Appropriateness of direct oral anticoagulant dosing in patients with atrial fibrillation according to the drug labelling and the EHRA Practical Guide☆
Introduction
For decades vitamin K antagonists (VKAs) were the only effective oral anticoagulants available for the prevention and treatment of thromboembolism in non-valvular atrial fibrillation (NVAF) [1]. However, VKAs have several limitations including their narrow therapeutic window with unpredictable anticoagulant response and multiple drug-drug and food-drug interactions [2]. The direct oral anticoagulants (DOACs) were developed to overcome these drawbacks and have shown non-inferiority to VKAs with less intracranial bleeding [[3], [4], [5], [6]]. Their emergence has caused a paradigm shift in anticoagulation therapy with DOACs being increasingly used compared to VKAs [7].
Selecting the preferable DOAC in an appropriate dose can be challenging in ‘real-world’ clinical practice for different reasons. First, all DOACs (dabigatran, rivaroxaban, apixaban and edoxaban) have different doses and specific dose reduction criteria that depend upon several patient-specific factors such as age, body weight, renal function and/or co-medications, making appropriate DOAC dosing more complicated. In addition, the approved doses and dose reduction criteria defined by the European Medicine Agency (EMA) and the Food and Drugs Administration (FDA) are not uniform [8]. Second, although DOACs have fewer interactions compared to VKAs, drug-drug interactions (DDIs) still need to be considered as all DOACs are substrate of the P-glycoprotein (P-gp) transporter, an efflux transporter located in the gut mucosa. Additionally, CYP3A4 type cytochrome P450 is involved in the hepatic elimination of rivaroxaban and apixaban. Competitive inhibition or induction of P-gp or CYP3A4 will therefore affect DOAC plasma levels [9]. For some DDIs, specific dosing algorithms have been evaluated during the pivotal randomised controlled trials (RCTs). However, for many potential DDIs, appropriate dosing remains unclear as clinical or pharmacokinetic data are lacking. Third, as strict inclusion and exclusion criteria were used in the pivotal RCTs, the study populations in these RCTs do not necessarily reflect ‘real-world’ situations [10]. Therefore, dosing recommendations based on these RCTs may not be applicable to all patients. ‘Real-world’ studies have identified a high prevalence of off-label DOAC dosing [8]. However, appropriate dosing is important to ensure the benefit of anticoagulation, as overdosing can increase the risk of major bleeding and compromise DOAC safety, while underdosing can increase the risk of thromboembolism and compromise the effectiveness of DOAC therapy [[11], [12], [13]].
To inform physicians on the safe and effective use of DOACs in specific clinical situations, the European Heart Rhythm Association (EHRA) developed a Practical Guide in 2013 [14] with updates in 2015 [9] and 2018 [15]. Among other topics, this guide formulates practical recommendations for appropriate DOAC dosing, taking into account the potential effect of DDIs.
In a previously published study, we evaluated implementation adherence to DOACs and explored patients' experiences with and beliefs about DOACs in a real-world sample of long-term DOAC users [16]. In this paper, we report on a subanalysis of this study where we aimed to evaluate the prevalence of potential DDIs and the appropriateness of DOAC dosing, as both components are essential to ensure effective and safe anticoagulation therapy. The data of this primary care sample of NVAF patients were analysed according to both the SmPC and the EHRA Practical Guide.
Section snippets
Study design and participants
The design of the study has been described elsewhere [16]. Briefly, a cross-sectional observational study was conducted in 158 community pharmacies in Belgium between October 2017 and August 2018. All patients visiting the pharmacy with a prescription for a DOAC were approached for enrolment until a total of five participants per pharmacy was reached or the study period ended. They were eligible for inclusion if they: (i) started taking a DOAC at least one year prior to inclusion, (ii) had
Study population
In total, 1851 patients were screened for eligibility of whom 1159 (62.6%) matched the inclusion criteria (Fig. 1). About two-thirds of them (n = 766) agreed to participate. For the analyses in this manuscript, 112 patients were excluded because data to calculate the CrCl using the CG formula were missing (n = 66) and/or DOAC was not prescribed for stroke prevention in NVAF patients (n = 57). This yielded a study population of 654 patients with a mean age of 77.1 ± 7.9 years and 55.2% male
Discussion
In about one-third of the study population, a potential DDI with DOAC was identified. PD DDIs were present twice as often as PK DDIs. PK DDIs mainly involved drugs that increase DOAC plasma concentration. The clinical significance of these potential DDIs is still unclear because the pivotal DOAC RCTs often excluded the use of interacting drugs [[3], [4], [5], [6]]. Until more prospective trials with guidance of DOAC dosing in patients with DDIs are available, these potential DDIs should be
Conclusions
This ‘real-world’ analysis of DOAC dosing demonstrated that in about one-third of NVAF patients potential DDIs were present. In 18.3% and 23.4% of patients, DOACs were dosed inappropriately according to the SmPC and EHRA Practical Guide respectively. In almost 10% of the study population dosing advice was inconsistent between both references. More research is needed to ensure appropriate DOAC dosing in this ‘grey zone’ population.
Funding
None
Declaration of Competing Interest
The authors report no relationships that could be construed as a conflict of interest.
Acknowledgements
The authors thank the patients and the pharmacists who participated in this study.
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All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation