De novo sirolimus and reduced-dose tacrolimus versus standard-dose tacrolimus after liver transplantation: the 2000-2003 phase II prospective randomized trial

Am J Transplant. 2014 Feb;14(2):356-66. doi: 10.1111/ajt.12543. Epub 2014 Jan 23.


We studied whether the use of sirolimus with reduced-dose tacrolimus, as compared to standard-dose tacrolimus, after liver transplantation is safe, tolerated and efficacious. In an international multicenter, open-label, active-controlled randomized trial (2000-2003), adult primary liver transplant recipients (n=222) were randomly assigned immediately after transplantation to conventional-dose tacrolimus (trough: 7-15 ng/mL) or sirolimus (loading dose: 15 mg, initial dose: 5 mg titrated to a trough of 4-11 ng/mL) and reduced-dose tacrolimus (trough: 3-7 ng/mL). The study was terminated after 21 months due to imbalance in adverse events. The 24-month cumulative incidence of graft loss (26.4% vs. 12.5%, p=0.009) and patient death (20% vs. 8%, p=0.010) was higher in subjects receiving sirolimus. A numerically higher rate of hepatic artery thrombosis/portal vein thrombosis was observed in the sirolimus arm (8% vs. 3%, p=0.065). The incidence of sepsis was higher in the sirolimus arm (20.4% vs. 7.2%, p=0.006). Rates of acute cellular rejection were similar between the two groups. Early use of sirolimus using a loading dose followed by maintenance doses and reduced-dose tacrolimus in de novo liver transplant recipients is associated with higher rates of graft loss, death and sepsis when compared to the use of conventional-dose tacrolimus alone.

Keywords: Black box; graft failure; hepatic artery thrombosis; patient death; portal vein thrombosis; rapamycin; renal failure.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Dose-Response Relationship, Drug
  • Female
  • Follow-Up Studies
  • Graft Rejection / drug therapy*
  • Graft Rejection / etiology
  • Graft Rejection / mortality
  • Graft Survival / drug effects*
  • Humans
  • Immunosuppressive Agents / therapeutic use*
  • International Agencies
  • Liver Diseases / complications
  • Liver Diseases / mortality
  • Liver Diseases / surgery*
  • Liver Transplantation*
  • Male
  • Middle Aged
  • Prognosis
  • Prospective Studies
  • Sirolimus / therapeutic use*
  • Survival Rate
  • Tacrolimus / therapeutic use*
  • Time Factors
  • Transplantation Immunology


  • Immunosuppressive Agents
  • Sirolimus
  • Tacrolimus