Effect of Treatment Delay, Age, and Stroke Severity on the Effects of Intravenous Thrombolysis With Alteplase for Acute Ischemic Stroke: A Meta-Analysis of Individual Patient Data From Randomised Trials

Study Questions:

What is the extent to which treatment delay affects the effect of alteplase, and does age or stroke severity affect treatment effects in acute ischemic stroke?


The investigators did a prespecified meta-analysis of individual data from 6,756 patients in nine randomized trials, comparing alteplase with placebo or open control. They included all completed randomized phase 3 trials of intravenous alteplase for treatment of acute ischemic stroke for which data were available. Retrospective checks confirmed that no eligible trials had been omitted. The authors defined a good stroke outcome as no significant disability at 3-6 months, defined by a modified Rankin Score of 0 or 1. Additional outcomes included symptomatic intracranial hemorrhage (defined by type 2 parenchymal hemorrhage within 7 days and, separately, by the SITS-MOST definition of parenchymal type 2 hemorrhage within 36 hours), fatal intracranial hemorrhage within 7 days, and 90-day mortality.


Alteplase increased the odds of a good stroke outcome, with earlier treatment associated with bigger proportional benefit. Treatment within 3 hours resulted in a good outcome for 259 (32.9%) of 787 patients who received alteplase versus 176 (23.1%) of 762 who received control (odds ratio [OR], 1.75; 95% confidence interval [CI], 1.35-2.27); delay of greater than 3 hours, up to 4.5 hours, resulted in good outcome for 485 (35.3%) of 1,375 versus 432 (30.1%) of 1,437 (OR, 1.26; 95% CI, 1.05-1.51); and delay of more than 4.5 hours resulted in good outcome for 401 (32.6%) of 1,229 versus 357 (30.6%) of 1,166 (OR, 1.15; 95% CI, 0.95-1.40). Proportional treatment benefits were similar irrespective of age or stroke severity. Alteplase significantly increased the odds of symptomatic intracranial hemorrhage (type 2 parenchymal hemorrhage definition, 231 [6.8%] of 3,391 vs. 44 [1.3%] of 3,365; OR, 5.55; 95% CI, 4.01-7.70; p < 0.0001; SITS-MOST definition 124 [3.7%] vs. 19 [0.6%], OR, 6.67; 95% CI, 4.11-10.84; p < 0.0001) and of fatal intracranial hemorrhage within 7 days (91 [2.7%] vs. 13 [0.4%]; OR, 7.14; 95% CI, 3.98-12.79; p < 0.0001). The relative increase in fatal intracranial hemorrhage from alteplase was similar irrespective of treatment delay, age, or stroke severity, but the absolute excess risk attributable to alteplase was bigger among patients who had more severe strokes. There was no excess in other early causes of death and no significant effect on later causes of death. Consequently, mortality at 90 days was 608 (17.9%) in the alteplase group versus 556 (16.5%) in the control group (hazard ratio, 1.11; 95% CI, 0.99-1.25; p = 0.07). Taken together, therefore, despite an average absolute increased risk of early death from intracranial hemorrhage of about 2%, by 3-6 months, this risk was offset by an average absolute increase in disability-free survival of about 10% for patients treated within 3 hours and about 5% for patients treated after 3 hours, up to 4.5 hours.


The authors concluded that irrespective of age or stroke severity, and despite an increased risk of fatal intracranial hemorrhage during the first few days after treatment, alteplase significantly improves the overall odds of a good stroke outcome when delivered within 4.5 hours of stroke onset.


The study provides robust evidence for improved odds of a good stroke outcome when treatment is started within 4.5 hours of ischemic stroke, with earlier treatment resulting in bigger proportional and absolute benefits. The proportional benefits were similar for patients ages >80 years compared with younger patients, and for patients with minor or severe strokes compared with other patients. Future studies are indicated to assess the potential independent effect on treatment effect of a range of other characteristics, including sex, blood pressure, and baseline imaging features.

Clinical Topics: Dyslipidemia, Lipid Metabolism

Keywords: Cause of Death, Thrombolytic Therapy, Stroke, Intracranial Hemorrhages, Research Personnel, Blood Pressure, Fibrinolytic Agents, Confidence Intervals, Probability, Tissue Plasminogen Activator

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