title: Everolimus with reduced tacrolimus improves renal function in de novo liver transplant recipients: a randomized controlled trial.
abstract: In a prospective, multicenter, open-label study, de novo liver transplant patients were randomized at day 30±5 to (i) everolimus initiation with tacrolimus elimination (TAC Elimination) (ii) everolimus initiation with reduced-exposure tacrolimus (EVR+Reduced TAC) or (iii) standard-exposure tacrolimus (TAC Control). Randomization to TAC Elimination was terminated prematurely due to a higher rate of treated biopsy-proven acute rejection (tBPAR). EVR+Reduced TAC was noninferior to TAC Control for the primary efficacy endpoint (tBPAR, graft loss or death at 12 months posttransplantation): 6.7% versus 9.7% (-3.0%; 95% CI -8.7, 2.6%; p<0.001 for noninferiority [12% margin]). tBPAR occurred in 2.9% of EVR+Reduced TAC patients versus 7.0% of TAC Controls (p = 0.035). The change in adjusted estimated GFR from randomization to month 12 was superior with EVR+Reduced TAC versus TAC Control (difference 8.50 mL/min/1.73 m(2) , 97.5% CI 3.74, 13.27 mL/min/1.73 m(2) , p<0.001 for superiority). Drug discontinuation for adverse events occurred in 25.7% of EVR+Reduced TAC and 14.1% of TAC Controls (relative risk 1.82, 95% CI 1.25, 2.66). Relative risk of serious infections between the EVR+Reduced TAC group versus TAC Controls was 1.76 (95% CI 1.03, 3.00). Everolimus facilitates early tacrolimus minimization with comparable efficacy and superior renal function, compared to a standard tacrolimus exposure regimen 12 months after liver transplantation.
authors.affiliation: General Surgery and Liver Transplantation, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. p.desimone@ao-pisa.toscana.it
authors.forename: P
authors.initials: P
authors.lastname: De Simone
authors.forename: F
authors.initials: F
authors.lastname: Nevens
authors.forename: L
authors.initials: L
authors.lastname: De Carlis
authors.forename: H J
authors.initials: HJ
authors.lastname: Metselaar
authors.forename: S
authors.initials: S
authors.lastname: Beckebaum
authors.forename: F
authors.initials: F
authors.lastname: Saliba
authors.forename: S
authors.initials: S
authors.lastname: Jonas
authors.forename: D
authors.initials: D
authors.lastname: Sudan
authors.forename: J
authors.initials: J
authors.lastname: Fung
authors.forename: L
authors.initials: L
authors.lastname: Fischer
authors.forename: C
authors.initials: C
authors.lastname: Duvoux
authors.forename: K D
authors.initials: KD
authors.lastname: Chavin
authors.forename: B
authors.initials: B
authors.lastname: Koneru
authors.forename: M A
authors.initials: MA
authors.lastname: Huang
authors.forename: W C
authors.initials: WC
authors.lastname: Chapman
authors.forename: D
authors.initials: D
authors.lastname: Foltys
authors.forename: S
authors.initials: S
authors.lastname: Witte
authors.forename: H
authors.initials: H
authors.lastname: Jiang
authors.forename: J M
authors.initials: JM
authors.lastname: Hexham
authors.forename: G
authors.initials: G
authors.lastname: Junge
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016001:Confidence Intervals; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D000068338:Everolimus; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D053208:Kaplan-Meier Estimate; D007668:Kidney / Q000187:drug effects; D007677:Kidney Function Tests; D017093:Liver Failure / Q000601:surgery; D016031:Liver Transplantation / Q000276:immunology* / Q000379:methods / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D018570:Risk Assessment; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016019:Survival Analysis; D016559:Tacrolimus / Q000008:administration & dosage*; D013997:Time Factors; D014181:Transplantation Immunology / Q000502:physiology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D000068338:Everolimus; D020123:Sirolimus; D016559:Tacrolimus