Comparison of the efficacy, safety, and adherence of oral anticoagulants

Abstract

Oral anticoagulants (OACs) are among the most commonly used medication worldwide. Vitamin K antagonists, such as warfarin, were the only available oral anticoagulants for over 60 years. However, in the 2010s, novel direct oral anticoagulants (DOACs) were approved that act by directly inhibiting either factor II (dabigatran) or factor X (apixaban, rivaroxaban, and edoxaban). The results of the initial randomized controlled trials demonstrated that DOACs were associated with similar thromboembolic rates and lower major bleeding rates compared to warfarin. As a result, DOACs are currently considered first-line therapy for patients with atrial fibrillation and venous thromboembolism. However, randomized controlled trials comparing DOACs head-to-head are currently lacking, and previous observational studies have important limitations. Additionally, data are largely lacking on other outcomes such as rates of upper and lower gastrointestinal bleeding (GIB) and epistaxis event rates. Similarly, it is still unknown whether medication adherence differs between warfarin and DOACs. The aims of this thesis were to compare the efficacy, safety, and adherence of different oral anticoagulants. Therefore, 5 studies were designed and are presented in 5 distinct papers. Specifically, the aim of paper I was to compare rates of thromboembolism and major bleeding between different DOACs, the aim of paper II was to compare rates of any clinically relevant GIB between DOACs, the aim of paper III was to compare rates of upper and lower GIB between warfarin and DOACs, the aim of paper IV was to compare rates of epistaxis between warfarin and DOACs, and the aims of paper V was to compare the likelihood of nonadherence between different OACs. A study outcome database was created that included all patients in Iceland who filled a prescription for an OAC from 1 March 2014 to 28 February 2019. The database combined data from the Icelandic Medicine Registry; the electronic healthcare databases of Landspitali University Hospital and the regional hospitals of Akranes, Akureyri, Ísafjörður, and Neskaupsstaður; the electronic healthcare databases of the primary healthcare centers around the country; and the Icelandic death registry. All thromboembolic and major bleeding events were manually verified by chart review. The study population included new users of apixaban, dabigatran, rivaroxaban, and warfarin (for papers III-V). Inverse probability weighting was used to yield balanced study groups and bleeding and thromboembolic events were compared using Cox regression. Kaplan-Meier curves were used to visualize the data. Nonadherence, defined as proportion of days covered below 80%, was compared between groups using logistic regression. Similarly, logistic regression was used to estimate patient characteristics associated with nonadherence. Rivaroxaban was associated with lower rates of any thromboembolism and myocardial infarction (MI) compared to dabigatran. Similarly, apixaban was associated with lower rates of MI compared to dabigatran, although this comparison did not reject the null hypothesis. Meanwhile, rivaroxaban was associated with higher rates of any major bleeding, any clinically relevant GIB, and any clinically relevant epistaxis compared to apixaban and dabigatran. Rates of stroke and all-cause mortality were similar between patients receiving different DOACs. Warfarin was associated with higher rates of upper but not lower or overall GIB compared to DOACs. Warfarin was also associated with higher epistaxis rates compared to DOACs. Dabigatran was associated with higher nonadherence compared to apixaban, rivaroxaban, and warfarin. Meanwhile, the odds of nonadherence was similar between apixaban, rivaroxaban, and warfarin. Apart from OAC type, female gender, hypertension, history of cerebrovascular accident, and concomitant statin use were all associated with lower odds of nonadherence. In summary, rivaroxaban was associated with higher rates of bleeding compared to other DOACs but lower rates of any thromboembolism and MI compared to dabigatran. Warfarin was associated with high rates of upper GIB and epistaxis compared to DOACs. Dabigatran was associated with poorer adherence than other oral anticoagulants.