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.

Combination therapy of intravenous glycoprotein IIB/IIIA inhibitors and tissue plasminogen activator for acute ischemic stroke

“…[14] Subsequently, Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke-Enhanced Regimen (CLEAR-ER) trial evaluated increased tPA dose (0.6 mg/kg, lower than standard tPA dose) in the combination therapy. [15] There was a reduction in the rate of symptomatic ICH in the combination arm compared to (14) Clear-ER trial (15) Gahn et al (16) Morris et al (17) NINDS trial (1) CT 69 101 13 5 -tPA 25 25 --168 Male CT -53 6 5 -tPA -13 --96 NIHSS at presentation CT 14 12 11 16 -tPA 10 17 --15 Base mRS 0-1 CT 61 85 ---tPA 25 18 --104 Time CT -Combination therapy, tPA -Tissue plasminogen activator, NIHSS -National institutes of health stroke scale the control standard tPA arm (OR, 0.15; 95% CI, 0.01-1.40; P = 0.053). There was also a trend towards improved functional outcome (mRS 0-1) at 3 months (OR, 1.74; 95% CI, 0.70-4.31; P = 0.23).…”

“…There was also a trend towards improved functional outcome (mRS 0-1) at 3 months (OR, 1.74; 95% CI, 0.70-4.31; P = 0.23). [15] Few small non-randomized case series have also been published demonstrating safety and efficacy of combination therapy in acute stroke. [16,17] Results of our retrospective pooled analysis are in consensus with a recent study which reported an absolute risk reduction of 6% in a matched analysis comparing outcomes in the CLEAR-ER trial to the NINDS tPA trial.…”

Pharmacological therapy of acute ischaemic stroke: Achievements and problems

“…More phase III RCTs are clearly required before these agents are approved (Jauch et al, 2013). The multicentre, double-blind, randomised phase II trial Combined Approach to Lysis Utilizing Eptifibatide and rtPA in Acute Ischemic Stroke-Enhanced Regimen trial (CLEAR-ER) (sponsored by the NIH/NINDS) indicates the safety (in terms of SICH incidence) and efficacy (mRS) of the combination of reduced-dose rtPA (0.6 mg/kg) and eptifibatide compared with full-dose alteplase (0.9 mg/kg) alone (Pancioli et al, 2013; see also the post hoc analysis using historical control data by Adeoye et al, 2015). This study can be regarded as hypothesis-generation, suggesting a phase III further investigation.…”

Treatment of acute stroke: an update

“…Several such strategies have been tested, including combination of a thrombolytic agent with aspirin [101], an anticoagulant (argatroban) [102,103] or a glycoprotein IIb/IIIa antagonist (eptifibatide) [104], combination of a thrombolytic agent with sonothrombolysis [52], the use of a new generation of thrombolytic agents such as tenecteplase [105] or lowering the dosage of alteplase. To date, only one Phase III trial has been completed, showing that early combined administration of intravenous aspirin and alteplase does not improve outcome but rather increases haemorrhagic complications [101].…”

“…Data regarding the combinations of anticoagulants [102,103,107] or glycoprotein IIb/IIIa [104] antagonists are promising, but definitive evidence of their efficacy has not been provided.…”