High tacrolimus trough level variability is associated with rejections after heart transplant

Abstract

Tacrolimus, the major immunosuppressant after heart transplant (HTx) therapy, is a narrow therapeutic index drug. Hence, achieving stable therapeutic steady state plasma concentrations is essential to ensure efficacy while avoiding toxicity. Whether high variability in steady state concentrations is associated with poor outcomes is unknown. We investigated the association between tacrolimus trough level variability during the first year post-HTx and outcomes during and beyond the first postoperative year. Overall, 72 patients were analyzed for mortality, of whom 65 and 61 were available for rejection analysis during and beyond the first year post-HTx, respectively. Patients were divided into high (median >28.8%) and low tacrolimus level variability (<28.8%) groups. Mean tacrolimus levels did not differ between the groups (12.7 ± 3.4 ng/mL vs 12.8 ± 2.4 ng/mL, P = .930). Patients in the high variability group exhibited higher long-term rejection rate (median total rejection score: 0.33 vs 0, P = .04) with no difference in rejection scores within the first year post-HTx. Multivariate analysis showed that high tacrolimus trough level variability was associated with >8-fold increased risk for any rejection beyond the first year post-HTx (P = .011). Mortality was associated only with cardiovascular complications (P = .018), with no effect of tacrolimus through level variability.

Keywords: clinical research / practice; drug toxicity; heart transplantation / cardiology; immunosuppressant - calcineurin inhibitor: tacrolimus; organ transplantation in general; pharmacokinetics / pharmacodynamics; pharmacology; rejection; risk assessment / risk stratification.