De novo sirolimus and reduced-dose tacrolimus versus standard-dose tacrolimus after liver transplantation: the 2000-2003 phase II prospective randomized trial.
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.
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN; William J. von Liebig Transplant Center, Mayo Clinic, Rochester, MN; Annette C and Harold-Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX.
S K
SK
Asrani
R H
RH
Wiesner
J F
JF
Trotter
G
G
Klintmalm
E
E
Katz
E
E
Maller
J
J
Roberts
N
N
Kneteman
L
L
Teperman
J J
JJ
Fung
J M
JM
Millis
D000328:Adult; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007390:International Agencies; D008107:Liver Diseases / Q000150:complications / Q000401:mortality / Q000601:surgery*; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011446:Prospective Studies; D020123:Sirolimus / Q000627:therapeutic use*; D015996:Survival Rate; D016559:Tacrolimus / Q000627:therapeutic use*; D013997:Time Factors; D014181:Transplantation Immunology
D007166:Immunosuppressive Agents; D020123:Sirolimus; D016559:Tacrolimus
Black box; graft failure; hepatic artery thrombosis; patient death; portal vein thrombosis; rapamycin; renal failure