Atrial Fibrillation and Dementia

A Report From the AF-SCREEN International Collaboration

Léna Rivard, MD, MSc; Leif Friberg, MD, PhD; David Conen, MD, MPH; Jeffrey S. Healey, MD, MSc; Trygve Berge, MD, PhD; Giuseppe Boriani, MD, PhD; Axel Brandes, MD, DMSc; Hugh Calkins, MD; A. John Camm, MD; Lin Yee Chen, MD; Josep Lluis Clua Espuny, MD, PhD; Ronan Collins, MD; Stuart Connolly, MD; Nikolaos Dagres, MD; Mitchell S.V. Elkind, MD, MSc; Johan Engdahl, MD, PhD; Thalia S. Field, MD, MHSc; Bernard J. Gersh, MB, ChB, DPhil; Taya V. Glotzer, MD; Graeme J. Hankey, MD; Joseph A. Harbison, MD, FD; Karl Georg Haeusler, MD; Mellanie T. Hills, BSc; Linda S.B. Johnson, MD, PhD; Boyoung Joung, MD, PhD; Paul Khairy, MD, PhD; Paulus Kirchhof, MD; Derk Krieger, MD, PhD; Gregory Y.H. Lip, MD; Maja-Lisa Løchen, MD, PhD; Malini Madhavan, MBBS; Georges H. Mairesse, MD; Joan Montaner, MD, PhD; George Ntaios, MD, MSc; Terence J. Quinn, MD; Michiel Rienstra, MD, PhD; Mårten Rosenqvist, MD, PhD; Roopinder K. Sandhu, MD, MPH; Breda Smyth, MD; Renate B. Schnabel, MD, MSc; Stavros Stavrakis, MD, PhD; Sakis Themistoclakis, MD; Isabelle C. Van Gelder, MD, PhD; Ji-Guang Wang, MD, PhD; Ben Freedman, MBBS, PhD

Disclosures

Circulation. 2022;145(5):392-40.

Abstract and Introduction

Abstract

Growing evidence suggests a consistent association between atrial fibrillation (AF) and cognitive impairment and dementia that is independent of clinical stroke. This report from the AF-SCREEN International Collaboration summarizes the evidence linking AF to cognitive impairment and dementia. It provides guidance on the investigation and management of dementia in patients with AF on the basis of best available evidence. The document also addresses suspected pathophysiologic mechanisms and identifies knowledge gaps for future research. Whereas AF and dementia share numerous risk factors, the association appears to be independent of these variables. Nevertheless, the evidence remains inconclusive regarding a direct causal effect. Several pathophysiologic mechanisms have been proposed, some of which are potentially amenable to early intervention, including cerebral microinfarction, AF-related cerebral hypoperfusion, inflammation, microhemorrhage, brain atrophy, and systemic atherosclerotic vascular disease. The mitigating role of oral anticoagulation in specific subgroups (eg, low stroke risk, short duration or silent AF, after successful AF ablation, or atrial cardiopathy) and the effect of rhythm versus rate control strategies remain unknown. Likewise, screening for AF (in cognitively normal or cognitively impaired patients) and screening for cognitive impairment in patients with AF are debated. The pathophysiology of dementia and therapeutic strategies to reduce cognitive impairment warrant further investigation in individuals with AF.

Abstract and Introduction
Proposed Mechanisms Underlying Association of AF and Cognitive Dysfunction
Role of Cerebral Imaging in Patients With AF
Definition and Assessment of Cognitive Function
Knowledge GAPS
Patient Perspective
Conclusions
References

Table 1. Factors Favoring Causality or Not
Factors favoring causality	Shared, potentially confounding risk factors
Association stronger in younger patients	Age
Association persists after adjustment with known risk factors	Arterial hypertension
Increased risk of dementia with longer time in AF (time since diagnosis and type of AF)	Diabetes
	Coronary artery disease
Temporality	Excessive alcohol consumption
	Heart failure
	Hyperlipidemia

AF indicates atrial fibrillation.

