Argatroban anticoagulation in patients with acute ischemic stroke (ARGIS-1) - A randomized, placebo-controlled safety study

Background and Purpose-Direct thrombin inhibitors, including argatroban, represent an anticoagulant class distinct from heparins. We investigated the safety of 2 levels of argatroban anticoagulation in acute ischemic stroke. Methods-This multicenter, randomized, double-blinded, placebo-controlled study included 171 patients with acute (less than or equal to12 hours from onset) stroke and National Institutes of Health Stroke Scale (NIHSS) scores of 5 to 22. Patients received continuous intravenous argatroban (100 mug/kg bolus) at 3 mug/kg per minute (n=59) or 1 mug/kg per minute (n=58), respectively, adjusted to target activated partial thromboplastin times (aPTTs) 2.25X and 1.75X baseline or placebo (n=54) for 5 days. The primary outcome was symptomatic intracranial hemorrhage (ICH) at 30 days. Results-Baseline characteristics including neurologic deficits (median NIHSS score 9) were comparable between groups. Argatroban at mean doses of 2.7 and 1.2 mug/kg per minute increased aPTTs significantly (P<0.001), with mean aPTTs at or near target values throughout infusion. Symptomatic ICH was not significantly different between groups (high-dose argatroban, 5.1%; low-dose argatroban, 3.4%; placebo, 0%; P >= 0.18), with 3 events during argatroban infusion and 2 events >= 7 days after stopping infusion. No significant between-group differences occurred in asymptomatic ICH (7 events), major systemic hemorrhage (no event), or 90-day mortality (13.4% overall). Conclusions-In this first North American randomized, double-blinded, placebo-controlled study of direct thrombin inhibition in acute ischemic stroke, argatroban at each dose evaluated significantly prolonged aPTTs without increasing ICH or major bleeding. These results suggest that argatroban provides safe anticoagulation in acute ischemic stroke, warranting future studies powered to evaluate its efficacy and more precisely estimate event rates.