Umstellung nach Lebertransplantation von zwei- zu einmal täglicher Gabe von Tacrolimus: 2-Jahres-Verlaufsbeobachtung zur Adhärenz, Sicherheit, und Wirksamkeit

Background – After a liver transplant, patients need to regularly take immunosuppressive drugs to prevent organ rejection. However, 15-40% experience difficulties adhering to their regimen. This increases their risk for graft loss, retransplantation, and death. The primary objective of this study was to explore whether simplifying the immunosuppressive regimen of stable liver transplant patients from conventional twice-daily (immediate-release Tacrolimus, IR-Tac, Prograf®) to novel once-daily Tacrolimus (novel extended-release Tacrolimus, LCP-Tac, Envarsus®) would improve adherence. In pharmacokinetic studies, LCP-Tac demonstrated lower dose requirements (-30%) and peak serum concentrations (-30%) compared to IR-Tac. The secondary objective was to determine whether these properties would translate into a reduction in typical side effects including nephrotoxicity, neurotoxicity, and diabetogenicity without an increase in rejection rates. Methods – We conducted a two-year, single arm, prospective conversion trial in 165 liver transplant recipients. At baseline, we converted patients from IR-Tac to LCP-Tac and conducted follow-up examinations at ten time points. We measured adherence using the Basel Assessment of Immunosuppressant Adherence (BAASIS©) questionnaire before conversion (t = 0) and at months 6, 12, 18, and 24. Any adverse event or changes to the medication regimen were noted. At each time point, we collected comprehensive laboratory values including liver, renal and metabolic panels. We compared the intra-patient variability (IPV) of Tacrolimus serum levels during the study period with the variability observed prior to conversion as a potential surrogate parameter for adherence. Results - A total of 161 patients received the study drug. Overall adherence on the BAASIS© increased from 50% at baseline with the twice-daily regimen to 80% at the time of completion under once-daily Tacrolimus (p < 0.001). After two years, patient and graft survival were 97%. No episodes of organ rejection occurred. 5 (3%) patients died and 22 (14%) withdrew from the study, mostly due to non-serious adverse events. There were no changes in graft, renal, or metabolic function. The intra-patient variability (IPV) of Tacrolimus serum levels did not change after conversion to LCP-Tac. Out of 51 patients who experienced tremor at study entry, 20 (40%) reported partial or complete symptom remission after conversion. Conclusion – The results of the study presented here implicate that the use of LCP-Tac might improve immunosuppressant adherence in liver transplant recipients as compared to conventional IR-Tac, while providing comparable safety and efficacy for the prevention of allograft rejection. Larger, randomized studies should examine potential positive long-term effects on patient and graft survival. In addition, patients who experience tremor with the IR-Tac formula might benefit from conversion to LCP-Tac.Hintergrund - Nach einer Lebertransplantation müssen Patienten regelmäßig Immunsuppressiva einnehmen, um eine Abstoßung des Organs zu verhindern. 15-40% haben jedoch Schwierigkeiten, dem Therapieplan zu folgen. Dies erhöht das Risiko für Transplantatverlust, Re-Transplantation und Tod. Das primäre Ziel dieser Studie war zu untersuchen, ob die Umstellung von Patienten mit stabilem Verlauf nach Lebertransplantation von einer zweimal täglichen (immediate release Tacrolimus, IR-Tac, Prograf®) auf eine einmal tägliche Tacrolimus Formel (novel once-daily Tacrolimus, LCP-Tac, Envarsus®) die Adhärenz verbessert. In früheren Studien zeigte LCP-Tac niedrigere Dosisanforderungen (-30%) und Serum-Spitzenspiegel (-30%) als IR-Tac. Das sekundäre Ziel war zu untersuchen, ob diese Eigenschaften zu einer Minderung typischer Nebenwirkungen wie Nephro-, Neurotoxizität, und Diabetogenität führen, ohne das Abstoßungsrisiko zu erhöhen. Methoden - Wir führten eine zweijährige, einarmige, prospektive Konversionsstudie mit 165 Patienten nach Lebertransplantation durch. Zu Studienbeginn wurden die Patienten von IR- auf LCP-Tac umgestellt und an zehn Zeitpunkten untersucht. Die Adhärenz wurde mithilfe des BAASIS©-Fragebogens (Basel Assessment of Immunosuppressant Adherence) vor Umstellung (t = 0) und den Monaten 6, 12, 18 und 24 bestimmt. Unerwünschte Ereignisse und Änderungen des Medikationsschemas wurden dokumentiert. Zudem bestimmten wir umfassende Laborwerte einschließlich Leber-, Nieren-, und Stoffwechselparameter. Als Surrogat-Parameter für die Adhärenz verglichen wir die Intra-Patienten-Variabilität (IPV) der Tacrolimus-Serumspiegel unter LCP-Tac mit der Variabilität vor Umstellung unter IR-Tac. Ergebnisse - 161 Patienten erhielten das Studienmedikament. Die Adhärenz (erhoben mit dem BAASIS©-Fragebogen) verbesserte sich von 50% unter einer zweimal täglichen, auf 80% mit einer einmal täglichen Gabe von Tacrolimus zum Studienende (p <0.001). Nach zwei Jahren betrug das Patienten- und Transplantatüberleben 97%. Es traten keine Abstoßungen auf. 5 (3%) Patienten starben und 22 (14%) schieden aus der Studie aus, primär infolge nicht schwerwiegender Ereignisse. Transplantat-, Nieren- und Stoffwechselfunktion waren stabil. Die IPV der Tacrolimus-Serumspiegel zeigte keine signifikante Änderung unter LCP-Tac. 20 von 51 (40%) Patienten, bei denen unter IR-Tac ein Tremor auftrat, berichteten von einer Besserung oder Remission der Symptome nach Umstellung. Schlussfolgerung – Die Ergebnisse der vorliegenden Studie sprechen dafür, dass sich die Medikamentenadhärenz bei Patienten nach Lebertransplantation durch Umstellung der Immunsuppression von IR-Tac auf LCP-Tac bei vergleichbarer Sicherheit und Effektivität verbessert. In größeren, kontrollierten Studien sollten mögliche positive Langzeiteffekte auf das Transplantat- und Patientenüberleben untersucht werden. Zudem könnten Patienten, bei denen unter IR-Tac Tremor auftritt, von einer Umstellung auf LCP-Tac profitieren

