Safety of Early Everolimus in De Novo Heart Transplant Recipients: Interim Analysis of the Randomized Study EVERHEART

Abstract

Purpose Recent data raised concerns regarding the safety of everolimus (EVR) in the early post-operative period in de novo heart transplant (HT) recipients. Thus, we felt appropriate performing an unplanned interim analysis of the first 100 patients (out of 194 planned) completing the multicenter randomized study EVERHEART (NCT01017029), which compares early vs. delayed EVR strategies in de novo HT recipients. Methods and Materials The study was designed to assess the incidence of a safety composite endpoint (pleural/pericardial effusions, wound healing delay, and acute renal failure) over a 6-month period in patients randomized to receive EVR 1-5 days vs. 4-6 weeks after HT. EVR was started at 0.5-1.5 mg daily dose, targeting 3-8 ng/ml through levels. Delayed arm received mycophenolate (MMF) as a bridge to EVR. Study was powered hypothesizing a 60% rate of the endpoint in the early arm vs. 40% in the delayed arm. Results 49 patients were randomized to early EVR and 51 to delayed EVR strategy. 36% received thymoglobuline induction. Primary endpoint occurred in 30 (61.2%) patients in the early arm and in 29 (56.9%) in the delayed arm, with pericardial effusion as the most common contributing event. One patient died in each arm, and serious adverse event rate was similar in the two study groups (36.7 vs. 43.1%). Of note, only 3% of patients had a mechanical assist device before HT. Rejection rate was numerically lower in the early EVR group (30.6 vs. 33.3%), as well as creatinine clearance at month 1 (71.9±25.5 vs. 82.4±30.4ml/min/1.73m 2 ) and at month 6 (64.6±18.2 vs. 67.5±24.3 ml/min/1.73m 2 ). Conclusions Despite the limited sizing, this analysis of the EVERHEART study is reassuring regarding the safety of EVR in the early post HT phase: we did not note excess of EVR-related early adverse events and the two arms similarly influenced the combined endpoint. Smooth introduction of early EVR and a limited number of patients with mechanical assist devices may explain the improved safety profile, as compared with previous studies.