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Association Between Oral Anticoagulants and the Risk of Dementia in Patients With Nonvalvular Atrial Fibrillation
BACKGROUND AND OBJECTIVES
Non-valvular atrial fibrillation (NVAF) is associated with an increased risk of dementia. Oral anticoagulants (OACs) are essential for stroke prevention in NVAF and studies have shown a possible protective effect on dementia. However, findings have been inconsistent and hampered by methodological limitations. Thus, we assessed whether the use of oral anticoagulants is associated with a decreased incidence of dementia in patients with non-valvular atrial fibrillation. In addition, we explored the impact of the cumulative duration of OAC use on the incidence of dementia.
Using the United Kingdom Clinical Practice Research Datalink, we formed a cohort of all patients aged 50 years or more, with an incident diagnosis of NVAF between 1988 and 2017 and no prior OAC use, with follow-up until 2019. Patients were considered unexposed until six months after their first OAC prescription for latency considerations and exposed thereafter until the end of follow-up. We used time-dependent Cox regression models to estimate hazard ratios (HRs), adjusted for 54 covariates, with 95% confidence intervals (CIs) for dementia associated with OAC use, compared with non-use. We also assessed whether the risk varied with cumulative duration of OAC use, compared with non-use, by comparing pre-specified exposure categories defined in a time-varying manner and by modelling the HR using a restricted cubic spline.
The cohort included 142,227 patients with NVAF, with 8,023 cases of dementia over 662,667 person-years of follow up (incidence rate 12.1, 95% CI 11.9-12.4 per 1,000 person-years). OAC use was associated with a decreased risk of dementia (HR 0.88, 95% CI 0.84-0.92) compared with non-use. A restricted cubic spline also indicated a decreased risk of dementia, reaching a low at approximately 1.5 years of cumulative OAC use and stabilizing thereafter. Moreover, OAC use decreased the risk in patients aged 75 years and above (HR 0.84, 95% CI: 0.80-0.89), but not in those younger (HR 0.99, 95% CI: 0.90-1.10).
In patients with incident NVAF, OACs were associated with a decreased risk of dementia, particularly in the elderly. This warrants consideration when weighing the risks and benefits of anticoagulation in this population.
CLASSIFICATION OF EVIDENCE
This study provides Class II evidence that in patients with NVAF, OAC use (vs. non use) is associated with a decreased risk of dementia.
Oral Anticoagulants and the Risk of Dementia in Patients With Nonvalvular Atrial Fibrillation: A Population-Based Cohort StudyNeurology 2022 Dec 29;[EPub Ahead of Print], A Rahman, J Michaud, S Dell'Aniello, EEM Moodie, JM Brophy, M Durand, JR Guertin, JF Boivin, C Renoux
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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Atrial fibrillation (AF) is associated with the risk of cognitive decline and multiple forms of dementia. One of the recognized mechanisms of cognitive decline in patients with AF is brain injury related to exposure to macro- and microembolic events. Anticoagulation can lower the risk of brain injury due to embolic events in patients with AF. However, its use can result in exposure to macro- and microbleeding events. In this regard, the use, timing of use, and efficacy of use of anticoagulation may help lower the risk of cognitive decline and dementia in patients with AF.
There are data to support the timing, use, and effective use of anticoagulation in patients with AF to specifically lower the risk of dementia. In a large retrospective study of cross-matched national registries comprising data from all individuals in Sweden with a diagnosis of AF (N = 444,106), treatment with anticoagulation lowered the risk of dementia by 29% after propensity score matching and falsification endpoints were used. In subgroup analysis, the greatest relative benefit of anticoagulation use was when patients were treated within 1 year of diagnosis of AF. If anticoagulation was started 3 years after diagnosis, no benefit was observed.1 In a study involving 2605 patients with AF without cognitive dysfunction or dementia referred for warfarin anticoagulation initiation, time in therapeutic range was directly associated with the risk of subsequent dementia ([vs >75%] <25%: HR, 5.3; 26%–50%: HR, 4.10; and 51%–75%: HR, 2.57).2 Although direct oral anticoagulants are more effective than warfarin in lowering the risk of stroke in patients with AF, two recent randomized control trials of warfarin versus dabigatran that performed cognitive testing over a period of 2 years failed to show a lower risk of cognitive decline with dabigatran.3,4 However, whether 2 years was a sufficient time to define treatment differences is unclear, and, in both studies, the study populations were small and underpowered.
In a recent study, using data from the UK Clinical Practice Research Datalink, a cohort of 444,106 patients aged older than 50 years was included to assess the value of exposure to anticoagulation in lowering the risk of dementia in patients diagnosed with AF. This represents approximately 7% of the population. Patients were considered exposed to oral anticoagulation after 6 months of use. The authors allowed the 6-month lag as anticoagulation initiated immediately before the diagnosis of dementia was unlikely to have influenced dementia onset. Among the 142,227 patients diagnosed with nonvalvular AF, 8023 were diagnosed with dementia over 662,667 person-years of follow-up (incidence rate 12.1 per 1000 person-years). The use of oral anticoagulation was associated with a lower multivariate-adjusted risk of dementia (HR, 0.88) compared with non-use. The benefit was noted primarily in older patients (age >75 years). No benefit was observed in lower-risk patients with a CHA2DS2-VASc score of 0 to 1. The risk reduction with anticoagulation was noted even when using exposure to antiplatelet therapy as a referent for comparison.
These data confirm other large population-based studies that have found a lower risk of dementia in patients treated with anticoagulation. The authors did not explore whether there was a relative benefit in using direct oral anticoagulants compared with warfarin. These data add to the findings of prior studies as they explore dementia risk by length of use of anticoagulation. There was a reduction in dementia risk across the range of anticoagulation exposures studied, with a reduction observed with an exposure of ≤2 years of 19%, 2–5 years of 14%, and >5 years of 11%. The relative value of length of exposure to anticoagulation might have declined slightly after 2 years as the patients with longer exposures were few and have bias related to their survival, dementia diagnosis in patients with AF tends to be more common among younger patients,5 and age-related causes for dementia are likely to increase both dependent and independent of anticoagulation exposure.
This large comprehensive population-based study continues to support the early diagnosis of AF and use of anticoagulation and maintenance of anticoagulation use as a means to lower the risk of stroke, cognitive decline, and dementia.