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Background: Intravenous thrombolysis with alteplase within a time window up to 4.5 h is the only approved pharmacological treatment for acute ischemic stroke. We studied whether acute ischemic stroke patients with penumbral tissue identified on magnetic resonance imaging 4.5-9 h after symptom onset benefit from intravenous thrombolysis compared to placebo., Methods: Acute ischemic stroke patients with salvageable brain tissue identified on a magnetic resonance imaging were randomly assigned to receive standard dose alteplase or placebo. The primary end point was disability at 90 days assessed by the modified Rankin scale, which has a range of 0-6 (with 0 indicating no symptoms at all and 6 indicating death). Safety end points included death, symptomatic intracranial hemorrhage, and other serious adverse events., Results: The trial was stopped early for slow recruitment after the enrollment of 119 (61 alteplase, 58 placebo) of 264 patients planned. Median time to intravenous thrombolysis was 7 h 42 min. The primary endpoint showed no significant difference in the modified Rankin scale distribution at day 90 (odds ratio alteplase versus placebo, 1.20; 95% CI, 0.63-2.27, P = 0.58). One symptomatic intracranial hemorrhage occurred in the alteplase group. Mortality at 90 days did not differ significantly between the two groups (11.5 and 6.8%, respectively; P = 0.53)., Conclusions: Intravenous alteplase administered between 4.5 and 9 h after the onset of symptoms in patients with salvageable tissue did not result in a significant benefit over placebo. (Supported by Boehringer Ingelheim, Germany; ISRCTN 71616222).

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.

Background and Purpose: Approved use of intravenous alteplase for ischemic stroke offers net benefit. Pooled randomized controlled trial analysis suggests additional patients could benefit but others be harmed with treatment initiated beyond 4·5 h after stroke onset. We proposed prognostic scoring methods to identify a strategy for patient selection., Methods: We selected 500 patients treated by intravenous alteplase and 500 controls from Virtual International Stroke Trials Archive, matching modified Rankin score outcomes to those from pooled randomized controlled trial 4·5-6 h data. We ranked patients by prognostic score. We chose limits to optimize our sample for a net treatment benefit significant at P = 0·01 by Cochran-Mantel-Haenszel test and by ordinal regression. For validation, we had these applied to the pooled randomized controlled trial data for 4·5-6 h, testing for net benefit by Cochran-Mantel-Haenszel test, ordinal regression, and also by dichotomized outcomes: modified Rankin score 0-1, mortality and parenchymal hemorrhage type 2 bleeds. All analyses were adjusted for age and National Institutes of Health Stroke Scale., Results: In the training dataset, limits of 56-95 on a prognostic score retained 714 patients in whom there was net benefit significant at P = 0·01. When applied to the 1120 patients in the pooled randomized controlled trial 4·5-6 h dataset, score limits of 56-95 retained 711 patients and gave odds ratio for improved modified Rankin score distribution of 1·13, 95% confidence interval 0·87-1·47, Cochran-Mantel-Haenszel P = 0·89. More patients achieved modified Rankin score 0-1 (odds ratio 1·44, 1·02-2·05, P = 0·04) but mortality and parenchymal hemorrhage type 2 bleeds were increased: odds ratio 1·56, 1·01-2·40, P = 0·04; odds ratio 15·6, 3·7-65·8, P = 0·0002, respectively., Conclusion: Selection of patients between 4·5 and 6 h based on simple clinical measures failed to deliver a population in whom the alteplase effect would be safe and effective., (© 2013 The Authors. International Journal of Stroke © 2013 World Stroke Organization.)

