Tacrolimus is superior to cyclosporine in liver transplantation

Abstract

WITH the addition of cyclosporine (CyA) to azathioprine and corticosteroids in the early 1980s, rejection rates were decreased and graft survival and patient survival rates were dramatically increased in liver allograft recipients. While CyA-based regimens became the standard for orthotopic liver transplant (OLT) recipients, issues such as the frequency and severity of acute and chronic rejection, steroid-induced adverse effects, and outcomes in pediatric liver transplants remained problematic. Tacrolimus (TAC) was approved by the Food and Drug Administration (FDA) in 1994 for primary immunosuppressive therapy in adult and pediatric OLT recipients. In animal models, TAC inhibited both T-cell-mediated immune, and to a lesser extent, humoral immune responses (B-cell proliferation). When compared to CyA, TAC appears to be 10 to 100 times more potent in its ability to inhibit interleukin-2 (IL-2). On the molecular level, TAC, once bound to its intracellular binding protein (FKBP), is believed to form a drug-isomerase complex with calcineurin and reduce its phosphatase activity. As a result, translocation of the nuclear factor of activated T cells (NF-AT) is prevented which ultimately results in a reduction of the transcription of IL-2. By limiting IL-2 transcription, TAC inhibits the proliferation of helper, cytotoxic T lymphocytes, and natural killer cells, which ultimately can be responsible for graft loss. The premise of the present position is that TAC is superior to CyA in liver transplantation. To validate this hypothesis, the following points will be demonstrated based on an analysis of the results of randomized controlled trials involving over 1000 patients in whom TAC was compared to CyA as the primary immunosuppressive therapy in liver transplantation and of several open-labeled trials enrolling up to 1500 patients. Data from these studies confirm the following advantages of TAC over CyA in liver transplant recipients: (1) TAC usage decreases acute rejection rates versus CyA (from 65% in CyA-treated patients to 56% in TAC-treated patients; P 5 .0001) and improves outcome; (2) use of TAC spares corticosteroid dose (cumulative prednisone dosages were significantly lower [P 5 .003] over 3 years in TAC-treated patients vs CyA-treated patients, with CyA patients receiving a mean of 25 mg/kg more steroid than TAC-treated patients) and reduces OKT3 usage (19% vs 36% in adults; 21% vs 32% in pediatric patients); (3) TAC is superior in preventing and treating chronic rejection (1.5% in TAC-treated patients vs 5.3% in CyA-treated patients; P 5 .032); (4) TAC use results in an improved 5-year patient and graft survival compared to CyA in patients transplanted with hepatitis C (78.9% and 73.7% vs 60.5% and 58.7%, respectively); (5) TAC is well tolerated over the long term; (6) TAC-based regimens improve cardiovascular risk profile; (7) TAC-based regimens improve long-term patient (80% vs 73%, respectively; P 5 .02) and graft survival (76% vs 68%, respectively; P 5 .04); (8) TAC demonstrates superior patient and graft half-lives compared to CyA-based regimens (25.1 6 5.1 and 20.6 6 4.0 vs 15.2 6 2.5 and 15.7 6 2.7 years, respectively); and of significant importance (10) TAC use results in improved outcomes in pediatric OLT recipients. Thus, the current data provide compelling evidence that TAC is the drug of choice in OLT recipients. TAC is superior to CyA in reducing acute rejection rates and improving outcome, as demonstrated by the US and European multicenter trials. In these trials involving over 1000 OLT recipients, A Kaplan-Meier estimate of the incidence of acute rejection at 1 year shows a marked reduction from 65% in CyA-treated patients to 56% in TAC-treated patients (P 5 .0001). The importance of achieving freedom from acute rejection cannot be underestimated. In fact, freedom from acute rejection is strongly associated with long-term patient and graft survival. As shown in Fig 1, TAC-treated patients who were free from early rejection had significantly better survival at 3 years compared to CyA-treated patients (80% vs 68%; P 5 .004). A similar advantage in graft survival was observed in the TAC group with a 3-year graft survival rate of 73% versus 61% for CyA (P 5 .007). In addition to decreasing acute rejection and improving outcome, another advantage of TAC is that it is steroid sparing and decreases the need for OKT3. For instance, in the European multicenter liver study, cumulative pred-