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

JACC Heart Fail. 2021 Apr;9(4):301-313. doi: 10.1016/j.jchf.2021.01.007.

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.

Keywords: calcineurin inhibition; cardiac transplantation; everolimus; fibrosis; hypertrophy; immunosuppression; remodeling; tacrolimus.