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Heart Rhythm. 2014 Dec;11(12):2206-13. doi: 10.1016/j.hrthm.2014.08.013. Epub 2014 Aug 9.

Time outside of therapeutic range in atrial fibrillation patients is associated with long-term risk of dementia.

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Intermountain Heart Institute, Intermountain Medical Center, Murray, Utah.
Intermountain Heart Institute, Intermountain Medical Center, Murray, Utah. Electronic address:



The mechanisms behind the association of atrial fibrillation (AF) and dementia are unknown. One possibility is that exposure to chronic microembolism or microbleeds results in repetitive cerebral injury that is manifest by cognitive decline.


The purpose of this study was to test the hypothesis that AF patients with a low percentage of time in the therapeutic range (TTR) are at higher risk for dementia due to under- or overanticoagulation.


Patients anticoagulated with warfarin (target international normalized ratio [INR] 2-3), managed by the Intermountain Healthcare Clinical Pharmacist Anticoagulation Service with no history of dementia or stroke/transient ischemic attack, were included in the study. The primary outcome was dementia incidence defined by ICD-9 codes. Percent time in TTR was calculated using the method of linear interpolation and stratified as >75%, 51%-75%, 26%-50%, and ≤25%. Multivariable Cox hazard regression was used to determine dementia incidence by percentage categories of TTR.


A total of 2605 patients (age 73.7 ± 10.8 years, 1408 [54.0%] male) were studied. The CHADS2 score distribution was 0: 216 (8.3%); 1: 579 (22.2%); 2: 859(33.0%); 3: 708 (27.2%); and ≥4: 243 (9.3%). The percent TTR averaged 63.1 ± 21.3, with percent INR <2.0: 25.6% ± 17.9% and percent INR >3.0: 16.2% ± 13.6%. Dementia was diagnosed in 109 patients (4.2%) (senile: 37 [1.4%]; vascular: 8 [0.3%]; Alzheimer: 64 (2.5%]). After adjustment, decreasing categories of percent TTR were associated with increased dementia risk (vs >75%): <25%: hazard ratio (HR) 5.34, P < .0001; 26%-50%: HR 4.10, P < .0001; and 51%-75%: HR = 2.57, P = .001.


Quality of anticoagulation management represented as percent TTR among AF patients without dementia was associated with dementia incidence. These data support the possibility of chronic cerebral injury as a mechanism that underlies the association of AF and dementia.


Atrial fibrillation; Dementia; Microbleed; Microembolus; Oral anticoagulation; Stroke; Time in therapeutic range; Warfarin

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