Lower Risk for Fractures Is Another Win for Direct Oral Anticoagulants

For patients requiring long-term anticoagulation for thromboembolism prevention, possible adverse effects outside of the risks for bleeding and recurrent thromboembolism are important considerations. Vitamin K antagonists (VKA) may contribute to decreased bone density by decreasing osteocalcin levels and inhibiting bone matrix proteins which could increase risk for osteoporosis and fractures.¹  In a previous systematic review and meta-analysis, direct oral anticoagulants (DOACs) and VKAs had similar fracture risks.²  Two recent studies shed new light on the comparative risk of fractures in oral anticoagulant users.

The first study by Casper Binding and colleagues examined patients in Danish national registries with nonvalvular atrial fibrillation (AF) who were new users of oral anticoagulation and had been treated for at least 180 days. Outcomes included an individual analysis and a composite outcome of hip fractures, major osteoporotic fractures, any fracture, and initiation of osteoporotic medications. After excluding 23,749 patients, 25,182 DOAC-treated patients and 12,168 VKA-treated patients were compared in a multivariate Cox proportional hazard model adjusted for baseline differences in comorbidities and other medications. Patients treated with DOACs were less likely to have a major osteoporotic fracture (HR, 0.85; 95% CI, 0.72-0.99), any fracture (HR, 0.85; 95% CI, 0.74-0.97), and initiation of osteoporosis medication (HR, 0.82; 95% CI, 0.71-0.95), but not specifically hip fractures (HR, 0.91; 95% CI, 0.74-1.13). The standardized absolute two-year risk of any fracture was 3.77 percent (95% CI, 3.37-4.19%) in VKA-treated patients and 3.09 percent (95% CI, 2.85-3.33%) in DOAC-treated patients. The frequency of the various DOACs included was not provided, and the results were not further stratified into outcomes for specific DOACs.

In the second study, Dr. Pamela Lutsey and colleagues performed a study using data from administrative claims databases in patients with nonvalvular AF from 2010 through 2015. A total of 167,275 new users of oral anticoagulation were included; they had a mean age of 68.9 years and were predominately male (62%). Outcomes defined by International Statistical Classificaiton of Diseases and Related Health Problems (ICD)-9 codes were hip fractures (inpatient), fractures requiring hospitalization, and all fractures (inpatient and outpatient). Warfarin was the most common anticoagulant (n=82,625) followed by rivaroxaban (n=35,252), dabigatran (n=31,647), and apixaban (n=17,751). DOACs as a group when compared to VKAs had a lower risk of all fractures (HR, 0.93; 95% CI, 0.88-0.98) and fractures requiring hospitalization (HR, 0.87; 95% CI, 0.79-0.96), but not hip fractures requiring hospitalization (HR, 0.91 [0.78-1.07]). When each DOAC was compared to warfarin individually, rivaroxaban and apixaban both had a lower risk for fractures requiring hospitalization and all fractures. Apixaban compared to warfarin was the only DOAC to show a statistically significant reduction for all outcomes including hip fractures requiring hospitalization (HR, 0.67; 95% CI, 0.45-0.98). Dabigatran did not show a statistically significant reduction in risk compared to warfarin; however, there was a trend toward lower risk for fractures requiring hospitalization (HR, 0.88; 95% CI, 0.78-1.00). In a subgroup analysis for dabigatran, there were differences based on patient characteristics. Patients treated with dabigatran did have a significantly decreased risk for hospitalized fracture if they had osteoporosis (HR, 0.74; 95% CI, 0.68-0.90), were women (HR, 0.78; 95% CI, 0.66-0.92), or were younger than 75 years (HR, 0.75; 95% CI, 0.59-0.96). A matched analysis was then performed comparing apixaban to rivaroxaban and apixaban to dabigatran and found no significant differences for any of the fracture outcomes.