Table 2. Comparison of Commonly Used Cognitive Screening Tools ⁷⁴
Variables	ACE-III	AMT-10	GP-Cog	6 CIT	MMSE	MoCA	OCS
Administration time, min	15 to 20	<5	<5	<5	10	10	15
Copyright	Free to use	Free to use	Free to use	Free to use	Pay per use	Pay to train	Free to use
Validated in AF	No	No	No	No	Yes	Yes	No
Non-English versions	Yes	Yes	Yes	No	Yes	Yes	Yes
Short form available	Yes	Yes	NA	NA	No	Yes	No
Training available	Yes	No	Yes	No	Yes	Yes	Yes
Recommended setting	Hospital	Hospital (acute)	Primary care	Various	Various	Various	Hospital
Attention	Yes	Yes	No	Yes	Yes	Yes	Yes
Executive function	No	No	Yes	No	No	Yes	Yes
Language	No	No	No	No	Yes	Yes	Yes
Memory	No	Yes	Yes	Yes	Yes	Yes	Yes
Perceptual-motor	No	No	Yes	No	Yes	Yes	Yes
Social cognition	No	No	No	No	No	No	No

6-CIT indicates 6-item Cognitive Impairment Test; ACE, Addenbrooke's Cognitive Examination–III; AF, atrial fibrillation; AMT-10, 10-item Abbreviated Mental Test; GP-Cog, General Practitioner Assessment of Cognition; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment; and OCS, Oxford Cognitive Screen.

Table 3. Definitions and Assessment of Cognitive Function
Domains	Assessment
Cognitive domains	Attention
	Memory
	Executive function, which is a set of mental skills that includes working memory, flexible thinking, and self-control (eg, skills to plan, organize, shift from 1 activity to another, pay attention)
	Language
	Visuospatial processing
Cognitive decline	Change in cognitive function that is greater than expected from normal aging
Cognitive decline	Can be diagnosed through changes in standardized cognitive test scores over time
Mild cognitive impairment	Characterized by cognitive decline that is greater than expected from normal aging, but without affecting activities of daily living
Amnestic	Characterized by memory complaints
Amnestic	High risk of progression toward Alzheimer disease
Single domain amnestic	Isolated memory impairment
Multiple domain amnesic	Memory impairments and deficits in one or more cognitive domains
Dementia	Defined as deficits in at least 2 cognitive domains that represent a decline from a previous level of functioning and that are sufficiently severe to affect activities of daily living

Components of cognitive domains are described in Supplemental Material 2.

Table 4. Knowledge Gaps and Questions to Address
Knowledge gaps	Questions to address	Importance*
Pathophysiology
Association between AF and cognitive dysfunction	Is there a direct causal association between AF and cognitive dysfunction?	+++
Association between AF and cognitive dysfunction	Is the strength of association modified by other risk factors?
Mechanisms	Do microemboli, hypoperfusion, and inflammation play important roles in the pathophysiology of cognitive dysfunction in AF?	++
	What is the role of genetics?
	How can the observed increased incidence of Alzheimer disease and other nonvascular types of dementia in AF be explained?
Prevention
Oral anticoagulation
Role of anticoagulation on the prevention of cognitive decline and dementia	Should OACs be extended to low-risk patients?	+++
	What is the minimum atrial burden associated with cognitive decline/dementia?
	How does progression of AF burden affect cognitive function?
	Are safety and efficacy similar between VKA and DOACs and among the various DOACs?
	Should atrial cardiomyopathy be considered an indication for OAC?
	What is the role of left atrial appendage occlusion?
	When should OAC treatment be initiated for dementia prevention? Is it advisable to think about a specific risk threshold for OAC initiation considering that cognitive decline is not a discrete event but a gradual process?
Rhythm control
Role of AF ablation and cardioversion	Does AF ablation prevent cognitive decline?	+
	If so, should indications for AF ablation be extended to asymptomatic patients?
	Is there a difference between energy sources (radiofrequency versus cryoablation)?
	What is the effect of multiple electric cardioversions and AF ablation? Should there be a threshold limit per patient?
Role of AADs	Do AADs have an effect on cognitive dysfunction and, if so, is there a difference among the agents?	+
Role of AADs	Do rhythm control interventions have an effect on cognition?
Role of irregularity of rhythm	Does irregularity of rhythm (premature atrial beats, short atrial runs) play a role in cognition? If so, should treatment be more aggressive?	+
	Should patients with extensive supraventricular activity (apart from AF) also receive OAC treatment?
	Is there a difference in risk of cognitive decline in patients with AF with regular rhythm (ie, pacing) or irregular rhythm?
Rate control
	What is the optimal rate control target for cognitive outcomes?	+
	What is the optimal pacing rate in patients with AV node ablation?
	Is there a difference between rate control drugs?
Drug therapy
	What is the role of anti-inflammatory drugs to prevent cognitive dysfunction in patients with AF?	+
	Role of statins?
Multidisciplinary approaches
	Is a systematic multidisciplinary approach effective in preventing cognitive dysfunction in patients with AF?	++
Biomarkers
	Can biomarkers be developed and validated to predict cognitive dysfunction in patients with AF?	++
	What is the role of such biomarkers in screening, treatment, and follow-up of patients with AF?
Brain MRI
	What is the role of brain MRIs in the screening and follow-up of patients with AF?	++

