Everolimus for the Prevention of Calcineurin-Inhibitor-Induced Left Ventricular Hypertrophy After Heart Transplantation (RADTAC Study).

Anthony, C; Imran, M; Pouliopoulos, J; Emmanuel, S; Iliff, JW; Moffat, KJ; Ross, J; Graham, RM; Kotlyar, E; Muthiah, K; Keogh, AM; Hayward, CS; Macdonald, P; Jabbour, A

Everolimus for the Prevention of Calcineurin-Inhibitor-Induced Left Ventricular Hypertrophy After Heart Transplantation (RADTAC Study).

Anthony, C Imran, M Pouliopoulos, J Emmanuel, S Iliff, JW Moffat, KJ Ross, J Graham, RM Kotlyar, E Muthiah, K Keogh, AM Hayward, CS Macdonald, P

Jabbour, A

Permalink

Publisher:: Elsevier BV
Publication Type:: Journal Article
Citation:: JACC Heart Fail, 2021, 9, (4), pp. 301-313
Issue Date:: 2021-04

Closed Access

	Filename	Description	Size
	Everolimus for the Prevention of Calcineurin-Inhibitor-Induced Left Ventricular Hypertrophy After Heart Transplantation (RADTAC Study).pdf	Published version	2.16 MB	Adobe PDF	View/Open

Copyright Clearance Process

Recently Added
In Progress
Closed Access

This item is closed access and not available.

Full metadata record

Field	Value	Language
dc.contributor.author	Anthony, C
dc.contributor.author	Imran, M
dc.contributor.author	Pouliopoulos, J
dc.contributor.author	Emmanuel, S
dc.contributor.author	Iliff, JW
dc.contributor.author	Moffat, KJ
dc.contributor.author	Ross, J
dc.contributor.author	Graham, RM
dc.contributor.author	Kotlyar, E
dc.contributor.author	Muthiah, K
dc.contributor.author	Keogh, AM
dc.contributor.author	Hayward, CS
dc.contributor.author	Macdonald, P https://orcid.org/0000-0001-5378-2825
dc.contributor.author	Jabbour, A
dc.date.accessioned	2022-04-04T03:06:22Z
dc.date.available	2021-01-24
dc.date.available	2022-04-04T03:06:22Z
dc.date.issued	2021-04
dc.identifier.citation	JACC Heart Fail, 2021, 9, (4), pp. 301-313
dc.identifier.issn	2213-1779
dc.identifier.issn	2213-1787
dc.identifier.uri	http://hdl.handle.net/10453/155923
dc.description.abstract	OBJECTIVES: This study aimed to determine the safety and efficacy of combined low-dose everolimus and low-dose tacrolimus compared with standard-dose tacrolimus in attenuating left ventricular hypertrophy (LVH) after orthotopic heart transplantation (OHT). BACKGROUND: Calcineurin inhibitors (CNIs) such as tactrolimus are important in preventing cardiac allograft rejection and reducing mortality after OHT. However CNIs are causatively linked to the development of LVH, and are associated with nephrotoxicity and vasculopathy. CNI-sparing agents such as everolimus have been hypothesized to inhibit adverse effects of CNIs. METHODS: In this prospective, randomized, open-label study, OHT recipients were randomized at 12 weeks after OHT to a combination of low-dose everolimus and tacrolimus (the RADTAC group) or standard-dose tacrolimus (the TAC group), with both groups coadministered mycophenolate and prednisolone. The primary endpoint was LVH indexed as the change in left ventricular mass (ΔLVM) by cardiovascular magnetic resonance (CMR) imaging from 12 to 52 weeks. Secondary endpoints included CMR-based myocardial performance, T1 fibrosis mapping, blood pressure, and renal function. Safety endpoints included episodes of allograft rejection and infection. RESULTS: Forty stable OHT recipients were randomized. Recipients in the RADTAC group had significantly lower tacrolimus levels compared with the TAC group (6.5 ± 3.5 μg/l vs. 8.6 ± 2.8 μg/l; p = 0.02). The mean everolimus level in the RADTAC group was 4.2 ± 1.7 μg/l. A significant reduction in LVM was observed in the RADTAC group compared with an increase in LVM in the TAC group (ΔLVM = -13.0 ± 16.8 g vs. 2.1 ± 8.4 g; p < 0.001). Significant differences were also noted in secondary endpoints measuring function and fibrosis (Δ circumferential strain = -2.9 ± 2.8 vs. 2.1 ± 2.3; p < 0.001; ΔT1 mapping values = -32.7 ± 51.3 ms vs. 26.3 ± 90.4 ms; p = 0.003). No significant differences were observed in blood pressure (Δ mean arterial pressure = 4.2 ± 18.8 mm Hg vs. 2.8 ± 13.8 mm Hg; p = 0.77), renal function (Δ creatinine = 3.1 ± 19.9 μmol/l vs. 9 ± 21.8 μmol/l; p = 0.31), frequency of rejection episodes (p = 0.69), or frequency of infections (p = 0.67) between groups. CONCLUSIONS: The combination of low-dose everolimus and tacrolimus compared with standard-dose tacrolimus safely attenuates LVH in the first year after cardiac transplantation with an observed reduction in CMR-measured fibrosis and an improvement in myocardial strain.
dc.format	Print
dc.language	eng
dc.publisher	Elsevier BV
dc.relation.ispartof	JACC Heart Fail
dc.relation.isbasedon	10.1016/j.jchf.2021.01.007
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	1102 Cardiorespiratory Medicine and Haematology
dc.subject.mesh	Calcineurin
dc.subject.mesh	Calcineurin Inhibitors
dc.subject.mesh	Drug Therapy, Combination
dc.subject.mesh	Everolimus
dc.subject.mesh	Graft Rejection
dc.subject.mesh	Graft Survival
dc.subject.mesh	Heart Failure
dc.subject.mesh	Heart Transplantation
dc.subject.mesh	Humans
dc.subject.mesh	Hypertrophy, Left Ventricular
dc.subject.mesh	Immunosuppressive Agents
dc.subject.mesh	Prospective Studies
dc.title	Everolimus for the Prevention of Calcineurin-Inhibitor-Induced Left Ventricular Hypertrophy After Heart Transplantation (RADTAC Study).
dc.type	Journal Article
utslib.citation.volume	9
utslib.location.activity	United States
utslib.for	1102 Cardiorespiratory Medicine and Haematology
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Health
utslib.copyright.status	closed_access	*
dc.date.updated	2022-04-04T03:06:20Z
pubs.issue	4
pubs.publication-status	Published
pubs.volume	9
utslib.citation.issue	4

