Argatroban anticoagulation in patients with acute ischemic stroke (ARGIS-1): a randomized, placebo-controlled safety study.
OBJECTIVE
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 (< or =12 hours from onset) stroke and National Institutes of Health Stroke Scale (NIHSS) scores of 5 to 22. Patients received continuous intravenous argatroban (100 microg/kg bolus) at 3 microg/kg per minute (n=59) or 1 microg/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 microg/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> or =0.18), with 3 events during argatroban infusion and 2 events > or =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.
LaMonte
Marian P
MP
University of Maryland School of Medicine, 22 South Greene St, Room N4W46, Baltimore, MD 21201-1595. mlamonte@umm.edu
Nash
Marshall L
ML
Wang
David Z
DZ
Woolfenden
Andrew R
AR
Schultz
John
J
Hursting
Marcie J
MJ
Brown
Philip M
PM
D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage / Q000627:therapeutic use*; D001120:Arginine / Q000031:analogs & derivatives; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D020300:Intracranial Hemorrhages; D008297:Male; D008875:Middle Aged; D010314:Partial Thromboplastin Time; D010875:Pipecolic Acids / Q000008:administration & dosage / Q000627:therapeutic use*; D020521:Stroke / Q000097:blood / Q000188:drug therapy*; D013449:Sulfonamides; D016019:Survival Analysis
D000925:Anticoagulants; D010875:Pipecolic Acids; D013449:Sulfonamides; D001120:Arginine; C031942:argatroban