High Variability in Tacrolimus Through Levels is Associated with Rejections After Heart Transplantation

Itai Gueta The Institute of Clinical Pharmacology, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Noa Markovits The Institute of Clinical Pharmacology, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Havtzelet Bilavsky-Yarden The Institute of Clinical Pharmacology, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Dov Freimark Olga and Lev Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Jacob Lavee Olga and Lev Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Ronen Loebstein The Institute of Clinical Pharmacology, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Yael Peled Olga and Lev Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Background:

Tacrolimus, the cornerstone of immunosuppressant therapy after heart transplantation (HTx) has a narrow therapeutic window, hence achieving stable therapeutic steady state plasma concentrations is essential to ensure efficacy while avoiding toxicity. We aimed to investigate the influence of tacrolimus trough-level variability at 3 to 12 months following HTx on long term outcomes.

Methods:

Seventy two consecutive de novo HTx recipients treated with tacrolimus in combination with mycophenolate mofetile were followed beyond the initial post-transplant year. Tacrolimus steady state trough-levels from 3 to 12 months after transplantation were used to calculate tacrolimus trough-level coefficient of variation (CV). Primary end points were histologic rejections and mortality.

Results:

Patients were divided into low trough tacrolimus CV (TacCV) group (≤28.8%, n=36) and high TacCV group (>28.8%, n=36) based on median CV. Mean tacrolimus levels, albumin blood level and absolute red cell count, did not differ between groups. High TacCV group was characterized by younger donor age (25.5±12.3 vs. 32.7±11.4,p=0.018, respectively), higher rate of post-HTx hypertension (57.1% vs. 30.6%, p=0.032) and longer post-HTx hospital stay (25 vs. 17 days, p=0.046). High TacCV group exhibited higher rejections rate (total rejection score; 0.33 vs. 0, p=0.04) . Consistently, multivariate analysis showed that high TacCV was independently associated with >7-fold increased risk for any rejection (p<0.03), but was not independently associated with mortality. Multivariate analysis showed that development of cardiovascular complications during follow-up was the only independent parameter associated with higher mortality (p=0.018).

Conclusions: High TacCV during the first year following HTx is associated with increased risk of rejections. Mortality was associated with development of cardiovascular complications.

Presentation