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.

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.

In this pilot prospective evaluation performed in the prehospital setting by EMS providers without formalized training, C-STAT is comparable to other published tools in test characteristics and may inform appropriate CSC triage beyond LVO ascertainment alone.

Background and Purpose The CLEAR-ER trial demonstrated safety of rt-PA plus eptifibatide in acute ischemic stroke (AIS). CLEAR-ER randomized AIS patients (5:1) to 0.6mg/kg rt-PA plus eptifibatide versus standard rt-PA (0.9mg/kg). IMS III randomized AIS patients to rt-PA plus endovascular therapy versus standard rt-PA. ALIAS Part 2 randomized patients to albumin ± rt-PA versus saline ± rt-PA. Our aim was to compare outcomes in CLEAR-ER combination arm patients to propensity score matched rt-PA only subjects in ALIAS Part 2 and IMS III. Methods The primary outcome was 90-day severity-adjusted mRS dichotomization based on baseline NIHSS. Secondary outcomes were 90-day mRS dichotomization as “excellent” (mRS 0–1); mRS dichotomization as “favorable” (mRS 0–2); and nonparametric analysis of the ordinal mRS. Results Eighty five combination arm CLEAR-ER subjects were matched with 169 ALIAS Part 2 and IMS III trials’ rt-PA only patients (controls). Median age in CLEAR-ER and control subjects was 68years; median NIHSS in the CLEAR-ER subjects was 11 and in control subjects 12. At 90 days, CLEAR-ER subjects had a non-significantly greater proportion of patients with favorable outcomes (45% vs 36%, unadjusted RR 1.24, 95% CI 0.91–1.69, p=0.18). Secondary outcomes were 52% vs 34% excellent outcomes (RR 1.51, 1.13–2.02, p=0.007); 60% vs 53% favorable outcome (RR 1.13, 0.90–1.41, p=0.31); and ordinal Cochran-Mantel-Haenszel p=0.10. Conclusion rt-PA plus eptifibatide showed a favorable direction of effect that was consistent across multiple approaches for AIS outcome evaluation. A phase III trial to establish the efficacy of rt-PA plus eptifibatide for improving AIS outcomes is warranted.