title: Everolimus Initiation With Early Calcineurin Inhibitor Withdrawal in De Novo Heart Transplant Recipients: Three-Year Results From the Randomized SCHEDULE Study.
abstract: In a randomized, open-label trial, de novo heart transplant recipients were randomized to everolimus (3-6 ng/mL) with reduced-exposure calcineurin inhibitor (CNI; cyclosporine) to weeks 7-11 after transplant, followed by increased everolimus exposure (target 6-10 ng/mL) with cyclosporine withdrawal or standard-exposure cyclosporine. All patients received mycophenolate mofetil and corticosteroids. A total of 110 of 115 patients completed the 12-month study, and 102 attended a follow-up visit at month 36. Mean measured GFR (mGFR) at month 36 was 77.4 mL/min (standard deviation [SD] 20.2 mL/min) versus 59.2 mL/min (SD 17.4 mL/min) in the everolimus and CNI groups, respectively, a difference of 18.3 mL/min (95% CI 11.1-25.6 mL/min; p < 0.001) in the intention to treat population. Multivariate analysis showed treatment to be an independent determinant of mGFR at month 36. Coronary intravascular ultrasound at 36 months revealed significantly reduced progression of allograft vasculopathy in the everolimus group compared with the CNI group. Biopsy-proven acute rejection grade ≥2R occurred in 10.2% and 5.9% of everolimus- and CNI-treated patients, respectively, during months 12-36. Serious adverse events occurred in 37.3% and 19.6% of everolimus- and CNI-treated patients, respectively (p = 0.078). These results suggest that early CNI withdrawal after heart transplantation supported by everolimus, mycophenolic acid and steroids with lymphocyte-depleting induction is safe at intermediate follow-up. This regimen, used selectively, may offer adequate immunosuppressive potency with a sustained renal advantage.
authors.affiliation: Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: A K
authors.initials: AK
authors.lastname: Andreassen
authors.affiliation: Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: B
authors.initials: B
authors.lastname: Andersson
authors.affiliation: Department of Cardiology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: F
authors.initials: F
authors.lastname: Gustafsson
authors.affiliation: Department of Cardiology, Aarhus University Hospital, Skejby, Denmark.
authors.forename: H
authors.initials: H
authors.lastname: Eiskjaer
authors.affiliation: Section for Heart Failure and Valvular Disease, Skåne University Hospital and Department of Clinical Sciences, Cardiology, Lund University, Lund, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Rådegran
authors.affiliation: Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: E
authors.initials: E
authors.lastname: Gude
authors.affiliation: Department of Cardiology, Heart and Medicine Center County Council of Ostergotland and Linkoping University, Linkoping, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Jansson
authors.affiliation: Novartis Norge AS, Oslo, Norway.
authors.forename: D
authors.initials: D
authors.lastname: Solbu
authors.affiliation: Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Karason
authors.affiliation: Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: S
authors.initials: S
authors.lastname: Arora
authors.affiliation: Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Dellgren
authors.affiliation: Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway.|K.G. Jebsen Cardiac Research Center and Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: L
authors.initials: L
authors.lastname: Gullestad
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D064591:Allografts; D065095:Calcineurin Inhibitors / Q000627:therapeutic use*; D016572:Cyclosporine / Q000627:therapeutic use; D000068338:Everolimus / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000175:diagnosis / Q000209:etiology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D006331:Heart Diseases / Q000601:surgery; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors; D066027:Transplant Recipients; D014652:Vascular Diseases / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology; D028761:Withholding Treatment; D055815:Young Adult
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus
keywords: cardiology, immunosuppression; clinical research; clinical trial modulation; heart transplantation; immune; immunosuppressant; mechanistic target of rapamycin (mTOR); mechanistic target of rapamycin: everolimus; practice