AAD indicates antiarrhythmic drug; AF, atrial fibrillation; AV, atrioventricular; DOAC, direct oral anticoagulant; MRI, magnetic resonance imaging; OAC, oral anticoagulant; and VKA, vitamin K antagonist.
*The importance of knowledge gaps was put to a vote at the 2020 Virtual AF-SCREEN International Collaboration Meeting.

Table 5. Ongoing Trials That Include Cognitive Function or Dementia as End Points
Questions to be addressed	Study name	Methods
Oral anticoagulation
Are safety and efficacy similar between VKA and DOACs?	ARISTA	Main inclusion criteria: NVAF and CHA₂DS₂VASC score ≥2
		Primary end point: change in cognitive function (using standardized neurocognitive assessment) and new silent cerebral infarcts on MRI
		Randomized, single-blinded
		Groups: apixaban and warfarin
		Follow-up 24 months, n=280
	CAF⁷⁵	Main inclusion criteria: NVAF, CHA₂DS₂VASC score ≥2, >65 years of age
		Primary end point: incident dementia determined by a formal diagnosis of dementia by a neurologist
		Randomized open-label
		Groups: dabigatran and warfarin
		Follow-up 24 months, n=120
What is the minimal amount of atrial burden associated with cognitive decline/dementia? Should OAC be extended to silent AF in high-risk patients?	ARTESiA Neurocognitive Substudy	Main inclusion criteria: SCAF ≥6 minutes but <24 hours and a high CHA₂DS₂VASC score
		Primary end point: change of cognitive functions (MoCA)
		RCT
		Groups: apixaban versus ASA 81 mg
		n=1000
	NOAH	Main inclusion criteria: SCAF ≥6 minutes and CHA₂DS₂VASC score ≥2
		RCT
		Primary end point: all-cause death
		Secondary outcome: change of cognitive functions (MoCA)
Should OACs be extended to low-risk patients?	BRAIN-AF⁷⁶	Main inclusion criteria: NVAF with low CHA₂DS₂VASC score
		Primary end point: cognitive decline (MoCA decreased ≥3 points from baseline) and/or stroke/TIA
		RCT
		Groups: rivaroxaban 15 versus standard of care (placebo or ASA 100 mg)
		Mean follow-up 5 years; n=2280
Should OAC be continued after a successful AF ablation?	OCEAN	Main inclusion criteria: absence of AF recurrence ≥12 months after AF ablation procedure
		Primary end point: composite of stroke, systemic embolism, and covert embolic stroke as detected by brain MRI
		Secondary end points: differences on neuropsychological testing (MoCA and MMSE)
		Randomized open-label
		Groups: rivaroxaban 15 versus ASA 81 mg
		n=1572
Rhythm control	AFCOG	Main inclusion criteria: NVAF and rhythm control strategy
		Primary end point: difference in cognitive score (CANTAB)
		Cohort
		Groups: standard of care interventions to convert patient from AF to normal rhythm
		n=600
	Comparison of Brain Perfusion in Rhythm Control and Rate Control of Persistent Atrial Fibrillation*	Main inclusion criteria: persistent NVAF
		Primary end point: cognitive functions (K-MoCA) and brain perfusion (CT)
		Groups
		Randomized open-label
		Follow-up 3 months; n=200
AF ablation
Does AF ablation prevent cognitive decline?	DIAL-F	Main inclusion criteria: AF and ≥50 years of age
		Primary end point: improvement or no worsening in MoCA score
		Case–control
		Groups = AAD versus AF ablation
		Follow-up 2 years; n=888
AF screening
Does AF screening prevent cognitive decline?	UK SAFER	Main inclusion criteria: ≥65 years and no known AF
		Primary end point: reduction in the number of strokes, heart attacks, and deaths
		Cognition is a secondary end point
		RCT
		Groups = AF screening versus no AF screening
		Follow-up 5 years; n=120 000
Other approaches
What is the role of left atrial appendage occlusion?	PLUG Dementia	Main inclusion criterion: left appendage closure for AF
		Primary end point: cognitive decline (11-item ADAS-Cog and DAD)
		Cohort
		Follow-up 24 months; n=60

