Reperfusion Benefits for Stroke Are Consistent Across Time Windows


The EXTEND and EPITHET trials selected patients by perfusion mismatch rather than the less sensitive noncontrast computed tomography, the findings providing reassurance of consistency for thrombolysis-induced reperfusion.

Bruce C. V. Campbell, PhD, professorial fellow, Department of Neurology, Royal Melbourne Hospital

Bruce C. V. Campbell, PhD

Alteplase had a consistent treatment effect and strong benefits of reperfusion in perfusion mismatch-selected patients throughout the 4.5- to 6-hour, the 6- to 9-hour, and wake-up stroke windows (within 9 hours of the midpoint of sleep for patients who woke with stroke symptoms) without a differential risk in symptomatic hemorrhage.

The EXTEND (Extending the Time for Thrombolysis in Emergency Neurological Deficits; NCT01580839) and EPITHET (Echoplanar Imaging Thrombolytic Evaluation Trial; NCT00238537) trials previously demonstrated the benefit of intravenous alteplase in reducing disability up to 9 hours after stroke, but did not analyze the differential in benefits across different time windows.1

This new meta-analysis, published in JAMA Neurology, of the EXTEND and EPITHET randomized clinical trials (RCTs) found that reperfusion was associated with improved functional outcome (common odds ratio [cOR], 7.7; 95% CI, 4.6–12.8; p <.001) over all time windows, in at least 1 modified Rankin scale (mRS) category.

Categories included early neurologic improvement, defined as an 8-point reduction on the National Institute of Health Stroke Scale (NIHSS) from baseline assessed pretreatment or reaching 0–1 on day 3; functional independence, defined as an mRS score of 0–2; or excellent functional outcome, defined as an mRS score of 0–1.

Bruce C. V. Campbell, PhD, professorial fellow, Department of Neurology, Royal Melbourne Hospital, and principal author of the study, and colleagues stated that “this study has demonstrated strong and consistent benefits of reperfusion in patients with favorable perfusion imaging in each of the... strata of onset-to-treatment time in the EXTEND and EPITHET trials... the benefits of intravenous alteplase are also likely to be consistent across the strata in patients with perfusion mismatch.”

READ MORE: Stroke Patients Who Present Outside of Thrombolysis Treatment Window May Be Targets for Reperfusion Therapy

Improved functional outcome in at least one mRS category was also statistically significant in the 4.5- to 6-hour window (cOR, 6.64; 95% CI, 2.62–16.86; P <.001), the 6- to 9-hour window (cOR, 3.99; 95% CI, 1.06–15.08; P <.001), and the wake-up stroke window (cOR, 11.66; 95% CI, 5.59–24.34; P <.001). There was no statistical significance of associations between beneficial effects of reperfusion and windows of time (P = .63).

Symptomatic hemorrhage occurred in 5.9% (n = 3) of the 4.5- to 6-hour group, 7.1% (n = 2) of the 6- to 9-hour group, and 5.5% (n = 4) in the wake-up stroke group, all treated with alteplase, with a fisher p value of .91 showing no difference between time windows.

“EXTEND consolidates the concept of determining treatment eligibility based on physiological imaging rather than noncontrast CT and the clock. Perfusion-based selection, as deployed in EXTEND, or magnetic resonance imaging-based selection... offer alternative imaging selection strategies that should be widely deployed for patient benefit. These findings significantly advance stroke treatment, but at the expense of additional complexity that will likely require review of systems of care,” Enrique C. Leira, MD and Weith W. Muir, MD commented about the trials in a related editorial.2

Campbell and colleagues analyzed data of patients from the EXTEND and EPITHET studies. Reperfusion was assessable in 92% (n = 270) of patients—51% (n = 68) in the alteplase group and 28% (n = 38) in the placebo reperfused group. In the reperfusion group, the median age of patients was 76 years (interquartile range [IQR], 66–81) and the median National Institutes of Health Stroke Scale (NIHSS) score was 10 (IQR, 7–15). In the placebo group, median age was 74 years (IQR, 64.5–81) and the median NIHSS score was 12 (IQR, 8.0–17.5).

These data are limited by the fact that true onset time of stroke was often unknown, especially in patients with wake-up stroke. However, all patients included were ineligible for thrombolysis using the standard criterion of within 4.5 hours of last well known.

Campbell and colleagues concluded the study by writing, “These data provide support to implementation of intravenous thrombolysis in patients who fall within the full-time window up to 9 hours since last known well or midpoint of sleep... Further trials will test whether intravenous thrombolysis can benefit patients with perfusion mismatch up to 24 hours after the time they were last known to be well.”

1. Campbell BCV, Ma H, Parsons MW, et. Al. Association of reperfusion after thrombolysis with clinical outcome across the 4.5-to-9-hours and wake-up stroke time window: A meta-analysis of the EXTEND and EPITHET randomized clinical trials. JAMA Neurol. Published online Nov 2, 2020. doi: 10.1001/jamaneurol.2020.4123
2. Leira EC, Muir KW. EXTEND trial: Towards a more inclusive but complex thrombolysis. Stroke. Published online August 6, 2020. doi: 10.1161/STROKEAHA.119.026249
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