DOACs Tied to Lower Fracture Risk vs Warfarin in AF

Batya Swift Yasgur MA, LSW

October 22, 2019

Direct-acting oral anticoagulants (DOACs) for atrial fibrillation (AF) are associated with a lower risk for osteoporotic fractures versus warfarin, a vitamin K antagonist (VKA), a new Danish study suggests.

Investigators analyzed the 2-year risk for osteoporotic fracture in more than 37,000 patients with AF, comparing those treated with DOACs and those treated with VKA, and found patients on DOACs had a roughly 20% reduced relative risk for any fracture or initiating osteoporosis medication.

"I think practicing clinicians need to be aware of the connection between VKA treatment and osteoporotic fractures and they should consider switching OAC treatment if patients are considered to be at risk of osteoporosis or osteoporotic fractures," lead author Caspar Binding, BMedSc, a research fellow at Copenhagen University, told | Medscape Cardiology.

The study was published online October 21 in the Journal of the American College of Cardiology.

Not Fully Examined

Traditionally, patients with AF have treated with warfarin, which has been associated with low bone mineral density (BMD) and potentially with increased fracture risk, the authors write.

DOACs are newer agents, which have "proven noninferior and in some cases superior to VKAs" with regard to risk for stroke/systemic embolism and major bleeding, without any impact on osteocalcin synthesis.

Binding said he and his colleagues were motivated to conduct the study after reading an "intriguing" study comparing risk for fractures in Chinese patients with AF being treated with OACs.

"We knew that AF patients were generally elderly patients and that fractures would have a severe impact on their health status," he said.

Other studies have also suggested a link between VKA and low BMD, but they felt that this "important" subject had "not yet been examined in full."

For this analysis, the researchers used the Danish National Patient Register to identify all patients with nonvalvular AF who were first-time users of either VKA or the DOACs dabigatran, rivaroxaban, apixaban, or edoxaban (n = 61,099)

Patients were required to be between the ages of 30 and 100 years and were followed starting 180 days after filling their first prescription for VKA or DOAC and for 2 years after or until outcome, emigration, death, or June 30, 2017, whichever came first.

The researchers identified five study outcomes: any fracture; major osteoporotic fracture; hip fracture; initiation of osteoporosis medication; and a combined end point of any fracture or initiation of osteoporosis medication, whichever came first.

Dietary Connection?

Of the 37,350 patients who met study criteria, 67.4% were treated with a DOAC, while 32.6% were treated with VKA, with a median age significantly higher in the DOAC than in the VKA group (73 years [67 - 81] vs 72 years [65 - 79]; < .001) and a larger number of women in the DOAC vs the VKA group (44.1% vs 38.2%; < .001).

More patients in the DOAC group than in the VKA group had experienced a previous fracture (4.1% vs 2.9%; < .001).

DOAC treatment was associated with lower 2-year standardized absolute risk and significantly lower adjusted relative risk in all four outcomes, compared to VKA.

Fracture Outcomes with DOAC vs VKA in AF at 2 Years
Outcome DOAC 2-Year Absolute Risk, % (95% CI) VKA 2-Year Absolute Risk, % (95% CI) Relative Risk, DOAC vs VKA, Hazard Ratio (95% CI)
Any fracture 3.09 (2.85–3.33) 3.77 (3.37–4.19) 0.85 (0.74–0.97)
Major osteoporotic fracture 2.29 (2.02–2.49) 2.82 (2.46–3.19) 0.85 (0.72–0.99)
Initiating osteoporosis medication 2.44 (2.22–2.66) 3.14 (2.79–3.51) 0.82 (0.71–0.95)
Combined end point 5.21 (4.90–5.52) 6.43 (5.89–6.94) 0.84 (0.76–0.93)

At 2 years, DOAC treatment was found to be associated with absolute risk reduction in all four domains, compared with VKA.

Fracture Outcomes: Absolute Risk Reduction at 2 Years
Outcome Absolute Risk Reduction at 2 years, % (95% CI)
Any fracture 0.68 (1.17–0.21 )
Major osteoporotic fracture 0.53 (0.94–0.13)
Initiating osteoporosis medication 0.71 (1.12–0.30)
Combined end point 1.22 (1.82–0.64)

"Taken together, this is equivalent to 6.8 fewer osteoporotic fractures and 7.1 fewer osteoporosis treatment initiations for each 1000 persons treated with DOAC as opposed to VKA for 2 years," the authors note.

They add that, although the HRs were adjusted for variables that can potentially have an impact on fractures and osteoporosis — including chronic obstructive pulmonary disease, previous syncope, hormone replacement therapy, heart failure diagnosis, and stroke — the risk for residual confounding nevertheless remained.

These potential confounders "might have persevered in this study because of unmeasured variables (e.g., international normalized ratio, body mass index, hemoglobin, and renal function)," they write.

"I think many factors might influence a person's skeletal profile, but when considering VKAs, I believe that VKAs' biochemical mechanisms and the dietary restrictions accompanied with VKA treatment are of great importance," Binding commented.

VKA inhibits γ-carboxylation of coagulation factors II, VII, IX, and X and has been linked to under-carboxylated osteocalcin, an enzyme associated with BMD, so as a result, patients in treatment with VKAs might have more fragile bones, Binding explained.

Further, patients in treatment with VKA are subjected to dietary restrictions with regard to several vegetables, and this could contribute to a low intake of folic acid, he noted, which could, in turn, result in low osteoblast activity and high osteoclast activity owing to the risk for hyperhomocysteinemia.

"It is possible to increase the intake of folic acid through other consumables, such as some fruits, but I don't think patients in treatment with VKAs are urged to do so, as the topic might be overlooked," he added.

Biochemical Basis

In an accompanying editorial, Brian Gage, MD, MSc, professor of medicine, Washington University School of Medicine, St. Louis, said that Binding et al "had a strong biochemical basis to search for a link between VKAs and osteoporotic fractures" and that their "well-done observational study provides additional evidence of that link."

Nevertheless, he cautioned, "residual confounding may have exaggerated the association."

For that reason, "at least for patients who have AF and no prior osteoporotic fracture (the population studied), the decision to prescribe a VKA or a DOAC should depend on the risks of ischemic stroke, hemorrhage, need for monitoring, and affordability, rather than on the risk of osteoporotic fracture," he concluded.

By contrast, Binding emphasized that the "take-home message from the study is to take skeletal health profile into account when assessing OAC treatment for AF patients."

This study was funded by a scholarship from The Copenhagen University Hospital Herlev and Gentofte . Binding and Gage disclose no relevant financial relationships. The other study authors' disclosures are listed on the original paper.

J Am Coll Cardiol. Published online October 21, 2019. Abstract, Editorial

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