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Epidemiology of subclinical atrial fibrillation in patients with cardiac implantable electronic devices: A systematic review and meta-regression

  • Author Footnotes
    1 These authors contributed equally to this work.
    Marco Proietti
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Geriatric Unit, IRCCS Istituti Clinici Scientifici Maugeri, Milan, Italy

    Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

    Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Giulio Francesco Romiti
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom

    Department of Translational and Precision Medicine, Sapienza-University of Rome, Rome, Italy
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  • Marco Vitolo
    Affiliations
    Cardiology Division, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Policlinico di Modena, Modena, Italy

    Clinical and Experimental PhD Program, University of Modena and Reggio Emilia, Modena, Italy
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  • Marco Borgi
    Affiliations
    Department of Clinical and Experimental Medicine, Policlinic "G Martino," University of Messina, Messina, Italy
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  • Arianna Di Rocco
    Affiliations
    Department of Public Health and Infectious Diseases, Sapienza-University of Rome, Rome, Italy
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  • Alessio Farcomeni
    Affiliations
    Department of Economics and Finance, University of Rome “Tor Vergata”, Rome, Italy
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  • Kazuo Miyazawa
    Affiliations
    Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan
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  • Jeff S Healey
    Affiliations
    Population Health Research Institute, McMaster University, Hamilton, ON, Canada

    Division of Cardiology, Department of Medicine, McMaster University, Hamilton, ON, Canada
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  • Deirdre A Lane
    Affiliations
    Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom

    Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
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  • Giuseppe Boriani
    Affiliations
    Cardiology Division, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Policlinico di Modena, Modena, Italy
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  • Stefania Basili
    Affiliations
    Department of Translational and Precision Medicine, Sapienza-University of Rome, Rome, Italy
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  • Gregory Y.H. Lip
    Correspondence
    Corresponding author at: Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom.
    Affiliations
    Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom

    Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
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  • Author Footnotes
    1 These authors contributed equally to this work.
Open AccessPublished:July 08, 2022DOI:https://doi.org/10.1016/j.ejim.2022.06.023

      Highlights

      • The epidemiology of Subclinical Atrial Fibrillation (SCAF) is unclear
      • Patients with SCAF have a higher burden of thromboembolic risk factors
      • SCAF is common in patients with Cardiac Implantable Electronic Devices
      • Age and follow-up times are associated with SCAF occurrence

      Abstract

      Background

      In recent years, attention to subclinical atrial fibrillation (SCAF), defined as the presence of atrial high-rate episodes (AHREs), in patients with cardiac implantable electronic devices (CIEDs), has gained much interest as a determinant of clinical AF and stroke risk. We aim to perform a systematic review and meta-regression of the available scientific evidence regarding the epidemiology of SCAF in patients receiving CIEDs.

      Methods

      PubMed and EMBASE were searched for all studies documenting the prevalence of AHREs in patients (n=100 or more, <50% with history of AF) with CIEDs from inception to 20th August 2021, screened by two independent blind reviewers. This study was registered in PROSPERO: CRD42019106994.

      Results

      Among the 2614 results initially retrieved, 54 studies were included, with a total of 72,784 patients. Meta-analysis of included studies showed a pooled prevalence of SCAF of 28.1% (95%CI: 24.3-32.1%), with high heterogeneity between studies (I2=98%). A multivariable meta-regression was able to explain significant proportion of heterogeneity (R2=61.9%, p<0.001), with age and follow-up time non-linearly, directly and independently associated with occurrence of SCAF. Older age, higher CHA2DS2-VASc score, history of AF, hypertension, CHF, and stroke/TIA were all associated with SCAF occurrence.

      Conclusions

      In this systematic review and meta-regression analysis, SCAF was frequent among CIED recipients and was non-linearly associated with age and follow-up time. Older age, higher thromboembolic risk, and several cardiovascular comorbidities were associated with presence of SCAF.

