| Summary: | <h4>Background</h4> <p>Thrombolytic therapy for acute ischemic stroke with lower than standard dose of intravenous alteplase may improve recovery with reduced risk of intracerebral hemorrhage (ICH).</p> <h4>Methods</h4> <p>Using a 2-by-2 quasi-factorial open label design, we randomly assigned 3310 patients eligible for thrombolytic therapy (median age 67 years, 63% Asian) within 4.5 hours of stroke onset, to test for noninferiority of low-dose (0.6mg/kg) compared with standard-dose (0.9mg/kg) intravenous alteplase. The trial included 940 patients co-randomized to intensive versus guideline-recommended blood pressure control. The primary outcome was death or disability at 90 days (scores 2 to 6 on the modified Rankin scale [mRS]; range 0, no symptoms, to 6, death). Secondary objectives included tests of superiority for centrally-adjudicated symptomatic ICH and noninferiority in ordinal analysis of the mRS (testing for improvement across scale categories). </p> <h4>Results</h4> <p>The primary outcome occurred in 855 of 1607 (53.2%) participants in low-dose and in 817 of 1599 (51.1%) in standard-dose group (odds ratio, 1.09; 95% confidence interval [CI], 0.95-1.25; exceeding noninferiority margin of 1.14, P=0.51 for noninferiority). Low-dose alteplase was non-inferior in the ordinal analysis of mRS (unadjusted common odds ratio 1.00; 95% CI, 0.89-1.13; P=0.04 for noninferiority). Major symptomatic ICH occurred in 1.0% and 2.1% in the low-dose and standard-dose groups (P=0.01); fatal ICH events occurred in 0.5% and 1.5% (P=0.01). Mortality at 90 days did not differ significantly (8.5% vs. 10.3%, P=0.07).</p> <h4>Conclusions</h4> <p>This trial of predominantly Asian patients with acute ischemic stroke did not demonstrate noninferiority of low-dose alteplase compared with standard-dose alteplase in death and disability at 90 days. There were significantly fewer symptomatic intracerebral hemorrhages with low-dose alteplase</p>
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