Atrial Fibrillation and Cognitive Function: JACC Review Topic of the Week

Numerous vascular risk factors and vascular diseases contribute to cognitive impairment and dementia. Many studies and registries show an association of atrial fibrillation (AF) with cognitive impairment, cognitive decline, and dementia. This is true for vascular dementia and Alzheimer's disease. The assumed multifactorial mechanisms include ischemic stroke, both apparent and silent, cerebral microinfarcts, cerebral hemorrhage, and reduced cerebral blood flow. A number of retrospective observational and prospective studies support that anticoagulation in patients with AF may reduce the risk of cognitive decline and dementia. This holds for both vitamin K antagonists (e.g., warfarin) and direct oral anticoagulants. However, it still remains unproven if anticoagulation reduces cognitive decline and dementia in AF patients based on randomized trials.     

Antithrombotic therapy in cardiac embolism

Anticoagulation is indicated in most cardioembolic ischemic strokes for secondary prevention. In many cardiac conditions, anticoagulation is also indication for primary stroke prevention, mainly when associated to vascular risk factors. Anticoagulation should be started as soon as possible, as it is safe even in moderate acute strokes. The efficacy of early anticoagulation after cardioembolic stroke in relation to outcome has not been assessed adequately, but there is evidence from animal models and clinical studies that anticoagulation with unfractionated heparin is associated with a better outcome mediated in part by its anti-inflammatory properties.     

Atrial fibrillation and cardioembolic stroke

The most disabling consequence of atrial fibrillation (AF) is stroke. In the elderly, AF is the single most important cause of stroke. The risk of stroke is increased at least 6-fold in subjects with AF. Strokes in patients with AF are in general severe, associated with higher risk of fatality and prone to early and long-term recurrence. The cardiac origin of stroke can be strongly suspected by anamnesis, clinical examination and findings on neuroimaging. Paroxysmal AF is an important cause of brain embolism, that is often difficult to document. Risk factors for stroke in AF include: previous embolism (including previous transient ischaemic attack (TIA), or ischaemic stroke), age >65 years, structural cardiac disease, rheumatic or other significant valvular heart disease, valvular artificial prosthesis, hypertension, heart failure and significant left ventricular systolic dysfunction, diabetes and coronary disease. All AF patients with TIA or stroke have a formal indication for long-term anticoagulation. Only patients without risk factors or with contraindications to warfarin should be put on aspirin. Treating 1 000 patients with AF for 1 year with oral anticoagulants rather than aspirin would prevent 23 ischaemic strokes while causing 9 major bleedings. Despite its enormous preventive potential, oral anticoagulants are underused in AF, because treating physicians often have lack of knowledge about trials and guidelines, underestimate the benefits and overestimate the risks associated with continuous oral anticoagulation. The introduction of anticoagulants that do not need frequent control tests, such as ximelagatran, will increase the proportion of AF patients with risk factors for stroke who are anticoagulated. There is no evidence to support routine immediate anticoagulation in acute ischeamic stroke associated with AF.     

Anticoagulation management in clinical practice: preventing stroke in patients with atrial fibrillation

Atrial fibrillation (AF) is a major and widely recognized risk factor for cardioembolic stroke. Prophylactic therapy for the prevention of stroke in patients with AF is often achieved through oral anticoagulation, specifically with warfarin, which has been used for this purpose for more than 50 years. Although warfarin therapy is effective when implemented appropriately, it is often underutilized and requires consistent monitoring to ensure both safety in avoiding bleeding and efficacy in preventing strokes. Because the burden of AF-related stroke continues to rise, healthcare professionals need to understand the strengths and limitations of current and emerging treatment options. This review outlines current practices for managing the risk of stroke with anticoagulation in patients with AF, and discusses how new oral anticoagulants may affect clinical practice.     

