4. Discussion
To the best of our knowledge, this is the first study to comprehensively
develop and evaluate different remedial strategies during non-adherence
events in edoxaban treated patients with NVAF. We developed an optimised
remedial strategy based on non-adherence scenarios using PK and PD
population modelling. Unlike previous studies that focused on PK, our
study considered both PK and PD 17-19. iFXa percentage
was used as a PD marker in our study, which provides a closer
relationship to the clinical outcome than exposure and can help to
achieve a more appropriate remedial strategy.
In our study, we used the on-therapy range to overcome the challenge of
lacking a defined therapeutic range. The on-therapy range provides a
dynamic goal based on the patient’s individual demographic and indicated
dosage regimen, which mimics the real-life situation. Additionally, we
performed sensitivity analysis to extend our recommendation to patients
receiving P-gp inhibitors and/or with low body weight.
According to our PK/PD modelling and simulation, the EHRA recommendation
is not optimal and can only be applied when the delay ≤ 11 hours. These
results are similar to those of our previous study, showing that EHRA
also does not provide optimal recommendations for rivaroxaban missing
dose20. Our study shows that from the PK/PD
perspective, there is potential room for improvement in the remedial
strategy in current practice. The current practice has missed the
opportunity to help patients address their missed or delayed drug in a
more appropriate manner.
In practice, patients can have different risks of bleeding and
thrombosis, which can be assessed through scoring systems such as
HAS-BLED or CHA2DS2-VASc for bleeding
and stroke, respectively 29, 30. Other risk factors,
including concomitant drug use, can also alter a patient’s risk of
bleeding and thrombosis. Optimal remedial strategies can be modified
based on the patient’s risk of bleeding and thrombosis. It is necessary
that healthcare providers balance patients’ risk of bleeding and
thrombosis by considering the deviation time above and below the
on-therapy range.
Our study has several limitations. First, the results of our study
represent the values from the modelling population and may not be
extrapolated to patients who do not match the modelling population,
especially in patients who take edoxaban for other indications,
including venous thromboembolism. Second, the results of our study were
not evaluated in real-world patients. However, due to ethical reasons,
PK/PD modelling and simulation is the preferred approach for developing
and testing remedial strategies in the target population.