New Study Shows Atrial Fibrillation Patients Treated With Warfarin Long-Term are at Increased Risk for Dementia
SAN FRANCISCO, May 5, 2016 – A new study has found an increased risk of dementia in patients with atrial fibrillation (AF) that receive long-term, blood thinner, warfarin (Coumadin) compared to patients that use warfarin for conditions other than AF. The study of more than 10,000 patients treated with warfarin long-term found that patients with AF experience higher rates of dementia, Alzheimer’s disease and vascular dementia compared to anticoagulated non-AF patients. The research was presented today at Heart Rhythm 2016, the Heart Rhythm Society’s 37th Annual Scientific Sessions.
AF is the most common sustained cardiac arrhythmia with incidence rates that are growing dramatically with population aging. Many other chronic disorders of aging, such as dementia, are also increasing. Dementia is a neurological disorder that impairs memory and other cognitive abilities, and it is now listed amongst the leading causes of morbidity and mortality in developed countries. AF can increase the risk of dementia because it exposes patients to both large and small clots that can affect brain function. Blood thinners used to prevent all forms of clots and strokes can increase the risk of both large and small brain bleeds that can also negatively impact brain function over time.
The study was conducted by the Intermountain Healthcare Clinical Pharmacist Anticoagulation Service, which is part of the Intermountain Healthcare system based in Salt Lake City. Researchers enrolled a total of 10,537 patients with no history of dementia prior to the study and who were treated with a blood thinner for AF and non-AF conditions like valvular heart disease and thromboembolism on a long-term basis. Other variables included age, hypertension, diabetes, hyperlipidemia, renal failure, smoking history, prior myocardial infarction or cerebral vascular accident, and heart failure. Participants were aged 18 years and older.
During a follow-up of approximately seven years, all types of dementia increased in the AF group more than the non-AF group. In both groups, however, the risk of dementia increased as the time in therapeutic range (TTR) decreased or became more erratic. When warfarin levels were consistently too high or too low, dementia rates increased regardless of why patients were receiving a blood thinner. However, regardless of the adequacy of anticoagulation, AF patients consistently experienced higher rates of all forms of dementia.
This finding indicates that the efficacy of therapy is strongly associated with dementia. Of note, researchers found that patients younger than 70 years tended to be the most susceptible to the risk of dementia.
“Our study results are the first to show that there are significant cognitive risk factors for patients treated with warfarin over a long period of time regardless of the indication for anticoagulation,” said lead author T. Jared Bunch, MD, director of heart rhythm research at Intermountain Medical Center Heart Institute and medical director for heart rhythm services for the Intermountain Healthcare system.
This study is important in many ways, Dr. Bunch said.
“First, as physicians we have to understand that although we need to use anticoagulants for many reasons including to prevent stroke in AF patients, at that same time there are risks that need to be considered some of which we are only right now beginning to understand. In this regard, only those that absolutely need blood thinners should be placed on them long-term,” he added. “Second, other medications like aspirin that may increase the blood thinners effect should be avoided unless there is a specific medical need. Finally, in people that are on warfarin in which the levels are erratic or difficult to control, switching to newer agents that are more predictable may lower risk.”
In further exploring the association between AF, anticoagulation and dementia, this study offers insight into future treatment for patients with AF and for those taking a blood thinner for other needs. With AF raising the risk of dementia in addition to and independent of anticoagulation, how the abnormal rhythm is treated may be a way to lower dementia risk.
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Neurology
Approximately 6 years ago, our center reported in an analysis of 37,025 patients with a mean age of 60.6 +/− 17.9 years that the presence of atrial fibrillation (AF) was associated with risk of all forms of dementia, including Alzheimer’s disease.1 The highest relative risk of developing an idiopathic dementia was in the younger AF patients (<70 years), a finding inconsistent with an epiphenomenon in a study examining two disease states that increase with age. A similar finding of a higher risk of dementia in younger AF patients (<67 years) compared with older AF patients was found in a recent subanalysis of the Rotterdam Study.2
We anticipated the disease states’ association was likely multifactorial; however, we explored one dominant hypothesis. This hypothesis was founded on a known fact that repetitive macro events, strokes, and/or intracranial bleeds are causes of dementia in AF patients. In this regard, it is conceivable that smaller cranial micro events (whether strokes or bleeds) in accumulation can lead to cognitive decline and dementia. If this latter hypothesis is true, then the efficacy and use of anticoagulation may impact the disease association between AF and all forms of dementia.
In order to evaluate the role of anticoagulation on dementia risk in AF patients, we studied 2605 patients who had no history of dementia and were managed long-term with warfarin by our clinical pharmacy anticoagulation service. The percent time in therapeutic range with warfarin was significantly associated with dementia risk in an incremental manner [(vs >75%) <25%: HR 5.34, P < .0001; 26%–50%: HR 4.10, P < .0001; and 51%–75%: HR 2.57, P = .001].3 Similar to our initial study, the highest relative risk was seen in subsequent analysis in the patients less than 80 years compared to those who were older. The risks of dementia based on anticoagulation efficacy were in a U-shaped curve, with increase both in those patients who tended toward significant exposure to under-anticoagulation as well as over-anticoagulation. In those AF patients who are consistently over-anticoagulated, the additional use of one or more antiplatelet drugs further augments dementia risk.4 These studies were supportive of both a potential micro-emboli and micro-bleed mechanism underlying dementia risk in AF patients.
These background data frame the need of why we performed our most recent analysis. We specifically asked if the majority of risk of dementia in AF patients was related to anticoagulation efficacy, or if the atrial arrhythmia further augmented the risk. In this study, which was presented at the Heart Rhythm Scientific Sessions (http://www.hrsonline.org/News/Press-Releases/2016/05/New-Study-Shows-Atrial-Fibrillation-Patients-Treated-with-Warfarin-Long-Term-are-at-Increased-Risk-for-Dementia), we analyzed 10,537 patients treated with long-term warfarin for both AF and non-AF indications. AF patients tended to be older and had higher rates of hypertension, heart failure, and prior strokes. In both groups, percent time in therapeutic range was significantly associated with dementia risk. In order to account for marked variance in baseline characteristics between AF and non-AF anticoagulated patients, we performed a propensity analysis of 6030 patients. In this analysis, AF independently increased risk of total dementia (HR, 2.42; P < .0001) and Alzheimer’s dementia (HR, 2.04; P < .0001). The elevated risk with AF persisted across all ranges of percent time in therapeutic range. This last study highlights the impact of variance of warfarin efficacy on dementia risk, regardless of the indication for which the warfarin was used. However, despite the impact of anticoagulation, AF conveys additive risk and provides a potential target to further lower dementia risk in these patients.
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