Effect of the Direct Oral Anticoagulants Rivaroxaban and Apixaban on the Disposition of Calcineurin Inhibitors in Transplant Recipients.

BACKGROUND: Calcineurin inhibitors (CNIs) and direct oral anticoagulants (DOACs) share certain metabolic pathways, but whether DOACs influence CNI exposure has not been assessed.

METHODS: A single-center retrospective analysis was performed including 39 organ recipients treated with the combination of a CNI and rivaroxaban (n = 29) or apixaban (n = 10). Dose-corrected CNI trough concentrations (C0/D) during 200 days before and after DOAC initiation were recorded (n = 261), together with covariates known to influence CNI disposition such as steroid dose and hematocrit. The average C0/D before and during DOAC therapy was compared using paired samples t test. Multivariable mixed models were constructed to estimate the effect of DOAC and other predictors on C0/D at each time point.

RESULTS: Group average C0/D was not significantly different before and during DOAC therapy for any CNI-DOAC combination (P = 0.089-0.761), although C0/D changed >20% in 19/39 patients (13 increases, 6 decreases). In multivariable analysis, independent predictors of tacrolimus C0/D were methylprednisolone dose (P = 0.039) and concomitant use of a CYP3A inhibitor (P = 0.007). The subgroup analysis per DOAC showed a limited but significant effect of rivaroxaban on tacrolimus C0/D (9.2% increase, P = 0.042). Independent predictors of ciclosporin C0/D were age (P = 0.018) and use of any DOAC (12.1% increase, P = 0.020).

CONCLUSIONS: Apixaban, and particularly rivaroxaban, may cause a limited (<20%) increase in CNI trough concentration, an effect that is unlikely to trigger a dose change. It may be prudent to perform an additional CNI trough concentration measurement 5-7 days after DOAC initiation, but preemptive CNI dose changes are not warranted based on these observations.