Abstract T P199: Severity-adjusted Re-analysis of the Phase 2 Clear-er Stroke Trial

Abstract

Background: The proportion of good outcome (modified Rankin score/mRS ≤1 or return to baseline mRS) in the intervention arm of the randomized Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke-Enhanced Regimen (CLEAR-ER) trial provided evidence for pursuing a phase 3 trial of IV rt-PA plus eptifibatide versus rt-PA alone in acute ischemic stroke (AIS). However, CLEAR-ER had unanticipated imbalances between groups. Using a sliding dichotomy, we compared the rates of good outcome in CLEAR-ER combinations arm to that in the rt-PA arm of the NINDS stroke trials. Methods: CLEAR-ER was a multi-center, double-blind, randomized study. rt-PA eligible AIS patients were randomized to 0.6mg/kg rt-PA plus eptifibatide (135mcg/kg bolus and 0.75mcg/kg/min two-hour infusion) versus standard rt-PA (0.9mg/kg). For this analysis, as previously suggested for acute stroke trials, good outcome was defined as: 90-day mRS 0 if pretreatment NIHSS scores were 1 to 7; 90-day mRS 0-1 if pretreatment NIHSS scores were 8 to 14; 90-day mRS 0-2 if pretreatment NIHSS scores were >14. As in CLEAR-ER, patients who returned to baseline mRS were considered good outcome. To match CLEAR-ER eligibility criteria, NINDS trial rt-PA arm patients aged 18-85 years with a baseline NIHSS score >5 were used for comparison. Logistic regression was used for analyses. Results: In the combination therapy arm CLEAR-ER patients, 45% (45 out of 101) had good outcomes compared with 39% (105 out of 266) of the rt-PA arm patients from the NINDS trial (unadjusted odds ratio 1.23, 95%CI 0.77-1.96, p=0.38). After adjusting for baseline NIHSS score, age, gender, pre-existing disability and time to IV rt-PA, the odds ratio was 1.14 (0.69-1.88, p=0.61). When the groups were collapsed by baseline NIH stroke scale <15 versus ≥15, the unadjusted odds ratio was 1.39 (0.88-2.21, p=0.16); after adjustment, the odds ratio was 1.27 (0.75-2.14, p=0.37). Conclusion: In this exploratory analysis, severity-adjustment confirmed a direction of effect that justifies a well-designed, adequately powered phase 3 trial to determine the efficacy of rt-PA plus eptifibatide for treatment of AIS.