Adherence to the novel oral anticoagulants: an unmet need

Keywords: :

• Adherence
• Atrial fibrillation
• NOACs
• Novel oral anticoagulants
• Persistence
• Venous thromboembolism
• Vitamin K antagonists

The availability of antithrombotic compounds that can be administered orally in a fixed dose, without the need for laboratory control owing to their predictable pharmacokinetics and pharmacodynamics, and that have a lower potential for drug and food interactions has opened new horizons for the treatment of patients with atrial fibrillation (AF) and venous thromboembolism (VTE)1. They include drugs that inhibit factor Xa (rivaroxaban, apixaban and edoxaban) and drugs that inhibit thrombin (dabigatran etexilate). With the advent of the direct novel oral anticoagulants (NOACs) it has become realistic to dissociate the antithrombotic from the hemorrhagic potential to a much greater extent than with the older drugs2^,3. Furthermore, the demonstration that a few compounds make it suitable to treat patients with VTE effectively and safely from the beginning, without the need for initial parenteral administrations of either heparins or fondaparinux, is likely to streamline the management of VTE disorders on an ambulatory basis4. Based on the results provided by the studies published so far, they have the potential to rapidly become the treatment of choice for both patients with AF and those with VTE.

However, there are conditions that may limit their use. For example, the NOACs cannot be used in patients with severe renal or liver failure, nor can they be used in patients with prosthetic heart valves, in those requiring parenteral nutrition or in pregnant women5. Based on available findings they cannot be recommended for patients with active cancer as yet6. Caution is required for patients at the extreme of body weight and for those with or at risk for gastrointestinal bleeding, as dabigatran and rivaroxaban have been associated with an increased risk of this complication7. In addition, although interactions with other drugs are far less important and frequent than those reported for the vitamin K antagonists (VKAs), their use in association with a number of drugs still requires caution8. Finally, their use raises concerns about adherence to the prescribed treatment. Indeed, patients may have difficulty in remembering to take their medication without the requirement of blood monitoring, with the consequent loss of clinical effectiveness9. This is especially true for drugs such as dabigatran and apixaban, which require twice daily administrations.

The safety and effectiveness of any medical therapy depends on patients taking their medication as prescribed. Typically, patients who have medication available >80% of the time (based on prescription refill data) are considered to have acceptable adherence for the treatment of cardiovascular conditions10. Adherence, as well as persistence (i.e., the duration of time from initiation to discontinuation of therapy) has a major impact on health care, as the lack of adherence interferes with the therapeutic benefits of medication. Poor medication adherence is frequently found across all types of pharmacological therapy, especially after the first three months of treatment11. For VKAs, rates of non-adherence have been reported in the range of 22–58%12–17. In real-world practice, the proportion of anticoagulated patients who are commonly found within the therapeutic range is lower than 40%, this proportion increasing up to 60% in the framework of randomized clinical trials18. Based on the results from a meta-analysis of 18 randomized trials including 101,801 patients, the rate of adherence and discontinuation of patients assigned to NOAC agents was found to be similar to that of patients allocated to warfarin for each of the investigated compounds19. In agreement with what is commonly seen for virtually all existing medications, the rate is expected to further decrease in the real world20.

While a few registries and cross-sectional cohort studies have so far reported satisfactory real-life persistence with the use of NOACs in patients with AF21–23, there are currently limited real-world data comparing adherence of the direct NOACs with standard therapy. A cross-sectional cohort study of patients receiving dabigatran in a real-life setting showed that 30% of patients had missed their medication and 12% had inadequate adherence24. Non-adherence is likely to be a true problem and a reason for concern when prescribing NOACs for long-term anticoagulation. Depending on the type of treatment regimen, adherence may be even harder to achieve25.

In this regard, the findings from the recent enquiry by McHorney et al. are of remarkable interest26. Using health insurance claims dated July 2013 through December 2014 from the Humana database, they had the opportunity to evaluate adherence, as defined by the Pharmacy Quality Alliance (PQA), of the NOACs rivaroxaban, dabigatran and apixaban during the year 2014 in the United States regardless of the indication for therapy. Patients included in the study had two or more dispensing of NOAC agents in 2014, had at least 180 days apart between two NOAC dispensings, had more than 60 days of supply, and had at least six months of continuous health plan enrolment before the index date. The main objective of the study was to assess adherence to medication based on the PQA’s adherence measure (i.e., patients with a proportion of days covered ≥0.8). A total of 11,095 rivaroxaban, 6548 dabigatran, and 3532 apixaban users were identified. Interestingly enough, a significantly higher proportion of rivaroxaban users (72.7%) was found to be adherent compared to dabigatran (67.2%: p < 0.001) and apixaban (69.5%: p < 0.001) users. After adjusting for a number of confounders including the indication for treatment, compared to apixaban users the likelihood of being adherent was significantly higher for rivaroxaban users (odds ratio [OR] = 1.20, p < 0.001) and significantly lower for dabigatran users (OR = 0.85, p < 0.001). These results expand those obtained by the same authors in 201327, and are consistent with those of recent analyses of real-world data from claims databases, where rivaroxaban was generally found to be associated with better treatment persistence than warfarin in patients with AF28^,29.

A number of factors can account for these findings. For example, dabigatran may induce intolerable dyspepsia in up to 10% of patients30. In addition, dabigatran is cleared through the urinary tract to a remarkably higher extent than the inhibitors of factor Xa (80% vs on average 30%), making it likely to switch patients to VKAs or an inhibitor of factor Xa whenever renal failure develops5. Finally, it requires twice daily administration. Apixaban shares with dabigatran the need for twice daily administration. This is the most likely explanation for the higher adherence to therapy in users of rivaroxaban25. Indeed, in a comprehensive overview of studies conducted in patients with chronic conditions, adherence to the prescribed medications was found to be considerably lower for drugs requiring twice daily dosing than those requiring once daily dosing31. Similar results were found in a recent review of studies addressing the treatment of cardiovascular disorders32.

The conclusions of this analysis are interesting and relevant to clinical practice, as they have the potential to have an impact on the prescription of NOAC agents. Although the choice of the proper NOAC has to take into account a number of considerations, including efficacy, risk of bleeding, patient’s renal function, comorbidities and preferences, the prescription of once daily rivaroxaban is more likely to favorably impact a patient’s adherence than that of twice daily dabigatran or apixaban. Anyway, the adherence to long-term treatment does not seem to exceed that reported for most drugs used for prevention or treatment of cardiovascular disorders. Accordingly, to meet the challenges faced by these innovative anticoagulants there is the urgent need for interventions aimed at increasing patient adherence, including patient education and regular follow-ups.

Transparency

Declaration of funding

This editorial was not funded.

Declaration of financial/other relationships

P.P. has disclosed that he has no significant relationships with or financial interests in any commercial companies related to this study or article.

CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.