ARTSS-2 Trial: Argatroban and tPA for Acute Stroke
What are the safety outcomes and probability of a favorable outcome for patients with acute ischemic stroke who are treated with argatroban in addition to recombinant tissue-type plasminogen activator (tPA)?
Patients receiving standard dose tPA for acute ischemic stroke (no endovascular therapy) were randomized (1:1:1) in an exploratory study to receive no argatroban, low-dose argatroban, or high-dose argatroban. Argatroban was administered as a 100 μg/kg intravenous bolus followed by either 1.0 μg/kg/min (low dose) or 3.0 μg/kg/min (high dose) infusion for 48 hours titrated to a target activated partial thromboplastic time of 1.75-2.25 times the baseline. Outcomes were the incidence of symptomatic intracerebral hemorrhage (ICH) and the probability of a clinical benefit as measured using a modified Rankin Scale score (0-1) at 90 days.
Ninety patients were randomized: 29 to tPA alone, 30 to tPA + low-dose argatroban, and 31 to tPA + high-dose argatroban. Rates of symptomatic ICH were similar in all three arms (3/29 [10%], 4/30 [13%], and 2/31 [7%], respectively). At 90 days, modified Rankin Scales of 0-1 were assessed in 6 (21%) of tPA only, 9 (30%) of tPA + low-dose argatroban, and 10 (32%) of tPA + high-dose argatroban patients. The probability that adjunctive argatroban was superior to tPA alone was estimated at 67% for low-dose and 74% for the high-dose protocol.
The authors concluded that in patients treated with tPA for acute ischemic stroke, adjunctive argatroban was not associated with an increased risk of symptomatic ICH and may offer net clinical benefit.
While tPA is a proven effective therapy for patients presenting with acute ischemic stroke, complete recovery occurs in a minority of patients (~1/3). This phase IIb randomized trial suggests safety and potential for benefit with adjunctive use of argatroban. Given the small sample size in this exploratory study, statistical benefit was not demonstrated, but use of Bayesian Poisson modeling suggests a high likelihood of benefit in an adequately powered, larger trial. A larger randomized, controlled trial is needed to prove efficacy and confirm safety before this strategy is used broadly for acute ischemic stroke patients.
Keywords: Anticoagulants, Cerebral Hemorrhage, Myocardial Ischemia, Stroke, Tissue Plasminogen Activator, Vascular Diseases, Aneurysm
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