      Keywords

      1. Introduction

      In 1958 Senning and Elmqvist implanted the first permanent cardiac pacemaker (PM) to Arne Larsson, who survived for more than 40 years and ultimately died from different causes [
      • Larsson B
      • Elmqvist H
      • Rydén L
      • Schüller H.
      Lessons from the first patient with an implanted pacemaker: 1958-2001.
      ]. Since then, the use of cardiac implanted electronic devices (CIEDs) is widespread thanks to the technological advances that progressively introduced implanted cardioverter-defibrillator (ICD) and cardiac resynchronization therapy (CRT) with only pacing activity (CRT-P) or also defibrillation (CRT-D) [
      • Raatikainen MJP
      • Arnar DO
      • Merkely B
      • Nielsen JC
      • Hindricks G
      • Heidbuchel H
      • et al.
      A decade of information on the use of cardiac implantable electronic devices and interventional electrophysiological procedures in the European society of cardiology countries: 2017 report from the European heart rhythm association.
      ], with increasing clinical indications [
      • Glikson M
      • Nielsen JC
      • Kronborg MB
      • Michowitz Y
      • Auricchio A
      • Barbash IM
      • et al.
      2021 ESC guidelines on cardiac pacing and cardiac resynchronization therapy.
      ,
      • McDonagh TA
      • Metra M
      • Adamo M
      • Gardner RS
      • Baumbach A
      • Böhm M
      • et al.
      2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure.
      ,
      • Priori SG
      • Blomström-Lundqvist C
      • Mazzanti A
      • Blom N
      • Borggrefe M
      • Camm J
      • et al.
      2015 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death.
      ]. Despite some geographical variability [
      • Bastian D
      • Ebrahim IO
      • Chen J-Y
      • Chen M-C
      • Huang D
      • Huang J-L
      • et al.
      Real-world geographic variations in the use of cardiac implantable electronic devices-the panorama 2 observational cohort study.
      ], in recent years increasing use of CIEDs is evident [
      • Raatikainen MJP
      • Arnar DO
      • Merkely B
      • Nielsen JC
      • Hindricks G
      • Heidbuchel H
      • et al.
      A decade of information on the use of cardiac implantable electronic devices and interventional electrophysiological procedures in the European society of cardiology countries: 2017 report from the European heart rhythm association.
      ,
      • Greenspon AJ
      • Patel JD
      • Lau E
      • Ochoa JA
      • Frisch DR
      • Ho RT
      • et al.
      Trends in permanent pacemaker implantation in the United States from 1993 to 2009: increasing complexity of patients and procedures.
      ].
      The increasing use of CIEDs and atrial leads for sensing purposes led to the identification of a clinical entity, the CIED-detected atrial high-rate episodes (AHRE) [
      • Freedman B
      • Boriani G
      • Glotzer TV
      • Healey JS
      • Kirchhof P
      • Potpara TS
      Management of atrial high-rate episodes detected by cardiac implanted electronic devices.
      ]. The occurrence of AHRE, which is nowadays assimilated as the term of ‘subclinical atrial fibrillation (SCAF), is defined as asymptomatic atrial tachyarrhythmias detected only with long-term continuous cardiac monitoring and not through usual electrocardiographic means [
      • Freedman B
      • Boriani G
      • Glotzer TV
      • Healey JS
      • Kirchhof P
      • Potpara TS
      Management of atrial high-rate episodes detected by cardiac implanted electronic devices.
      ]. In this clinical context, AHRE/SCAF has been associated with an increased risk of developing clinical AF and an increased risk of stroke and systemic embolism [
      • Freedman B
      • Boriani G
      • Glotzer TV
      • Healey JS
      • Kirchhof P
      • Potpara TS
      Management of atrial high-rate episodes detected by cardiac implanted electronic devices.
      ,
      • Vitolo M
      • Imberti JF
      • Maisano A
      • Albini A
      • Bonini N
      • Valenti AC
      • et al.
      Device-detected atrial high rate episodes and the risk of stroke/thrombo-embolism and atrial fibrillation incidence: a systematic review and meta-analysis.
      ]. Thus far, a highly variable incidence of AHRE/SCAF has been reported, basically depending on patients’ clinical characteristics [
      • Freedman B
      • Boriani G
      • Glotzer TV
      • Healey JS
      • Kirchhof P
      • Potpara TS
      Management of atrial high-rate episodes detected by cardiac implanted electronic devices.
      ].
      In this study, we performed a systematic review of all studies reporting about AHRE/SCAF prevalence in patients with CIEDs and provide pooled estimates to obtain a comprehensive assessment of its’ epidemiology. Second, we performed a meta-regression analysis to investigate study setting and clinical factors that would be more likely associated with AHRE/SCAF.

