Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue-Type Plasminogen Activator in Acute

Intravenous recombinant tissue-type plasminogen activator (r-tPA) remains the only proven medical therapy for improving functional outcomes after acute ischemic stroke (AIS). Unfortunately, r-tPA alone is often inadequate for opening occluded intracranial arteries with recanalization of large arterial occlusions in only ≈50% with subsequent reocclusion of 14% to 34% of initially recanalized arteries. Recent trials of endovascular therapy found that carefully selected patients treated with endovascular and intravenous r-tPA have improved outcomes compared with r-tPA alone, but half of all r-tPA treated patients do not have a proximal arterial occlusion. Furthermore, access of patients with stroke to centers capable of delivering endovascular therapy is limited. Thus, intravenous medical treatments that augment reperfusion and improve functional outcomes beyond that seen with r-tPA alone remain sorely needed. We have previously conducted 2 randomized phase 2 clinical trials of escalating doses of intravenous r-tPA plus intravenous eptifibatide, a platelet glycoprotein 2b/3a inhibitor that prevents platelet aggregation, versus r-tPA alone in AIS patients treated with r-tPA within 3 hours of symptom onset. The 94-patient Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue-Type Plasminogen Activator (CLEAR) stroke trial randomized patients with AIS to low-dose r-tPA (tier 1, 0.3 mg/kg and tier 2, 0.45 mg/kg) plus eptifibatide (75 μg/kg bolus followed by 0.75 μg/kg per Background and Purpose—The Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue-Type Plasminogen Activator (r-tPA; CLEAR) in Acute Ischemic Stroke (AIS) and CLEAR-Enhanced Regimen (CLEAR-ER) trials demonstrated safety of reduced dose r-tPA plus the glycoprotein 2b/3a inhibitor, eptifibatide, in AIS compared with r-tPA alone. The objective of the CLEAR-Full Dose Regimen (CLEAR-FDR) trial was to estimate the rate of symptomatic intracerebral hemorrhage (sICH) in AIS patients treated with the combination of full-dose r-tPA plus eptifibatide. Methods—CLEAR-FDR was a single-arm, prospective, open-label, multisite study. Patients aged 18 to 85 years treated with 0.9 mg/kg IV r-tPA within 3 hours of symptom onset were enrolled. After obtaining consent, eptifibatide (135 μg/ kg bolus and 2-hour infusion at 0.75 μg/kg per minute) was administered. The primary end point was the proportion of patients who experienced sICH within 36 hours. An independent clinical monitor adjudicated if an sICH had occurred and an independent neuroradiologist reviewed all images. The stopping rule was 3 sICHs within the first 19 patients or 4 sICHs within 29 patients. Results—From October 2013 to December 2014, 27 patients with AIS were enrolled. Median age was 73 years (range, 34–85; interquartile range, 65–80) and median National Institute of Health stroke scale score was 12 (range, 6–26; interquartile range, 9–16). One sICH (3.7%; 95% confidence interval, 0.7%–18%) was observed. Conclusions—These results demonstrate comparable safety of full-dose r-tPA plus eptifibatide with historical rates of sICH with r-tPA alone and support proceeding with a phase 3 trial evaluating full-dose r-tPA combined with eptifibatide to improve outcomes after AIS. (Stroke. 2015;46:2529-2533. DOI: 10.1161/STROKEAHA.115.010260.)