AAD indicates antiarrhythmic drug; ADAS-Cog, Alzheimer's Disease Assessment Scale–Cognitive Subscale; AF, atrial fibrillation; AFCOG, Acute Cognitive Changes During Atrial Fibrillation Episodes (URL: https://www.clinicaltrials.gov; Unique identifier: NCT04033510); ARISTA, Trial of Apixaban Versus Warfarin in Reducing Rate of Cognitive Decline, Silent Cerebral Ischemia and Cerebral Microbleeds in Patients With Atrial Fibrillation (URL: https://www.clinicaltrials.gov; Unique identifier: NCT03839355); ARTESiA, Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation (URL: https://www.clinicaltrials.gov; Unique identifier: NCT01938248); ASA, acetylsalicylic acid; BRAIN-AF, Blinded Randomized Trial of Anticoagulation to Prevent Ischemic Stroke and Neurocognitive Impairment in Atrial Fibrillation (URL: https://www.clinicaltrials.gov; Unique identifier: NCT02387229); CAF, Cognitive Decline and Dementia in Atrial Fibrillation Patients (URL: https://www.clinicaltrials.gov; Unique identifier: NCT03061006); CANTAB, Cambridge Neuropsychological Test Automated Battery; CHA2DS2VASc score, congestive heart failure (1 point), hypertension (1 point), age ≥75 (2 points), diabetes (1 point), previous stroke or transient ischemic attack (2 points), vascular disease (1 point), age 65 to 74 (1 point), and sex (female; 1 point); CT, computed tomography; DAD, Disability Assessment for Dementia; DIAL-F, Cognitive Impairment in Atrial Fibrillation (URL: https://www.clinicaltrials.gov; Unique identifier: NCT01816308); DOAC, direct oral anticoagulant; K-MoCA, Korean version of the Montreal Cognitive Assessment; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment; MRI, magnetic resonance imaging; NOAH, Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial High Rate Episodes (URL: https://www.clinicaltrials.gov; Unique identifier: NCT02618577); NVAF, nonvalvular atrial fibrillation; OAC, oral anticoagulant; OCEAN, Optimal Anticoagulation for Higher Risk Patients Post-Catheter Ablation for Atrial Fibrillation Trial (URL: https://www.clinicaltrials.gov; Unique identifier: NCT02168829); PLUG Dementia, Overall and MRI-Based Impact of Percutaneous Left Atrial Appendage Closure on the Cognitive Decline and Dementia in Patients With Atrial Fibrillation (URL: https://www.clinicaltrials.gov; Unique identifier: NCT03091855); RCT, randomized controlled trial; SCAF, subclinical atrial fibrillation; TIA, transient ischemic attack; UK SAFER, Screening for Atrial Fibrillation with ECG to Reduce Stroke; and VKA, vitamin K antagonist.
*Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02633774.

Authors and Disclosures

Léna Rivard, MD, MSc, Leif Friberg, MD, PhD, David Conen, MD, MPH, Jeffrey S. Healey, MD, MSc*, Trygve Berge, MD, PhD, Giuseppe Boriani, MD, PhD, Axel Brandes, MD, DMSc, Hugh Calkins, MD*, A. John Camm, MD*, Lin Yee Chen, MD, Josep Lluis Clua Espuny, MD, PhD, Ronan Collins, MD, Stuart Connolly, MD, Nikolaos Dagres, MD, Mitchell S.V. Elkind, MD, MSc, Johan Engdahl, MD, PhD, Thalia S. Field, MD, MHSc, Bernard J. Gersh, MB, ChB, DPhil, Taya V. Glotzer, MD, Graeme J. Hankey, MD, Joseph A. Harbison, MD, FD, Karl Georg Haeusler, MD, Mellanie T. Hills, BSc, Linda S.B. Johnson, MD, PhD, Boyoung Joung, MD, PhD, Paul Khairy, MD, PhD, Paulus Kirchhof, MD, Derk Krieger, MD, PhD, Gregory Y.H. Lip, MD, Maja-Lisa Løchen, MD, PhD, Malini Madhavan, MBBS, Georges H. Mairesse, MD, Joan Montaner, MD, PhD, George Ntaios, MD, MSc, Terence J. Quinn, MD, Michiel Rienstra, MD, PhD, Mårten Rosenqvist, MD, PhD*, Roopinder K. Sandhu, MD, MPH, Breda Smyth, MD, Renate B. Schnabel, MD, MSc*, Stavros Stavrakis, MD, PhD, Sakis Themistoclakis, MD, Isabelle C. Van Gelder, MD, PhD, Ji-Guang Wang, MD, PhD* and Ben Freedman, MBBS, PhD*

