Adjunctive treatment with argatroban or eptifibatide does not improve post-stroke functional outcomes

1. In this randomized controlled trial, among ischemic stroke patients treated with intravenous thrombolysis, it was found that adjunctive intravenous argatroban or eptifibatide did not reduce disability 90 days post-stroke compared with placebo.

2. Symptomatic intracranial hemorrhage did not occur more frequently among patients treated with adjunctive intravenous argatroban or eptifibatide. 

Evidence Rating Level: 1 (Excellent)

Study Rundown: Cerebral reperfusion via intravenous thrombolysis is currently the mainstay of therapy for ischemic stroke. In recent years, numerous studies have explored the efficacy of combining thrombolysis with intravenous antithrombotic agents. Among these studies are several promising effects of combining thrombolysis with either argatroban, an anticoagulant, or eptifibatide, an antiplatelet. However, other trials indicate that adding an antithrombotic agent increases bleeding or provides no additional benefit. The present trial assessed the efficacy and safety of adjunctive intravenous argatroban or eptifibatide compared with placebo among ischemic stroke patients treated with intravenous thrombolysis. Compared to placebo, argatroban or eptifibatide resulted in no improvement in disability or incidence of symptomatic intracranial hemorrhage, but the proportion of patients who died within 90 days was higher in the argatroban group. The study was limited by its single-blind design. Additionally, as a result of the study’s response-adaptive randomization protocol, which favored the treatment group showing greater benefit starting from the 150th enrollment, only a small number of patients were assigned to the argatroban group. Finally, the use of thrombectomy in patients with large-artery occlusions, who may also have benefited the most from enhanced medical reperfusion, could have obscured any benefits of adjunctive antithrombotic agents. Nevertheless, these findings provide novel insights regarding whether the addition of antithrombotic therapy to the standard approach of intravenous thrombolysis for ischemic stroke provides any additional benefit.

Click to read the study in NEJM

In-Depth [randomized controlled trial]: This phase three, three-group randomized-controlled trial compared the effects of adjunctive intravenous argatroban or eptifibatide with those of placebo on post-stroke disability, incidence of intracranial hemorrhage and mortality within 90 days in patients with ischemic stroke treated with intravenous thrombolysis. Patients 18 years or older with a baseline National Institutes of Health Stroke Scale score of six or more who received intravenous thrombolysis within three hours of symptom onset and could receive adjuvant therapy or a placebo within 75 minutes of thrombolysis initiation were included. A total of 514 patients underwent randomization, with the trial being stopped for futility following an interim analysis, which showed that both treatment groups had predictive probabilities of success of less than 0.001. The mean 90-day utility-weighted modified Rankin scale score was 5.2 in the argatroban group (standard deviation [SD], 3.7), 6.3 in the eptifibatide group (SD, 3.2), and 6.8 in the placebo group (SD, 3.0), with the posterior probability that argatroban was better than placebo being 0.002 and the probability that eptifibatide was better than placebo being 0.041. The incidence of symptomatic intracranial hemorrhage was 4% in the argatroban group, 3% in the eptifibatide group, and 2% in the placebo group. Patients in the argatroban group had lower odds of favorable outcomes than those in the placebo group (odds ratio, 0.50; 95% Confidence Interval [CI], 0.28 to 0.90), whereas there was no substantial difference between the eptifibatide and placebo groups (odds ratio, 0.80; 95% CI, 0.55 to 1.16). In summary, adjunctive intravenous argatroban or eptifibatide did not reduce neurologic disability or incidence of symptomatic intracranial hemorrhage 90 days post-stroke compared with placebo, but argatroban was associated with higher 90-day mortality compared to eptifibatide and placebo.

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