Optimizing the Safety Profile of Everolimus by Delayed Initiation in De Novo Heart Transplant Recipients: Results of the Prospective Randomized Study EVERHEART

EVERHEART Investigators

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Although everolimus potentially improves long-term heart transplantation (HTx) outcomes, its early postoperative safety profile had raised concerns and needs optimization.

METHODS: This 6-month, open-label, multicenter randomized trial was designed to compare the cumulative incidence of a primary composite safety endpoint comprising wound healing delays, pericardial effusion, pleural effusion needing drainage, and renal insufficiency events (estimated glomerular filtration rate ≤30/mL/min per 1.73 m) in de novo HTx recipients receiving immediate everolimus (EVR-I) (≤144 hours post-HTx) or delayed everolimus (EVR-D) (4-6 weeks post-HTx with mycophenolate mofetil as a bridge) with reduced-dose cyclosporine A. Cumulative incidence of biopsy-proven rejection ≥ 2R, rejection with hemodynamic compromise, graft loss, or death was the secondary composite efficacy endpoint.

RESULTS: Overall, 181 patients were randomized to the EVR-I (n = 89) or EVR-D (n = 92) arms. Incidence of primary safety endpoint was higher for EVR-I than EVR-D arm (44.9% vs 32.6%; P = 0.191), mainly driven by a higher rate of pericardial effusion (33.7% vs 19.6%; P = 0.04); wound healing delays, acute renal insufficiency events, and pleural effusion occurred at similar frequencies in the study arms. Efficacy failure was not significantly different in EVR-I arm versus EVR-D arm (37.1% vs 28.3%; P = 0.191). Three patients in the EVR-I arm and 1 in the EVR-D arm died. Incidence of clinically significant adverse events leading to discontinuation was higher in EVR-I arm versus EVR-D arm (P = 0.02).

CONCLUSIONS: Compared with immediate initiation, delayed everolimus initiation appeared to provide a clinically relevant early safety benefit in de novo HTx recipients, without compromising efficacy.

Original languageEnglish
Pages (from-to)493-501
Number of pages9
JournalTransplantation
Volume102
Issue number3
DOIs
Publication statusPublished - Mar 2018

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Arm
Prospective Studies
Safety
Pericardial Effusion
Incidence
Pleural Effusion
Wound Healing
Mycophenolic Acid
Transplant Recipients
Everolimus
Heart Transplantation
Glomerular Filtration Rate
Acute Kidney Injury
Cyclosporine
Multicenter Studies
Renal Insufficiency
Drainage
Hemodynamics
Transplants
Biopsy

Keywords

  • Everolimus/adverse effects
  • Female
  • Heart Transplantation
  • Humans
  • Immunosuppressive Agents/adverse effects
  • Male
  • Prospective Studies

Cite this

Optimizing the Safety Profile of Everolimus by Delayed Initiation in De Novo Heart Transplant Recipients : Results of the Prospective Randomized Study EVERHEART. / EVERHEART Investigators.

In: Transplantation, Vol. 102, No. 3, 03.2018, p. 493-501.

Research output: Contribution to journalArticle

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abstract = "BACKGROUND: Although everolimus potentially improves long-term heart transplantation (HTx) outcomes, its early postoperative safety profile had raised concerns and needs optimization.METHODS: This 6-month, open-label, multicenter randomized trial was designed to compare the cumulative incidence of a primary composite safety endpoint comprising wound healing delays, pericardial effusion, pleural effusion needing drainage, and renal insufficiency events (estimated glomerular filtration rate ≤30/mL/min per 1.73 m) in de novo HTx recipients receiving immediate everolimus (EVR-I) (≤144 hours post-HTx) or delayed everolimus (EVR-D) (4-6 weeks post-HTx with mycophenolate mofetil as a bridge) with reduced-dose cyclosporine A. Cumulative incidence of biopsy-proven rejection ≥ 2R, rejection with hemodynamic compromise, graft loss, or death was the secondary composite efficacy endpoint.RESULTS: Overall, 181 patients were randomized to the EVR-I (n = 89) or EVR-D (n = 92) arms. Incidence of primary safety endpoint was higher for EVR-I than EVR-D arm (44.9{\%} vs 32.6{\%}; P = 0.191), mainly driven by a higher rate of pericardial effusion (33.7{\%} vs 19.6{\%}; P = 0.04); wound healing delays, acute renal insufficiency events, and pleural effusion occurred at similar frequencies in the study arms. Efficacy failure was not significantly different in EVR-I arm versus EVR-D arm (37.1{\%} vs 28.3{\%}; P = 0.191). Three patients in the EVR-I arm and 1 in the EVR-D arm died. Incidence of clinically significant adverse events leading to discontinuation was higher in EVR-I arm versus EVR-D arm (P = 0.02).CONCLUSIONS: Compared with immediate initiation, delayed everolimus initiation appeared to provide a clinically relevant early safety benefit in de novo HTx recipients, without compromising efficacy.",
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author = "{EVERHEART Investigators} and Luciano Potena and Carlo Pellegrini and Francesco Grigioni and Cristiano Amarelli and Ugolino Livi and Massimo Maccherini and Gabriella Masciocco and Giuseppe Faggian and {Lilla Della Monica}, Paola and Gino Gerosa and Nicola Marraudino and Marco Corda and Massimo Boffini",
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T1 - Optimizing the Safety Profile of Everolimus by Delayed Initiation in De Novo Heart Transplant Recipients

