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Randomized, Multicenter Trial of ARTSS-2 (Argatroban With Recombinant Tissue Plasminogen Activator for Acute Stroke)
Andrew D Barreto1, Gary A Ford2, Loren Shen2
1From the Department of Neurology (A.D.B., L.S.), Center for Clinical Research and Evidence-Based Medicine (A.D.B., C.P., J.T.), and Division of Clinical and Translational Sciences (DCTS), Department of Internal Medicine (C.C., M.H.R.), McGovern Medical School at The University of Texas Health Science Center at Houston; Newcastle Clinical Trials Unit (NCTU), Newcastle University, United Kingdom (G.A.F.); Division of Medical Sciences, Oxford University, and Oxford University Hospitals NHS Foundation Trust, Headley Way, United Kingdom (G.A.F.); and Clinical Innovation and Research Institute, Memorial Hermann Hospital, Texas Medical Center, Houston (J.C.G.). andrew.d.barreto@uth.tmc.edu.
Background And Purpose:
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.
Methods:
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).
Results:
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.
Conclusions:
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.
Clinical Trial Registration:
URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01464788.
