Effects of alteplase for acute stroke according to criteria defining the European Union and United States marketing authorizations: Individual-patient-data meta-analysis of randomized trials

Werner Hacke, Patrick Lyden, Jonathan Emberson, Colin Baigent, Lisa Blackwell , Gregory W. Albers, Erich Bluhmki, Thomas G Brott, Geoffrey R. Cohen, Stephen M. Davis, Geoffrey A. Donnan, James C. Grotta, George Howard, Markku Kaste, Masatoshi Koga, Rüdiger von Kummer, Maarten G. Lansberg, Richard I Lindley, Jean Marc Olivot, Mark ParsonsPeter Sandercock, Danilo Toni, Kazunori Toyoda , Nils Wahlgren, Joanna Wardlaw, William Whiteley, Gregory J. del Zoppo, Kennedy R. Lees

Research output: Contribution to journalArticlepeer-review

Abstract

Background: The recommended maximum age and time window for intravenous alteplase treatment of acute ischemic stroke (AIS) each differ between Europe (EU) and United States (US).
Aims: To compare the effects of alteplase according to cohorts defined by current EU or US marketing approval labels, or by hypothetical revisions of the labels that would remove the EU upper age limit or extend the US treatment time window to 4.5 hours.
Methods: Individual-patient-data meta-analysis of 8 randomized trials of intravenous alteplase (0.9 mg/kg) versus control for AIS. Outcomes included excellent outcome (modified Rankin score [mRS] 0-1) at 3-6 months, the distribution of mRS, symptomatic intracerebral hemorrhage, and 90 day mortality.
Results: Among 2449/6136 (40%) patients who met the current EU label and 3491 (57%) patients who met the age-revised label, alteplase increased the odds of mRS 0-1 (odds ratio 1.42, 95% CI 1.21−1.68 and 1.43, 1.23−1.65, respectively) but not in those outside the age-revised label (1.06, 0.90−1.26). By 90 days, there was no increased mortality in the current and age-revised cohorts (hazard ratios 0.98, 95% CI 0.76−1.25 and 1.01, 0.86–1.19 respectively) but mortality remained higher outside the age-revised label (1.19, 0.99–1.42). Similarly, among 1174/6136 (19%) patients who met the current US approval and 3326 (54%) who met a 4.5-hour revised approval, alteplase increased the odds of mRS 0-1 (OR 1.55, 1.19−2.01 and 1.37, 1.17−1.59, respectively) but not for those outside the 4.5-hour revised approval (1.14, 0.97−1.34). By 90 days no increased mortality remained for the current and 4.5-hour revised label cohorts (hazard ratios 0.99, 0.77−1.26 and 1.02, 0.87–1.20 respectively) but mortality remained higher outside the 4.5-hour revised approval (1.17, 0.98–1.41).
Conclusions: An age-revised EU label or 4.5-hour-revised US label would each increase the number of patients deriving net benefit from alteplase by 90 days after acute ischemic stroke, without excess mortality.
Original languageEnglish
JournalInternational Journal of Stroke
Early online date24 Nov 2017
DOIs
Publication statusE-pub ahead of print - 24 Nov 2017

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