Review articleEnsuring medication adherence with direct oral anticoagulant drugs: Lessons from adherence with vitamin K antagonists (VKAs)
Introduction
Once properly prescribed, medications are only effective if they are taken on a regular basis under limited supervision. This is known as medication adherence. It should be distinguished from maintenance (the extent to which a patient continues good health practices without professional supervision) and from compliance/concordance (the extent to which a patient implements a prescribed remedy). Medication adherence is higher during treatment of acute conditions while, for a chronic disease, it declines dramatically after the first three months of therapy [1]. However, even in conditions of good (i.e. short-term) medication adherence (4–6 weeks post-discharge prophylaxis of venous thromboembolism following high-risk orthopaedic surgery), a regular use of subcutaneous low-molecular weight heparin highly depends on patient education, access to treatment, the cost of the drug, the person responsible for administering injections, country, and type of hospital ward at discharge [2].
Non-adherence to medications is found across all types of treatments and can limit their effectiveness. Variables (Table 1) associated with a poor adherence are common to the most chronic conditions [3] including those treated with vitamin K antagonists (VKAs) [4]. In medical patients with chronic diseases, non-adherence varies between 25 and 55% [5]. In those aged 65 years or older [6], with chronic conditions such as atrial fibrillation (AF), non-adherence to anticoagulation may impact major clinical outcomes (i.e. increase stroke rates) and, in turn, hospital admission and residential care, and increase costs to health care system.
Dabigatran (a thrombin inhibitor), edoxaban, rivaroxaban and apixaban (all factor Xa inhibitors) are direct oral anticoagulant drugs (DOACs) approved for the prevention and treatment of venous thromboembolism and poised to replace VKAs for stroke prevention in the setting of AF [7], [8]. These new medications are easier to use than VKAs, with fewer drug and food interactions and no need for routine blood monitoring. Since dabigatran 110 mg bid and apixaban were safer than (i.e., less major bleeding) and dabigatran 150 mg bid and rivaroxaban had similar rates of major bleeding than warfarin, and since all are at least as effective as VKAs, [9] the hope is that a proper use of DOACs improves patient’s adherence and clinicians' inclination to treat with anticoagulation in accordance with current guidelines. This is expected to reduce the risk of stroke [10], [11]. However, in clinical settings where no laboratory monitoring is needed, poor medication adherence is common [12]. In a randomized trial comparing warfarin to dabigatran for acute deep venous thrombosis, treatment was stopped for non-adherence in 1.6% of patients on dabigatran and in 2.8% of those on VKAs [13]. Likewise, in a real world setting, [14] the rates of non-adherence to dabigatran were similar to those of VKAs. Treatment intensification is common in those who are non-adherent to treatment [15]. In a 30-day study of adherence with dabigatran in orthopedic surgery, 31% of patients forgot to take their medication for few days, and 15% became over-compliant by taking three doses (instead of two) to compensate for the missing doses [16].
The ATRIA Study showed that ≈ 25% of older AF patients newly started on VKAs discontinue therapy within 1 year [17]. This figure is consistent with data from other trials (22% VKAs withdrawal in the first year; 33% during the mean study period of 2.7 years) [18], [19], [20]. Only in one of them, 19 hemorrhagic events partially accounted for such discontinuation rate. In the Re-Ly trial, the rates of discontinuation for 110 mg of dabigatran, 150 mg of dabigatran, and warfarin were 14.5%, 15.5%, and 10.2%, respectively, at 1 year and 20.7%, 21.2%, and 16.6% at 2 years. Discontinuations due to gastrointestinal symptoms were 2.2% (n = 134) for dabigatran 110 mg; 2.1% (n = 130) for dabigatran 150 mg and 0.6% (n = 38) for Warfarin. In the ROCKET AF study, the proportions of patients who permanently stopped their assigned therapy before an end-point event and before the termination date were 23.7% in the rivaroxaban group and 22.2% in the warfarin group. Fewer patients (P = 0.001) in the apixaban group (25.3%, with 3.6% of the discontinuations due to death) than in the warfarin group (27.5%, with 3.8% due to death) discontinued treatment before the end of the ARISTOTLE study. The data on discontinuation rates for DOACs from each of the major recent trials on AF patients (Table 2) should be taken with caution with respect to non-adherence. Unless protocols call for exclusion of the patients from the trial(s) for non-adherence, discontinuation and non-adherence are different concepts. Secondly, compared to data from the ROCKET AF study, lower rates of discontinuation (11.8% at 9 months) with rivaroxaban have been recently reported in "a real world" setting in AF patients (the Dresden registry) [21].
In the management of chronic disorders, a careful delivery of established drug treatments would save more lives than would the discovery of innovations [22]. In an attempt to define strategies to ensure medication adherence to DOACs, lessons from VKAs and the major drugs commonly employed in the management of chronic disorders will be briefly reviewed.
Section snippets
Factors that Affect Compliance with VKA
In a case–control study in the Anticoagulation Therapy Unit at Massachusetts General Hospital, 43 patients who had been discharged from the Unit for non-compliance (cases) and 89 randomly selected compliant patients (controls) were interviewed; relevant data on compliance to VKAs emerged [23].Noncompliant cases had self-discontinued VKA or were taking VKA with inadequate monitoring of international normalized ratio (INR) levels. Telephone interviews assessed that non-compliant cases were more
Factors that Affect Medication Adherence with VKA
While the failure to initiate therapy accounts for a large percentage of under-use of VKAs [25], [26], [27]. The difficulty for patients appropriately initiated on VKAs to remain in a narrow therapeutic window (INR-adjusted range: 2–3) is a major determining factor of poor medication adherence to such regimens [28], [29]. The rates of non-adherence for VKAs range between 22 and 58%, which is strongly related to a low proportion of time in therapeutic range (i.e. INR) [30], [31] as well as to a
Improving Medication Adherence with VKA
In a questionnaire administered in two Italian Anticoagulation Clinics, [50] the doctor-patient relationship was considered very important by 96% of patients; 93% considered it important to be seen by the (same) doctor; 83% believed that the doctor should always hand out the results personally, and 78% reported health problems other than those leading to the use of VKAs. The project of nurse-coordinated AF Centers specifically focused on adherence issues during patient follow-ups [51] should
Ensuring Medication Adherence with DOACs: Proposed Directions
An approach for medication adherence that requires a continuous interaction of patients with the healthcare chain is more complex than one relying on laboratory assays. However, while the PT-INR was central to monitor medication adherence with VKA, the activated partial thromboplastin time (aPTT) and the prothrombin time (PT) are suitable for qualitatively rather than quantitatively assessing anticoagulation by DOACs. Tests that reliably quantify anticoagulation by DOACs (the Hemoclot assay for
Conclusions
The anticoagulant effect of NOACs fades rapidly 12–24 h after the last intake. Therefore, strict medication adherence by the patient is crucial. The suggestions reported above for ensuring medication adherence and persistence (patients continue to take drugs properly throughout long-term treatment) for DOACs are in keeping with general priorities to improve medication adherence in the elderly with chronic conditions that need long-term use of medications.4 However, presently, most of them are
Conflicts of Interest Statement
DP has served on advisory boards for and/or has received fees as a speaker at meetings organized by GSK, Bayer-Schering Pharma and Daiichi Sankyo. GDM has served on advisory boards for and has received fees as a speaker at meetings organized by Boehringer-Ingelheim, Bristol-Myers Squibb, Pfizer and Daiichi Sankyo. All the others have nothing to declare.
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