1. Introduction
Medication nonadherence has long been a persistent and yet unsolved challenge 1. Adherence is important to achieve the desired therapeutic outcome, especially for drugs associated with a quick loss of therapeutic effect when non-adherence occurs, including non-vitamin K oral anticoagulants (NOACs) 2. It is concerning that patients implement variable and potentially inappropriate remedial strategies in real life 3.
Edoxaban is a commonly used non-vitamin K oral anticoagulant (NOAC). It has been approved for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF), as it selectively inhibits active clotting factor X (FXa) 4. Edoxaban reaches its maximum plasma concentration within 1–2 h after oral administration with a volume distribution of 107 L in adults. It has a terminal elimination half-life of approximately 10–14 h with equal renal and non-renal clearance. Additionally, Edoxaban is a substrate of P-glycoprotein (P-gp) and hence, should not be used with strong P-gp inducers (e.g., rifampin) or inhibitors 5 . According to previous research, dose adjustment can be applied to underweight patients, patients with impaired renal function, and patients concomitantly using a P-gp inhibitor 6.
Edoxaban is a drug with fast-on and fast-off effects, similar to other NOACs 7 . The anticoagulant effect of edoxaban can disappear at 12–24 h after discontinuation 8 . Research has shown that adherence to NOACs is unsatisfactory and decreases over time. In patients with NVAF, adherence to NOACs was < 70% after 12 months of treatment 9 . Low adherence to NOACs is associated with an increased risk of stroke and death. According to a retrospective study enrolled >60,000 patients from the United States, non-adherent atrial fibrillation patients with CHA2DS2‐VASc score ≥ 2 were at a higher risk of stroke comparing to adherent patients10. Due to the undesired outcomes of non-adherence, the American Heart Association and European Heart Rhythm Association (EHRA) emphasise the importance of a strict adherence to NOACs in atrial fibrillation patients 11, 12. However, the proportion of non-adherent patients is still high, and developeing approaches to help non-adherent patient to restore anticoagulant effect as soon as possible is essential. Several generic recommendations are available for edoxaban. According to the package inserts approved by the Food and Drug Administration (FDA), the patient need to, “If a dose of edoxaban is missed, the dose should be taken as soon as possible on the same day. Dosing should resume the next day according to the normal dosing schedule. The dose should not be doubled to make up for a missed dose”13. EHRA recommends, “for NOACs with a once-a-day dosing regimen, a delayed dose can be taken up until 12 h after the scheduled intake. After this time point, the dose should be skipped, and the next scheduled dose should be taken” 12. Similar recommendations were found in the Electronic Medicines Compendium in the United Kingdom14. However, none of the available recommendation is based on clinical evidence or validated. Additionally, it is unclear whether these recommendations can be applied to specific subpopulations, such as underweight patients, patients with renal impairment, and patients that use P-gp inhibitors.
Due to ethical reasons, it is difficult to conduct clinical studies to explore and evaluate remedial strategies. Population pharmacokinetic/pharmacodynamic (PK/PD) modelling and simulations provide a practical approach 15. This method has also been successfully applied to antiepileptic, antipsychotic, and immunosuppressive agents 16-19. In our previous study, we have successfully developed model-informed remedial strategies for rivaroxaban based on PK/PD modelling and found that the EHRA guide may not provide best solution for dealing with delayed or missed dose20. In this study, we aimed to assess the effect of non-adherence and explore appropriate remedial strategies through modelling and simulation in patients with NVAF treated with edoxaban.