Alteplase for Acute Ischemic Stroke and Subgroups | Journal Scan

Study Questions:

What are the factors that modify the benefits (improvement in functional outcome at 6 months) or hazards (early symptomatic intracranial hemorrhage defined as those events occurring within 7 days; or early death, defined as those occurring within 7 days) when treated with alteplase for acute ischemic stroke?


The IST-3 (Third International Stroke Trial) was an international randomized trial of the intravenous recombinant tissue-plasminogen activator (r-tPA) alteplase (0.9 mg/kg) versus control in 3,035 (1,515 vs. 1,520) patients. The investigators analyzed the effect of r-tPA on 6-month functional outcome, early death, and symptomatic intracranial hemorrhage (both ≤7 days). The authors tested for any differences in treatment effect between subgroups by a test of interaction. The 13 protocol prespecified subgroups were time to randomization, age, sex, stroke subtype, atrial fibrillation, early ischemic change (clinician and expert panel), prior antiplatelet use, stroke severity, diastolic and systolic blood pressure at randomization, center’s thrombolysis experience, and trial phase. Analyses were adjusted for key baseline prognostic factors.


There were no significant interactions in the subgroups analyzed that were consistent across all three outcomes. Treatment with r-tPA increased the odds of symptomatic intracranial hemorrhage by a greater amount in patients taking prior antiplatelets than those who were not (p = 0.019 for test of interaction), but had no clear detrimental effect on functional outcome at 6 months in this group (p = 0.781 for test of interaction).


The authors concluded that among the types of patients in the IST-3, this secondary analysis did not identify any subgroups for whom treatment should be avoided.


This study suggests that the risks and benefits of stroke thrombolysis were consistent across a wide range of patient characteristics, with no clearly significant (p < 0.01) interactions between r-tPA and baseline clinical characteristics. These results do not provide sufficient evidence to exclude any particular category of patient included in IST-3 from treatment in the future, but perhaps more importantly, suggest that many of the previously suggested contraindications to treatment may not be justified (such as those with a history of diabetes mellitus and prior stroke). If confirmed in future studies, a wider range of patients can be considered for stroke thrombolysis, thus increasing the public health impact of this intervention for those with acute ischemic stroke.

Clinical Topics: Arrhythmias and Clinical EP, Dyslipidemia, Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism

Keywords: Stroke, Intracranial Hemorrhages, Tissue Plasminogen Activator, Thrombolytic Therapy, Atrial Fibrillation, Blood Pressure, Diabetes Mellitus, Random Allocation

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