Atrial Fibrillation, Warfarin, and Dementia: Is There a Relationship?
Atrial fibrillation is one of the most common and often difficult cardiovascular arrhythmias to treat. It is increasing in prevalence, projected to affect almost 16 million adults in the United States by 2050.1 Treatment involves heart rate control, acute anticoagulation to prevent ischemic stroke, reestablishment of normal sinus rhythm, occasionally anti-arrhythmic drugs, and often long-term anticoagulation with a vitamin K antagonist (VKA) or a direct oral anticoagulant (DOAC). With dose-adjusted VKA, time in the therapeutic range (TTR) of an international normalized ratio (INR) maintained between 2 to 3 is correlated with prevention of thromboembolism.1
Dementia is defined as the diminished memory combined with 1 or more cognitive deficits. In concert with atrial fibrillation it most often occurs in the elderly, affecting all of a person’s activities of daily living. Because of the similar prevalence with age, researchers have hypothesized that a risk association may be occur.2-3 Interestingly; the highest relative risk of dementia and AF is found in younger adults.
So what is the potential mechanism that may lead to this association? Perhaps multiple small microemboli or microbleeds may occur that lead to dementia? Thereby, the TTR would be very important to prevent these repetitive small cerebral injuries.
A recent study by investigators at Intermountain Medical Center, in Salt Lake City, Utah, have found that in a population-based, retrospective study of 2,605 adult patients with a CHADS2 score primarily of 1 to 3 the percent TTR averaged 63.1±21.3 with an INR < 2.0 25.6±17.9%, > 3.0 16.2±13.6%, dementia is not uncommon.4 Dementia was diagnosed in 4.2%, senile in 1.4%, vascular in 0.3%, and Alzheimer’s in 2.5%. After adjustment, the percent TTR was associated with dementia risk, <25% (HR) 5.34, P<0.001; 25% to 50% (HR) 4.10, P<0.001, and 51% to 75% (HR) 2.57, P<0.001 versus 75% control value.
These preliminary findings have multifactorial implications. First and most importantly, these findings need to be verified by other population-based studies or by a controlled clinical trial. Second, TTR is increasingly becoming very important, not just above 55% as has been implicated by the RE-LY trial data, but for chronic quality of life. Third, no matter what anticoagulant is chosen, close follow-up of safety and efficacy are paramount. Fourth, this has implications for the need to maintain anticoagulation clinics, even in the era of DOACs where routine monitoring is stated to the main reason to prescribe these agents. Perhaps, more importantly, is the close follow-up to the need for medication adherence, monitoring for even small bleeds in any organ system, and constant patient education for attentive anticoagulation with dose adjustment, when necessary. Another pharmacist call to arms!
Mark A. Munger, PharmD, FCCP, FACC, is a Professor of Pharmacotherapy and Adjunct Professor of Internal Medicine, at the University of Utah, where he also serves as the Associate Dean, Academic Affairs for the College of Pharmacy.
1. Lip GY, Tse HF, Lane DA. Atrial fibrillation. Lancet. 2012;379(9816);648-661.
2. Bunch TJ, Weiss JP, Crandall BG, et al. Atrial fibrillation is independently associated with senile, vascular and Alzheimer’s dementia. Heart Rhythm. 2010;7(4):433-437.
3. Santangeli, P, Di Biase L, Bai R, et al. Atrial fibrillation and the risk of incident dementia: a meta-analysis. Heart Rhythm. 2012;9(11):1761-1768.
4. Jacobs V, Woller SC, Stevens S, et al. Time outside of therapeutic range in atrial fibrillation patients is associated with long-term risk of dementia. Heart Rhythm. 2014; 11(12):2206-2213.