The importance of adherence and persistence with oral anticoagulation treatment in patients with atrial fibrillation

This editorial refers to ‘Long-term persistence and adherence with non-vitamin K oral anticoagulants in patients with atrial fibrillation and their associations with stroke risk’, by J.J. Komen et al., pp. f72–f80. The introduction of non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) has dramatically changed the landscape of thromboprophylaxis due to their generally safer profile, more convenient management, and more stable pharmacological properties when compared with VKAs,1 which has contributed to the increased prescription and uptake of oral anticoagulants (OACs). The lack of frequent monitoring due to the predictable and fixed-dose anticoagulant effect of NOACs is a notable benefit from the patient’s perspective, but it also raises some concerns over treatment adherence and persistence. Nevertheless, it should be noted that poor adherence to VKAs was also frequently reported2 despite international normalized ratio (INR) monitoring. In addition, a low time in therapeutic range (TTR) is consistently observed in adherent VKA patients, significantly affecting the efficacy of anticoagulation treatment.3 On the other hand, from a strictly pharmacokinetic point of view, it is acknowledged that even one or two missed doses of NOACs could potentially increase the risk of stroke due to their shorter half-lives. Regardless of the type of anticoagulant chosen (VKA or NOAC), lack of adherence is associated with poorer outcomes.4 Indeed, treatment adherence defined as ‘the extent to which a patient acts in accordance with the prescribed interval, and dose of a dosing regimen’ and treatment persistence, namely ‘the duration of time from initiation to discontinuation of therapy’ are crucial for improving outcomes and reducing mortality, morbidity, and healthcare costs among patients with atrial fibrillation (AF).5 Data available on this topic are somewhat limited to early usage of NOACs, and new data on large and more recent cohorts of patients are welcome. In this issue of the European Heart Journal – Cardiovascular Pharmacotherapy, Komen et al.6 report long-term adherence and persistence to NOAC treatment in a large cohort of 21 028 AF patients from the Stockholm healthcare database, with a median follow-up time of 2.0 years [interquartile range (IQR) 1.0–3.2], and highlight some important issues that are worthy of further discussion.6 First, Komen and colleagues6 found very high persistence and adherence rates with NOACs, reporting a remarkable medication possession rate (MPR) among persistent patients of ∼90%, with ∼75% having reached an MPR >95% throughout the study. These results are in line with recent studies7,8 and underline the efforts made by the NOAC practical guide in emphasizing to physicians the importance of regularly checking NOAC adherence in order to achieve optimal protection against stroke and to reduce the likelihood of other adverse outcomes.9 In a recent analysis10 of >27 000 anticoagulant-naïve patients from the UK primary care Clinical Practice Research Datalink, treatment persistence for high-risk patients (CHA2DS2-VASc ≥2) was >80% for NOACs. In contrast, the persistence rate of anticoagulation treatment in VKA patients was only 65.3%.10 Komen and colleagues6 adopted a more appropriate methodology by measuring adherence only in those patients who were taking their NOACs, i.e. persistent users. However, the use of pharmacy claims data does not allow an in-depth analysis of the numerous factors which could impact on treatment adherence and persistence. When investigating long-term adherence in AF patients, several variables, such as socio-economic factors, patient education level, differences in healthcare systems, and geographical regions, should also be taken into account.11,12 Additionally, how NOAC treatment decisions are reached (patient–physician discussions) and the degree of patient education, regarding the benefits/risks of OAC treatment and the importance of medication adherence and lifelong persistence, are not readily available from claims databases, but are important factors in determining a patient’s health behaviours.12 For example, data from a large hospital-based cohort in China from 2011 to 2017 showed that the OAC treatment persistence was significantly higher for warfarin than for NOACs, probably reflecting the high variability between European and non-European cohorts and healthcare systems.13 Adherence to OAC treatment is a complex interaction between patients’ preferences, physicians’ clinical choice, and healthcare system (Figure 1). Factors accounting for non-adherence and interventions aimed at improving adherence to anticoagulant treatment in atrial fibrillation patients. OAC, oral anticoagulant. Factors accounting for non-adherence and interventions aimed at improving adherence to anticoagulant treatment in atrial fibrillation patients. OAC, oral anticoagulant. Secondly, as reported by several previous studies, Komen et al.6 also highlighted that both non-persistence and poor adherence were associated with an increased stroke risk in a nested case–control subanalysis [non-persistence adjusted odds ratio (aOR), 2.05; 95% confidence interval (CI) 1.49–2.82; 1% reduction MPR aOR, 1.03; 95% CI 1.01–1.05].4 In particular, patients with MPR <80% were at higher risk for stroke, while a protective effect of the NOACs was intact at an MPR >90%.6 Although near-perfect adherence and persistence are desirable, real-world data show that achieving such results is challenging in clinical practice. In a retrospective analysis of a large US commercial insurance database, enrolling >64 000 patients with AF from 2010 to 2014, adherence to anticoagulation in NOAC patients was poor at 47.5% during 1.1 years of follow-up;14 however, it should be noted that was one of the first analyses of adherence in the NOAC era.14 Moreover, as expected, adherent high risk-patients (CHA2DS2-VASc score ≥2) had a lower stroke risk with a relatively small increase in bleeding risk, reinforcing the need to strictly follow guideline recommendations on stroke prevention.14 Another interesting finding from Komen et al.6 was the absence of large differences in the persistence rate among different NOACs. Whether twice- or once-daily dosing of NOACs significantly influences adherence to OAC treatment has been discussed for many years and is still the subject of debate.7 Nevertheless, available data do not convincingly demonstrate the superiority of one treatment regimen over another (in terms of the dosing frequency). Therefore, the choice of OAC (and the dosing regimen) is a part of the complex NOAC prescription process that should be individualized to the patient’s clinical characteristics and preferences.8 What strategies can we adopt to improve patient’s adherence to and persistence with OAC? Over recent years, there has been increased digitalization and technical development, and electronic monitoring and feedback could significantly influence adherence, in addition to medication reminders via smartphone applications.15 Indeed, we should also remember that treatment adherence is strongly influenced by the doctor–patient relationship. Prescribing OAC treatment, either an NOAC or a VKA, requires physicians to discuss in detail with their patients (and their families) the pros and cons, and how/when to take the medication, and to highlight the importance of adherence. This informed decision-making process, with structured follow-up, improves the likelihood of treatment adherence and persistence, resulting in better patient outcomes. The term adherence indeed, rather than compliance, which implies a passive patient attitude, indicates the active and collaborative involvement of the patient together with the prescriber who participates in the planning and implementation of the therapy. Quoting the famous Renaissance physician Paracelsus ‘Every physician must be rich in knowledge, and not only of that which is written in books; his patients should be his book, they will never mislead him’ The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal – Cardiovascular Pharmacotherapy or of the European Society of Cardiology.