Poor Correlation of Rivaroxaban Concentration with the Routine Coagulation Screening Test in Chinese Patients with Atrial Fibrillation

Aims. The aim of this study is to assess the relationship between rivaroxaban plasma concentration quantified by the gold standard and anticoagulant activities measured by routine coagulation assays in Chinese atrial fibrillation (AF) patients. Whether the normal results of these tests were reliable to rule out clinically relevant rivaroxaban levels at various thresholds was also explored. The effect of clinical drug-drug interactions (DDIs) on the exposure and anticoagulant effect of rivaroxaban were further evaluated. Methods. 116 patients receiving rivaroxaban for the management of nonvalvular AF were recruited. Rivaroxaban concentrations and coagulation tests were measured by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and a blood coagulation analyzer, respectively. Results. The correlation of trough concentration (C-trough) and prothrombin time (PT) or international normalized ratio (INR) was moderate with Spearman's correlation coefficient of 0.495 and 0.506, respectively. A normal PT/INR was unable to rule out C-trough levels of >30 ng/mL and >50 ng/mL, but the negative predictive value reached 100% to exclude C-trough of >100 ng/mL. C-trough showed a small correlation with activated partial thromboplastin time (aPTT) (Spearman's correlation coefficient: 0.241) and no correlation with thrombin time (TT) (Spearman's correlation coefficient: 0.074). Neither aPTT nor TT accurately predicted C-trough at any concentration. Peak concentration (C-peak) did not correlate with any coagulation parameters. The presence of digoxin and febuxostat significantly increased rivaroxaban C-trough by 2.18 fold and prolonged PT and INR by 44.16% and 43.60%, respectively. Conclusions. Normal routine coagulation assays were insufficient to monitor therapy with rivaroxaban. Poor correlations between rivaroxaban concentration and routine coagulation assays were observed in Chinese AF patients. The use of digoxin/febuxostat alone had no effect on rivaroxaban concentrations; however, combined strong breast cancer resistance protein inhibitor (febuxostat) and P-glycoprotein probe (digoxin) in patients with renal impairment is likely to cause clinically significant DDI with rivaroxaban. More studies are needed to establish routine therapeutic drug monitoring of rivaroxaban in clinical practice.