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

Abstract

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.

Keywords: acute stroke; adjunctive therapy; anticoagulation; argatroban; randomized controlled trial; thrombin inhibitor; thrombolysis.

Figure 1

A) Patient flow diagram. One patient was lost-to-follow-up for 90-day assessment. B) Box-whisker plot of absolute aPTT changes (seconds) over the 48 hour infusion. Goal aPTT = 1.75 and 2.25 times the patient’s own baseline value in the low and high-dose argatroban arms, respectively.

Figure 2

A) Distribution of 90-day modified Rankin Scale scores. B) Graphical depiction of Bayesian results. The neutral prior is centered at Relative Risk=1.0 indicating a 50:50 chance of argatroban+rt-PA superiority or inferiority. The area under the curve located on the right-hand side of RR=1.0 for each posterior, represents the probability that combination is superior (i.e., RR >1.0) to rt-PA-alone (67%-low; 74%-high and 79%-low+high dose). Note: the x-axis is set to logarithmic scale. C) Forest-plots of i) 90-day excellent clinical outcome; and ii) symptomatic ICH within 48-hours of rt-PA, analyzed using frequentist approach and adjusted for stratification variables.