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Warfarin vs. Direct Oral Anticoagulant Fracture Risk
Study Questions:
Is the oral anticoagulant (warfarin vs. direct oral anticoagulant) used among patients with atrial fibrillation (AF) associated with bone fracture risk?
Methods:
Taiwan’s National Health Insurance Research Database was used for a retrospective nationwide cohort study of all adult patients in Taiwan newly diagnosed with AF between 2012 and 2016 who were treated with a nonvitamin K antagonist oral anticoagulant (NOAC) or warfarin; patients were followed until 2017. Patients treated with a NOAC were subgrouped according to the agent used (dabigatran, rivaroxaban, or apixaban). Propensity score matching was performed for each head-to-head comparison. Cox regression analysis, with a shared frailty model, was used to calculate the adjusted hazard ratios (HRs) for hip, vertebral, and humerus/forearm/wrist fractures.
Results:
After matching, 19,414 patients were included (9,707 in both NOAC and warfarin groups). The median follow-up time was 2.4 years. Compared with warfarin, NOACs were associated with a reduced fracture risk (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.77–0.93; p < 0.001). Subanalyses revealed that each NOAC, namely dabigatran (HR, 0.88; 95% CI, 0.78–0.99; p = 0.027), rivaroxaban (HR, 0.81; 95% CI, 0.72–0.90; p < 0.001), and apixaban (HR, 0.67; 95% CI, 0.52–0.87; p = 0.003), had a reduced fracture risk compared to warfarin. Additional analyses including all eligible patients, without propensity score matching, generated similar results.
Conclusions:
Compared with warfarin, NOAC use among patients with AF was associated with a reduced fracture risk. The authors concluded that, although further studies are needed to investigate the underlying mechanisms and elucidate causality, a NOAC rather than warfarin should be considered to lower the risk of fracture when anticoagulation is indicated.
Perspective:
An association between warfarin use and an increased risk for osteoporotic fractures has been previously suggested, but the evidence remains controversial. In antagonizing vitamin K-dependent processes, warfarin may interfere with actions that contribute to bone formation, including impairing the γ-carboxylation of osteocalcin and other bone matrix proteins, which play important roles in bone mineralization. This retrospective nationwide cohort study from Taiwan found a significantly lower risk for hip, vertebral, and humerus/forearm/wrist fractures among patients with AF treated with a NOAC (dabigatran, rivaroxaban, or apixaban) compared to warfarin. Other studies have demonstrated at least noninferiority of NOACs in stroke risk reduction, and superiority in lowering hemorrhagic risk; the 2019 AHA/ACC/HRS focused update of the 2014 guideline for the management of AF patients already includes a Class I, Level of Evidence A indication for the use of a NOAC over warfarin among NOAC-eligible patients (excluding patients with moderate-to-severe mitral stenosis or a mechanical heart valve) with AF.
Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Dyslipidemia, Geriatric Cardiology, Prevention, Anticoagulation Management and Atrial Fibrillation, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism
Keywords: Anticoagulants, Arrhythmias, Cardiac, Atrial Fibrillation, Calcification, Physiologic, Frail Elderly, Humeral Fractures, Osteocalcin, Osteogenesis, Osteoporotic Fractures, Risk Reduction Behavior, Secondary Prevention, Stroke, Vitamin K, Warfarin
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