      2. Methods

      This systematic review was performed according to the ‘Meta-analysis Of Observational Studies in Epidemiology’ guidelines [
      • Stroup DF
      • Berlin JA
      • Morton SC
      • Olkin I
      • Williamson GD
      • Rennie D
      • et al.
      Meta-analysis of observational studies in epidemiology: a proposal for reporting.
      ] and reported according to the ‘Preferred Reporting Items for Systematic Reviews and Meta-Analyses’ guidelines [
      • Moher D
      • Liberati A
      • Tetzlaff J
      • Altman DG
      • Altman D
      • Antes G
      • et al.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ]. A protocol for this systematic review has been registered into the international prospective register of systematic reviews PROSPERO (Center for Reviews and Dissemination, University of York) (CRD42019106994).
      We performed a systematic and comprehensive literature search PubMed and EMBASE databases from inception up to 20th August 2021. The search was performed combining the terms ‘AHRE’, ‘SCAF’, and ‘CIED’. The full search strategy is reported in the Supplementary Materials (Supplemental Table 1).

      2.1 Studies selection

      Two co-authors (MB and GFR) independently screened the search results. Disagreements were resolved by discussion with a third author (MP). All articles retrieved from the searches were evaluated according to titles and abstracts sequentially. From here on, for simplicity and consistency, only the term SCAF will be used.
      Full-text eligibility was assessed independently by two co-authors (MB and GFR). Disagreements were resolved by discussion with a third author (MP). All full-texts that: (i) reported data about the prevalence of SCAF in patients implanted with PM, ICD, CRT-P or CRT-D; (ii) evaluated SCAF according to a reliable assessment of episodes; (iii) included <50% of patients with a history of AF; and (iv) included at least 100 patients were included. Exclusion criteria were: (i) conference abstracts, letters, comments, case reports, editorials; (ii) studies not published in English; (iii) all the studies that defined SCAF only based on algorithms (e.g., atrial mode switch episodes). To improve consistency among the studies included in the analysis, we also excluded studies reporting only SCAF of very short or long duration (i.e., <30 s and >15 min).

      2.2 Data extraction and quality assessment

      Data were extracted independently by two of the co-authors (MB and GFR), alongside the supervision of a third author (MP). The following data were extracted: sample size, SCAF events and follow-up time, SCAF definition, type of CIED implanted, geographical location, study design and patients clinical characteristics in the overall cohort and according to SCAF presence (age, sex, body mass index [BMI], hypertension, diabetes, coronary artery disease [CAD], chronic heart failure [CHF], history of atrial fibrillation, history of stroke/transient ischemic attack [TIA], chronic kidney disease, left ventricular ejection fraction [LVEF], baseline treatments). SCAF definition was subdivided according to a atrial rate (<180 bpm, 180–200 bpm, >200 bpm and other/unclear definition) and a duration (<5 min, 5, 6 min, >6 min, and other/unclear definition) criterion, according to the cut-offs adopted by the included studies.
      All studies were evaluated independently to assess risk of bias by two co-authors (MB and GFR), according to the Newcastle-Ottawa Scale for cross-sectional studies, composed of 5 items across three domains (Selection, Comparability, Outcome), with a maximum of 5 points. Any study with a score equal or less than 3 was categorized as high risk of bias.

