Tacrolimus versus microemulsified ciclosporin in liver transplantation: the TMC randomised controlled trial

• Published in: The Lancet (British edition) 2002-10, Vol.360 (9340), p.1119-1125
• Main Authors: O'Grady, JG, Burroughs, A, Hardy, P, Elbourne, D, Truesdale, A
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult; Antihypertensives; Calcineurin; Calcineurin inhibitors; Clinical trials; Cyclosporine - adverse effects; Cyclosporine - therapeutic use; Diabetes; Drug dosages; Drug therapy; Drug Therapy, Combination; Emulsions; Evidence-based medicine; Failure analysis; Female; Follow-Up Studies; Graft Rejection - immunology; Graft Rejection - mortality; Graft Rejection - prevention & control; Hepatic artery; Humans; Hyperglycemia; Immunology; Immunosuppression; Immunosuppressive agents; Immunosuppressive Agents - adverse effects; Immunosuppressive Agents - therapeutic use; Insulin; Liver; Liver transplantation; Liver Transplantation - immunology; Liver Transplantation - mortality; Liver transplants; Male; Middle Aged; Motivation; Patients; Rank tests; Renal function; Reoperation - statistics & numerical data; Risk allocation; Risk Factors; Sepsis; Survival Analysis; Tacrolimus; Tacrolimus - adverse effects; Tacrolimus - therapeutic use; Therapy; Thromboembolism; Thrombosis; Transplantation; Transplants & implants
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(02)11196-2

Calcineurin inhibitors are the most commonly used immunosuppressive drugs in liver transplantation, but the optimum initial immunosuppression regimen is not known. The aim of our study was to compare tacrolimus with microemulsified ciclosporin, in a regimen with standardised concomitant immunosuppressive therapy. In all liver transplant centres in the UK and Republic of Ireland, 606 patients undergoing a first orthotopic liver transplantation were randomly assigned open-label tacrolimus or microemulsified ciclosporin. Primary outcome was the combined frequency (whichever occurred first) of death, retransplantation, or treatment failure for immunological reasons, analysed by intention to treat. 96% of patients received the treatment allocated to them. The primary outcome was reached in 62 (21%) of 301 patients in the tacrolimus group versus 99 (32%) of 305 allocated microemulsified ciclosporin (relative risk 0·63 [95% Cl 0·48-0·84], p=0·001; time-to-event analysis log-rank test p=0·002): deaths (50 [17%] vs 72 [24%]); retransplantations (11 [4%] vs 31 [10%]) treatment failure for immunological reasons (6 [2%] vs 12 [4%]). The relative risk for the composite outcome was in favour of tacrolimus. The main causes of death in both trial groups were sepsis and multiple organ failure (31 [10%] vs 30 [10%]), and the main cause for retransplantation was hepatic artery thrombosis (6 [2%] vs 17 [6%]). Renal dysfunction and the need for antihypertensive therapy were much the same in both groups. Tacrolimus was more diabetogenic. Clinical outcome at 1 year was better with tacrolimus-based immunosuppression than with micro-emulsified ciclosporin during the first year after liver transplantation. Tacrolimus should be the first choice of calcineurin inhibitor for patients receiving their first liver graft.