03533nas a2200469   4500000000100000008004100001260001600042100001700058700001800075700002000093700002200113700001800135700001900153700002400172700002000196700001900216700001700235700001800252700001900270700001800289700001700307700001900324700001700343700001800360700001700378700001900395700002100414700002100435700002100456700001600477700002000493700001800513700002100531700002200552700001700574700005700591245019600648300001200844490000700856520218600863022001403049       2018                            d  c514654714601 aParsons Mark1 aDavis Stephen1 aDonnan Geoffrey1 aEmberson Jonathan1 aBaigent Colin1 aBlackwell Lisa1 avon Kummer Rüdiger1 aLindley Richard1 aWardlaw Joanna1 aHacke Werner1 aLyden Patrick1 aAlbers Gregory1 aBluhmki Erich1 aBrott Thomas1 aCohen Geoffrey1 aGrotta James1 aHoward George1 aKaste Markku1 aKoga Masatoshi1 aLansberg Maarten1 aOlivot Jean-Marc1 aSandercock Peter1 aToni Danilo1 aToyoda Kazunori1 aWahlgren Nils1 aWhiteley William1 aDel Zoppo Gregory1 aLees Kennedy1 aStroke Thrombolysis Trialists’ Collaborators Group00aEffects 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.  a175-1890 v133 a<p>Background The recommended maximum age and time window for intravenous alteplase treatment of acute ischemic stroke differs between the Europe Union and United States. Aims We compared the effects of alteplase in cohorts defined by the current Europe Union or United States marketing approval labels, and by hypothetical revisions of the labels that would remove the Europe Union upper age limit or extend the United States treatment time window to 4.5 h. Methods We assessed outcomes in an individual-patient-data meta-analysis of eight randomized trials of intravenous alteplase (0.9 mg/kg) versus control for acute ischemic stroke. Outcomes included: excellent outcome (modified Rankin score 0-1) at 3-6 months, the distribution of modified Rankin score, symptomatic intracerebral hemorrhage, and 90-day mortality. Results Alteplase increased the odds of modified Rankin score 0-1 among 2449/6136 (40%) patients who met the current European Union label and 3491 (57%) patients who met the age-revised label (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, alteplase increased the odds of modified Rankin score 0-1 among 1174/6136 (19%) patients who met the current US approval and 3326 (54%) who met a 4.5-h revised approval (odds ratio 1.55, 1.19-2.01 and 1.37, 1.17-1.59, respectively), but not for those outside the 4.5-h revised approval (1.14, 0.97-1.34). By 90 days, no increased mortality remained for the current and 4.5-h 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-h revised approval (1.17, 0.98-1.41). Conclusions An age-revised European Union label or 4.5-h-revised United States label would each increase the number of patients deriving net benefit from alteplase by 90 days after acute ischemic stroke, without excess mortality.</p>  a1747-4949