      2.3 Data synthesis and analysis

      We calculated the pooled prevalence of SCAF as reported in the original studies included, with a generalised linear mixed model (random intercept logistic regression model) [
      • Stijnen T
      • Hamza TH
      • Özdemir P.
      Random effects meta-analysis of event outcome in the framework of the generalized linear mixed model with applications in sparse data.
      ] using logit transformation of proportions.
      Mean age, CHA2DS2-VASc, BMI and LVEF differences, number of males, and number of patients with a history of hypertension, diabetes mellitus, CAD, CHF, history of stroke/TIA, and history of atrial fibrillation were pooled and compared between SCAF and non-SCAF patients using random-effect models. For continuous outcomes, mean, SD and total number in each group were pooled and compared with the inverse variance method. Pooled estimates were reported as Odds Ratios (OR) and 95% confidence intervals (CI), or mean difference and 95% CI for continuous variables.
      The inconsistency index (I2) was calculated to measure heterogeneity. According to pre-specified cut-offs, low heterogeneity was defined as an I2 of <25%, moderate heterogeneity as I2 between 25 and 75%, and high heterogeneity when I2 was >75%.
      For the pooled prevalence rate of SCAF, a pre-specified sensitivity analysis was performed with a “leave-one-out” approach, in which all studies are removed iteratively one at a time to evaluate their influence on the pooled estimate and heterogeneity.
      To account for potential sources of heterogeneity in the pooled prevalence of SCAF, we performed several subgroup analyses, according to geographical location, study design, risk of bias, atrial rate and duration cut-offs for SCAF, and type of SCAF definition (manual review vs. device-based).
      We also performed a multivariable meta-regression, with relevant baseline characteristics of the included studies. To account for the potential non-linear relationship between continuous variables and pooled effect size, we fitted meta-regression with the use of restricted cubic splines [
      • Gauthier J
      • Wu Q V
      • Gooley TA.
      Cubic splines to model relationships between continuous variables and outcomes: a guide for clinicians.
      ], with default placement of 3 knots. All analyses were conducted with R version 4.0.3, using the ‘meta’, [
      • Balduzzi S
      • Rücker G
      • Schwarzer G.
      How to perform a meta-analysis with R: a practical tutorial.
      ] ‘metafor’, [
      • Viechtbauer W.
      Conducting meta-analyses in R with the metafor package.
      ] ‘dmetar’ [

      Harrer M, Cuijpers P, Furukawa T, Ebert DD. dmetar: Companion R Package For The Guide “Doing Meta-Analysis in R” 2019.

      ] and ‘rms’ [

      Harrell Jr FE. rms: Regression Modeling Strategies 2021.

      ] packages.