Antithrombotic therapies for stroke prevention in atrial fibrillation

Atrial fibrillation (AF) is now regarded as the arrhythmia for which patients are hospitalized the most frequently, an arrhythmia that is responsible for significant morbidity and mortality. Of particular importance is that the arrhythmia is associated with a significant incidence of thromboembolism which may induce disabling and incapacitating strokes, sometimes fatal. In the past, it was thought that in patients with AF restoration and maintenance of sinus rhythm prevent the development of strokes, a presumption that has not been vindicated by controlled clinical trials. On the other hand, over many decades, it has been established that appropriate anticoagulation especially with warfarin can reduce stroke rate in nonvalvular AF by about 70%, and mortality by 26%. Aspirin reduces stroke rate by 26%, mortality by about 10%. Thus, in AF oral anticoagulants have become the focal point of therapy for the prevention of strokes and the safety and efficacy of such a therapy has been established by controlled clinical trials; moreover, the subsets of patients with AF in whom anticoagulation is mandatory have been defined on the basis of defined risk factors. Warfarin is now the anticoagulant of choice although its limitations are considerable in terms of drug-drug interactions, narrow range of therapeutic index requiring strict monitoring of intensity of anticoagulation, among other limitations which influence compliance of therapy with the agent. In this review, the continuing role of warfarin in the prevention of stroke in patients with AF is discussed as a background for the development of newer anticoagulants. The issue is of particular importance in the older patients, in whom the development of safer antithrombotic therapies remain a major challenge. In this context, the potential role of the direct thrombin inhibitors hold promise for the future and the evolving data on leading compounds of this class which may be competitive with warfarin are discussed.     

The Impact of Atrial Fibrillation and Its Treatment on Dementia

Atrial fibrillation (AF) is a very common tachyarrhythmia and is becoming increasingly prevalent, while dementia is a neurological condition manifested as loss of memory and cognitive ability. Both these conditions share several common risk factors. It is becoming increasingly evident that AF increases the risk of dementia. There are several pathophysiological mechanisms by which AF can cause dementia. AF increases the stroke risk and strokes are strongly associated with dementia. Besides stroke, altered cerebral blood flow in AF and cerebral microbleeds from anticoagulation may enhance the risk of dementia. Maintaining sinus rhythm may therefore decrease this risk. Catheter ablation is emerging as an effective alternative to maintain patients in sinus rhythm. This procedure has also shown promise in decreasing the risk of all types of dementia. Besides maintaining sinus rhythm and oral anticoagulation, aggressive risk factor modification may reduce the likelihood or delay the onset of dementia.     

Atrial fibrillation,cognition and dementia: A review

Atrial fibrillation (AF) is one of the most common types of cardiac arrhythmia, particularly among older adults. AF confers a 5‐fold risk for thromboembolic stroke as well as a 2‐fold higher risk for congestive heart failure, morbidity, and mortality. Although stroke remains an important and impactful complication of AF, recent studies have shown that AF is independently associated with other neurological disorders, including cognitive impairment and dementia, even after adjusting for prior ischemic stroke. We performed a review of the published literature on the association between AF and cognitive status. Further, we reviewed studies investigating the underlying mechanisms for this association and/or reporting the impact of AF treatment on cognitive function. While most published studies demonstrate associations between AF and impaired cognition, no AF treatment has yet been associated with a reduced incidence of cognitive decline or dementia.     

Confronting atrial fibrillation in the elderly: stroke risk stratification and emerging antithrombotic therapies

As many as one in four patients over age 40 will develop atrial fibrillation (AF), a significant risk factor for stroke. Although most clinicians are aware of the benefits of antithrombotic therapy, especially warfarin, for prevention of stroke, current guidelines for selection of antithrombotic therapy are confusing and inconsistently applied. The CHADS2 risk-stratification scheme, based on a clinical history of heart failure, hypertension, age >75, diabetes, or prior stroke, is a useful clinical tool to identify patients likely to benefit from warfarin, distinguishing these patients from patients at lower risk for whom aspirin is sufficient. Risk factors for intracerebral hemorrhage include anticoagulation intensity, hypertension, age, and previous stroke or cerebrovascular disease. Cerebral amyloid angiopathy and leukoaraiosis identified by high-resolution brain imaging are under investigation, but better schemes for stratifying bleeding risk are needed. In the future, new anticoagulants that are safer and easier to administer than warfarin will improve the benefit/risk burden for elderly patients with AF.     

