Immunosuppression
Low-dose Tacrolimus/Sirolimus and Steroid Withdrawal in Heart Recipients Is Highly Efficacious

https://doi.org/10.1016/j.healun.2007.03.011Get rights and content

Heart transplant recipients treated with long-term calcineurin inhibitors (CNIs) experience significant nephrotoxicity and transplant vasculopathy. Signal proliferation inhibitors might prevent the development of transplant vasculopathy. In an open, prospective pilot study, 33 primary heart transplant recipients received tacrolimus (Tac) and sirolimus (rapamycin, Rapa) with steroids. To reduce both nephrotoxicity and transplant vasculopathy at the same time, both Tac and Rapa exposure was kept low (6 to 8 ng/ml). Steroids were withdrawn successfully from all patients within 6 months. Just one acute rejection occurred at 54 days post-transplant, resulting in 0.03 acute rejection episode per patient at 1-year (primary end-point) and 2-year follow-up. Transplant vasculopathy assessed by angiogram was absent at 2 years. Graft and patient survival were 100% at 1 and 2 years. Accordingly, the survival estimate for freedom from first acute rejection, transplant vasculopathy, graft loss or death was 0.97 at 1 and 2 years. The regimen was well tolerated with only 3 patients requiring a change of study medication. Mean serum creatinine increased during the first year but returned to baseline at 2 years.

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Study Design

The study was carried out as a single-center, prospective pilot study of primary heart transplant recipients. Thirty-three patients were notified with the intention to secure 30 evaluable patients (assuming a 10% drop-out rate), beginning enrollment in January 2001. The study was performed in accordance with the ethics principles described in the Declaration of Helsinki. The ethics committee of Ludwig Maximilian University, Munich, approved the protocol prior to study commencement. A single

Patient Demographics and Disposition

Prior to transplant, 17 of 33 (52%) patients were listed on the high-urgency waiting list. Time on the ventilator was 1.5 ± 0.9 days and 4.8 ± 2.2 days were required in intensive care. Demographics are summarized in Table 1. Eight patients received statins prior to transplant. After transplant, simvastatin (Zocor) was administered routinely to all patients from Weeks 1 to 2 onward.

All patients received study drug and were included for the 2-year follow-up. Three (9.1%) patients required a

Discussion

Based on the evidence of this open, prospective study, we have demonstrated the Tac–Rapa combination to be highly effective in the prevention of acute rejection in heart recipients. During the 2-year follow-up we observed just one acute rejection episode. This is consistent with a recently published report of a randomized, 3-arm study comparing Tac with MMF or Rapa vs CsA with MMF.7 Although there was no difference in survival between the three groups, the Tac/Rapa group had the lowest

References (13)

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    Missing data in some sub-categories are due to the movement of 7 patients to another transplantation center. Study medication (initially intravenously, subsequently orally) was administered as described previously.11–14 All drugs were adjusted to defined target levels: in the lowTAC/SIR group, target TAC trough levels from 0 to 12 months 6 to 8 ng/ml, 2nd to 4th year 5 to 7 ng/ml, and 5th to 8th year 4 to 6 ng/ml and target SIR trough levels from 0 to 6 months 6 to 8 ng/ml and afterward 5 to 7 ng/ml; in the TAC/MMF group, target TAC trough levels from 0 to 6 months 13 to 15 ng/ml, 7 to 12 months 10 to 12 ng/ml, 2nd year 8 to 10 ng/ml, 3rd to 4th year 6 to 8 ng/ml, and 5th to 8th year 4 to 7 ng/ml, and target mycophenolic acid trough levels from 0 to 6 months 2.5 to 4.0 µg/ml, and 7 months to 8th year 1.5 to 2.5 µg/ml.

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    At 12 months baseline creatinine increased to 144 ± 44 µM/l and it decreased again to 121 ± 35 µM/l by month 24. Survival was 100% and only one rejection was detected during the 24 month follow-up [70]. Based on these early experiences, there is agreement that CsA must be reduced to low levels in order to achieve the goal of renal function improvement with CsA + everolimus (or sirolimus), but there are as yet no data available on CsA target levels at which renal function can be improved without the risk of insufficient immunosuppression.

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    In heart transplantation, benefits of MPA therapy were identified especially in regards to chronic graft vasculopathy.81 However, more recent data have revealed further improvement of this problem when using mTOR inhibitors in combination with CNI.82 The 2 main side effects of MPA are gastrointestinal problems, mainly diarrhea and abdominal pain, and bone marrow depression, leading to severe leucopenia and specifically lymphopenia.

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