      3. Results

      After the electronic search, we retrieved 1486 articles from PubMed and 1128 articles from EMBASE. After the selection process, a total of 205 full-text articles were assessed for inclusion in the systematic review and meta-analysis (Supplemental Fig. 1). Fifty-four papers were included in the analysis, with a total of 72784 patients. [
      • Arai S
      • Kawamura M
      • Gokan T
      • Yoshikawa K
      • Ogawa K
      • Ochi A
      • et al.
      Relationship between device-detected subclinical atrial fibrillation and heart failure in patients with cardiac resynchronization therapy defibrillator.
      • Zhang H
      • Pan C
      • Zhang J
      • Zhu L-L
      • Huang K
      • Zhong Y
      • et al.
      Olmesartan reduces new-onset atrial fibrillation and atrial fibrillation burden after dual-chamber pacemaker implantation in atrioventricular block patients.
      ] Baseline characteristics of the studies included are reported in Table 1.
      Table 1General Characteristics of the Studies Included in the Systematic Review.
      STUDYYearGeographic LocationDesignNN SCAFAGE (mean)AF HistoryAtrial Rate Cut-Off (bpm)Duration Cut-Off (min)SCAF ConfirmationFU (years)
      Arai
      • Arai S
      • Kawamura M
      • Gokan T
      • Yoshikawa K
      • Ogawa K
      • Ochi A
      • et al.
      Relationship between device-detected subclinical atrial fibrillation and heart failure in patients with cardiac resynchronization therapy defibrillator.
      2020AsiaObservational Retrospective1537565.6No180-2005-6Other/Unclear4.17
      Banerjee
      • Banerjee S
      • Majumdar S
      • Konar A.
      Prevalence of atrial high-rate episodes and the risk factors in Indian patients with cardiac implantable electronic devices: real-world data.
      2019AsiaObservational Retrospective2344866.9No180-2005-6Manual Confirm3.74‡
      Benezet-Mazuecos
      • Benezet-Mazuecos J
      • Rubio JM
      • Cortés M
      • Iglesias JA
      • Calle S
      • De La
      • Vieja JJ
      • et al.
      Silent ischaemic brain lesions related to atrial high rate episodes in patients with cardiac implantable electronic devices.
      2015EuropeObservational Prospective1092874No>2005-6Manual Confirm1.42‡
      Bertini
      • Bertini M
      • Borleffs CJW
      • Delgado V
      • Ng ACT
      • Piers SRD
      • Shanks M
      • et al.
      Prediction of atrial fibrillation in patients with an implantable cardioverter-defibrillator and heart failure.
      2010EuropeObservational Prospective49514262.221%180-200>6Other/Unclear1.37‡
      Boriani
      • Boriani G
      • Glotzer TV
      • Santini M
      • West TM
      • De Melis M
      • Sepsi M
      • et al.
      Device-detected atrial fibrillation and risk for stroke: an analysis of >10 000 patients from the SOS AF project (stroke prevention strategies based on atrial fibrillation information from implanted devices).
      2014MultinationalObservational Prospective10016428770§24%Other/UnclearOther/UnclearOther/Unclear
      Borleffs
      • Borleffs CJWJW
      • Ypenburg C
      • van Bommel RJRJ
      • Delgado V
      • van Erven L
      • Schalij MJMJ
      • et al.
      Clinical importance of new-onset atrial fibrillation after cardiac resynchronization therapy.
      2009EuropeObservational Retrospective2235565No180-200>6Device-based2.75‡
      Bukari
      • Bukari A
      • Wali E
      • Deshmukh A
      • Aziz Z
      • Broman M
      • Beaser A
      • et al.
      Prevalence and predictors of atrial arrhythmias in patients with sinus node dysfunction and atrial pacing.
      2018North AmericaObservational Retrospective32219968.823%Other/Unclear<5Manual Confirm5.60‡
      Campbell
      • Campbell NG
      • Cantor EJ
      • Sawhney V
      • Duncan ER
      • DeMartini C
      • Baker V
      • et al.
      Predictors of new onset atrial fibrillation in patients with heart failure.
      2014EuropeObservational Retrospective1978766.7No180-200<5Manual Confirm2.80§
      Cheung
      • Cheung JW
      • Keating RJ
      • Stein KM
      • Markowitz SM
      • Iwai S
      • Shah BK
      • et al.
      Newly detected atrial fibrillation following dual chamber pacemaker implantation.
      2006North AmericaObservational Prospective2627774NoOther/Unclear5-6Manual Confirm1.63‡
      Ghali
      • Ghali JK
      • Orlov MV
      • Araghi-Niknam M
      • Sherfesee L
      • Hettrick DA
      The influence of symptoms and device detected atrial tachyarrhythmias on medical management: insights from A-HIRATE. PACE - pacing.
      2007MultinationalObservational Prospective4272327523%180-200<5Manual Confirm1.75‡
      Gonzalez
      • Gonzalez M
      • Keating RJRJ
      • Markowitz SMSM
      • Liu CFCF
      • Thomas G
      • Ip JEJE
      • et al.
      Newly detected atrial high rate episodes predict long-term mortality outcomes in patients with permanent pacemakers.
      2014North AmericaObservational Retrospective2243974No<1805-6Manual Confirm0.5
      Healey
      • Healey JS
      • Connolly SJ
      • Gold MR
      • Israel CW
      • Van Gelder IC
      • Capucci A
      • et al.
      Subclinical atrial fibrillation and the risk of stroke.
      2012MultinationalRCT258026176No180-2005-6Manual Confirm0.25
      Healey
      • Healey JS
