title: Everolimus and early calcineurin inhibitor withdrawal: 3-year results from a randomized trial in liver transplantation.
abstract: The feasibility of de novo everolimus without calcineurin inhibitor (CNI) therapy following liver transplantation was assessed in a multicenter, prospective, open-label trial. Liver transplant patients were randomized at 4 weeks to start everolimus and discontinue CNI, or continue their current CNI-based regimen. The primary endpoint was adjusted estimated GFR (eGFR; Cockcroft-Gault) at month 11 post randomization. A 24-month extension phase followed 81/114 (71.1%) of eligible patients to month 35 post randomization. The adjusted mean eGFR benefit from randomization to month 35 was 10.1 mL/min (95% confidence interval [CI] -1.3, 21.5 mL/min, p = 0.082) in favor of CNI-free versus CNI using Cockcroft-Gault, 9.4 mL/min/1.73 m(2) (95% CI -0.4, 18.9, p = 0.053) with Modification of Diet in Renal Disease (four-variable) and 9.5 mL/min/1.73 m(2) (95% CI -1.1, 17.9, p = 0.028) using Nankivell. The difference in favor of the CNI-free regimen increased gradually over time due to a small progressive decline in eGFR in the CNI cohort despite a reduction in CNI exposure. Biopsy-proven acute rejection, graft loss and death were similar between groups. Adverse events led to study drug discontinuation in five CNI-free patients and five CNI patients (12.2% vs. 12.5%, p = 1.000) during the extension phase. Everolimus-based CNI-free immunosuppression is feasible following liver transplantation and patients benefit from sustained preservation of renal function versus patients on CNI for at least 3 years.
authors: Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: M
authors: M
authors: Sterneck
authors: G M
authors: GM
authors: Kaiser
authors: N
authors: N
authors: Heyne
authors: N
authors: N
authors: Richter
authors: F
authors: F
authors: Rauchfuss
authors: A
authors: A
authors: Pascher
authors: P
authors: P
authors: Schemmer
authors: L
authors: L
authors: Fischer
authors: C G
authors: CG
authors: Klein
authors: S
authors: S
authors: Nadalin
authors: F
authors: F
authors: Lehner
authors: U
authors: U
authors: Settmacher
authors: P
authors: P
authors: Neuhaus
authors: D
authors: D
authors: Gotthardt
authors: M
authors: M
authors: Loss
authors: S
authors: S
authors: Ladenburger
authors: E M
authors: EM
authors: Paulus
authors: M
authors: M
authors: Mertens
authors: H J
authors: HJ
authors: Schlitt
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000008:administration & dosage* / Q000009:adverse effects; D000068338:Everolimus; D005240:Feasibility Studies; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000188:drug therapy* / Q000209:etiology; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D008107:Liver Diseases / Q000601:surgery*; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011446:Prospective Studies; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives*; D013997:Time Factors; D028761:Withholding Treatment; D055815:Young Adult
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D020123:Sirolimus
keywords: Calcineurin inhibitor; everolimus; liver transplantation; long-term; withdrawal