Heart and Lung Transplant Program, Academic Hospital S. Orsola-Malpighi, Bologna, Italy.
Cardiac Surgery Department, University of Pavia-Hospital Policlinico, San Matteo, Pavia, Italy.
Transplantation. 2018 Mar;102(3):493-501. doi: 10.1097/TP.0000000000001945.
Although everolimus potentially improves long-term heart transplantation (HTx) outcomes, its early postoperative safety profile had raised concerns and needs optimization.
This 6-month, open-label, multicenter randomized trial was designed to compare the cumulative incidence of a primary composite safety endpoint comprising wound healing delays, pericardial effusion, pleural effusion needing drainage, and renal insufficiency events (estimated glomerular filtration rate ≤30/mL/min per 1.73 m) in de novo HTx recipients receiving immediate everolimus (EVR-I) (≤144 hours post-HTx) or delayed everolimus (EVR-D) (4-6 weeks post-HTx with mycophenolate mofetil as a bridge) with reduced-dose cyclosporine A. Cumulative incidence of biopsy-proven rejection ≥ 2R, rejection with hemodynamic compromise, graft loss, or death was the secondary composite efficacy endpoint.
Overall, 181 patients were randomized to the EVR-I (n = 89) or EVR-D (n = 92) arms. Incidence of primary safety endpoint was higher for EVR-I than EVR-D arm (44.9% vs 32.6%; P = 0.191), mainly driven by a higher rate of pericardial effusion (33.7% vs 19.6%; P = 0.04); wound healing delays, acute renal insufficiency events, and pleural effusion occurred at similar frequencies in the study arms. Efficacy failure was not significantly different in EVR-I arm versus EVR-D arm (37.1% vs 28.3%; P = 0.191). Three patients in the EVR-I arm and 1 in the EVR-D arm died. Incidence of clinically significant adverse events leading to discontinuation was higher in EVR-I arm versus EVR-D arm (P = 0.02).
Compared with immediate initiation, delayed everolimus initiation appeared to provide a clinically relevant early safety benefit in de novo HTx recipients, without compromising efficacy.
依维莫司（everolimus）有可能改善心脏移植（HTx）的长期预后，但它在术后早期的安全性引起了关注，需要进行优化。
这是一项 6 个月、开放性、多中心、随机试验，旨在比较新诊断 HTx 受者在接受依维莫司（EVR）时（HTx 后≤144 小时）或延迟依维莫司（EVR-D）（HTx 后 4-6 周，用吗替麦考酚酯作为桥接）时的累积发生率，分别为早期复合安全性终点（包括伤口愈合延迟、心包积液、需要引流的胸腔积液和肾功能不全事件[估计肾小球滤过率≤30/ml/min/1.73m]），以环孢素 A 为基础的小剂量。主要复合疗效终点是活检证实的排斥反应≥2R、合并血流动力学障碍的排斥反应、移植物丢失或死亡的发生率。
共有 181 名患者被随机分配到 EVR-I（n=89）或 EVR-D（n=92）组。EVR-I 组的主要安全性终点发生率高于 EVR-D 组（44.9%比 32.6%；P=0.191），主要是由于心包积液发生率较高（33.7%比 19.6%；P=0.04）；伤口愈合延迟、急性肾功能不全事件和胸腔积液在两组中的发生率相似。EVR-I 组与 EVR-D 组的疗效失败率无显著差异（37.1%比 28.3%；P=0.191）。EVR-I 组 3 例和 EVR-D 组 1 例患者死亡。EVR-I 组因临床显著不良事件而停药的发生率高于 EVR-D 组（P=0.02）。
与即刻起始相比，新诊断 HTx 受者延迟起始依维莫司治疗似乎具有临床相关的早期安全性益处，而不影响疗效。
