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Improved Survival in Liver Transplant Patients Receiving Prolonged-release Tacrolimus-based Immunosuppression in the European Liver Transplant Registry (ELTR)

An Extension Study

Adam, René MD, PhD1; Karam, Vincent PhD1; Cailliez, Valérie1; Trunečka, Pavel MD, PhD2; Samuel, Didier MD, PhD1; Tisone, Giuseppe MD, PhD3; Němec, Petr MD, PhD4; Soubrane, Olivier MD, PhD5; Schneeberger, Stefan MD, PhD6; Gridelli, Bruno MD, PhD7; Bechstein, Wolf O. MD, PhD8; Risaliti, Andrea MD, PhD9; Line, Pal-Dag MD, PhD10; Vivarelli, Marco MD, PhD11; Rossi, Massimo MD, PhD12; Pirenne, Jacques MD, PhD13; Klempnauer, Jurgen L. MD, PhD14; Rummo, Aleh MD, PhD15; Di Benedetto, Fabrizio MD, PhD16; Zieniewicz, Krzysztof MD, PhD17; Troisi, Roberto MD, PhD18; Paul, Andreas MD, PhD19; Vali, Toomas MD, PhD20; Kollmar, Otto MD, PhD21; Boudjema, Karim MD, PhD22; Hoti, Emir MD, PhD23; Colledan, Michele MD, PhD24; Pratschke, Johan MD, PhD25; Lang, Hauke MD, PhD26; Popescu, Irinel MD, PhD27; Ericzon, Bo-Goran MD, PhD28; Strupas, Kestutis MD, PhD29; De Simone, Paolo MD, PhD30; Kochs, Eberhard MD, PhD31; Heyd, Bruno MD, PhD32; Gugenheim, Jean MD, PhD33; Pinna, Antonio D. MD, PhD34; Bennet, William MD, PhD35; Kazimi, Mirjalal MD, PhD36; Bachellier, Philippe MD, PhD37; Wigmore, Stephen J. MD, PhD38; Rasmussen, Allan MD, PhD39; Clavien, Pierre-Alain MD, PhD40; Hidalgo, Ernest MD, PhD41; O’Grady, John G. MD, PhD42; Zamboni, Frausto MD, PhD43; Kilic, Murat MD, PhD44; Duvoux, Christophe MD, PhD45 all contributing centers (www.eltr.org) and the European Liver and Intestine Transplant Association (ELITA)

doi: 10.1097/TP.0000000000002700
Original Clinical Science—Liver
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Background. We compared, through the European Liver Transplant Registry, long-term liver transplantation outcomes with prolonged-release tacrolimus (PR-T) versus immediate-release tacrolimus (IR-T)–based immunosuppression. This retrospective analysis comprises up to 8-year data collected between 2008 and 2016, in an extension of our previously published study.

Methods. Patients with <1 month follow-up were excluded; patients were propensity score matched for baseline characteristics. Efficacy measures included: univariate/multivariate analyses of risk factors influencing graft/patient survival up to 8 years posttransplantation, and graft/patient survival up to 4 years with PR-T versus IR-T. Overall, 13 088 patients were included from 44 European centers; propensity score–matched analyses comprised 3006 patients (PR-T: n = 1002; IR-T: n = 2004).

Results. In multivariate analyses, IR-T-based immunosuppression was associated with reduced graft survival (risk ratio, 1.49; P = 0.0038) and patient survival (risk ratio, 1.40; P = 0.0215). There was improvement with PR-T versus IR-T in graft survival (83% versus 77% at 4 y, respectively; P = 0.005) and patient survival (85% versus 80%; P = 0.017). Patients converted from IR-T to PR-T after 1 month had a higher graft survival rate than patients receiving IR-T at last follow-up (P < 0.001), or started and maintained on PR-T (P = 0.019). One graft loss in 4 years was avoided for every 14.3 patients treated with PR-T versus IR-T.

Conclusions. PR-T-based immunosuppression might improve long-term outcomes in liver transplant recipients than IR-T-based immunosuppression.

1 Hepato-Biliary Center, AP-HP Paul Brousse Hospital, University of Paris-Sud, INSERM U935, Villejuif, France.

2 Transplant Center, Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic.

3 Liver Transplant Unit, Tor Vergata Polyclinic, University of Rome Tor Vergata, Rome, Italy.

4 Center of Cardiovascular Surgery and Transplantation, Brno, Czech Republic.

5 Department of Digestive Surgery, AP-HP Beaujon Hospital, Clichy, France.

6 Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria.

7 Mediterranean Institute for Transplantation and Advanced Specialized Therapies, Palermo, Sicily, Italy.

8 Department of General and Visceral Surgery, Goethe University Hospital and Clinics, Frankfurt, Germany.

9 Department of Surgery, Liver Transplant Unit, University Hospital Udine, Udine, Italy.

10 Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.

11 Hepatobiliary and Abdominal Transplantation Surgery, Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy.

12 Department of General Surgery, Organ Transplant Unit “Paride Stefanini”, Umberto 1 Policlinico of Rome, Rome, Italy.

13 Abdominal Transplant Surgery, University Hospital Leuven, Leuven, Belgium.

14 Department of General, Visceral and Transplantation Surgery, Hannover Medical School, Hannover, Germany.

15 Republican Scientific and Practical Center (RSPC) for Organ and Tissue Transplantation, Minsk, Belarus.

16 Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, University of Modena and Reggio Emilia, Modena, Italy.

