patients with known follow‐up status (dead/alive) for a given year are included in the denominator for that year in (A); (B and C) further restrict the denominator to those who were alive at the start of each year. These numbers are shown below (A and C) respectively. Bars (solid for all‐cause, dashed for stroke‐related deaths) represent 95% confidence intervals. mRS, indicates modified Rankin Scale.