TY - JOUR
T1 - Early Everolimus-Facilitated Reduced Tacrolimus in Liver Transplantation
T2 - Results From the Randomized HEPHAISTOS Trial
AU - Nashan, Björn
AU - Schemmer, Peter
AU - Braun, Felix
AU - Schlitt, Hans J.
AU - Pascher, Andreas
AU - Klein, Christian G.
AU - Neumann, Ulf P.
AU - Kroeger, Irena
AU - Wimmer, Peter
AU - Hephaistos Study Group
N1 - Funding Information:
The authors thank the patients who participated in this study and the study investigators. Medical writing support, under the guidance of the authors, was provided by Sarabjeet Kaur and Aruna Meka, senior scientific writers for Novartis, India. We would also like to thank the principal investigators of the HEPHAISTOS study group: Andreas Pascher at Universitätsmedizin Charité, Thomas Becker at Universitätsklinikum Schleswig Holstein Campus Kiel, Markus Guba at Universitätsklinikum München Ludwig Maximilian Universität; Volker Mueller and Aristotelis Perrakis at Universitätsklinikum Erlangen-Nürnberg; Juergen Klempnauer and Frank Lehner at Medizinische Hochschule Hannover; Peter Schemmer and Karl Heinz Weiss at Universitätsklinikum Heidelberg; Joerg-Matthias Pollok and Steffen Manekeller at Universitätsklinikum Bonn; Silvio Nadalin at Universitätsklinikum Tübingen; Sven Jonas, Michael Bartels, Daniel Seehofer, and Hans-Michael Tautenhahn at Universitätsklinikum Leipzig Anstalt öffentlichen Rechts; Hans Juergen Schlitt at Universitätsklinikum Regensburg; Michael Heise at Klinikum der Johannes-Gutenberg Universität; Gernot Kaiser and Christian Georg Klein at Universitätsklinikum Essen; Christian Moench, Frank Ulrich, and Andreas Schnitzbauer at Universitätsklinikum Frankfurt; Björn Nashan and Lutz Fischer at Universitätsklinikum Hamburg-Eppendorf; and Ulf Peter Neumann at Universitätsklinikum Aachen.
Funding Information:
This study and the analyses were funded by Novartis Pharma GmbH, Nürnberg, Germany.
Funding Information:
Irena Kroeger is employed by Novartis. Felix Braun is on thespeakers’ bureau for and received grants from Novartis. Peter Schemmer consultsfor, advises, is on the speakers' burearu for and recieved grants fromAllergosan, ArgosMed, Astellas, Bard Medical, Biotest, Chiesi, Dr. Fanz KohlerChemie, Ethicon, Medtronic, Merck, Neovi, Novartis, Panacea, Biotec, Sandoza,and Shire. Hans J. Schlitt advises and received grants from Chiesi. He receivedgrants from Takeda and Novartis. Andreas Pascher is on the speakers' bureau forAstellas, Novartis, Takeda, and Johnson & Johnson. Christian G.Klein is on the speakers' bureau for Novartis Björn Nashan consultsfor Novartis. Ulf Peter Neumann is on the speakers’ bureau for and receivedgrants from Roche, Bristol Myers Squibb, Novartis, Celgene, and Merck AG. PeterWimmer was employed by Novartis.
Publisher Copyright:
© 2021 The Authors. Liver Transplantation published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.
PY - 2022/6/1
Y1 - 2022/6/1
N2 - 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.
AB - 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.
U2 - 10.1002/lt.26298
DO - 10.1002/lt.26298
M3 - Article
SN - 1527-6465
VL - 28
SP - 998
EP - 1010
JO - Liver Transplantation
JF - Liver Transplantation
IS - 6
ER -