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Circ Heart Fail. 2018 Sep;11(9):e004050. doi: 10.1161/CIRCHEARTFAILURE.117.004050.

Effect of Everolimus Initiation and Calcineurin Inhibitor Elimination on Cardiac Allograft Vasculopathy in De Novo Heart Transplant Recipients.

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Department of Cardiology, Oslo University Hospital, Rikshospitalet, Norway (S.A., A.K.A., E.G., L.G.).
Center for Heart Failure Research, University of Oslo and Faculty of Medicine, University of Oslo, Norway (S.A.).
Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden (K.K., D.I.).
Department of Cardiology, Rigshospitalet, Copenhagen, Denmark (F.G.).
Department of Cardiology, Aarhus University Hospital, Denmark (H.E., H.E.B.).
The Section for Heart Failure and Valvular Disease, VO Heart and Lung Medicine, Skåne University Hospital and Department of Clinical Sciences, Lund University, Sweden (G.R.).
Novartis Norge AS, Oslo, Norway (D.S.).
Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden (G.D.).
Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Norway (T.U., P.A.).
K.G. Jebsen Inflammatory Research Center, Faculty of Medicine, University of Oslo, Norway (T.U., P.A.).
K. G. Jebsen Thrombosis Research and Expertise Center, University of Tromsø, Norway (T.U., P.A.).
Faculty of Medicine, University of Oslo, Norway (T.U., P.A., L.G.).
Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Norway (P.A.).


Background Cardiac allograft vasculopathy (CAV) limits survival after heart transplantation, and the effect of different immunosuppressive regimens on CAV is not fully understood. The randomized SCHEDULE trial (Scandinavian Heart Transplant Everolimus De Novo Study With Early Calcineurin Inhibitors Avoidance) evaluated whether initiation of the proliferation signal inhibitor everolimus and early cyclosporine elimination can reduce CAV development. Methods and Results The SCHEDULE trial was a multicenter Scandinavian trial, where 115 de novo heart transplantation recipients were randomized to everolimus with complete cyclosporine withdrawal 7 to 11 weeks after heart transplantation or standard cyclosporine-based immunosuppression. Seventy-six (66%) patients had matched intravascular ultrasound examinations at baseline and 12 and 36 months. Intravascular ultrasound analysis evaluated maximal intimal thickness, percent atheroma volume, and total atheroma volume. Qualitative plaque analysis using virtual histology assessed fibrous, fibrofatty, and calcified tissue as well as necrotic core. Serum inflammatory markers were measured in parallel. The everolimus group (n=37) demonstrated significantly reduced CAV progression as compared with the cyclosporine group (n=39) at 36 months (Δ maximal intimal thickness, 0.09±0.05 versus 0.15±0.16 mm [ P=0.03]; Δ percent atheroma volume, 5.3±2.8% versus 7.6±5.9% [ P=0.03]; and Δ total atheroma volume, 33.9±71.2 versus 54.2±96.0 mm3 [ P=0.34], respectively]. At 36 months the number of everolimus patients with rejection graded ≥2R was 15 (41%) as compared with 5 (13%) in the cyclosporine group ( P=0.01). Everolimus did not affect CAV morphology or immune marker activity during the follow-up period. Conclusions The SCHEDULE trial demonstrates that everolimus initiation and early cyclosporine elimination significantly reduces CAV progression at 12 months, and this beneficial effect is clearly sustained at 36 months. Clinical trial registration URL: . Unique identifier: NCT01266148.


allograft; calcineurin inhibitors; cyclosporine; everolimus; heart transplantation

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