Time in Therapeutic Tacrolimus Range Predicts 1-Year Clinical Rejection and Survival: Time For a Paradigm Shift?

Purpose Calcineurin inhibitors are a cornerstone of immunosuppression post-orthotopic heart transplantation (OHT). The relationship of tacrolimus exposure, measured by time within therapeutic range (TTR), and level variability, measured by standard deviation (SD) of trough blood levels, to post-OHT acute rejection is unclear. We evaluated if tacrolimus TTR or variability in the 1-year post OHT impacted rejection. Methods This was a single-center, retrospective cohort study of consecutive adult OHT patients receiving standard immunosuppression with tacrolimus, MMF, and prednisone. Tacrolimus TTR was calculated up to 1 year using protocol goal ranges (10-15 ng/mL for months 0-2, 8-12 ng/mL for months 2-6 and 5-10 ng/mL for months 6-12) using the Rosendaal method. The primary outcomes included the association of TTR and level variability with 1-year clinical rejection (defined as any patient receiving ≥ 125 mg of IV methylprednisolone from post-op day 7-365). We analyzed categorical and continuous variables using chi-square and Mann Whitney-U respectively. Time-to-event analysis was conducted for 1-yr clinical rejection using both Kaplan-Meier and Cox Proportional Hazards methods, whereby TTR was calculated until event or censor date and reported using hazard ratio (HR) and 95% confidence interval (CI). Results 78 patients underwent OHT (age, 56.2 ± 12.7 years) with a median 1-yr TTR of 50.2%. Clinical rejection occurred in 31 (39.7%) patients. Those with clinical rejection had a significantly lower median TTR (45.9%) and higher level variability (5.8) than those without rejection (TTR 56.5%, variability 4.9; p=0.021 and p=0.005, respectively) (Figure A&B) . Time to therapeutic tacrolimus level (median 9 days) did not predict 1-year clinical rejection (p=0.274). In a univariable Cox Proportional Hazards Model (median TTR=40%), TTR Figure C ). Five (6.4%) patients died in the first year after OHT. TTR 50% (p=0.018, Figure D ). Conclusions Lower tacrolimus TTR and/or greater level variability predicts clinical rejection and death in the first year after OHT. TTR and and level variability should be monitored in addition absolute levels.