Montreal Heart Institute, Université de Montréal, Canada (L.R., P. Khairy). Karolinska Institute, Stockholm, Sweden (L.F., M.R.). Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada (D.C., J.S.H., S.C.). Vestre Viken Hospital Trust, Norway (T.B.). Cardiology Division, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Policlinico di Modena, Italy (G.B.). Odense University Hospital, Denmark (A.B.). Johns Hopkins University, Baltimore, MD (H.C.). Cardiovascular Clinical Academic Group, St Georges Hospital, London, UK (A.J.C.). University of Minnesota, Minneapolis (L.Y.C.). Catalonian Health Institute, Spain (J.L.C.E.). Tallaght Hospital, Dublin, Ireland (R.C.). Department of Electrophysiology, Heart Center Leipzig at University of Leipzig, Germany (N.D.). Columbia University, New York (M.S.V.E.). Karolinska Institutet, Department of Clinical Sciences, Danderyds Hospital, Stockholm, Sweden (J.E.). University of British Columbia, Vancouver Stroke Program, Canada (T.S.F.). Mayo Clinic, Rochester, MN (B.J.G.). Hackensack University Medical Centre, NJ (T.V.G.). Medical School, Faculty of Health and Medical Sciences, The University of Western Australia (G.J.H.). Trinity College, Dublin, Ireland (J.H.). Department of Neurology, Universitätsklinikum Würzburg, Germany (K.G.H.). StopAfib.org, Decatur, TX (M.T.H.). Lund University, Sweden (L.J.). Yonsei University College of Medicine, Seoul, South Korea (B.J.). University Heart and Vascular Center UKE Hamburg, Germany (P. Kirchhof). German Center for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Germany (P. Kirchhof). Institute of Cardiovascular Sciences, University of Birmingham, UK, and AFNET, Münster, Germany (P. Kirchhof). University Hospital of Zurich, Switzerland (D.K.). Aalborg University, Denmark (G.Y.H.L.). Department of Community Medicine, UiT The Arctic University of Norway, Tromsø (M.L.L.). Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (M.M.). Cliniques du Sud Luxembourg, Arlon, Belgium (G.H.M.). Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain (J.M.). Stroke Research Program, Institute of Biomedicine of Seville, Spain (J.M.). IBiS/Hospital Universitario Virgen del Rocío/CSIC/University of Seville, Spain (J.M.). Department of Neurology, Hospital Universitario Virgen Macarena, Seville, Spain (J.M.). University of Thessaly, Greece (G.N.). University of Glasgow, Glasgow Royal Infirmary, UK (T.J.Q.). University of Groningen, University Medical Center Groningen, the Netherlands (M.R., I.C.V.G.). Cedars-Sinai, Los Angeles, CA (R.K.S.). Department of Public Health, Health Service Executive West, Galway, Ireland (B.S.). University Heart Centre, Hamburg, Germany (R.B.S.). University of Oklahoma Health Sciences Center, Oklahoma City (S.S.). Ospedale dell'Angelo Venice-Mestre, Venice, Italy (S.T.). Jiaotong University School of Medicine, China (J.G.W.). Charles Perkins Centre and Concord Hospital Cardiology, University of Sydney, Australia (B.F.).

