title: Time outside of therapeutic range in atrial fibrillation patients is associated with long-term risk of dementia.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Intermountain Heart Institute, Intermountain Medical Center, Murray, Utah.
authors.forename: Victoria
authors.initials: V
authors.lastname: Jacobs
authors.affiliation: Intermountain Heart Institute, Intermountain Medical Center, Murray, Utah.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Woller
authors.affiliation: Intermountain Heart Institute, Intermountain Medical Center, Murray, Utah.
authors.forename: Scott
authors.initials: S
authors.lastname: Stevens
authors.affiliation: Intermountain Heart Institute, Intermountain Medical Center, Murray, Utah.
authors.forename: Heidi T
authors.initials: HT
authors.lastname: May
authors.affiliation: Intermountain Heart Institute, Intermountain Medical Center, Murray, Utah.
authors.forename: Tami L
authors.initials: TL
authors.lastname: Bair
authors.affiliation: Intermountain Heart Institute, Intermountain Medical Center, Murray, Utah.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Anderson
authors.affiliation: Intermountain Heart Institute, Intermountain Medical Center, Murray, Utah.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Crandall
authors.affiliation: Intermountain Heart Institute, Intermountain Medical Center, Murray, Utah.
authors.forename: John D
authors.initials: JD
authors.lastname: Day
authors.affiliation: Intermountain Heart Institute, Intermountain Medical Center, Murray, Utah.
authors.forename: Katie
authors.initials: K
authors.lastname: Johanning
authors.affiliation: Intermountain Heart Institute, Intermountain Medical Center, Murray, Utah.
authors.forename: Yenh
authors.initials: Y
authors.lastname: Long
authors.affiliation: Intermountain Heart Institute, Intermountain Medical Center, Murray, Utah.
authors.forename: Charles
authors.initials: C
authors.lastname: Mallender
authors.affiliation: Intermountain Heart Institute, Intermountain Medical Center, Murray, Utah.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Olson
authors.affiliation: Intermountain Heart Institute, Intermountain Medical Center, Murray, Utah.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Osborn
authors.affiliation: Intermountain Heart Institute, Intermountain Medical Center, Murray, Utah.
authors.forename: J Peter
authors.initials: JP
authors.lastname: Weiss
authors.affiliation: Intermountain Heart Institute, Intermountain Medical Center, Murray, Utah. Electronic address: Thomas.bunch@imail.org.
authors.forename: T Jared
authors.initials: TJ
authors.lastname: Bunch
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects; D001281:Atrial Fibrillation / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology*; D015331:Cohort Studies; D015897:Comorbidity; D003704:Dementia / Q000453:epidemiology* / Q000209:etiology / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D018570:Risk Assessment; D012720:Severity of Illness Index; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D000925:Anticoagulants; D014859:Warfarin
keywords: Atrial fibrillation; Dementia; Microbleed; Microembolus; Oral anticoagulation; Stroke; Time in therapeutic range; Warfarin