Association Between Renal Dysfunction and Major Adverse Cardiac Events After Liver Transplantation: Evidence from an International Randomized Trial of Everolimus-Based Immunosuppression

Abstract

BACKGROUND Prospective evidence is lacking regarding the association between renal dysfunction and cardiovascular events after liver transplantation. MATERIAL AND METHODS Data were analyzed post hoc regarding renal function and major adverse cardiac events in a two-year prospective trial of de novo liver transplant recipients randomized at 30 days post-transplant to (i) everolimus [EVR]/reduced tacrolimus [EVR/rTAC] (ii) EVR with tacrolimus discontinued [TAC Elimination] or (iii) standard tacrolimus [TAC Control]. RESULTS By month 24 post-transplant, 32/716 patients had experienced a first major cardiac event (4.5%): 4.1% (10/245), 2.2% (5/229) and 7.0% (17/242) of patients in the EVR/rTAC, TAC Elimination and TAC Control groups, respectively (p=0.043). The cumulative eGFR area under the curve (AUC) from randomization to month 24 was 119 706, 123 082, and 105 946 mL in the EVR/rTAC, TAC Elimination, and TAC Control groups, respectively, corresponding to a mean eGFR AUC of 82.4, 83.0, and 71.9 mL/min/1.73 m². Cox regression modeling showed that mean eGFR AUC was inversely associated with time to first major cardiac event: the hazard ratio per mL/min/1.73 m² was -0.0000015 [95% CI -0.00000078; -0.0000024] (p<0.001). CONCLUSIONS These findings confirm retrospective evidence that the risk of major cardiac events increases with deteriorating renal function after liver transplantation and demonstrate the need for careful cardiovascular risk management in patients with renal impairment. Immunosuppression based on everolimus with tacrolimus withdrawal, or to a lesser extent tacrolimus reduction, improves both renal function and the risk of major cardiac events compared to standard tacrolimus therapy in liver transplant recipients.

Figure 1

Kaplan-Meier (KM) plot of major cardiac events (MACE) to month 24 according to treatment group (ITT population). EVR – everolimus; rTAC – reduced tacrolimus; TAC – tacrolimus.

Figure 2

Area under the curve (AUC) of estimated GFR (eGFR) from baseline to month 24 according to treatment group (ITT population). EVR – everolimus; rTAC – reduced tacrolimus; TAC – tacrolimus.