Abstract:

OBJECTIVES: This study aimed to determine the safety and efficacy of combined low-dose everolimus and low-dose tacrolimus compared with standard-dose tacrolimus in attenuating left ventricular hypertrophy (LVH) after orthotopic heart transplantation (OHT). BACKGROUND: Calcineurin inhibitors (CNIs) such as tactrolimus are important in preventing cardiac allograft rejection and reducing mortality after OHT. However CNIs are causatively linked to the development of LVH, and are associated with nephrotoxicity and vasculopathy. CNI-sparing agents such as everolimus have been hypothesized to inhibit adverse effects of CNIs. METHODS: In this prospective, randomized, open-label study, OHT recipients were randomized at 12 weeks after OHT to a combination of low-dose everolimus and tacrolimus (the RADTAC group) or standard-dose tacrolimus (the TAC group), with both groups coadministered mycophenolate and prednisolone. The primary endpoint was LVH indexed as the change in left ventricular mass (ΔLVM) by cardiovascular magnetic resonance (CMR) imaging from 12 to 52 weeks. Secondary endpoints included CMR-based myocardial performance, T1 fibrosis mapping, blood pressure, and renal function. Safety endpoints included episodes of allograft rejection and infection. RESULTS: Forty stable OHT recipients were randomized. Recipients in the RADTAC group had significantly lower tacrolimus levels compared with the TAC group (6.5 ± 3.5 μg/l vs. 8.6 ± 2.8 μg/l; p = 0.02). The mean everolimus level in the RADTAC group was 4.2 ± 1.7 μg/l. A significant reduction in LVM was observed in the RADTAC group compared with an increase in LVM in the TAC group (ΔLVM = -13.0 ± 16.8 g vs. 2.1 ± 8.4 g; p < 0.001). Significant differences were also noted in secondary endpoints measuring function and fibrosis (Δ circumferential strain = -2.9 ± 2.8 vs. 2.1 ± 2.3; p < 0.001; ΔT1 mapping values = -32.7 ± 51.3 ms vs. 26.3 ± 90.4 ms; p = 0.003). No significant differences were observed in blood pressure (Δ mean arterial pressure = 4.2 ± 18.8 mm Hg vs. 2.8 ± 13.8 mm Hg; p = 0.77), renal function (Δ creatinine = 3.1 ± 19.9 μmol/l vs. 9 ± 21.8 μmol/l; p = 0.31), frequency of rejection episodes (p = 0.69), or frequency of infections (p = 0.67) between groups. CONCLUSIONS: The combination of low-dose everolimus and tacrolimus compared with standard-dose tacrolimus safely attenuates LVH in the first year after cardiac transplantation with an observed reduction in CMR-measured fibrosis and an improvement in myocardial strain.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/155923