Are the Direct Oral Anticoagulants Better for Patients with Low Time in the Therapeutic Range on Vitamin K Antagonist Therapy?

Introduction

Effect of Previous INR Control during VKA Therapy on Subsequent DOAC Adherence and Persistence, in Patients Switched from VKA to DOAC

The direct oral anticoagulants (DOACs: apixaban, dabigatran, edoxaban, and rivaroxaban) are first-line anticoagulants for many patients with nonvalvular atrial fibrillation (NVAF) and venous thromboembolism (VTE).[1] [2] This is due to their efficacy, safety profile, ease of administration, lack of a routine laboratory monitoring, and limited food or drug interactions. The landmark clinical trials that led to their approval showed generally high rates of mediation adherence.[3] Of course, taking anticoagulants as directed (medication adherence) is critical to realizing the beneficial results seen in studies.[4] However, it is uncertain if the high rates of adherence seen in a clinical trial population will be realized in actual clinical practice. Specific to DOAC therapy, it is uncertain if patients with low time in the therapeutic range (TTR) and high levels of international normalized ratio (INR) variability while on vitamin K antagonist (VKA) therapy are better served by transitioning to a DOAC, in large part due to questions of medication adherence. There have been concerns that adherence and persistence may be lower in this group with mixed study results to date.[5] [6] [7] [8]

In this issue of Thrombosis and Haemostasis, Elling et al reported a retrospective cohort study of 437 patients anticoagulated for any indication, switching from VKAs to DOACs from 2012 to 2019.[9] Medication adherence was evaluated by proportion of days covered by an anticoagulant prescription. Of this cohort, nearly 70% had VKA TTRs under 70%. However, this was not associated with subsequent good DOAC adherence (defined as >90% adherence), which was high for most patients (∼80%). Poor INR control (low TTR, high time under the therapeutic range, or high INR variability) while on a VKA was also not associated with lower persistence on DOACs compared to patients with better INR control. The results suggest that poor INR control should not dissuade clinicians from transitioning patients from a VKA to a DOAC. However, the study has notable limitations, including the potential for confounding and misclassification.[9] These issues are common in studies relying on prescription claims or fill data. The study was also small and may not capture important subgroups. Finally, the reason for poor INR control is not well described.

DOAC Adherence after VKA Therapy

Predicting or monitoring DOAC medication adherence is desirable clinically to prevent patients from experiencing the potentially devastating or even deadly consequences of inadequate anticoagulation. Most commonly, patients are anticoagulated for VTE and/or NVAF. Such patients could be anticipated to suffer pulmonary embolism and/or stroke in the setting of nonadherence, a risk that is likely proportional to the degree of thrombotic risk of the individual patient. DOACs relative to VKAs have (1) less routine laboratory monitoring, (2) different pharmacokinetics,[10] [11] and (3) more challenges to access.[12] These factors could put patients at greater risk for or from nonadherence. Understanding these risk factors for anticoagulant nonadherence helps clinicians and patients select the most appropriate medication. Even if prior VKA control (as measured by a TTR) is not a good predictor of future DOAC adherence, clinicians and health systems may still want to offer closer follow-up and support for patients believed to be at risk for nonadherence. How best to identify those patients remains an area of important future investigation.

The Advantage and Concern with Less Monitoring

The lack of routine laboratory monitoring is one of the most attractive features of the DOACs compared to VKAs. However, the laboratory and clinical follow-up required for INR monitoring provides an opportunity to monitor medication adherence that is not as easily accomplished with the DOACs. Patients may have less clinical follow-up by anticoagulation clinic or other clinicians when on DOAC therapy.[13]

Studies have shown mixed results when evaluating DOAC adherence—notable with variation by indication for anticoagulation, duration of time on anticoagulation, patient age, sex, and more.[9] [10] [14] There may be subgroups that are more or less adherent to anticoagulant therapy. The specific reason for poor INR control may also be a significant factor for certain patients but not others.[15] This hypothesis requires more investigation. For instance, patients with poor INR control due to variable vitamin K intake or dietary issues may do better on a DOAC without this same concern. Patients with poor INR control due to time, transportation, or other barriers to completing INR monitoring also may do better on a DOAC. Similar benefits have been seen when VKA-treated patients transition to home INR monitoring. In contrast, patients with poor INR control due to other reasons (e.g., missing medication doses) may continue to have poor adherence after changing to a DOAC.

DOAC drug levels,[13] refill patterns, and patient self-report are the primary tools to assess for DOAC adherence. If a patient experiences a breakthrough thrombotic event on a DOAC, nonadherence may be a potential explanation. Efforts to improve medication adherence, potentially through educational interventions or closer follow-up, should be prioritized, along with efforts to detect patients not adherent to DOACs.[16]

DOAC versus VKA Pharmacokinetics

While it is suggested that 60 to 70% TTR is desirable for warfarin-treated patients to achieve optimal outcomes,[9] [17] it is not clear what level of DOAC adherence is needed, or how this may differ between patients. It is notable that DOAC half-lives are 5 to 17 hours.[18] Missing one dose of a daily-dosed DOAC would result in <25% drug levels encountered the time the dose was next due; missing one dose of a twice-daily DOAC would result in <50% drug levels by the time the next dose was due. In contrast, VKAs often have a longer half-life (∼40 hours for warfarin) and a missed dose may be less likely to be associated with low anticoagulant drug levels. Therefore, it is unclear if patients who occasionally miss doses of anticoagulant are better protected with longer half-life drugs.

Elling et al's study included the twice-daily anticoagulants apixaban and dabigatran, along with the daily rivaroxaban. Previous studies have shown that medication adherence may be better for once-daily dosing compared to twice daily.[19] [20] However, comparative efficacy studies between the most commonly used DOACs, apixaban and rivaroxaban, remain limited.

Drug Access

Sociodemographic factors are another important influence of medication persistence and adherence. Historically disadvantaged populations in the United States are less likely to switch to a DOAC.[21] This is partially driven by cost and/or medication access issues.[22] While not applicable to all patients, health systems, or countries, it is an important consideration for many patients considering VKA to DOAC transition.

Should Patients with Poor INR Control Be Changed to DOACs?

The available data seem to suggest that in general, DOACs may be appropriate for patients with poor INR control. However, further research should confirm this hypothesis, especially in key patient subgroups. Until such data are available, the approach outlined in the figure ([Fig. 1]) may be reasonable. It is important to engage patients and the entire health care team to try to optimize adherence as a part of anticoagulant stewardship. Barriers and facilitators of nonadherence should be identified. Clinicians, nurses, pharmacists, and social workers all play an important role in promoting anticoagulant adherence and should assess adherence in patient interactions.

Fig. 1 Approach to selecting oral anticoagulant therapy for patients with poor INR control.

Finally, oral anticoagulation is but one pillar of the holistic or integrated care management of many chronic long-term conditions, such as NVAF. Indeed, current guidelines promote such a holistic management approach.[23] Even then, adherence to such integrated care impacts on overall prognosis in patients with NVAF.[24] [25] Hence, assessment of adherence should not only extend to drugs, but also to the overall holistic management plan, to improve outcomes in our patients.

Conflict of Interest

J.K.S. received consulting fees from Pfizer, Sanofi. G.D.B. received grant funding from Boston Scientific; Consulting: Pfizer, Bristol-Myers Squibb, Janssen, Bayer, AstraZeneca, Sanofi, Anthos, Abbott Vascular, Boston Scientific; He also is a member of Board of Directors for Anticoagulation Forum.

• References

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Publication History

Received: 08 May 2024

Accepted: 13 May 2024

Article published online:
01 June 2024