T2 - Results of the Prospective Randomized Study EVERHEART

AU - EVERHEART Investigators

AU - Potena, Luciano

AU - Pellegrini, Carlo

AU - Grigioni, Francesco

AU - Amarelli, Cristiano

AU - Livi, Ugolino

AU - Maccherini, Massimo

AU - Masciocco, Gabriella

AU - Faggian, Giuseppe

AU - Lilla Della Monica, Paola

AU - Gerosa, Gino

AU - Marraudino, Nicola

AU - Corda, Marco

AU - Boffini, Massimo

PY - 2018/3

Y1 - 2018/3

N2 - BACKGROUND: Although everolimus potentially improves long-term heart transplantation (HTx) outcomes, its early postoperative safety profile had raised concerns and needs optimization.METHODS: This 6-month, open-label, multicenter randomized trial was designed to compare the cumulative incidence of a primary composite safety endpoint comprising wound healing delays, pericardial effusion, pleural effusion needing drainage, and renal insufficiency events (estimated glomerular filtration rate ≤30/mL/min per 1.73 m) in de novo HTx recipients receiving immediate everolimus (EVR-I) (≤144 hours post-HTx) or delayed everolimus (EVR-D) (4-6 weeks post-HTx with mycophenolate mofetil as a bridge) with reduced-dose cyclosporine A. Cumulative incidence of biopsy-proven rejection ≥ 2R, rejection with hemodynamic compromise, graft loss, or death was the secondary composite efficacy endpoint.RESULTS: Overall, 181 patients were randomized to the EVR-I (n = 89) or EVR-D (n = 92) arms. Incidence of primary safety endpoint was higher for EVR-I than EVR-D arm (44.9% vs 32.6%; P = 0.191), mainly driven by a higher rate of pericardial effusion (33.7% vs 19.6%; P = 0.04); wound healing delays, acute renal insufficiency events, and pleural effusion occurred at similar frequencies in the study arms. Efficacy failure was not significantly different in EVR-I arm versus EVR-D arm (37.1% vs 28.3%; P = 0.191). Three patients in the EVR-I arm and 1 in the EVR-D arm died. Incidence of clinically significant adverse events leading to discontinuation was higher in EVR-I arm versus EVR-D arm (P = 0.02).CONCLUSIONS: Compared with immediate initiation, delayed everolimus initiation appeared to provide a clinically relevant early safety benefit in de novo HTx recipients, without compromising efficacy.

AB - BACKGROUND: Although everolimus potentially improves long-term heart transplantation (HTx) outcomes, its early postoperative safety profile had raised concerns and needs optimization.METHODS: This 6-month, open-label, multicenter randomized trial was designed to compare the cumulative incidence of a primary composite safety endpoint comprising wound healing delays, pericardial effusion, pleural effusion needing drainage, and renal insufficiency events (estimated glomerular filtration rate ≤30/mL/min per 1.73 m) in de novo HTx recipients receiving immediate everolimus (EVR-I) (≤144 hours post-HTx) or delayed everolimus (EVR-D) (4-6 weeks post-HTx with mycophenolate mofetil as a bridge) with reduced-dose cyclosporine A. Cumulative incidence of biopsy-proven rejection ≥ 2R, rejection with hemodynamic compromise, graft loss, or death was the secondary composite efficacy endpoint.RESULTS: Overall, 181 patients were randomized to the EVR-I (n = 89) or EVR-D (n = 92) arms. Incidence of primary safety endpoint was higher for EVR-I than EVR-D arm (44.9% vs 32.6%; P = 0.191), mainly driven by a higher rate of pericardial effusion (33.7% vs 19.6%; P = 0.04); wound healing delays, acute renal insufficiency events, and pleural effusion occurred at similar frequencies in the study arms. Efficacy failure was not significantly different in EVR-I arm versus EVR-D arm (37.1% vs 28.3%; P = 0.191). Three patients in the EVR-I arm and 1 in the EVR-D arm died. Incidence of clinically significant adverse events leading to discontinuation was higher in EVR-I arm versus EVR-D arm (P = 0.02).CONCLUSIONS: Compared with immediate initiation, delayed everolimus initiation appeared to provide a clinically relevant early safety benefit in de novo HTx recipients, without compromising efficacy.

KW - Everolimus/adverse effects

KW - Female

KW - Heart Transplantation

KW - Humans

KW - Immunosuppressive Agents/adverse effects

KW - Male

KW - Prospective Studies

U2 - 10.1097/TP.0000000000001945

DO - 10.1097/TP.0000000000001945

M3 - Article

C2 - 28930797

VL - 102

SP - 493

EP - 501

JO - Transplantation

JF - Transplantation

SN - 0041-1337

IS - 3

ER -