Anticoagulants Linked to Reduced Dementia Risk in AF

Batya Swift Yasgur, MA, LSW

October 12, 2018

Older adults with atrial fibrillation (AF) experience faster global cognitive decline and have an increased risk for dementia compared with people of similar age who do not have AF, although use of anticoagulant drugs may reduce this risk, new research suggests.

In a study of more than 2000 dementia-free older adults who were followed for an average of 6 years, the rate of cognitive decline was faster for participants with AF than for those without AF. Patients with AF were also 40% more likely to develop dementia.

Participants who took anticoagulant drugs had a 60% decreased risk for dementia. There was no reduction in risk among those who took antiplatelet drugs.

"In this population study of older adults, we found that AF was associated with faster decline in global cognitive function — such as thinking and memory skills — and a greater risk of dementia, and notably, that older people with AF who were taking anticoagulant drugs were less likely to develop dementia than those who did not take any anticoagulant drugs," study author Chengxuan Qiu, PhD, associate professor and senior lecturer, Aging Research Center, Karolinska Institute, Stockholm, Sweden, told Medscape Medical News.

"Our study suggests that older people with AF could have higher dementia risk; however, taking anticoagulant drugs may decrease the risk of dementia due to AF," he said.

The study was published online October 10 in Neurology.

Seeking Modifiable Risk Factors

"Growing evidence has suggested that AF may have an important role in cognitive dysfunction," but the association has been consistently shown only among stroke patients and those aged <75 years, the authors write.

Inconsistencies in previous findings might be attributable to methodologic variations; for example, incident AF has rarely been taken into consideration. Additionally, the potentially protective effect of anticoagulants for cognitive function and in delaying the onset of dementia has been insufficiently explored, they note.

Qiu said the motivation for the study was the "tremendous burden posed by dementia on individuals and the society" and the lack of a cure or disease-modifying therapy.

"Identifying modifiable risk factors for dementia that can be targeted for therapeutic or preventive intervention to reduce its risk is critically relevant," he said.

The researchers used data from the population-based Swedish National Study on Aging and Care in Kungsholmen (SNACK), Stockholm, to examine the associations of AF with dementia, dementia subtypes, and cognitive decline in people aged ≥60 years. They took into account prevalent and incident AF and explored the impact of antithrombotic treatment on the development of dementia.

The final study sample consisted of 2263 participants who were dementia-free at baseline (mean age, 73.1 years; SD, 10.5, years; 65% women).

Follow-up assessments were performed for patients aged <78 years after 6 years; for those aged ≥78 years, assessments were performed every 3 years.

Assessments consisted of face-to-face interviews, clinical examinations, and laboratory testing, including APOE genotyping and measurements of total cholesterol and glycated hemoglobin levels.

Participants with AF at baseline were classified as having prevalent AF; those who developed AF during the follow-up period before the diagnosis of dementia or death were considered to have incident AF.

Global cognitive function was assessed using the Mini–Mental Status Examination (MMSE); DSM-IV criteria were used to diagnose dementia.

Covariates included education, excessive alcohol consumption, smoking, and physical activity, as well as conditions such as hypertension, diabetes, heart failure, coronary heart disease, and abnormal kidney function.

Antiplatelets Ineffective, Potentially Damaging

The investigtors found that participants with prevalent AF were older, less educated, more likely to be male, and more likely to be physically inactive.

In addition, they were more likely to have morbidities such as hypertension, diabetes, heart failure, ischemic stroke/transient ischemic attack (TIA), and coronary heart disease, compared to those without prevalent AF.

During the 9-year follow-up period (2001-2004 to 2010-2013; mean follow-up per person, 5.8 years; SD, 2.2 years), 11.4% of the AF-free participants developed incident AF.

Of the sample, 14.9% of patients developed incident dementia, including 6.2% with AD and 2.5% with either vascular dementia or mixed dementia.

