Lutsey PL, Norby FL, Ensrud KE, et al. Association of Anticoagulant Therapy With Risk of Fracture Among Patients With Atrial Fibrillation. JAMA Intern Med. 2019 Nov 25. pii: 2755293. doi: 10.1001/jamainternmed.2019.5679. (Original study)

Importance: Warfarin is prescribed to patients with atrial fibrillation (AF) for the prevention of cardioembolic complications. Whether warfarin adversely affects bone health is controversial. The availability of alternate direct oral anticoagulant (DOAC) options now make it possible to evaluate the comparative safety of warfarin in association with fracture risk.

Objective: To test the hypothesis that, among patients with nonvalvular AF, use of DOACs vs warfarin is associated with lower risk of incident fracture.

Design, Setting, and Participants: This comparative effectiveness cohort study used the MarketScan administrative claims databases to identify patients with nonvalvular AF and who were prescribed oral anticoagulants from January 1, 2010, through September 30, 2015. To reduce confounding, patients were matched on age, sex, CHA2DS2-VASc (congestive heart failure, hypertension, age [>65 years = 1 point; >75 years = 2 points], diabetes, and previous stroke/transient ischemic attack [2 points], vascular disease) score, and high-dimensional propensity scores. The final analysis included 167?275 patients with AF. Data were analyzed from February 27, 2019 to September 18, 2019.

Exposures: Warfarin and DOACs (dabigatran etexilate, rivaroxaban, and apixaban).

Main Outcomes and Measures: Incident hip fracture, fracture requiring hospitalization, and all clinical fractures (identified using inpatient or outpatient claims) defined by International Classification of Diseases, Ninth Revision, Clinical Modification codes.

Results: In the study population of 167?275 patients with AF (38.0% women and 62.0% men; mean [SD] age, 68.9 [12.5] years), a total of 817 hip fractures, 2013 hospitalized fractures, and 7294 total fractures occurred during a mean (SD) follow-up of 16.9 (13.7) months. In multivariable-adjusted, propensity score-matched Cox proportional hazards regression models, relative to new users of warfarin, new users of DOACs tended to be at lower risk of fractures requiring hospitalization (hazard ratio [HR], 0.87; 95% CI, 0.79-0.96) and all clinical fractures (HR, 0.93; 95% CI, 0.88-0.98), whereas the association with hip fractures (HR, 0.91; 95% CI, 0.78-1.07) was not statistically significant. When comparing individual DOACs with warfarin, the strongest findings were for apixaban (HR for hip fracture, 0.67 [95% CI, 0.45-0.98]; HR for fractures requiring hospitalization, 0.60 [95% CI, 0.47-0.78]; and HR for all clinical fractures, 0.86 [95% CI, 0.75-0.98]). In subgroup analyses, DOACs appeared more beneficial among patients with AF who also had a diagnosis of osteoporosis than among those without a diagnosis of osteoporosis.

Conclusions and Relevance: In this real-world population of 167?275 patients with AF, use of DOACs-particularly apixaban-compared with warfarin use was associated with lower fracture risk. These associations were more pronounced among patients with a diagnosis of osteoporosis. Given the potential adverse effects of warfarin on bone health, these findings suggest that caution should be used when prescribing warfarin to patients with AF at high risk of fracture.

Discipline Area Score
Internal Medicine 7 / 7
Family Medicine (FM)/General Practice (GP) 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Hemostasis and Thrombosis 6 / 7
Cardiology 6 / 7
Public Health 5 / 7
Comments from MORE raters

Hemostasis and Thrombosis rater

As a hematologist, I am not typically the prescriber of anticoagulation for atrial fibrillation, but this is certainly useful information for hematologists who consult in the care of patients with atrial fibrillation and for cardiologists who routinely prescribe anticoagulation for atrial fibrillation.

Hemostasis and Thrombosis rater

Outcome study that suggests DOAC therapy may be associated with lower fracture rates than warfarin in patients with afib.

Hemostasis and Thrombosis rater

Although more prospective studies may be needed for this comparison, this study does provide additional information to reiterate the advantage of DOACs over warfarin. However, I would be hesitant to draw a premature conclusion that warfarin has a direct affect on bone health.

Internal Medicine rater

Not a population-based database, so likely considerable selection bias along with the usual unmeasured confounders.

Public Health rater

The evaluation seems relatively robust, but there may still be residual confounding. More patients with unmeasured frailty beyond the secondary data analysis with fall risk may be prescribed warfarin since warfarin is more easily reversed. The other issue that I don't think was discussed was duration of use. Average follow-up was 16 months or so. Do they think the adverse effect of warfarin on bone density would take place so quickly? Increasing risk with time of use would enhance evidence for a causal relationship. Finally, the NNT is large and practitioners will need to take that into account. Fractures are feared, however. More evidence may be needed to guide practitioners.
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