Adjunctive Intravenous Argatroban or Eptifibatide for Ischemic Stroke

Abstract

Background: Intravenous thrombolysis is a standard treatment of acute ischemic stroke. The efficacy and safety of combining intravenous thrombolysis with argatroban (an anticoagulant agent) or eptifibatide (an antiplatelet agent) are unclear.

Methods: We conducted a phase 3, three-group, adaptive, single-blind, randomized, controlled clinical trial at 57 sites in the United States. Patients with acute ischemic stroke who had received intravenous thrombolysis within 3 hours after symptom onset were assigned to receive intravenous argatroban, eptifibatide, or placebo within 75 minutes after the initiation of thrombolysis. The primary efficacy outcome, the utility-weighted 90-day modified Rankin scale score (range, 0 to 10, with higher scores reflecting better outcomes), was assessed by means of centralized adjudication. The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours after randomization.

Results: A total of 514 patients were assigned to receive argatroban (59 patients), eptifibatide (227 patients), or placebo (228 patients). All the patients received intravenous thrombolysis (70% received alteplase, and 30% received tenecteplase), and 225 patients (44%) underwent endovascular thrombectomy. At 90 days, the mean (±SD) utility-weighted modified Rankin scale scores were 5.2±3.7 with argatroban, 6.3±3.2 with eptifibatide, and 6.8±3.0 with placebo. The posterior probability that argatroban was better than placebo was 0.002 (posterior mean difference in utility-weighted modified Rankin scale score, -1.51±0.51) and that eptifibatide was better than placebo was 0.041 (posterior mean difference, -0.50±0.29). The incidence of symptomatic intracranial hemorrhage was similar in the three groups (4% with argatroban, 3% with eptifibatide, and 2% with placebo). Mortality at 90 days was higher in the argatroban group (24%) and the eptifibatide group (12%) than in the placebo group (8%).

Conclusions: In patients with acute ischemic stroke treated with intravenous thrombolysis within 3 hours after symptom onset, adjunctive treatment with intravenous argatroban or eptifibatide did not reduce poststroke disability and was associated with increased mortality. (Funded by the National Institute of Neurological Disorders and Stroke; MOST ClinicalTrials.gov number, NCT03735979.).

Figure 1.. Forest Plot of Subgroups According to Utility-Weighted Modified Rankin Scale Score.

Scores on the utility-weighted 90-day modified Rankin scale range from 0 to 10, with higher scores reflecting better outcomes. In all subgroups, the lower limit of the 95% confidence interval for the mean difference in the utility-weighted modified Rankin scale score as compared with placebo was less than 0, which indicates that the active treatment is no better than placebo in any subgroup. Race and ethnic group were reported by the patient. Scores on the National Institutes of Health Stroke Scale (NIHSS) range from 0 to 42, with higher scores indicating worse neurologic deficit. Values for the Alberta Stroke Program Early Computed Tomography Score (ASPECTS) range from 0 to 10, with lower values indicating larger infarcts. For location of large-vessel occlusion (LVO) during endovascular thrombectomy (EVT) and time from onset of stroke to final reperfusion, data are for patients in whom EVT was performed. ICA denotes internal carotid artery, and MCA middle cerebral artery.

Figure 2.. Distribution of Modified Rankin Scale Scores at Day 90 According to Trial Group.

Secondary efficacy outcomes included a 90-day modified Rankin scale score of 0 or 1 and 0 to 2. Scores on the modified Rankin scale range from 0 to 6, with higher scores indicating greater disability. Percentages may not total 100 because of rounding.