Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue-Type Plasminogen Activator in Acute Ischemic Stroke-Full Dose Regimen Stroke Trial

Abstract

Background and Purpose The Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke (CLEAR) and CLEAR-Enhanced Regimen (CLEAR-ER) trials demonstrated safety of reduced dose recombinant tissue plasminogen activator (rt-PA) plus the glycoprotein 2b/3a inhibitor, eptifibatide, in acute ischemic stroke (AIS) compared to rt-PA 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 rt-PA plus eptifibatide. Methods CLEAR-FDR was a single-arm, prospective, open-label, multi-site study. Patients aged 18-85 years treated with 0.9 mg/kg IV rt-PA within three hours of symptom onset were enrolled. After obtaining consent, eptifibatide (135 mcg/kg bolus and 2 hour infusion at 0.75 mcg/kg/min) was administered. The primary endpoint was the proportion of patients who experienced sICH within 36 hours. An independent clinical monitor adjudicated if a sICH had occurred and an independent neuroradiologist reviewed all images. The stopping rule was three sICHs within the first 19 patients or four sICHs within 29 patients. Results From October 2013 to December 2014, 27 AIS patients were enrolled. Median age was 73 years (Range 34-85, IQR 65-80) and median NIHSS was 12 (Range 6-26, IQR 9-16). One sICH (3.7%, 95% CI 0.7%-18%) was observed. Conclusion These results demonstrate comparable safety of full dose rt-PA plus eptifibatide with historical rates of sICH with rt-PA alone and support proceeding with a phase 3 trial evaluating full dose rt-PA combined with eptifibatide to improve outcomes after AIS.

Randomized, Multicenter Trial of ARTSS-2 (Argatroban With Recombinant Tissue Plasminogen Activator for Acute Stroke)

“…We feel this is an advantage of the design as it adds to the building evidence of medical adjunctive antithrombotic amplification of IV-rt-PA. 6,24 After terminating the trial at 90 patients, we tested the feasibility and explored safety and reperfusion outcomes in a small cohort treated with IV-rt-PA, high-dose argatroban and endovascular therapy in 0–6 hour AIS with large vessel occlusion (clinicaltrials.gov NCT02448069). The results will be reported separately but demonstrated the feasibility and safety of combining the ARTSS-2 protocol with endovascular thrombectomy.…”

Association of Clinical, Imaging, and Thrombus Characteristics With Recanalization of Visible Intracranial Occlusion in Patients With Acute Ischemic Stroke

“…ancillary drug therapies such as argatroban or eptifibitide. 27,28 Nonpermeable thrombi recanalize more slowly and less commonly and may require mechanical means to disrupt the thrombus and increase surface area for enzymatic access with therapies such as ultrasound. 29 Clinical trial design of novel thrombolytic or ancillary reperfusion treatments might therefore be optimized using the expected recanalization prevalence data from this study.…”

Therapeutic Strategies to Attenuate Hemorrhagic Transformation After Tissue Plasminogen Activator Treatment for Acute Ischemic Stroke

“…However, reperfusion was not commonly evaluated. We look forward to new studies that will reexamine the neuroprotection hypothesis in an era of proven early reperfusion 83) . The glycoprotein IIb/IIIa receptor antagonists (GPIs) in terms of platelet inhibition eptifibatide have demonstrated that AIS patients with tPA plus eptifibatide showed lower incident rates of symptomatic HT than those with tPA alone.…”