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.