1. Alteplase (recombinant tissue plasminogen activator, or rtPA) administration within 4.5 hours hours following the onset of an ischemic stroke improves the odds of good stroke outcomes regardless of age or stroke severity, with greater proportional benefits seen with earlier treatment.
2. Administration of alteplase carried an increased risk of fatal intracranial hemorrhage within the first few days following treatment.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Intravenous administration of alteplase within 4.5 hours following the onset of an ischemic stroke has been shown to be beneficial in many patients. Controversy exists, however, regarding alteplase treatment either within 3 or 4.5 hours, after 4.5 hours, in patients greater than 80 years of age, or in patients with mild or severe strokes. This study aimed to clarify these controversies by utilizing a meta-analysis that combined data from several large randomized trials comparing alteplase with placebo or open control.
The results showed that alteplase can be used in patients of any age group or stroke severity up to 4.5 hours after ischemic stroke onset with greater proportional benefits seen with earlier treatment. However, treatment with alteplase also led to increased risks of fatal intracranial hemorrhage within the first few days following treatment. Strengths of this analysis include its large study population as well as that individual data sets could be extracted for many of these patients. Additionally, the large number of patients over the age of 80 allowed for better representation of the general population and comparison to treatment in patients under 80 years of age. A drawback to this study is that the estimates of intracranial hemorrhage may be exaggerated due to broad definition utilized by one of the studies included in the analysis. The authors conclude that despite early increased risks of fatal intracranial hemorrhage, alteplase significantly improves the long-term odds of a good stroke outcome at 3-6 months.
This study was funded by the UK Medical Research Council, British Heart Foundation, University of Glasgow, and University of Edinburgh
Relevant Reading: The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial
In-Depth [meta-analysis]: This meta-analysis included data from 6,756 different patients from nine randomized phase 3 trials. Primary measure of treatment efficacy was the proportion of patients with a good stroke outcome, defined as a modified Rankin Score of 0 or 1 (symptom free or residual symptoms without loss of activity) at 3-6 months. Symptomatic intracranial hemorrhage within 7 days of treatment, fatal intracranial hemorrhage within 7 days, and 90-day mortality were assessed as secondary outcomes.
Overall, 2,110 (31%) of 6,756 patients achieved a good stroke outcome at 3-6 months. Alteplase resulted in greater odds of a good outcome, with earlier treatment resulting in a greater proportional benefit (p=0.016). The time at which alteplase was estimated to have no effect was 6.3 hours (95% Confidence Interval [CI] 5.0-13.8). Alteplase treatment resulted in a good outcome for 259 (32.9%) of 787 patients treated within 3.0 hours vs. 176 (23.1%) of 762 controls (Odds Ration [OR] 1.75, 95% CI 1.35-2.27); 485 (35.3%) of 1,375 patients treated between 3.0-4.5 hours vs. 432 (30.1%) of 1,437 controls (OR 1.26, 95% CI 1.05-1.51); and 401 (32.5%) of 1,229 patients treated greater than 4.5 hours vs. 357 (30.6%) of 1,166 controls (OR 1.15, 95% CI 0.95-1.40). All treatment benefits were similar regardless of patient age or stroke severity. 231 (6.8%) of 3,391 alteplase patients experienced type 2 parenchymal hemorrhages as compared to 44 (1.3%) of 3,365 controls (OR 5.55, 95% CI 4.01-7.70, p<0.0001) within 7 days, and 91 (2.7%) alteplase patients vs. 13 (0.4%) controls experienced fatal intracranial hemorrhage (OR 7.14, 95% CI 3.98-12.79, p<0.0001). The increase in risk of fatal intracranial hemorrhage was similar regardless of delay in treatment, age, or stroke severity.
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