Recombinant Tissue Plasminogen Activator for Acute Ischemic Stroke: An Updated Systematic Review and Meta-Analysis

Study Questions:

What is the overall effect of intravenous recombinant tissue plasminogen activator (rt-PA) when given up to 6 hours after stroke for important early and late outcomes?


The investigators searched for randomized trials of intravenous rt-PA versus control given within 6 hours of onset of acute ischemic stroke up to March 30, 2012. They estimated summary odds ratios (ORs) and 95% confidence intervals (CIs) in the primary analysis for prespecified outcomes within 7 days and at the final follow-up of all patients treated up to 6 hours after stroke.


In up to 12 trials (7,012 patients), rt-PA given within 6 hours of stroke significantly increased the odds of being alive and independent (modified Rankin Scale [mRS], 0-2) at final follow-up (1,611/3,483 [46.3%] vs. 1,434/3,404 [42.1%]; OR, 1.17; 95% CI, 1.06-1.29; p = 0.001), absolute increase of 42 (19-66) per 1,000 people treated, and favorable outcome (mRS, 0-1) absolute increase of 55 (95% CI, 33-77) per 1,000. The benefit of rt-PA was greatest in patients treated within 3 hours (mRS, 0-2; 365/896 [40.7%] vs. 280/883 [31.7%]; 1.53; 1.26-1.86; p < 0.0001), absolute benefit of 90 (46-135) per 1,000 people treated, and mRS 0-1 (283/896 [31.6%] vs. 202/883 [22.9%]; 1.61; 1.30-1.90; p < 0.0001), absolute benefit 87 (46-128) per 1,000 treated. Numbers of deaths within 7 days were increased (250/2,807 [8.9%] vs. 174/2,728 [6.4%]; 1.44; 1.18-1.76; p = 0.0003), but by final follow-up the excess was no longer significant (679/3,548 [19.1%] vs. 640/3,464 [18.5%]; 1.06; 0.94-1.20; p = 0.33). Symptomatic intracranial hemorrhage (272/3,548 [7.7%] vs. 63/3,463 [1.8%]; 3.72; 2.98-4.64; p < 0.0001) accounted for most of the early excess deaths. Patients older than 80 years achieved similar benefit to those ages 80 years or younger, particularly when treated early.


The authors concluded that intravenous rt-PA increased the proportion of patients who were alive and independent at final follow-up.


This systemic review suggests that intravenous rt-PA increased the proportion of patients who were alive with favorable outcome and alive and independent at final follow-up. The analysis strengthens previous evidence to treat patients as early as possible after acute ischemic stroke, although some patients might benefit up to 6 hours after stroke. The key message from contemporary trials and the meta-analysis is that many eligible patients from subgroups excluded by the current drug labeling may benefit from rt-PA. Every stroke patient should, therefore, be evaluated as a candidate for thrombolysis and managed as a medical emergency irrespective of age, severity, and clinical presentation.

Clinical Topics: Dyslipidemia, Lipid Metabolism

Keywords: Thrombolytic Therapy, Stroke, Intracranial Hemorrhages, Follow-Up Studies, Cardiology, Cardiovascular Diseases, Fibrinolytic Agents, Tissue Plasminogen Activator

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