Deciding on anticoagulating the oldest old with atrial fibrillation: insights from cost-effectiveness analysis

OBJECTIVES: To better understand the tradeoffs between the efficacy of anticoagulation with warfarin and its side effects in the oldest old with nonrheumatic atrial fibrillation (AF). DESIGN: Cost-effectiveness analysis. SETTING: Published literature, including meta-analyses when available, and web-based sources. PARTICIPANTS: Those aged 65 to 100 with AF. INTERVENTION: Anticoagulation with warfarin. MEASUREMENTS: Quality-adjusted life expectancy and cost. RESULTS: Anticoagulation is not effective in persons with AF who do not have other risk factors, even in the oldest old. The best argument for its use (prolongation of life at an acceptable cost) can be made in those at major risk for stroke because of previous stroke or transient ischemic attack, diabetes mellitus, and hypertension, but poor quality of life before anticoagulation and comorbidities that carry their own risks of dying diminish benefits. The decision to anticoagulate the oldest old with AF must take into consideration the risk of hemorrhagic stroke and of death from hemorrhagic stroke that existed before anticoagulation, the increased risk of hemorrhagic stroke and of death from hemorrhagic stroke while anticoagulated, and the efficacy of anticoagulation. Cost-effectiveness is also influenced by the cost of warfarin, the risk of major extracranial bleeding, the risk (natural and anticoagulated) of death from hemorrhagic stroke, the rate of ischemic stroke, the cost of major extracranial bleeding and hemorrhagic strokes, the cost of nursing home care, and the fraction of patients with stroke who need nursing home care. CONCLUSION: There is no compelling evidence to date that anticoagulation prolongs quality-adjusted life expectancy in the oldest old with nonrheumatic AF. More studies that better estimate the risk of intracranial bleeding with and without anticoagulation in the oldest old are needed before recommendations can be made. The oldest old who are most likely to benefit are those who have a high risk of stroke secondary to risk factors other than age alone, although quality of life and life expectancy related to these risk factors limit obtained benefit. Recommendations that all older persons with AF should be anticoagulated are premature.     

Dementia and Atrial Fibrillation: Pathophysiological Mechanisms and Therapeutic Implications

Atrial fibrillation increases the risk of stroke by a factor of four- to fivefold, and dementia is a common consequence of stroke. However, atrial fibrillation has been associated with cognitive impairment and dementia, even in patients without prior overt stroke. Nonischemic mechanisms include cerebral hypoperfusion, vascular inflammation, brain atrophy, genetic factors, and shared risk factors such as age or hypertension. Critical appraisal of studies evaluating the association between atrial fibrillation and dementia in stroke-free patients reveals that several suffer from methodological issues, such as not including silent stroke or anticoagulation therapy in multivariate analyses. Some studies show a close relationship between atrial fibrillation and dementia due to silent stroke, in the absence of overt stroke. Evidence is accumulating that anticoagulation may be effective to decrease the risk of dementia in atrial fibrillation patients. Overall, the pathogenesis linking atrial fibrillation to dementia is likely multifactorial. Cerebral infarctions, including silent stroke, play a central role. These findings underscore the importance of stroke prevention measures in atrial fibrillation patients.     

Anticoagulation in patients at high risk of stroke without documented atrial fibrillation. Time for a paradigm shift?

Atrial fibrillation (AF) is currently considered a risk factor for stroke. Depending on the severity of clinical factors (risk scores) a recommendation for full anticoagulation is made. Although AF is most certainly a risk factor for ischemic stroke, it is not necessarily the direct cause of it. The causality of association between AF and ischemic stroke is questioned by the reported lack of temporal relation between stroke events and AF paroxysms (or atrial high‐rate episodes detected by devices). In different studies, only 2% of patients had subclinical AF > 6 minutes in duration at the time of stroke or systemic embolism. Is it time to consider AF only one more factor of endothelial disarray rather than the main contributor to stroke? In this “opinion paper” we propose to consider not only clinical variables predicting AF/stroke but also electrocardiographic markers of atrial fibrosis, as we postulate this as a strong indicator of risk of AF/stroke. We ask if it is time to change the paradigm and to consider, in some special situations, to protect patients (preventing stroke) who have no evidence of AF.     

