Tacrolimus in cardiac transplantation: efficacy and safety of a novel dosing protocol.

BACKGROUND: Although used for more than 20 years, optimal dosing strategies of most immunosuppressants have never been determined. Tacrolimus, one of the newer agents used in solid-organ transplantation, is gaining increasing popularity because of its ability to reverse refractory rejection in cyclosporine-treated patients and its favorable side-effect profile. As with many other immunosuppressive agents, absorption and metabolism vary between individuals, which complicates dosing. METHODS: We hypothesized that a 1-mg dose of tacrolimus may be used to gauge each patient's metabolism. A novel dosing scheme was evaluated to establish the safety and efficacy of this approach. Outcomes were incidence of renal insufficiency and treatment efficacy as assessed by the rejection grade on the first endomyocardial biopsy. RESULTS: The risk of renal insufficiency was low, with only a 3% rise in creatinine at 7 days posttransplant. The risk of renal insufficiency was highest during the first 3 days of tacrolimus therapy, and the change in tacrolimus level during this time was identified as the single best predictor of renal insufficiency. From days 4 to 7, the rise in tacrolimus level had much less influence on renal function. Ninety-two percent of patients had a low- or intermediate-grade first cardiac biopsy. CONCLUSIONS: It was shown that this conservative initial dosing approach, which guarantees renal safety, is not associated with an increased risk of allograft rejection. We conclude that administration of tacrolimus via a tailored protocol soon after transplantation ensures a safe and effective means of immunosuppression.

Long-term results of tacrolimus monotherapy in cardiac transplant recipients.

BACKGROUND: Conventional immunosuppression for heart transplantation is associated with various adverse effects. Tacrolimus monotherapy (TM) is an alternative strategy that minimizes exposure to additional immunosuppressants. METHODS: We retrospectively reviewed clinical data for all adult transplant recipients between January 1, 1996 and May 1, 2004. Clinical outcomes were analyzed according to immunosuppressive regimen. RESULTS: A total of 167 heart transplants were performed at our center. Eight patients died before receiving calcineurin inhibitors and were excluded from analysis. The mean follow-up for the 159 surviving patients was 1,520 +/- 78 days. Ninety of 124 patients initially treated with tacrolimus and corticosteroids were weaned to TM without the use of an anti-proliferative agent (Group A), resulting in an overall success rate of 75% at an average of 271 +/- 18 days after transplant. The remaining 69 recipients were treated with other tacrolimus- or cyclosporine-based regimens (Group B). Survival was significantly greater in Group A. The prevalence of high-grade rejection within the first year and incidence of cardiac allograft vasculopathy were similar between groups. Ten patients (11%) in Group A required recommencement of combination immunosuppression at an average of 768 +/- 772 days. CONCLUSIONS: TM is achievable in the majority of cardiac transplant recipients. Patients who tolerated reduced immunosuppression enjoyed greater survival than those treated with other regimens, without additional high-grade rejection or vasculopathy. These promising results remain to be confirmed in a prospective trial.

Lack of sensitization and equivalent post-transplant outcomes with the Novacor left ventricular assist device.

BACKGROUND: Ventricular assist devices (VADs) are increasingly used to support critically ill heart failure patients awaiting transplantation. Previous work has focused on the Thoratec Heartmate VE device, use of which is associated with pre-formed antibody production. We reviewed our cumulative experience with the Worldheart Novacor VAD as a bridge to transplantation (BTT). METHODS: From January 1989 through October 2002, 39 patients required a VAD bridge, with 26 of 39 surviving to transplantation. Antibody levels were assessed by complement-dependent cytotoxicity assay at routine intervals and expressed as panel reactive antibody (PRA) levels. Post-transplant allograft rejection, coronary vasculopathy, and survival were compared between Novacor-supported patients and non-VAD transplant recipients. RESULTS: PRA values did not significantly change after VAD implantation (12.4% +/- 11.2% vs 14.8% +/- 12.3%, p = 0.28). Survival for the BTT patients was 80.4%, 75.7%, 64.0%, 64.0%, and 64.0%, respectively, for 1, 3, 5, 7, and 10 years post-transplant, with similar results for non-BTT patients. The freedom from coronary vasculopathy was 90.2%, 90.2%, 72.2%, and 72.2%, respectively, at 1, 3, 5, and 7 years post-transplant. CONCLUSIONS: First, to our knowledge, this study is the first to examine the incidence of allosensitization after Novacor implant in detail. In contrast with previous results of work with other VAD systems, as assessed by PRA levels, Novacor patients did not become sensitized. Second, compared with 220 non-BTT patients who received transplants during a similar time frame, Novacor BTT patients had equivalent rejection profiles and survival. Finally, the incidence of transplant-associated coronary artery disease was lower than in previous reports.