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) utilityweighted 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.)

요약

• 소개 : 급성 허혈성 뇌졸중 증상 발생 3시간 이내에 정맥 내 혈전용해술을 받은 환자를 대상으로 정맥 내 아르가트로반(Argatroban) 혹은 엡티피바타이드(Eptifibatide) 주사의 효과를 알아보고자 하는 무작위 배정 임상연구이다.

  
  

• 방법 : 급성 허혈성 뇌졸중이 발생하여 증상 발생 3시간 이내에 정맥 내 혈전용해술을 받은 환자를 대상으로 한다. 환자들은 정맥 내 혈전용해술 시작 75분 이내에 각각 정맥 내 아르가트로반, 정맥 내 엡티피바타이드, 위약 주사를 맞는 그룹으로 무작위 배정되었다. 주요 유효성 결과는 'utility-weighted 90-day modified Rankin scale score'로 평가되었고, 주요 안전성 결과는 치료 36시간 이내 발생한 증상이 있는 내뇌출혈로 설정하였다.

  
  

• 결과 1) 증상이 있는 내뇌출혈 발생률은 세 그룹에서 모두 비슷하였다. (아르가트로반 그룹 4%, 엡티피바타이드 그룹 3%, 위약 그룹 2%) 2) 치료 후 90일의 사망률은 아르가트로반 그룹이 24%로 가장 높았고, 엡티파바타이드 그룹 12%, 위약 그룹 8%였다.

  
  

• 결론 : 급성 허혈성 뇌졸중 환자에서 증상이 시작된 후 3시간 이내에 정맥 내 혈전용해술을 받은 경우, 정맥 내 아가트로반 또는 엡티파바타이드의 보조 치료는 뇌졸중 후 장애를 줄이지 않은 반면, 사망률 증가와 관련이 있다.