Remedial dosing recommendation for delayed or missed rivaroxaban doses for patients with non-valvular atrial fibrillation based on Monte Carlo simulation

Background Rivaroxaban is a non-vitamin K oral anticoagulant used widely for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). During long-term anticoagulant therapy, delayed or missed doses are common. However, a lack of practical instructions on remedial methods has created a barrier for patients to maximise the benefit of their medications. This study aimed to explore appropriate remedial dosing regimens for rivaroxaban-treated patients with NVAF. Methods Monte Carlo simulation based on a previously established rivaroxaban population pharmacokinetic/pharmacodynamic model for patients with NVAF was employed to design remedial dosing regimens. Both the European Heart Rhythm Association (EHRA) recommendations and the model were used to establish remedial dosing regimens, which were assessed considering the on-therapy range of drug concentration, factor Xa activity, and prothrombin time under various scenarios of non-adherence. Results Recommendations: of EHRA guide may not be optimal. Our findings suggested that a missed dose is taken immediately when the delay is less than or equal to 6 h; a half dose is advisable when the delay exceeds 6 h but is less than 4 h before the next dose. It is recommended to skip a dose when there are less than 4 h before the next dose. Age or renal function do not significantly influence the remedial dosing regimen. Conclusion A remedial dosing regimen based on model-based Monte Carlo simulation was systematically developed for rivaroxaban-treated patients with NVAF with poor adherence to quickly restore drug concentrations to the on-therapy range and to reduce the risk of bleeding and thromboembolism. What is known on this topic? Remedial recommendations for delayed or missed rivaroxaban dose have been mentioned in package inserts and guide, but lack of solid supporting evidence. Monte Carlo simulation based on population analysis have been proved as an appropriate method to explore the remedial dosing strategy. What does this paper add? Remedial recommendations for delayed or missed rivaroxaban in different population are established based on Monte Carlo simulation. The choice of optimal remedial strategy is related to delay duration. This paper provides a more time-specific and individualized recommendations compared with previous recommendations.