Using linear mixed models with AF as a time-varying variable, the researchers found that AF was significantly associated with an accelerated average annual decline in MMSE score after adjusting for demographic and lifestyle factors and chronic diseases (β coefficient = -0.24; 95% confidence interval, [CI], -0.31 to -0.16).

Cox regression models demonstrated that AF was significantly associated with increased risk for dementia, after adjusting for confounders (hazard ratio [HR], 1.40; 95% CI, 1.11 - 1.77); however, the association was statistically evident only among women and APOE ε4 carriers (HR, 1.46; 95% CI, 1.10 - 2.94; and HR, 1.74; 95% CI, 1.17 - 2.59, respectively).

Excluding people with prevalent stroke/TIA at baseline and censoring people at the dates when incident stroke/TIA occurred did not substantially change the results.

Cox regression analyses also revealed that AF was significantly associated with an increased risk for combined vascular and mixed dementia (HR, 1.88; 95% CI, 1.09 - 3.23) but not with risk for AD (HR, 1.33; 95% CI, 0.92 - 1.94).

Propensity score–weighted Cox regression models showed that among participants with prevalent AF at baseline or incident AF that developed during the 6-year follow-up period, use of anticoagulant drugs was associated with a reduced risk for dementia (HR, 0.40; 95% CI, 0.18 - 0.92).

Use of antiplatelet drugs was not significantly associated with an increased dementia risk (HR, 1.84; 95% CI, 0.99 - 3.42).

"Assuming that there was a causal relationship between use of anticoagulant drugs and a reduced risk of dementia, we estimated that approximately 54% of the dementia cases (population attributable risk 0.46, 95% CI: 0.22 – 0.95) would have been hypothetically prevented if all patients with AF had received anticoagulant drugs," the authors comment.

"People with AF have low cardiac output, systemic blood stasis, and hypercoagulable state, which may cause blood clots as well as insufficient brain blood perfusion and brain ischemia, and ischemic condition in the brain could promote deposits of toxic proteins," Qiu hypothesized.

"All these pathways can link AF to cognitive decline and, eventually, dementia," he said.

He noted that current guidelines for AF management recommend anticoagulant drugs such as warfarin instead of antiplatelets such as low-dose aspirin for stroke prevention, "since antiplatelets are not only ineffective for stroke prevention but they also increase the risk of bleeding among patients with AF."

It is therefore likely that patients with AF who are taking antiplatelets may experience both bleeding and ischemia in the brain, "which, in turn, increase the risk of dementia," he said.

Improve Clinical Management of AF

Commenting on the study for Medscape Medical News, Luciana Sposato, MD, MBA, associate professor of neurology, Western University, Ontario, Canada, who was not involved with the study, said that its "most important finding is that the use of oral anticoagulant was associated with a 60% reduction in the risk of dementia in patients with AF, which is twice the benefit found in a recent systematic review and meta-analysis."

The current study also showed that the association between AF and dementia was only found among women and APOE ε4 carriers, suggesting that "degenerative changes may also play a role in the pathophysiology of dementia," said Sposato, who is the coauthor of an accompanying editorial.

He noted that attempts to prove that oral anticoagulants prevent dementia by conducting a randomized controlled trial would be "infeasible, since most of the patients would require oral anticoagulants for stroke prevention, and this would preclude them from being randomized to no treatment or aspirin."

For this reason, "large and well-conducted observational studies, such the current study, provide the best available evidence to test this hypothesis."

Qiu added, "These findings emphasize the need to improve the clinical management of patients with AF, especially given that a considerable proportion of older people with AF are not using anticoagulant drugs."

He cautioned that the findings regarding the association of antiplatelet drugs with dementia risk are "only suggestive, not conclusive, and highlight the need for more research on this issue."

The study was funded by the Swedish Ministry of Health and Social Affairs and the Swedish Research Council.Dr Qiu was supported by the Swedish Research Council for Health, Working Life and Welfare and the Swedish Research Council. Relevant financial relationships of the other study authors and the editorialists are listed in the published articles.

Neurology. Published online October 10, 2018. Abstract, Editorial

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