Correspondence to
Léna Rivard, MD, MSc, Montreal Heart Institute, Université de Montréal, 5000 Belanger Street, Montreal, Quebec H1T 1C8, Canada. Email lena. rivard@umontreal.ca

*AF-SCREEN International Collaboration Steering Committee member

Disclosures
Dr Rivard reports research grants from Bayer Inc, Heart and Stroke Foundation, and FRSQ (Fonds de Recherche Santé du Québec). Dr Berge reports speaker fees from Bayer, Boehringer Ingelheim, BMS, and Pfizer. Dr Boriani reports speaker's fees of small amounts from Bayer, Boehringer, Boston, and Medtronic. Dr Brandes reports research grants from the Region of Southern Denmark and Theravance and has been a speaker for Bayer, Boehringer Ingelheim, BMS/Pfizer, and MSD. Dr Camm reports consulting fees from Bayer, Daiichi Sankyo, Boehringer Ingelheim, Boston Scientific, and Abbott; and research funding from Bayer, Daiichi Sankyo, Boehringer Ingelheim, Pfizer BMS, Boston Scientific, and Abbott. Dr Conen holds a McMaster University Department of Medicine Mid-Career Research Award and reports honoraria from Servier Canada and Roche Diagnostics, both outside of the current work. Dr Elkind reports receiving study drug in kind from the BMS-Pfizer Alliance for Eliquis® and ancillary funding from Roche for an National Institutes of Health–funded trial of stroke prevention; royalties from UpToDate; and serving as an unpaid Officer of the American Heart Association. Dr Engdahl reports lecture or consultant fees from Pfizer, Bristol Myers Squibb, Merck Sharpe & Dome, Medtronic, Boehringer Ingelheim, and Roche Diagnostics. Dr Hankey reports personal fees from the American Heart Association (as Associate Editor for Circulation) and speaker and consulting fees from Bayer and Medscape. Dr Häeusler reports speaker honoraria, consulting fees, lecture honoraria, and/or study grants from Abbott, AstraZeneca, Bayer, Biotronik, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Edwards Lifescience, Medtronic, Pfizer, Portola, Premier Research, Sanofi, and WL Gore and Associates. Dr Wang reports research grants from National Natural Science Foundation of China (grants 91639203 and 82070435), Beijing, and the Shanghai Commission of Science and Technology (grant 19DZ2340200), Shanghai, China, and lecture and consulting fees from Novartis, Omron, Servier, and Takeda. Dr Kirchhof is partially supported by European Union BigData@Heart (grant agreement EU IMI 116074 and Horizon 2020 AFFECT-EU, 847770), British Heart Foundation (FS/13/43/30324; PG/17/30/32961 and PG/20/22/35093; AA/18/2/34218), German Center for Cardiovascular Research supported by the German Ministry of Education and Research (DZHK), and Leducq Foundation; has received honoraria from companies active in atrial fibrillation and cognitive function in the past, but not in the past 3 years; and is listed as inventor on 2 patents held by the University of Birmingham (Atrial fibrillation therapy WO 2015140571 and Markers for atrial fibrillation WO 2016012783). Dr Lip reports honoraria from Bayer/Janssen, BMS/Pfizer, Medtronic, Boehringer Ingelheim, Novartis, Verseon, and Daiichi-Sankyo and speaking for Bayer, BMS/Pfizer, Medtronic, Boehringer Ingelheim, and Daiichi-Sankyo; no fees are directly received personally. Dr Madhavan reports a significant research grant from BMS/Pfizer. Dr Montaner reports research funding from Fundación Marató de TV3: "Atrial Fibrillation Research in Catalonia (AFRICAT): Sequential Clinic-Electro-Biological Screening Among High Risk Individuals," code 20152830, and H2020 program (AFFECT-EU grant agreement 847770) for digital, risk-based screening for atrial fibrillation in the European community. Dr Ntaios reports speaker fees/advisory boards/research support from Abbott, Amgen, Bayer, Boehringer-Ingelheim, BMS, and Pfizer. Drs Rienstra and Van Gelder report research grants from the Netherlands Cardiovascular Research Initiative: An Initiative With Support of the Dutch Heart Foundation: CVON 2014–9: Reappraisal of Atrial Fibrillation: Interaction Between Hypercoagulability, Electric Remodelling, and Vascular Destabilisation in the Progression of AF (RACE V) and grant support from Medtronic to the institution outside this work. Dr Sandhu reports research grants from Servier and BMS/Pfizer. Dr Schnabel reports research grants from the European Research Council under the European Union's Horizon 2020 research and innovation program under grant agreements 648131 and 847770 (AFFECT-EU), the German Center for Cardiovascular Research (DZHK eV; 81Z1710103), the German Ministry of Research and Education (BMBF 01ZX1408A), and ERACoSysMed3 (031L0239) and has received lecture fees and advisory board fees from BMS/Pfizer outside this work. The other authors report no conflicts.