Advanced

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

, ; Arora, Satish; Andreassen, Arne K.; Karason, Kristjan; Gustafsson, Finn; Eiskjær, Hans; Bøtker, Hans Erik; Rådegran, Göran LU ; Gude, Einar and Ioanes, Dan, et al. (2018) In Circulation. Heart failure 11(9). p.004050-004050
Abstract

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.... (More)

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: https://www.clinicaltrials.gov . Unique identifier: NCT01266148.

(Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
allograft, calcineurin inhibitors, cyclosporine, everolimus, heart transplantation
in
Circulation. Heart failure
volume
11
issue
9
pages
004050 - 004050
publisher
American Heart Association
external identifiers
  • scopus:85055596367
ISSN
1941-3297
DOI
10.1161/CIRCHEARTFAILURE.117.004050
language
English
LU publication?
yes
id
654ec271-fd40-4397-b8d6-54528c648f80
date added to LUP
2018-11-16 13:44:52
date last changed
2019-02-20 11:36:29
@article{654ec271-fd40-4397-b8d6-54528c648f80,
  abstract     = {<p>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: https://www.clinicaltrials.gov . Unique identifier: NCT01266148.</p>},
  author       = {,  and Arora, Satish and Andreassen, Arne K. and Karason, Kristjan and Gustafsson, Finn and Eiskjær, Hans and Bøtker, Hans Erik and Rådegran, Göran and Gude, Einar and Ioanes, Dan and Solbu, Dag and Dellgren, Göran and Ueland, Thor and Aukrust, Pål and Gullestad, Lars},
  issn         = {1941-3297},
  keyword      = {allograft,calcineurin inhibitors,cyclosporine,everolimus,heart transplantation},
  language     = {eng},
  number       = {9},
  pages        = {004050--004050},
  publisher    = {American Heart Association},
  series       = {Circulation. Heart failure},
  title        = {Effect of Everolimus Initiation and Calcineurin Inhibitor Elimination on Cardiac Allograft Vasculopathy in De Novo Heart Transplant Recipients},
  url          = {http://dx.doi.org/10.1161/CIRCHEARTFAILURE.117.004050},
  volume       = {11},
  year         = {2018},
}