title: Three-year Outcomes in De Novo Liver Transplant Patients Receiving Everolimus With Reduced Tacrolimus: Follow-Up Results From a Randomized, Multicenter Study.
abstract: BACKGROUND
  Data are lacking regarding the long-term effect of preemptive conversion to everolimus from calcineurin inhibitors early after liver transplantation to avoid renal deterioration.
  
  
  METHODS
  In a prospective, multicenter, open-label study, de novo liver transplant patients were randomized at day 30 to (i) everolimus + reduced exposure tacrolimus (EVR + Reduced TAC), (ii) everolimus + tacrolimus elimination (TAC Elimination), or (iii) standard exposure tacrolimus (TAC Control).
  
  
  RESULTS
  Randomization to TAC Elimination was terminated prematurely due to a higher rate of treated biopsy-proven acute rejection (tBPAR) during TAC withdrawal. Of 370 patients who completed the 24-month core study on-treatment, 282 (76.2%) entered an additional 12-month extension phase. The composite efficacy failure endpoint (tBPAR, graft loss or death) occurred in 11.5% of EVR+Reduced TAC patients versus 14.6% TAC Controls from randomization to month 36 (difference, -3.2%; 95% confidence interval, -10.5% to 4.2%; P = 0.334). Treated BPAR occurred in 4.8% versus 9.2% of patients (P = 0.076). From randomization to month 36, mean (SD) estimated glomerular filtration rate decreased by 7.0 (31.3) mL/min per 1.73 m in the EVR+Reduced TAC group, and 15.5 (22.7) mL/min per 1.73 m in the TAC Control group (P = 0.005). Rates of adverse events, serious adverse events, and discontinuation due to adverse events were similar in both groups during the extension.
  
  
  CONCLUSIONS
  A clinically relevant renal benefit after introduction of everolimus with reduced-exposure tacrolimus at 1 month after liver transplantation was maintained to 3 years in patients who continued everolimus therapy to the end of the core study, with comparable efficacy and no late safety concerns.
authors.affiliation: 1 University Medical Centre Hamburg-Eppendorf, Hamburg, Germany. 2 Hôpital Paul Brousse, Villejuif, France. 3 University Hospital Essen, University Duisburg-Essen, Essen, Germany. 4 Niguarda "Cà Granda" Hospital, Milan, Italy. 5 Erasmus MC, University Hospital Rotterdam, Rotterdam, Netherlands. 6 Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. 7 Hôpital Henri Mondor, Créteil, France. 8 University Hospital Gasthuisberg, KU Leuven, Belgium. 9 Cleveland Clinic Foundation, Cleveland, OH. 10 Novartis Pharmaceuticals Corporation, East Hanover, NJ. 11 Novartis Pharma AG, Basel, Switzerland.
authors.forename: Lutz
authors.initials: L
authors.lastname: Fischer
authors.forename: Faouzi
authors.initials: F
authors.lastname: Saliba
authors.forename: Gernot M
authors.initials: GM
authors.lastname: Kaiser
authors.forename: Luciano
authors.initials: L
authors.lastname: De Carlis
authors.forename: Herold J
authors.initials: HJ
authors.lastname: Metselaar
authors.forename: Paolo
authors.initials: P
authors.lastname: De Simone
authors.forename: Christophe
authors.initials: C
authors.lastname: Duvoux
authors.forename: Frederik
authors.initials: F
authors.lastname: Nevens
authors.forename: John J
authors.initials: JJ
authors.lastname: Fung
authors.forename: Gaohong
authors.initials: G
authors.lastname: Dong
authors.forename: Barbara
authors.initials: B
authors.lastname: Rauer
authors.forename: Guido
authors.initials: G
authors.lastname: Junge
mesh_terms: D000328:Adult; D000368:Aged; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005060:Europe; D000068338:Everolimus / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006084:Graft Rejection / Q000175:diagnosis / Q000276:immunology / Q000401:mortality / Q000517:prevention & control*; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D016031:Liver Transplantation / Q000009:adverse effects / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012307:Risk Factors; D016559:Tacrolimus / Q000008:administration & dosage* / Q000009:adverse effects; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D000068338:Everolimus; D016559:Tacrolimus