Abstract
Aims: Observational studies of various dose levels of direct oral anticoagulants (DOACs) for patients with atrial fibrillation (AF) found that a high proportion of patients received a dose lower than the target dose tested in randomized controlled trials. There is a need to compare low-dose DOACs with warfarin or other DOACs on effectiveness and safety. Methods: Using administrative data from Quebec province, Canada, we built a cohort of new warfarin or DOAC users discharged from hospital between 2011 and 2017. We determined CHA2DS2-VASc and HAS-BLED scores, and comorbidities for 3-year prior cohort entry. The primary effectiveness endpoint was a composite of ischemic stroke/systemic embolism (SE), and secondary outcomes included a safety composite of major bleeding (MB) events and effectiveness composite (stroke/SE, death) at 1-year follow-up. We contrasted each low-dose DOAC with warfarin or other DOACs as references using inverse probability of treatment weighting to estimate marginal Cox hazard ratios (HRs). Results: The cohort comprised 22,969 patients (mean age: 80–86). We did not find a significant risk reduction for the stroke/SE primary effectiveness endpoint for DOACs vs. warfarin; however, we observed a significantly lower risk for low-dose dabigatran vs. warfarin (HR [95%CI]: 0.59 [0.42–0.81]) for effectiveness composite, mainly due to a lower death rate. The differences in effectiveness and safety composites between low-dose rivaroxaban vs. warfarin were not significant. However, low-dose apixaban had a better safety composite (HR: 0.68 [0.53–0.88]) vs. warfarin. Comparisons of dabigatran vs. apixaban showed a lower risk of stroke/SE (HR: 0.53 [0.30–0.93]) and a 2-fold higher risk of MB. The MB risk was higher for rivaroxaban than for apixaban (HR: 1.58 [1.09–2.29]). Conclusions: The results of this population-based study suggest that low-dose dabigatran has a better effective composite than warfarin. Compared with apixaban, low-dose dabigatran had a better effectiveness composite but a worse safety profile. Low-dose apixaban had a better safety composite than warfarin and other low-dose DOACs. Given that the comparative effectiveness and safety seem to vary from one DOAC to another, pharmacokinetic data for specific populations are now warranted.
Highlights
Atrial fibrillation (AF) is known to cause embolic stroke, and the prevalence of AF is likely to increase (Colilla et al, 2013)
Comparisons of dabigatran vs. apixaban showed a lower risk of stroke/systemic embolism (SE) (HR: 0.53 [0.30–0.93]) and a 2-fold higher risk of major bleeding (MB)
The MB risk was higher for rivaroxaban than for apixaban (HR: 1.58 [1.09–2.29])
Summary
Atrial fibrillation (AF) is known to cause embolic stroke, and the prevalence of AF is likely to increase (Colilla et al, 2013). Oral anticoagulant (OAC) therapy with direct oral anticoagulants (DOACs, such as dabigatran, rivaroxaban, apixaban, and edoxaban) or vitamin K antagonists (e.g., warfarin) can effectively prevent ischemic events (including strokes) in patients with non-valvular AF (Hart et al, 2007; Culebras and Messé, 2014; January et al, 2014; Lip et al, 2018). DOACs are associated with a lower risk of drug interactions, are less influenced by dietary factors, and constitute alternatives to warfarin for the prevention of stroke and systemic embolism (SE) in patients with non-valvular AF (January et al, 2014; Lip et al, 2018)
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