Cardiac transplantation practice guidelines
Suggested guidelines for the use of tacrolimus in cardiac transplant recipients

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Clinical trials of tacrolimus in heart transplantation

Tacrolimus use in heart transplantation began at the University of Pittsburgh in the early 1990s, initially as “rescue” therapy and later as primary therapy.1 Multicenter, comparative trials of tacrolimus and cyclosporine in heart transplantation have been performed in Europe2 and the United States.3 In addition, a single-center pilot study of tacrolimus therapy in combination with mycophenolate mofetil (MMF) has been completed.4 A summary of the design, patient enrollment, tacrolimus dosing

Efficacy based on clinical trials experience

Patient survival and the probability of freedom from rejection were similar between treatment groups in the European2 and U.S.3 trials. The pilot study of tacrolimus in combination with MMF suggests that the use of mycophenate mofetil, when dosed to maintain mycophenolic acid trough levels between 2.5 and 4.5 μg/ml, may allow a lower incidence of rejection than current historical cyclosporine- and tacrolimus-based protocols, with similar toxicities.4 A similar protocol of monitoring

Safety

No significant differences between tacrolimus and cyclosporine therapy with respect to renal dysfunction, hyperglycemia, hypomagnesemia, or hyperkalemia were reported in the U.S. or European multicenter studies. The U.S. trial showed significantly less hypercholesterolemia requiring treatment among patients receiving tacrolimus therapy (41% vs 71%; p = 0.01). The incidence of new-onset hypertension was also significantly lower among tacrolimus-treated patients (48% vs 71%; p = 0.05).

Indications

While the current clinical trials data suggest similar efficacy, several groups of patients may benefit from tacrolimus rather than cyclosporine as primary therapy following cardiac transplant. Unlike cyclosporine, hirsutism and gingival hyperplasia occur infrequently with tacrolimus, thus tacrolimus-based therapy may improve compliance and quality of life in female and pediatric patients. However, alopecia has been documented with tacrolimus, but often improves with dose reductions. Given the

Dosing and blood trough levels

We recommend that the target level of tacrolimus be achieved as soon as possible (within the first few days posttransplant), particularly if no lympholytic induction therapy is used. Given the relatively good oral bioavailability of tacrolimus, it can be administered orally (enterally) in the early posttransplant period. However, as with perioperative cyclosporine use, continuous intravenous infusion protocols are associated with more consistent levels early after transplant. Meiser et al.8

Summary

The guidelines presented in this report and summarized in Table II represent our consensus view based on current clinical experience. Ongoing experience with tacrolimus in heart transplant recipients will undoubtedly refine these recommendations in the future.

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