Prescribers' compliance with SmPC recommendations for dabigatran, rivaroxaban, and Apixaban: A European comparative drug utilization study

Background: Despite a tremendous increase in prescribing of direct oral anticoagulants (DOACs) in recent years limited data is available on prescribers' adherence to registered indications (ICs), contraindications (CIs), special warnings/precautions (SW/PCs), and potential drug-drug interactions (pDDIs). Objectives: The aim of this study was to assess in six European databases prescribers' adherence to the Summary of Product Characteristics (SmPC) of three DOAC compounds (dabigatran, rivaroxaban, and apixaban) with a special focus on IC, CI, SW/PC, and pDDI. Methods: This retrospective cohort study was conducted in databases covering regionally/nationally representative populations in five European countries (Denmark, Germany, Spain, the Netherlands, and United Kingdom). The study cohort consisted of adult patients (≥18 years) initiating dabigatran, rivaroxaban or apixaban between 2008 and 2015. ICs, CIs, SW/Ps and pDDIs as registered in the SmPC of the DOACs were mapped to respective coding systems. Results: 407,576 patients initiated DOACs during the study period (rivaroxaban: 240,985 [59.1%], dabigatran: 95,303 [23.4%], apixaban: 71,288 [17.5%]). In 2015, non-valvular atrial fibrillation was the most common IC registered, representing more than 60% of incident DOAC users in most databases. For the whole study period, a substantial variety between the databases was found regarding the proportion of patients with at least one CI (interdatabase range [IDR]: 8.2% to 55.7%), with at least one SW/PC (IDR: 35.8% - 75.2%), and with at least one pDDI (22.4% to 54.1%). In 2015, the most frequent CI was 'malignant neoplasm' (IDR: 0.7% - 21.3%) whereas the most frequent SW/Pc were 'prescribing to the elderly (75 years or older)' with an IDR from 25.0% to 66.4%. The most common single compound class pDDI was 'concomitant use of nonsteroidal antinflammatory drugs' with an IDR between 3.0% to 25.3%. Conclusions: CIs, SW/Ps, and pDDIs were present in a significant number of new DOAC users. Differences between all databases might be related to 'true' differences in prescription behaviour, but could also be partially due to differences in database characteristics.