De novo sirolimus and reduced-dose tacrolimus versus standard-dose tacrolimus after liver transplantation: the 2000-2003 phase II prospective randomized trial.
Asrani SK, Wiesner RH, Trotter JF, et al.American Journal of Transplantation. 2014; 14, 356-66.
Aims
To investigate the efficacy of sirolimus with reduced dose tacrolimus compared to standard dose tacrolimus in liver transplant recipients.
Interventions
Participants received either tacrolimus (0.06-0.10mg/kg/day) to achieve a trough of 7-15ng/mL within 3 months and 5-10 ng/mL thereafter or tacrolimus (0.03-0.05mg/kg/day) to achieve a trough of 3-7ng/mL within the first three months and 3-5ng/mL thereafter. Sirolimus was administered 48h after transplantation and a loading dose of 15mg was administered on day one and adjusted to achieve a trough level of 4-11ng/mL.
Participants
300 participants undergoing deceased donor orthotopic liver transplantation.
Outcomes
The primary outcome included biopsy proven acute rejection requiring treatment within 48h, graft loss or patient death. The secondary outcomes included patient and graft survival, biopsy confirmed acute rejection (assessed at 6, 12 and 24 months of treatment), renal function (at 12 and 24 months), efficacy failure, rate of post-transplant diabetes mellitus, incidence of hepatic artery thrombosis (HAT) and portal vein thrombosis (PVT), and the development of infection or malignancy.
Follow-up
24 months.
CET Conclusions
In this study patients who were receiving sirolimus with reduced dose tacrolimus had inferior graft and patient survival to those patients allocated to standard dose tacrolimus. The adverse events occurring in the reduced dose tacrolimus and sirolimus arm lead to discontinuation of the study after 21 months. It was also noted that in addition to a higher graft loss and patient death in the interventional arm there was a higher rate of hepatic artery thrombosis and portal vein thrombosis in the patients on sirolimus and reduced dose tacrolimus. Furthermore there was essentially no difference in renal function in the interventional arm. Thus the data from this study does not suggest that this is an appropriate protocol in liver transplantation.
Data analysis
Modified intention-to-treat analysis
Trial registration
Not reported.