Background: Safe Implementation of Thrombolysis in Stroke-Non-European Union World was a multinational, prospective, open, monitored, observational study of intravenous alteplase as thrombolytic therapy in clinical practice. Safe Implementation of Thrombolysis in Stroke-Non-European Union World was required to assess the safety of alteplase in an Asian population by comparison with results from the European Safe Implementation of Thrombolysis in Stroke-Monitoring Study and pooled results from randomized controlled trials., Aims And/or Hypothesis: To evaluate the efficacy and safety of intravenous alteplase (0·9 mg/kg) as thrombolytic therapy within three-hours of onset of acute ischaemic stroke in an Asian population., Methods: The 591 patients included were treated at 48 centers in four countries (South Korea, China, India, and Singapore) between 2006 and 2008. Primary outcomes were symptomatic (deterioration in National Institutes of Health Stroke Scale score ≥4 or death within the first 24 h) intracerebral haemorrhage type 2 22-36 h after the thrombolysis and mortality at three-month follow-up. The secondary outcome was functional independence (modified Rankin Scale score 0-2) at three-months. Results were compared with those from Safe Implementation of Thrombolysis in Stroke-Monitoring Study (n = 6483) and pooled results of patients (n = 415) who received intravenous alteplase (0·9 mg/kg) zero- to three-hours from onset of stroke symptoms in four randomized controlled trials (National Institute of Neurological Disorders and Stroke A and B, Altephase Thrombolysis for Acute Noninterventional Therapy in Ischaemic Stroke, and European Cooperative Acute Stroke Study II)., Results: Results are presented as Safe Implementation of Thrombolysis in Stroke-Non-European Union World vs. Safe Implementation of Thrombolysis in Stroke-Monitoring Study vs. pooled randomized controlled trials. Median age was 64 vs. 68 vs. 70 years, National Institutes of Health Stroke Scale score at baseline was 12 vs. 12 vs. 13, time from stroke onset to treatment was 130 vs. 140 vs. 135 mins, and females were 36·4% vs. 39·8% vs. 41·2%. Main outcomes (proportion of patients and 95% confidence intervals) were symptomatic intracerebral haemorrhage: 1·9% (1·1-3·3) vs. 1·7% (1·4-2·0) vs. 3·1% (1·8-5·3); mortality: 10·2% (8·0-12·9) vs. 11·3% (10·5-12·1) vs. 16·4% (13·1-20·3); and functional independence: 62·5% (58·5-66·4) vs. 54·8% (53·5-56·0) vs. 50·1% (45·3-54·9) at three-months. Adjusted odds ratio (95% confidence intervals) between Safe Implementation of Thrombolysis in Stroke-Non-European Union World and Safe Implementation of Thrombolysis in Stroke-Monitoring Study, and between Safe Implementation of Thrombolysis in Stroke-Non-European Union World and the pooled trials were 1·83 (0·89-3·77; P = 0·1156) and 0·63 (0·19-2·07; P = 0·4470) for symptomatic intracerebral haemorrhage, 0·90 (0·64-1·25; P = 0·5092) and 0·93 (0·52-1·64; P = 0·7915) for mortality at three-months, and 1·57 (1·25-1·96; P < 0·0001) and 1·35 (0·91-2·00; P = 0·1325) for functional independence., Conclusions: These data demonstrate the safety and efficacy of the standard dose of intravenous alteplase (0·9 mg/kg) in an Asian population, as previously observed in the European population studied in Safe Implementation of Thrombolysis in Stroke-Monitoring Study and the populations in pooled randomized controlled trials, when used in routine clinical practice within three-hours of stroke onset. The findings should encourage wider use of thrombolytic therapy in Asian countries for suitable patients treated in stroke centers., (© 2012 The Authors. International Journal of Stroke © 2012 World Stroke Organization.)

Background: Clinical trials for acute ischemic stroke treatment require large numbers of participants and are expensive to conduct. Methods that enhance statistical power are therefore desirable., Aims: We explored whether this can be achieved by a measure incorporating both early and late measures of outcome (e.g. seven-day NIH Stroke Scale combined with 90-day modified Rankin scale)., Methods: We analyzed sensitivity to treatment effect, using proportional odds logistic regression for ordinal scales and generalized estimating equation method for global outcomes, with all analyses adjusted for baseline severity and age. We ran simulations to assess relations between sample size and power for ordinal scales and corresponding global outcomes. We used R version 2·12·1 (R Development Core Team. R Foundation for Statistical Computing, Vienna, Austria) for simulations and SAS 9·2 (SAS Institute Inc., Cary, NC, USA) for all other analyses., Results: Each scale considered for combination was sensitive to treatment effect in isolation. The mRS90 and NIHSS90 had adjusted odds ratio of 1·56 and 1·62, respectively. Adjusted odds ratio for global outcomes of the combination of mRS90 with NIHSS7 and NIHSS90 with NIHSS7 were 1·69 and 1·73, respectively. The smallest sample sizes required to generate statistical power ≥80% for mRS90, NIHSS7, and global outcomes of mRS90 and NIHSS7 combined and NIHSS90 and NIHSS7 combined were 500, 490, 400, and 380, respectively., Discussion: When data concerning both early and late outcomes are combined into a global measure, there is increased sensitivity to treatment effect compared with solitary ordinal scales. This delivers a 20% reduction in required sample size at 80% power. Combining early with late outcomes merits further consideration., (© 2013 The Authors. International Journal of Stroke © 2013 World Stroke Organization.)