Abstract 94: Mortality Review For The First 400 Patients Enrolled In The Clot Lysis: Evaluation Of Accelerated Resolution Of Intraventricular Hemorrhage Trial (CLEAR III)

Abstract

Objective: CLEAR III is a Phase III, 500-subject, multicenter, double-blind, randomized study comparing extraventricular drainage (EVD) plus intraventricular recombinant tissue plasminogen activator (rtPA) vs. EVD plus placebo for treatment of intraventricular hemorrhage (IVH) in patients with intracerebral hemorrhage (ICH) volume <30cc. We compared proximate causes of death in the acute and post-hospitalization phase of the first 400 subjects enrolled. Methods: We reviewed serious adverse event (SAE) reports for 106 events that resulted in death within 1 year follow-up. We recorded clinical and volumetric data including ICH and IVH volumes on diagnostic, stability, and end-of-treatment (EOT) computed tomography (CT) scans. EOT was defined as the CT at 72 hours post administration of last dose of test article. Results: Of the first 400 subjects enrolled, 27% (106) died, 12% (47) within 30 days of symptom onset. Median [iqr] time to death was 41.5 [71] days. Mean age (±SEM) was 64.0(±1.0) years. Proximate cause of death was neurologic in 52.8% (56), followed by respiratory (14.1%; 15), cardiac (10.4%; 11), multi-organ failure (5.7%; 6), infection (3.8%; 4) and unknown (11.3%; 12). Withdrawal of care (WOC) occurred in 46.2% (49); the majority of deaths were neurologic. Median time to death depended on proximate cause (p=0.0005): Neurologic deaths occurred at 25.5 [36] days vs. 67 [102] days for non-neurologic deaths (p=0.0002). WOC led to death 22 [53] days after ICH and cardiac arrest at 27 [25] days. Patients with no WOC and non-neurologic death died at 76 [106.5] days after ICH. After adjusting for diagnostic IVH volume, age and WOC, factors independently associated with early (≤30d) vs. later (>30-365d) death were male gender (p=0.01), lower admission Glasgow coma scale (p=0.02), no pneumonia (p=0.02) and higher EOT IVH volume (trend p=0.06). Conclusion: The CLEAR III mortality rate for the first 400 subjects enrolled remains below literature estimates for severe IVH and is below the pre-specified recruitment suspension threshold of 40%. Approximately half of known causes of death are directly due to neurologic events and occur significantly earlier than non-neurologic causes. Reduction in IVH volume may lower early mortality risk.