A Multicenter Phase II Randomized Trial of a HIF-Prolyl Hydroxylase Inhibitor for Neuroprotection in High Risk Thoracic Aortic Repair

Introduction: Thoracic aortic repair has risk of brain and spinal cord ischemia. We hypothesized that GSK1278863, an oral prolyl hydroxylase inhibitor (PHI) will reduce cerebrospinal fluid (CSF) markers of injury, clinical strokes, and spinal infarcts via upregulation of hypoxia inducible factor and erythropoietin (EPO).Methods: Double blind randomized trial at 15 sites in North America (funded by GSK) comparing GSK1278863 to placebo in patients undergoing thoracic aortic repair with lumbar drain, stratified by open surgery or stenting. Subjects received 300mg study medication the evening before surgery and then 100mg daily for 4 days. The primary outcome was change in CSF S100β and Glial Fibrillary Acidic Protein (GFAP) from baseline to peak within 48 hours.Results: The study planned to enroll 160 patients but halted early due to more serious adverse events (SAEs) in patients on GSK1278863. Fifty-five patients were enrolled, 39 (71[percnt]) open surgery and 16 (29[percnt]) stenting, mean age 61.5 (±14.5), 19 (35[percnt]) female, 12 (22[percnt]) non-white. Treatment arms were balanced at baseline except for higher risk surgical anatomy in patients receiving GSK1278863. There were trends toward greater changes in CSF S100β (2772 vs 543 ng/L, p=0.08) and GFAP (1070 vs 292 ug/L, p=0.2) on GSK1278863. Change in CSF EPO level from baseline to peak was greater in patients given GSK1278863 (18 vs -16 U/L, pu003c0.001). Stroke occurred in 7 patients (4 GSK1278863 and 3 placebo, p=0.70) and spinal ischemia in 12 (9 GSK1278863 and 3 placebo, p=0.06). Patients given GSK1278863 had more SAEs, 20 (74[percnt]) vs 14 (50[percnt]), p=0.10, and deaths, 6 (22[percnt]) vs 2 (7[percnt]), p=0.14.Conclusions: Perioperative GSK1278863 was associated with more clinical events and SAEs but this is potentially confounded by imbalanced surgical risk in this small study. Overall, neurologic complications were common in this high risk population and additional studies of neuroprotection are needed. Disclosure: Dr. Messe has received personal compensation for activities with GlaxoSmithKline as a consultant. Dr. Messe has received research support from WL Gore and GlaxoSmithKline. Dr. Demopoulos has received personal compensation for activities with GlaxoSmithKline as an employer. Dr. Demopoulos holds stock in GlaxoSmithKline. Mr. Haws holds stock and/or stock options in Glaxo Smith Kline. Dr. Khonezhad has nothing to disclose. Dr. Leshnower has received personal compensation for activities with Cryolife, Inc. as a consultant. Dr. Coselli has received royalty payments from Vascutek, Inc. Dr. Appoo has nothing to disclose. Dr. Hughes has nothing to disclose. Dr. Reece has nothing to disclose. Dr. Brinster has nothing to disclose. Dr. Kasner has nothing to disclose. Dr. Kern has nothing to disclose. Dr. Desai has nothing to disclose. Dr. Ballard holds and/or stock options in Glaxo Smith Kline. Dr. Fang has stock in GlaxoSmithKline, Inc Dr. Lepore holds stock and/or stock options in GlaxoSmithKline. Dr. Bavaria has received personal compensation for activities with Glaxo Smith Kline as a consultant.