Can DOACs protect AF patients against dementia?
Atrial fibrillation (AF) and dementia are diseases of aging and share several common risk factors, such as diabetes mellitus, heart failure, uncontrolled blood pressure, smoking, sleep apnea and diseases vascular.
Evidence from a number of prospective and retrospective studies indicates that AF is associated with cognitive impairment, cognitive decline and dementia (here and here). The association is independent of prior clinical stroke, as well as the many risk factors common to both conditions. This is true for both vascular dementia and Alzheimer’s disease, the most common dementia subtypes.
Several pathophysiological mechanisms have been proposed to explain the development of dementia and cognitive decline in patients with AF. These include silent strokes secondary to microcerebral infarcts, cerebral hemorrhages and chronic cerebral hypoperfusion, and blood flow disturbances such as occur during AF, causing potential disruption of blood-brain barrier and leaving the brain more vulnerable to damage.
Clinically recognized strokes are just the tip of the iceberg of AF-induced ischemia. In patients with AF, subclinical embolic cerebral ischemia (hidden cerebral infarcts, microcerebral infarcts) is more common than overt strokes and is associated with cognitive dysfunction. These suggested mechanisms warrant examination of the role of anticoagulation in preventing dementia, as opposed to preventing ischemic stroke, in patients with AF.
Several observational studies (here) suggest that anticoagulation reduces the risk of cognitive decline or dementia in AF. A systematic review and meta-analysis including six studies found that oral anticoagulants (OACs) reduce the risk of dementia by around 20%. In patients taking warfarin, an increased proportion of time for the international normalized ratio (INR) spent in the therapeutic range has also been reported to be correlated with a lower risk of dementia.
In recent years, the use of direct-acting oral anticoagulants (DOACs) has overtaken warfarin in Australia. This was not unexpected as DOACs have better efficacy and safety, and current treatment guidelines recommend them as first-line agents in stroke prevention in patients with AF (here and here).
The question then arises: are DOACs better than warfarin in protecting against dementia in AF?
In our recent retrospective study using the NPS MedicineInsight dataset, we found that in patients with AF, compared to warfarin, DOACs were associated with a 54% reduced risk of new-onset dementia over the course of with a mean follow-up of 3.7 years. In this study, we adjusted for differences in baseline patient characteristics with propensity score matching and excluded patients with a history of stroke/transient ischemic attack, development of dementia in the year post-follow-up or patients who received CAO for
Only a few other studies have compared the risk of dementia in patients on DOACs with those on warfarin. A US study reported that dementia occurred more frequently in patients with AF receiving warfarin than in DOACs (0.7% of patients on warfarin v 0.3% of people with DOA; P = 0.03). The mean duration of follow-up was 392 days in the warfarin group and 292 days in the DOAC group. Another study (mean follow-up time 1.3 years), using the Korea National Claims Database, found that DOA use was associated with a lower risk of dementia than warfarin in certain subgroups. groups of patients, mainly in people aged 65 to 74 years ( Dangerousness rate [HR], 0.82; 95% CI, 0.71 to 0.94) and in people with previous stroke (RR, 0.90; 95% CI, 0.82 to 0.97). A Swedish study that followed patients for an average of 4.9 years reported that DOAC use was associated with a 38% lower risk of dementia than non-prescribed patients, but no difference in risk was found. was seen when DOACs were compared to warfarin. .
Interestingly, we did not find a significant difference in dementia risk between warfarin users and OAC nonusers (RR, 1.08; 95% CI, 0.70-1.70; P = 0.723). This contrasts with a meta-analysis of five studies, showing that vitamin K antagonists reduced the risk of dementia by 23% compared to treatment without OAC. We were therefore unable to further examine the risk of dementia in patients taking warfarin with sub-analyses based on INR monitoring.
Needless to say, CAOs aren’t just prescribed to AF patients to prevent dementia.
More information from ongoing randomized clinical trials (rivaroxaban, NCT04073316; and apixaban, NCT03839355) is needed to more firmly guide the use of DOACs in the prevention of dementia in addition to stroke in patients with AF, including those with a low stroke risk score. Evidence comparing individual DOACs with each other is also limited and further studies are needed.
Dr Woldesellassie Bezabhe is a Lecturer in Medicines Safety at the School of Pharmacy and Pharmacology, University of Tasmania.
Professor Jan Radford is Professor of General Medicine at the Launceston Clinical School, University of Tasmania.
Distinguished Professor Gregory Peterson works in the School of Pharmacy and Pharmacology at the University of Tasmania.
Statements or opinions expressed in this article reflect the views of the authors and do not represent the official policy of WADA, the MJA or Preview+ unless otherwise stated.
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