Introduction
Arterial and venous thromboembolic conditions are estimated to account for 1 in 4 deaths worldwide in 2010 and are a leading cause of mortality [1]. As atrial fibrillation (AF) (with a prevalence of 1-3% in Europe) is associated with an estimated fivefold rise in ischemic stroke risk, it is a major contributor to arterial thrombosis. [2]. Diagnosed in 1-2 per 1000 persons per year venous thromboembolism (VTE) including both deep vein thrombosis (DVT) and pulmonary embolism (PE) is the third  most common cardiovascular disorder after acute coronary syndrome and ischemic stroke [3].
Given the impact of ischemic stroke and VTE, adequate pharmacotherapy to reduce the incidence and burden of ischemic stroke and VTE is essential. Both direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) are highly effective in stroke prevention (relative risk reduction ≈64%) and prevention of venous thrombotic events (relative risk reduction ≈80%) [3]. In most clinical guidelines DOACs are preferred over VKAs due to their simpler fixed dose regime, no need for international normalised ratio (INR) monitoring and fewer intracranial bleedings. Medication adherence is, however, a prerequisite for optimal protection against thromboembolic complications [4]. Paradoxically, no need for INR monitoring for DOACs also means no monitoring of adherence as the INR can be seen as a surrogate marker for proper VKA use [5].
Recent studies have shown that medication adherence and persistence cannot be taken for granted for patients on DOACs. Various studies demonstrated that either the implementation adherence (defined as the extent to which a patient’s actual dosing corresponds to the prescribed dosing regimen, from initiation until the last dose) and medication persistence (defined as unjustified discontinuation of the drug) is suboptimal. An international study by Banerjee et al. showed that adherence to DOACs does not exceed 55.2% [5], while according to a Dutch follow-up study by Zielinski et al. the non-persistence after 1 year of follow-up was 34% [6]. In an observational study conducted in a primary care setting Capiau et al. found that half of the study population did not take their DOAC (mainly non-intentional) on at least 17 cumulative days per year and that 21% were non-adherent [7]. Ruff et al. estimated long-term adherence for DOACs to be only in the 40-60% range [8]. One of the findings from the Switching Study conducted by Bartoli-Abdou et al. was that after switching from VKA to DOAC 39% of patients had sub-optimal adherence measured by self-report [9].
In contrast, a study by Toorop et al. found a clearly higher self-reported adherence of 86% [10]. In a meta-analysis by Ozaki et al. it was calculated that the percentage of patients with good adherence is 69% [11]. Another important finding in this study was that reduced adherence was associated with poorer clinical outcomes.
Medication adherence and persistence are influenced by different factors like medication beliefs, treatment knowledge, patient’s self-efficacy and also side effects. For example, a study by Rolfes et al. concluded that 9% of DOAC users stopped their DOAC therapy because of side effects [12,13]. Minor bleeding is according to Toorop et al. an important predictor for non-persistence [10]. Mitrovic et al. have also shown that minor bleeds are common among DOAC users and are associated with discontinuation, although no associations were found between minor bleeds and non-adherence, lack of trust or concerns. However, they showed that on an individual basis, there were patients that reported a high burden of minor bleeds [14,15,16]. Despite two-thirds of DOAC users in the aforementioned study by Capiau et al. reported side effects (with easy bleeding (40.2%) being the most common for all DOACs), there was an overall positive attitude towards DOAC use [7]. Bartoli-Abdou et al. found that believing that medications in general were overused in healthcare at baseline and that increasing concerns about anticoagulation over time while also having doubts concerning the necessity of the drug treatment were both associated with lower self-reported adherence [9].
Given the variation between adherence estimates found in the literature, inconclusive findings regarding the role of side effects, their burden and ambiguity regarding the role of specific personal beliefs that can impede good adherence, this study aims to assess implementation adherence among DOAC users and associations between beliefs about medication, perceived side effects, their burden and implementation adherence.