Department of Hepatobiliary Surgery and Visceral Transplantation University Medical Center Hamburg-Eppendorf Hamburg Germany Department of General, Visceral and Transplant Surgery University Hospital Heidelberg Heidelberg Germany Department of General, Visceral, Thoracic, Transplant and Pediatric Surgery University Medical Center Schleswig-Holstein Kiel Germany Department of Surgery University Hospital Regensburg Regensburg Germany Department of General, Visceral and Transplant Surgery Charité-Universitätsmedizin Berlin Berlin Germany Department of General, Visceral and Transplantation Surgery University Hospital Essen Essen Germany Department of General, Visceral and Transplant Surgery University Hospital Aachen Aachen Germany Novartis Pharma GmbH Nürnberg Germany Organ Transplantation Center The First Affiliated Hospital of University of Science and Technology of ChinaAnhui Provincial Hospital Hefei China General, Visceral and Transplant SurgeryDepartment of Surgery Medical University of Graz Graz Austria Department of General, Visceral and Transplantation Surgery University Hospital Münster Münster Germany Department of GeneralVisceral and Transplant Surgery University Hospital Aachen Aachen Germany Department of General Surgery Maastricht University Medical Centre (MUMC) Maastricht the Netherlands.
Liver Transpl. 2022 Jun;28(6):998-1010. doi: 10.1002/lt.26298. Epub 2021 Oct 12.
Everolimus-facilitated reduced-exposure tacrolimus (EVR + rTAC) at 30 days after liver transplantation (LT) has shown advantages in renal preservation. This study evaluated the effects of early initiation of EVR + rTAC in de novo LT recipients (LTRs). In HEPHAISTOS (NCT01551212, EudraCT 2011-003118-17), a 12-month, multicenter, controlled study, LTRs were randomly assigned at 7 to 21 days after LT to receive EVR + rTAC or standard-exposure tacrolimus (sTAC) with steroids. The primary objective was to demonstrate superior renal function (assessed by estimated glomerular filtration rate [eGFR]) with EVR + rTAC versus sTAC at month 12 in the full analysis set (FAS). Other assessments at month 12 included the evaluation of renal function in compliance set and on-treatment (OT) patients, efficacy (composite endpoint of graft loss, death, or treated biopsy-proven acute rejection [tBPAR] and individual components) in FAS, and safety. In total, 333 patients (EVR + rTAC, 169; sTAC, 164) were included in the FAS. A high proportion of patients was nonadherent in maintaining tacrolimus trough levels (EVR + rTAC, 36.1%; sTAC, 34.7%). At month 12, the adjusted least square mean eGFR was numerically higher with EVR + rTAC versus sTAC (76.2 versus 72.1 mL/minute/1.73 m , difference: 4.1 mL/minute/1.73 m ; P = 0.097). A significant difference of 8.3 mL/minute/1.73 m (P = 0.03) favoring EVR + rTAC was noted in the compliance set. Incidence of composite efficacy endpoint (7.7% versus 7.9%) and tBPAR (7.1% versus 5.5%) at month 12 as well as incidence of treatment-emergent adverse events (AEs) and serious AEs were comparable between groups. A lower proportion of patients discontinued EVR + rTAC than sTAC treatment (27.2% versus 34.1%). Early use of everolimus in combination with rTAC showed comparable efficacy, safety, and well-preserved renal function versus sTAC therapy at month 12. Of note, renal function was significantly enhanced in the compliance set.
在肝移植（LT）后 30 天，依维莫司辅助低剂量他克莫司（EVR + rTAC）在肾脏保护方面显示出优势。本研究评估了在初治 LT 受者（LTR）中早期使用 EVR + rTAC 的效果。在 HEPHAISTOS（NCT01551212，EudraCT 2011-003118-17）中，一项为期 12 个月的多中心、对照研究，LT 后 7 至 21 天的 LTR 随机分为 EVR + rTAC 组或标准暴露他克莫司（sTAC）+ 类固醇组。主要终点是在全分析集（FAS）中，EVR + rTAC 与 sTAC 相比在第 12 个月时具有更好的肾功能（通过估算肾小球滤过率[eGFR]评估）。第 12 个月的其他评估包括在依从性集和治疗中（OT）患者的肾功能评估、FAS 中的疗效（移植物丢失、死亡或治疗性活检证实的急性排斥反应[tBPAR]和单个成分的复合终点）和安全性。共纳入 333 例患者（EVR + rTAC，169 例；sTAC，164 例）入 FAS。很大比例的患者在维持他克莫司谷浓度方面不依从（EVR + rTAC，36.1%；sTAC，34.7%）。在第 12 个月时，EVR + rTAC 与 sTAC 相比，调整后的最小二乘均数 eGFR 数值更高（76.2 与 72.1mL/min/1.73m2，差值：4.1mL/min/1.73m2；P=0.097）。在依从性集，EVR + rTAC 具有 8.3mL/min/1.73m2（P=0.03）的显著优势。第 12 个月时，复合疗效终点（7.7%比 7.9%）和 tBPAR（7.1%比 5.5%）的发生率以及治疗中出现的不良事件（AE）和严重 AE 的发生率在两组间相当。与 sTAC 治疗相比，EVR + rTAC 停药的患者比例更低（27.2%比 34.1%）。依维莫司早期联合 rTAC 治疗与 sTAC 治疗相比，在第 12 个月时具有相似的疗效、安全性和良好的肾功能。值得注意的是，在依从性集，肾功能明显增强。