17 Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland.

18 Department of General Hepato-Biliary and Liver Transplantation Surgery, Ghent University Hospital Medical School, Belgium.

19 Department of General and Transplant Surgery, University Hospital Essen, Essen, Germany.

20 Surgery Clinic, Tartu University Hospital, Tartu, Estonia.

21 Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.

22 Department of Visceral Surgery, University Hospital Rennes, Pontchaillou Hospital, Rennes, France.

23 Liver Unit, St. Vincent’s Hospital, Dublin, Ireland.

24 Department of Surgery, Pope John XXIII Hospital, Bergamo, Italy.

25 Department of General, Visceral and Transplantation Surgery, Charité Campus Virchow-Klinikum (CVK), Berlin, Germany.

26 General, Visceral and Transplantation Surgery Clinic, Johannes Gutenberg University Mainz, Mainz, Germany.

27 Department of Surgery and Liver Transplantation, Fundeni Clinical Institute, University of Medicine “Carol Davila”, Bucharest, Romania.

28 Department of Transplantation Surgery, Karolinska University Hospital, Huddinge, Sweden.

29 Department for Gastroentrology, Nephrology and Surgery, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania.

30 Hepatobiliary Surgery and Liver Transplantation Unit, University of Pisa Medical School Hospital, Pisa, Italy.

31 Surgical Clinic and Polyclinic, University Hospital Klinikum rechts der Isar Munich, Munich, Germany.

32 Department of Visceral Surgery, University Hospital Besançon, University of Franche-Comté, Besançon, France.

33 Department of Digestive Surgery, Archet 2 Hospital, Nice, France.

34 University of Bologna, Transplant and HPB Institute, Bologna, Italy.

35 Surgery Department, Transplantation and Liver Surgery Unit, Sahlgrenska University Hospital, Gothenburg, Sweden.

36 Surgery and Organ Transplantation Center, Central Hospital of Oil Workers, Baku, Azerbaijan.

37 Department of Surgery, Hospital Hautepierre, University Hospitals of Strasbourg, Strasbourg, France.

38 Liver Transplantation Unit, University of Edinburgh Royal Infirmary, Edinburgh, United Kingdom.

39 Department for Surgery and Transplantation, University Hospital Copenhagen, Copenhagen, Denmark.

40 Department of Visceral and Transplant Surgery, University Hospital Zurich, Zurich, Switzerland.

41 St James and Seacroft University Hospital, Leeds, United Kingdom.

42 Liver Unit, King’s College Hospital, London, United Kingdom.

43 Department of General Surgery and Transplantation, Hospital G. Brotzu, Cagliari, Italy.

44 Kent Hospital, Izmir, Turkey.

45 Department of Hepatology and Gastroenterology, University Hospital of Henri-Mondor, Creteil, France.

Received 30 November 2018. Revision received 17 January 2019.

Accepted 4 February 2019.

P.T. has received speaker honorarium from Pfizer and has been involved in advisory boards and received consultancy agreements from Astellas. D.S. has received consultant fees from Astellas, Novartis, and Roche. P.N. has received speaker honoraria from Astellas and Novartis. W.O.B. has received honoraria and served on advisory boards for Astellas. M.V. and M.C. have received honorarium for an advisory board for Novartis. J.L.K. has received support from Astellas, Novartis, Roche, BMS, and Genzyme. B.G.E. has received speaker honorarium from Pfizer, Astellas, and Novartis. P.D.S. has received speaker fees and served as an advisory board member for Astellas. C.D. has received grants from Astellas, grants from Novartis, grants and other from Chiesi, personal fees from Sandoz, and nonfinancial support from Biotest. The other authors declare no conflict of interests.

The ELTR was supported by a grant from Astellas, Novartis, and Institut Georges Lopez, and logistic support was obtained from the Paul Brousse Hospital (Assistance Publique—Hôpitaux de Paris). Editorial support was funded by a grant from Astellas Pharma, Inc.

R.A. participated in research design, participated in the writing of the paper, and participated in data analysis. V.K. participated in research design, participated in the writing of the paper, and participated in data analysis. V.C. participated in research design and participated in data analysis. P.T., D.S., G.T., P.N., O.S., S.S., B.G., W.O.B., A.R., P.D.L., M.V., M.R., J.P., J.L.K., A.R., F.D.B., K.Z., R.T., A.P., T.V., O.K., K.B., E.H., M.C., J.P., H.L., I.P., B.G.E., K.S., P.D.S., E.K., B.H., J.G., A.D.P., W.B., M.K., P.B., S.J.W, A.R., P.A.C., E.H., J.G.O., F.Z., M.K., and C.D. participated in the performance of the research.

Correspondence: René Adam, MD, PhD, Centre Hépatobiliaire, Hôpital Paul Brousse, Avenue Paul Vaillant Couturier, 94804 Villejuif, France. (rene.adam@aphp.fr).

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