Remedial dosing regimens for delayed or missed rivaroxaban doses in
patients with non-valvular atrial fibrillation based on Monte Carlo
simulation
Abstract
Background: Rivaroxaban is an 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 to maximise the benefit of the medications. This
study aimed to explore appropriate remedial dosing regimens for
non-adherent rivaroxaban-treated patients. Methods: Monte Carlo
simulation based on a previously established rivaroxaban population
pharmacokinetic/pharmacodynamic (PK/PD) model for patients with NVAF was
employed to design remedial dosing regimens. The proposed regimens were
compared with remedial strategies in the European Heart Rhythm
Association (EHRA) guide by assessing deviation time in terms of drug
concentration, factor Xa activity, and prothrombin time under various
scenarios of non-adherence. Results: The proposed remedial dosing
regimens were dependent on delay duration. The missed dose should be
taken immediately when the delay does not exceed 6 h; a half dose is
advisable when the delay is between 6-20 h. A missed dose should be
skipped if less than 4 h remains before the next dose. Age or renal
function does not significantly influence remedial dosing regimens. The
proposed regimens resulted in shorter deviation time than that of the
EHRA guide in most non-adherence scenarios. Conclusion: EHRA guide may
not provide optimal remedial strategies for rivaroxaban-treated
non-adherent patients based on simulation. PK/PD and simulation provide
valid evidence on the remedial dosing regimen of rivaroxaban for
patients with NVAF, which could help to minimise the risk of bleeding
and thromboembolism.