Reducing the Pill Burden: Immunosuppressant Adherence and Safety after Conversion from a Twice-Daily (IR-Tac) to a Novel Once-Daily (LCP-Tac) Tacrolimus Formulation in 161 Liver Transplant Patients

Non-adherence to immunosuppressant therapy reduces long-term graft and patient survival after solid organ transplantation. The objective of this 24-month prospective study was to determine adherence, efficacy and safety after conversion of stable liver transplant (LT) recipients from a standard twice-daily immediate release Tacrolimus (IR-Tac) to a novel once-daily life cycle pharma Tacrolimus (LCP-Tac) formulation. We converted a total of 161 LT patients at baseline, collecting Tacrolimus trough levels, laboratories, physical examination data and the BAASIS(C) questionnaire for self-reported adherence to immunosuppression at regular intervals. With 134 participants completing the study period (17% dropouts), the overall adherence to the BAASIS(C) increased by 57% until month 24 compared to baseline (51% vs. 80%). Patients who required only a morning dose of their concomitant medications reported the largest improvement in adherence after conversion. The intra-patient variability (IPV) of consecutive Tacrolimus trough levels after conversion did not change significantly compared to pre-conversion levels. Despite reducing the daily dose by 30% at baseline as recommended by the manufacturer, Tac-trough levels remained stable, reflected by an increase in the concentration-dose (C/D) ratio. No episodes of graft rejection or loss occurred. Our data suggest that the use of LCP-Tac in liver transplant patients is safe and can increase adherence to immunosuppression compared to conventional IR-Tac

Orthotopic Liver Transplantation for Budd-Chiari Syndrome: Observations from a 30-Year Liver Transplant Program

Background and objectives Budd-Chiari syndrome (BCS) refers to a complete thrombotic obstruction of the venous hepatic outflow tract due to various etiologies and constitutes a rare indication for ortothopic liver transplantation (LT). Few studies investigated long-term outcomes after LT for BCS. The aim of this study was to examine potential risk factors for late mortality and to evaluate long-term outcomes after LT for BCS. Materials and methods: 46 patients received an LT for BCS between 1989 and 2019 at the transplant center of the Charité-Universitätsmedizin Berlin. We analyzed potential effects of disease etiology, vascular events, rejection, and immunosuppression on long-term survival after transplantation using Kaplan-Meier curves and Cox logistic regression. Results: Of the 46 patients, 70% were female and 30% were male. Median age at the time of transplantation was 36 years. A total of 41 vascular events, including 26 thrombotic and 17 hemorrhagic incidents, occurred. The 1 year, the 5 year, the 10 year, and the 20 year survival rates were 87%, 83%, 76%, and 60%, respectively. By comparison, survival rates of the liver transplant cohort across all other indications at our center were slightly inferior with 85%, 75%, 65%, and 46%, respectively. In the study population, patients with myeloproliferative disorders showed worse outcomes compared to patients with other causes of BCS. Conclusion: Liver transplantation for BCS showed excellent results, even superior to those for other indications. Vascular events (i.e., thrombotic or hemorrhagic complications) did not have any prognostic value for overall mortality. Patients with myeloproliferative disorders seem to have a disadvantage in survival