More Evidence of Lower Fracture Risk With DOACs Versus Warfarin

Use of a direct oral anticoagulant (DOAC) over warfarin is associated with fewer osteoporotic fractures in patients with newly diagnosed A-fib, a study out of Hong Kong shows.

The difference, which is consistent with prior studies, appears to be consistent across specific DOACs, researchers led by Wallis Lau, PhD (University of Hong Kong), report in a study published online May 18, 2020, ahead of print in the Annals of Internal Medicine.

“These findings may help inform the benefit-risk assessment when choosing between anticoagulants,” the authors conclude.

But even though the study “is showing consistency in the safety of the direct oral anticoagulants, at least with regards to fracture risk,” it is unlikely to have an impact on clinical decision-making, commented Geoffrey Barnes, MD (University of Michigan, Ann Arbor), who was not involved in the effort.

“To be honest, it is rarely a question that comes up for patients,” Barnes told TCTMD, referring to fracture risk. Effectiveness in terms of preventing strokes or blood clots and safety regarding bleeding usually take precedence, he said. “Things like fracture risk are not really things they’re even aware of. They’re issues that we as clinicians are somewhat aware of but frankly don’t come up in our risk-benefit conversations all that often.”

That said, Barnes continued, studies like these “provide reassurance that long-term use of these drugs is probably safe, and that’s really a question that does come up from patients.”

Lower Risks in Both Men and Women

Warfarin has long been suspected of increasing the risk of osteoporotic fracture, Lau et al note. “Preclinical studies showed that several vitamin K-dependent proteins, such as matrix Gla protein and osteopontin, play a role in bone metabolism, and this has led to concerns that warfarin may increase the risk for osteoporotic fracture,” they write. “However, most of the previous studies that investigated the link between warfarin and fracture were done in previous decades and have yielded inconsistent findings.”

More recent studies, including one using national data from Denmark, have suggested that fracture risk is lower with the DOACs, which operate through different pathways.

To further explore the issue, Lau and colleagues examined electronic health records from the Hong Kong Hospital Authority. The analysis included 23,515 patients (mean age 74.4 years; roughly half women) who were newly diagnosed with A-fib between 2010 and 2017 and who received a new prescription for warfarin or one of the following DOACs: apixaban (Eliquis; Bristol-Myers Squibb), dabigatran (Pradaxa; Boehringer Ingelheim), or rivaroxaban (Xarelto; Bayer/Janssen). Edoxaban (Savaysa; Daiichi Sankyo), the most recently approved DOAC, was not included because of the limited number of patients taking it.

Through a median follow-up of 423 days, there were 401 osteoporotic hip or vertebral fractures identified. After inverse probability of treatment weighting based on propensity scores, incidence rates (per 100 patient-years) were 1.11 for warfarin, 0.82 for apixaban, 0.76 for dabigatran, and 0.67 for rivaroxaban. Women tended to have higher rates than did men.

At the 24-month mark, DOAC use was associated with a lower fracture risk relative to warfarin, with a lower adjusted cumulative incidence of fractures for apixaban (-0.88%), dabigatran (-0.81%), and rivaroxaban (-1.13%). Cox proportional hazards modeling provided similar results, with comparable findings in men and women. There were no significant differences when individual DOACs were compared with each other.

“Given its limited power to compare between DOACs, this study can only rule out more than a twofold higher or a 50% lower relative risk for osteoporotic fractures between individual DOACs,” the authors note. “However, any absolute risk differences were small and would likely be of minor clinical significance.”

Important Aspect of Anticoagulant Management?

Lau et al acknowledge some limitations of their analysis, including the possibility that asymptomatic fractures were missed and the lack of information on body mass index, bone mineral density, alcohol consumption, and smoking status. But, they say, because these variables “are not a common set of factors to inform the choice of oral anticoagulants, it is unlikely that the joint effect of these unmeasured confounders could have accounted for an association of this strength.”

Limitations notwithstanding, the researchers say the study has important implications for clinicians.

“Osteoporotic fracture and atrial fibrillation share common risk factors, such as older age, hypertension, and diabetes, but in practice, the risk for osteoporotic fractures is often neglected when choosing an oral anticoagulant for patients with atrial fibrillation. Surgery is often required to treat a fracture, making perioperative management of anticoagulation difficult because a balance between the risk for stroke and excessive bleeding must be achieved,” they explain. “Therefore, prevention of fracture is an important aspect of anticoagulant management in patients with atrial fibrillation.”

With this study, combined with prior experimental and clinical data, “there exists a compelling case for evaluating whether the risk for osteoporotic fractures should be considered at the point of prescribing an oral anticoagulant to minimize fracture risk,” Lau et al argue.

Barnes remained skeptical, saying “it’s unlikely to become a more prominent part of discussion. Yet I think for those of us who develop recommendations and guidance statements it can provide a little bit more reassurance that, yes, this is a safe long-term drug to use.”

What really sets this analysis apart from others, Barnes added, is that it examined oral anticoagulant use in a primarily Asian population, providing findings similar to those from analyses of US or European cohorts. For that reason, it “can reassure us that these are safe drugs to use in any patients that we encounter who have prothrombotic conditions,” he said.