Combined approach to lysis utilizing eptifibatide and recombinant tissue plasminogen activator in acute ischemic stroke-enhanced regimen stroke trial

Abstract

Background and purpose: In a previous study, 0.3 and 0.45 mg/kg of intravenous recombinant tissue plasminogen activator (rt-PA) were safe when combined with eptifibatide 75 mcg/kg bolus and a 2-hour infusion (0.75 mcg/kg per minute). The Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke-Enhanced Regimen (CLEAR-ER) trial sought to determine the safety of a higher-dose regimen and to establish evidence for a phase III trial.

Methods: CLEAR-ER was a multicenter, double-blind, randomized safety study. Ischemic stroke patients were randomized to 0.6 mg/kg rt-PA plus eptifibatide (135 mcg/kg bolus and a 2-hour infusion at 0.75 mcg/kg per minute) versus standard rt-PA (0.9 mg/kg). The primary safety end point was the incidence of symptomatic intracranial hemorrhage within 36 hours. The primary efficacy outcome measure was the modified Rankin Scale (mRS) score ≤1 or return to baseline mRS at 90 days. Analysis of the safety and efficacy outcomes was done with multiple logistic regression.

Results: Of 126 subjects, 101 received combination therapy, and 25 received standard rt-PA. Two (2%) patients in the combination group and 3 (12%) in the standard group had symptomatic intracranial hemorrhage (odds ratio, 0.15; 95% confidence interval, 0.01-1.40; P=0.053). At 90 days, 49.5% of the combination group had mRS ≤1 or return to baseline mRS versus 36.0% in the standard group (odds ratio, 1.74; 95% confidence interval, 0.70-4.31; P=0.23). After adjusting for age, baseline National Institutes of Health Stroke Scale, time to intravenous rt-PA, and baseline mRS, the odds ratio was 1.38 (95% confidence interval, 0.51-3.76; P=0.52).

Conclusions: The combined regimen of intravenous rt-PA and eptifibatide studied in this trial was safe and provides evidence that a phase III trial is warranted to determine efficacy of the regimen.

Clinical trial registration url: http://www.clinicaltrials.gov. Unique identifier: NCT00894803.

Keywords: clinical trial; eptifibatide; ischemic stroke; tissue plasminogen activator.

Figures

Figure 1

Schematic of blinded administration of recombinant tissue plasminogen activator (rt-PA) plus eptifibatide vs standard rt-PA.

Figure 2

Symptomatic intracranial hemorrhage (sICH) in the Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke–Enhanced Regimen (CLEAR-ER) trial. NIHSS indicates National Institutes of Health Stroke Scale.