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Atrial fibrillation (Afib) patients generally did not enjoy extra protection from dementia if they took direct oral anticoagulants (DOACs) instead of warfarin, but there may be exceptions, a large Korean cohort study found.

Nationwide claims data showed new-onset dementia to occur at a rate of 4.87 per 100 person-years in more than 72,000 people with nonvalvular Afib and no previous dementia, according to Eue-Keun Choi, MD, PhD, of Seoul National University Hospital, and colleagues.

Warfarin and DOAC users shared a similar risk of incident dementia on inverse probability of treatment weighting, and this was consistent in both vascular dementia and Alzheimer dementia, Choi's group reported in .

The authors noted that only people ages 65 to 74 and those with prior stroke seemed to have a lower risk of dementia on DOACs versus warfarin (P<0.01 for interaction for both).

Among individual DOACs, edoxaban (Savaysa) alone was associated with a lower risk of dementia compared with warfarin (HR 0.830, 95% CI 0.740-0.931). However, a sensitivity analysis censoring incident strokes during follow-up linked both rivaroxaban (Xarelto) and edoxaban to lower risk.

On the other hand, dabigatran (Pradaxa) and apixaban (Eliquis) did not appear to reduce incident dementia over warfarin in the study.

U.S. guidelines currently recommend Afib patients take DOACs (or non-vitamin K oral anticoagulants) in lieu of warfarin for stroke prevention -- the specific DOAC of choice remains uncertain due to the limited data available, however.

The idea that oral anticoagulation may have a protective effect on dementia is supported by indirect evidence: rates of Afib-associated dementia have fallen over the last 3 decades with increasing anticoagulant use, and increased time in therapeutic range is protective, according to Sarah Pendlebury, DPhil, of John Radcliffe Hospital and the University of Oxford in England.

"Taken together with the observed lower dementia incidence in those with prior stroke, the findings suggest that DOACs may be superior to warfarin in real-world prevention of vascular dementia through reduction in clinical stroke but also of subclinical stroke and microembolism," Pendlebury wrote in an .

The retrospective study included people 40 years or older with oral anticoagulant-naive nonvalvular Afib who were new users of warfarin (n=25,948) and DOACs (n=46,898) from 2014 to 2017. Follow-up was relatively short, lasting 1.3 years on average.

The cohort had a mean age of 71.8 years, and 58% of participants were men. The average CHA₂DS₂-VASc score was 4.0.

Compared with patients treated with warfarin, those treated with DOACs were older and had a higher CHA₂DS₂-VASc score.

The observational study left room for residual confounding and lacked data on whether patients actually adhered to their prescribed oral anticoagulant, Choi and collaborators acknowledged.

In addition, Pendlebury complained that dementia is often underdiagnosed in the real world and estimated that "the sensitivity of dementia diagnostic coding for the true prevalence of dementia may be much lower at around 30% to 40%."

Therefore, the study's use of diagnostic coding to ascertain dementia likely led to inclusion of some individuals with dementia at baseline and under-detection of new dementia on follow-up. "These factors will have reduced the overall power of studies to detect differences in dementia incidence between groups," Pendlebury cautioned.

Further studies using clinical ascertainment of dementia to determine the effects of individual DOACs on long-term dementia risk are required, she said.

And in line with common practice in Asia, Korean patients on DOACs received only a reduced dose in about half of cases in the study, according to Choi's team.

"Although the clinical impact of off-label underdosed DOAC is still controversial, off-label underdosed DOAC might be associated with the increased risk of ischemic stroke," the authors noted. "Further investigation is needed to find the clinical impact of off-label underdosed DOACs in Asian patients with Afib, especially for the risk of dementia."

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