The Multiple Causes of Stroke in Atrial Fibrillation: Thinking Broadly

Atrial fibrillation (AF) is numerically the most important risk factor for stroke. It is well established that patients with AF have a 5-fold increased risk of stroke relative to those without and that anticoagulation reduces the risk of stroke by approximately two-thirds. Definitively attributing the mechanism of an individual stroke to AF is more problematic, however. In fact, there is no way to reliably establish the etiology of any ischemic infarction. This necessitates screening for all potential stroke risk factors and treating accordingly. The pattern of infarction is often used to classify the presumed mechanism of infarction as thrombotic or embolic, although even this is approach is based on association and increasingly is recognized as not completely reliable. Furthermore, it should not dictate management—patients with perforating arterial territory infarcts with AF also require and benefit from anticoagulation. Likewise, if other potential embolic sources beyond AF are identified, anticoagulation remains the standard of care. The traditional conceptual model of the mechanistic link between AF and cardioembolic infarction is likely oversimplified. Long-term cardiac rhythm recording studies indicate an inconsistent temporal relationship between AF and infarction. This suggests that cardioembolic stroke in patients with AF may result from the underlying atrial cardiopathy, rather than the rhythm disturbance leading to atrial stasis and thromboembolism. We reviewed traditional and current concepts, as well as evidence for the role of AF in ischemic stroke.     

Large-scale screening studies for atrial fibrillation – is it worth the effort?

Atrial fibrillation (AF) is a common disease with increasing prevalence, approximately 3.2% in the adult population. In addition, about one third of AF cases are considered asymptomatic. Due to increased longevity, increased detection and increased prevalence of risk factors, the prevalence of AF is expected to at least double by the year 2060. Patients with AF have an increased risk for ischaemic stroke, heart failure, death and cognitive decline. Treatment with oral anticoagulation reduces the risk of ischaemic stroke and mortality, and the effect on cognitive decline is being studied. Based on the increasing prevalence of AF, its often asymptomatic and paroxysmal presentation and the efficacy of oral anticoagulation treatment, screening for AF has been proposed. AF seems to fulfil most of the Wilson–Jungner criteria for screening issued by the World Health Organization, but some knowledge gaps remain, gaps that will be addressed by several ongoing studies. The knowledge gaps in AF screening consist of the magnitude of the net benefit or net harm inflicted by AF screening because the oral anticoagulation treatment will also increase the risk of bleeding, and the psychological effects of AF screening are not very well studied. So far, the AF screening recommendations issued by the European Society of Cardiology have had limited impact on national and regional AF screening activities. Several large-scale AF screening studies will report results on hard endpoints within the next few years, and these results will hopefully manifest AF as a cardiovascular disease which we need to pay more attention to.     

Atrial fibrillation (AF) and cognitive impairment in the elderly: a case-control study

AF is able not only to increase the risk of cognitive decline due to acute cerebrovascular events, but also to reduce cardiac output, with the consequence of impaired cerebral perfusion. The aim of this study was to evaluate the association between AF, dementia and depression in patients with negative anamnesis for past strokes. Our sample included 26 patients with a diagnosis of AF (paroxystic, persistent, permanent) and 31 patients with sinus rhythm, enrolled as controls. All selected patients underwent a Multidimensional Geriatric Assessment in order to investigate cognitive and behavioral functions. Statistical analysis of results showed a greater frequency of latent cognitive impairment in patients with AF, even in the absence of memory disorders. As a matter of facts, AF patients showed Mini Mental State Examination (MMSE) scores significantly lower than those with sinus rhythm (p<0.05) and Geriatric Depression Scale (GDS) scores higher than those without AF, evidencing a greater risk of depression too (p<0.02). Results showed a statistically significant association between AF, depression and cognitive impairment in early stage. In conclusion, AF is not only associated with the risk of developing cognitive impairment, but it can also be considered as a risk factor for dementia and depression, even in the absence of medical history of past stroke.     

Anticoagulation remains underused in prevention of stroke associated with atrial fibrillation: Insights from two consecutive national surveys

Background

Atrial fibrillation (AF) is a major risk factor of ischemic stroke. We tested whether the adoption of the CHADS₂ score in clinical guidelines has impacted treatment strategies for stroke prevention, and examined how AF affects stroke outcome.

