Early Everolimus-Facilitated Reduced Tacrolimus in Liver Transplantation: Results From the Randomized HEPHAISTOS Trial

Björn Nashan, Peter Schemmer, Felix Braun, Hans J Schlitt, Andreas Pascher, Christian G Klein, Ulf P Neumann, Irena Kroeger, Peter Wimmer, Hephaistos Study Group, Björn Nashan, Peter Schemmer, Felix Braun, Hans J Schlitt, Andreas Pascher, Christian G Klein, Ulf P Neumann, Irena Kroeger, Peter Wimmer, Hephaistos Study Group

Abstract

Everolimus-facilitated reduced-exposure tacrolimus (EVR + rTAC) at 30 days after liver transplantation (LT) has shown advantages in renal preservation. This study evaluated the effects of early initiation of EVR + rTAC in de novo LT recipients (LTRs). In HEPHAISTOS (NCT01551212, EudraCT 2011-003118-17), a 12-month, multicenter, controlled study, LTRs were randomly assigned at 7 to 21 days after LT to receive EVR + rTAC or standard-exposure tacrolimus (sTAC) with steroids. The primary objective was to demonstrate superior renal function (assessed by estimated glomerular filtration rate [eGFR]) with EVR + rTAC versus sTAC at month 12 in the full analysis set (FAS). Other assessments at month 12 included the evaluation of renal function in compliance set and on-treatment (OT) patients, efficacy (composite endpoint of graft loss, death, or treated biopsy-proven acute rejection [tBPAR] and individual components) in FAS, and safety. In total, 333 patients (EVR + rTAC, 169; sTAC, 164) were included in the FAS. A high proportion of patients was nonadherent in maintaining tacrolimus trough levels (EVR + rTAC, 36.1%; sTAC, 34.7%). At month 12, the adjusted least square mean eGFR was numerically higher with EVR + rTAC versus sTAC (76.2 versus 72.1 mL/minute/1.73 m2 , difference: 4.1 mL/minute/1.73 m2 ; P = 0.097). A significant difference of 8.3 mL/minute/1.73 m2 (P = 0.03) favoring EVR + rTAC was noted in the compliance set. Incidence of composite efficacy endpoint (7.7% versus 7.9%) and tBPAR (7.1% versus 5.5%) at month 12 as well as incidence of treatment-emergent adverse events (AEs) and serious AEs were comparable between groups. A lower proportion of patients discontinued EVR + rTAC than sTAC treatment (27.2% versus 34.1%). Early use of everolimus in combination with rTAC showed comparable efficacy, safety, and well-preserved renal function versus sTAC therapy at month 12. Of note, renal function was significantly enhanced in the compliance set.

© 2021 The Authors. Liver Transplantation published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.

Figures

FIG. 1
FIG. 1
Patient disposition.
FIG. 2
FIG. 2
Evolution of renal function (eGFR; MDRD‐4) over month 12: (A) overall population and (B) subgroups with baseline eGFR 2.
FIG. 3
FIG. 3
Median UPCR over month 12 (safety set).
FIG. 4
FIG. 4
Kaplan‐Meier curve plot for composite endpoint (Full analysis set over month 12).

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Source: PubMed

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