Increased Levels of Rivaroxaban in Patients After Liver Transplantation Treated With Cyclosporine A (2014)

Calcineurin inhibitors (CNIs) form the backbone of immunosuppression in solid organ transplantation, but are also frequently used in patients with autoimmune diseases. It is important to understand drug-drug interactions in transplant patients treated with cyclosporine A (CsA) or tacrolimus (Tac), but no data on the interactions between these CNIs and new oral anticoagulants are available. We investigated differences in rivaroxaban blood levels in liver transplant patients treated with CsA or Tac. Trough levels of rivaroxaban (determined by a chromogenic anti-Xa activity assay; Haemochrom Diagnostica, Germany) were evaluated in patients after liver transplantation treated with CNIs, and results were compared between the CsA and Tac groups. Bleeding events and thrombembolic events were retrospectively evaluated. The Mann-Whitney U test and Fisher’s exact test were used for statistical analysis. Statistical analyses were performed using IBM Statistical Package for the Social Sciences version 21 (IBM Corp, Armonk, NY). All patients provided written informed consent, and the study was previously approved by the local ethics committee. Overall, nine patients were included, five in the CsA group and four in the Tac group. Reasons for anticoagulant therapy included atrial fibrillation (n=2), pulmonary embolism (n=2), peripheral vein thrombosis (n=1), portal vein thrombosis (n=1), liver vein thrombosis (n=2), and hepatic artery thrombosis (n=1). Demographic and medical characteristics of the patients are summarized in Table 1. Mean (± standard deviation) for rivaroxaban trough level was 131.7 ng/mL (±119.5) in patients treated with CsA compared to 20.3 ng/mL (±14.4) in the Tac group (P=0.014), even though one patient in the CsA group received a lower rivaroxaban dose than recommended.TABLE 1: Patients characteristics and results for rivaroxaban trough levelsFurthermore, in the CsA group, in three of five patients with initially increased rivaroxaban level (therapeutic range, 7–65 ng/mL; internal reference range, adopted from (1)), the dose was reduced by 5 mg, resulting in trough levels within the therapeutic range. No dose reductions were necessary in the Tac group (P=0.164). Median time between start of rivaroxaban and last follow-up was 11 months (range, 0–19 months). During this time, three of the five patients in the CsA group reported bleeding complications. Two patients reported about ecchymosis, one patient experienced prolonged bleeding after ENT surgery. Two of them demonstrated rivaroxaban levels above the upper limit of the therapeutic range. In the Tac group, one patient with trough levels within the therapeutic range experienced chronic gastrointestinal bleeding, most likely caused by terminal ileitis. No thromboembolic events occurred in the study group during treatment with rivaroxaban. There also were significant differences in renal function between the two groups, with lower glomerular filtration rates reported for the CsA group (P=0.027). Rivaroxaban had been adjusted to renal function in all these patients according to the recommendations (20 mg once daily if GFR > 50 mL/min, 15 mg once daily if GFR 30–49 mL/min). Using these rivaroxaban doses, no differences in trough levels of rivaroxaban were found in a stroke prevention trial in patients with atrial fibrillation (2). Further bleeding rates between reduced doses of rivaroxaban in patients with impaired renal function yielded in similar bleeding rates compared to warfarin (3). In our study, there also was no trend for a correlation between rivaroxaban trough levels and renal function in patients receiving CsA. Notably, the highest trough level was measured in a patient with a GFR of 99 mL/min. Comedications varied widely among patients, but no difference between the groups, especially in drugs interacting with CYP3A4 or P-glycoprotein (P-gp), was noted. Approximately two thirds of the administered rivaroxaban undergoes metabolic degradation and is subsequently equally eliminated by means of renal and fecal routes. The final third undergoes renal excretion without prior metabolism. Rivaroxaban is metabolized by CYP3A4, CYP2J2, and by CYP-independent mechanisms and is a substrate of P-gp (4). Calcineurin inhibitors interact with CYP enzymes as well as P-gp. A previous study on stable renal transplant patients revealed significantly decreased P-gp activity in CsA-treated patients compared to Tac-treated patients (5), and this might explain the higher rivaroxaban levels in these patients. In conclusion, rivaroxaban levels varied widely among patients treated with CNIs and were particularly high in combination with CsA. Yet, further studies are needed to investigate whether this is associated with an increased risk of bleeding. Currently, we therefore suggest to only use rivaroxaban in these patients after thorough consideration and to monitor blood levels, especially in patients with chronic kidney disease or receiving CsA. Andreas Wannhoff 1 Karl H Weiss1 Peter Schemmer2 Wolfgang Stremmel1 Daniel N Gotthardt1 1Department of Internal Medicine IV University Hospital Heidelberg Heidelberg, Germany 2Department of General and Transplant Surgery, University Hospital Heidelberg Heidelberg, Germany