Randomized, Multicenter Trial of ARTSS-2 (Argatroban With Recombinant Tissue Plasminogen Activator for Acute Stroke)

• Published in: Stroke (1970) 2017-06, Vol.48 (6), p.1608-1616
• Main Authors: Barreto, Andrew D, Ford, Gary A, Shen, Loren, Pedroza, Claudia, Tyson, Jon, Cai, Chunyan, Rahbar, Mohammad H, Grotta, James C
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Antithrombins - administration & dosage; Antithrombins - adverse effects; Antithrombins - pharmacokinetics; Brain Ischemia - drug therapy; Cerebral Hemorrhage - chemically induced; Drug Therapy, Combination; Female; Fibrinolytic Agents - administration & dosage; Fibrinolytic Agents - pharmacology; Humans; Male; Middle Aged; Outcome Assessment (Health Care) - statistics & numerical data; Pipecolic Acids - administration & dosage; Pipecolic Acids - adverse effects; Pipecolic Acids - pharmacology; Severity of Illness Index; Stroke - drug therapy; Tissue Plasminogen Activator - administration & dosage; Tissue Plasminogen Activator - pharmacology
• ISSN: 0039-2499; 1524-4628
• DOI: 10.1161/strokeaha.117.016720

We conducted a randomized exploratory study to assess safety and the probability of a favorable outcome with adjunctive argatroban, a direct thrombin-inhibitor, administered to recombinant tissue-type plasminogen activator (r-tPA)-treated ischemic stroke patients. Patients treated with standard-dose r-tPA, not receiving endovascular therapy, were randomized to receive no argatroban or argatroban (100 μg/kg bolus) followed by infusion of either 1 (low dose) or 3 μg/kg per minute (high dose) for 48 hours. Safety was incidence of symptomatic intracerebral hemorrhage. Probability of clinical benefit (modified Rankin Scale score 0-1 at 90 days) was estimated using a conservative Bayesian Poisson model (neutral prior probability centered at relative risk, 1.0 and 95% prior intervals, 0.33-3.0). Ninety patients were randomized: 29 to r-tPA alone, 30 to r-tPA+low-dose argatroban, and 31 to r-tPA+high-dose argatroban. Rates of symptomatic intracerebral hemorrhage were similar among control, low-dose, and high-dose arms: 3/29 (10%), 4/30 (13%), and 2/31 (7%), respectively. At 90 days, 6 (21%) r-tPA alone, 9 (30%) low-dose, and 10 (32%) high-dose patients were with modified Rankin Scale score 0 to 1. The relative risks (95% credible interval) for modified Rankin Scale score 0 to 1 with low, high, and either low or high dose argatroban were 1.17 (0.57-2.37), 1.27 (0.63-2.53), and 1.34 (0.68-2.76), respectively. The probability that adjunctive argatroban was superior to r-tPA alone was 67%, 74%, and 79% for low, high, and low or high dose, respectively. In patients treated with r-tPA, adjunctive argatroban was not associated with increased risk of symptomatic intracerebral hemorrhage and provides evidence that a definitive effectiveness trial is indicated. URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01464788.