Characterising the risk of major bleeding in patients with Non- Valvular Atrial Fibrillation: non-interventional study of patients taking Direct Oral Anticoagulants in the EU

Title

Rationale and background

To describe a pharmacoepidemiological study using longitudinal data collected in 8 electronic health care databases from 6 EU countries to characterize the use of Direct Oral Anticoagulants (DOAC) as well as the risk of major bleeding in a real-world setting to help establish the effectiveness of existing and future risk minimization measures.

Research question and objectives

Objective 1. The risk of major bleeding associated with use of DOACs when compared to other oral anticoagulants (OACs) in patients with non-valvular atrial fibrillation (NVAF) overall and in relevant clinical and demographical subgroups in a real-life setting.
Objective 2. The utilization of DOACs in the EU for treatment of NVAF, including the characterization of new DOAC users in NVAF patients.
Objective 3. Prescribers’ compliance with recommendations included in sections 4.1, 4.3, 4.4, and 4.5 of the SmPC of each DOAC.

Abstract objective 1
Aim: To characterize the risk of major bleeding in DOAC users in a real-world setting using longitudinal data collected in four electronic health care databases from different EU countries.

Methods: A study cohort among consisted of 251,719 new users (≥18 years) of DOACs or VKAs with non-valvular atrial fibrillation from the UK, Spain, Germany and Denmark. We compared current use of DOACs with current use of VKAs with respect to the occurrence of major bleeding events.

Results:Overall hazard ratios of major bleeding risk for DOACs versus VKAs ranged between 0.84 (Denmark) and 1.13 (UK CPRD). When stratifying according to the type of bleeding event, the risk of gastrointestinal bleeding was statistically significantly increased by 48-67% in users of dabigatran users and 30-50% for rivaroxaban users compared to VKA users in all data sources except for Denmark.

Conclusion: Compared to VKAs, apixaban was not associated with an increased risk of GI bleeding in all data sources and seemed to be associated with the lowest risk of major bleeding events compared to dabigatran and rivaroxaban. Future exploration of reasons for non-adherence to DOAC treatment and its impact on bleeding risk are interesting to explore in more detail.
 

Abstract objective 2
Aim: To estimate the incidence of Direct Oral Anticoagulant Drug (DOACs) use in nonvalvular atrial fibrillation (NVAF) and to describe user and treatment characteristics in 8 European health databases (Mondriaan, Bavarian CD, AOK Nordwest, BIFAP, SIDIAP, CPRD, EGB and NRD ) representing 6 European countries (Denmark, France, Germany, United Kingdom, The Netherlands and Spain) .

Methods: Descriptive cohort study of new DOAC users with NVAF from January 2008 to December 2015. A common protocol approach was applied to each database. Annual period incidences and direct standardisation by age and sex were performed. A incidence percentage change in DOAC use was assessed from 2012-2013 (apixaban 2013-2014) to 2014-2015. Dose adjustment related to change in age and by renal function as well as concomitant use of potential interacting drugs were assessed.

Results: A total of 186,405 new DOAC users (≥18 years) were identified. The standardized incidence increased for all DOACs over the study period, with the highest increase for apixaban (554.5%) followed by rivaroxaban (80.7%). The highest incidence for all DOACs was found in Denmark and Germany, with lower values and slight differences among the remaining databases. The incidence of DOAC use increased for both genders in most databases and especially in those older than 75 years. Concomitant use of contraindicated drugs varied between 16..4% (SIDIAP), and 70.5% (EGB) and dose adjustment ranged from 4.6% in the Spanish (BIFAP) to 15.6% in the French (EGB) study population.

Conclusion: The overall incidence of new DOAC users increased, with the highest increase for apixaban. Cross national drug utilization studies with a standard protocol may help to compare drug use and identify sources of variation enabling health care decisions.

Abstract objective 3
Aim: To analyse prescribers’ adherence to registered indications (IC), contraindications (CI), special warnings/precautions (SW/P), and potential drug-drug interactions (pDDIs).

Methods: This retrospective cohort study was conducted in six databases covering regionally / nationally representative populations in 5 European countries. The study cohort consisted of patients (≥18 years) initiating dabigatran, rivaroxaban or apixaban between 2008 and 2015. ICs, CIs, SW/Ps, and pDDIs as registered in the Summary of Product Characteristics (SmPC) were mapped to respective coding systems.

Results: Within the study period and the six included database, a DOAC was initiated in 407,576 patients (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.

Between the databases, a substantial variety was found regarding the proportion of patients with at least one CI (inter-database range: 8.2% to 55.7%) with highest values for dabigatran in most databases. SW/Pc were present in a higher proportion of incident DOAC users (inter-database range: 35.8% – 75.2%) reaching highest values in incident apixaban users. Inter-database range for potential DDIs was 22.4% to 54.1% reaching highest values in dabigatran initiators.

Conclusion: CIs, SW/Ps, and potential DDIs were present in a substantial number of new DOAC users. Differences found between the databases might be related to ‘true’ differences in prescription behaviour but also due to discrepancies in database characteristics. (EMA/2015/27/PH; EU PAS Register No: 16014).