Methods

In the setting of two national surveys [National Acute Stroke Israeli Surveys; all patients hospitalized for stroke in Israel during February-March 2004, and March-April 2007] data of patients with and without AF were analyzed with respect to patient characteristics, use of anticoagulation, stroke severity, clinical course, and long-term outcome.

Results

Of 3040 patients with acute ischemic stroke, 586 patients (19%) had a history of AF. Severe strokes on admission were significantly more frequent in patients with AF, as was the proportion of total anterior circulation strokes. Ischemic stroke associated with AF predicted poor outcome at discharge (adjusted OR 1.56; 95%CI 1.24-1.96) and higher mortality rates throughout follow-up. Among patients with a CHADS₂ score ≥ 2 prior to the index stroke and without known contraindications, 41% received anticoagulation. This proportion increased to only 62% after the index stroke, even after excluding patients with severe disability and no significant increase between 2004 and 2007 was detectable. Increasing age, in-hospital infectious complications, and unfavorable functional status at discharge were independently associated with decreased likelihood of receiving anticoagulation.

Conclusions

In deviation from current recommendations and in spite of the introduction of CHADS₂ criteria, anticoagulation for stroke prevention remains underutilized, despite the particularly poor outcome of strokes associated with AF.     

Stroke Prevention in Atrial Fibrillation: Concepts and Controversies

Atrial fibrillation (AF) is the commonest cardiac rhythm disorder worldwide, affecting 1% of the general population. It is estimated that up to 16 million people in the US will suffer from the arrhythmia by 2050. AF is an independent stroke risk factor and associated with more severe strokes. For six decades, warfarin has been the only truly effective therapy to protect against stroke for patients with atrial fibrillation. Despite the proven worth of warfarin, its limitations have seen reluctance amongst physicians and patients to utilise this efficacious agent. This has meant that substantial numbers of patients are either unprotected against stroke or suboptimally protected with antiplatelet therapy.Contemporary well-validated stroke risk factor schemes (CHA₂DS₂-VASc) now permit rapid but comprehensive evaluation of a patient’s risk for thromboembolism, allowing better identification of low-risk patients who do not require antithrombotic therapy, and whilst for those with ≥1 stroke risk factors require formal oral anticoagulation. Aspirin has been proven to be inferior to anticoagulation, and is not free of bleeding risk. We also have simple scores to easily evaluate a patient’s risk of haemorrhage (e.g. HAS-BLED).The emergence of new oral anticoagulants should further improve stroke prevention in AF, and they successfully negotiate many of the hurdles to oral anticoagulation generated by warfarin’s limitations. Monitoring, reversal, and perioperative management are areas which require further investigation to enhance our ability to safely and effectively utilise the new agents.     

Relationship between atrial fibrillation and cognitive decline in individuals aged 80 and older

BackgroundAtrial fibrillation (AF) and dementia are largely prevalent and incident in progressively older subjects, suggesting a link between the two conditions. While in the general population there are several findings supporting a causal relationship between AF and dementia, it is unclear whether or not this association is still present in individuals aged 80 and older.ResultsSo far, the few studies that analysed this issue did not provide enough evidence supporting the causative role of AF in increasing the risk of cognitive decline or dementia in patients aged 80 and older. Conversely, a relevant role of optimal anticoagulation control in determining a significant reduction in the risk of cognitive decline is suggested, in AF subjects aged 80 years or older.ConclusionsFurther data, coming from population-based studies specifically investigating very old individuals and based upon large samples and comprehensive cognitive assessments, are needed to fully elucidate the relationship between AF and dementia in very old individuals.     

心房颤动和认知功能下降的关系研究

心房颤动(房颤)是老年人常见的心律失常,并随着年龄增长发病率及病死率增高.众多的血管危险因素和血管疾病导致认知功能障碍和痴呆,而年龄亦是认知功能障碍的最主要因素.房颤和认知功能障碍相关的可能机制有:共同危险因素及共患病、缺血性卒中(有症状或无症状)和房颤的促炎状态等.房颤患者窦律的恢复和抗凝治疗有可能降低认知功能障碍的...