      • Martin JL
      • Duncan A
      • Connolly SJ
      • Ha AH
      • Morillo CA
      • et al.
      Pacemaker-detected atrial fibrillation in patients with pacemakers: prevalence, predictors, and current use of oral anticoagulation.
      2013North AmericaObservational Retrospective44524673.125%180-2005-6Manual Confirm4.29‡
      Ishiguchi
      • Ishiguchi H
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      Association between atrial high-rate episodes and ischemic/major bleeding events in patients with a cardiac implantable electronic device - a 10-year, single-center historical cohort study.
      2021AsiaObservational Retrospective7103507829%<1805-6Other/Unclear4.5§
      Kaplan
      • Kaplan RM
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      • Passman RS.
      Use of oral anticoagulation in a real-world population with device detected atrial fibrillation.
      2020North AmericaObservational Retrospective357791293871.836%Other/UnclearOther/UnclearDevice-Based0.5
      Kawakami
      • Kawakami H
      • Nagai T
      • Saito M
      • Inaba S
      • Seike F
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      Clinical significance of atrial high-rate episodes for thromboembolic events in Japanese population.
      2017AsiaObservational Retrospective3431658024%<1805-6Device-Based4.33‡
      Kim
      • Kim BS
      • Chun KJ
      • Hwang JK
      • Park S-J
      • Park K-M
      • Kim JS
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      Predictors and long-term clinical outcomes of newly developed atrial fibrillation in patients with cardiac implantable electronic devices.
      2016AsiaObservational Retrospective88012262.7No180-2005-6Manual Confirm4.6§
      Kim
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      Prevalence and predictors of clinically relevant atrial high-rate episodes in patients with cardiac implantable electronic devices.
      2021AsiaObservational Prospective81611273§No>2005-6Manual Confirm1.5§
      Kishima
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      • Ishihara M.
      Left ventricular stiffness assessed by diastolic wall strain predicts asymptomatic atrial high-rate episodes in patients with pacemaker implantation.
      2021AsiaObservational Retrospective1475075.2No180-2005-6Manual Confirm3.19‡
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      Predictive value of atrial high-rate episodes for arterial stiffness and endothelial dysfunction in dual-chamber pacemaker patients.
      2017EuropeObservational Prospective1012472.1No>200<5Device-Based1
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      Atrial high-rate episodes and thromboembolism in patients without atrial fibrillation: the west birmingham atrial fibrillation project.
      2019EuropeObservational Retrospective59417569No<1805-6Manual Confirm4.2‡
      Liao
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      High-sensitivity c-reactive protein is a predictor of subsequent atrial high-rate episodes in patients with pacemakers and preserved ejection fraction.
      2019AsiaObservational Prospective1716674.112%180-2005-6Device-Based1.68§
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      2016OtherRCT3006375.2No<180<5Manual Confirm1.31‡
      Lorenzoni
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      2014EuropeObservational Prospective5822074§30%Other/UnclearOther/UnclearManual Confirm0.42
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      2020AsiaObservational Retrospective3985959.9NoOther/UnclearOther/UnclearDevice-Based1.55§
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      2008North AmericaObservational Prospective148215074No180-2005-6Device-Based0.5‡
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      Legend: ‡Mean; §Median; AF= Atrial Fibrillation; BPM= Beat Per Minute; FU= Follow-Up; N/A= Not Available; RCT= Randomized Controlled Trial; SCAF= Subclinical Atrial Fibrillation.
      Among the papers included 8 papers derived from randomized controlled trials; 30 from observational retrospective studies; and 16 from observational prospective studies. Of the included studies, 18 studies were conducted in Europe; 18 in Asia; 8 in North America, and 10 in other geographical locations, including multinational studies. Twenty-three studies involved patients implanted with PM; 7 studies with patients implanted with CRT; 4 studies involved patients implanted with ICD; and remaining 20 studies involved patients which were not selectively implanted with a specific type of CIED.
      Of note, 31 studies adopted manual confirmation of SCAF, while 13 studies used device-based definition, and the remaining 10 articles used other or unclear assessments. Different durations were used to define SCAF. Four studies used duration of ≥6 min; in 13 cohorts a duration of <5 min was adopted, while 32 used cut-offs between 5 and 6 min. In 5 studies, other or unclear duration of SCAF was reported. As for the atrial rate, 10 studies adopted a cut-off of less than 180 beats per min (bpm); 7 studies used a cut-off over 200 bpm, 22 studies used a cut-off comprised between 180 and 200 bpm, and in 15 studies other or unclear velocity cut-offs were used. Overall, 15 (28%) studies were considered at significant risk of bias. All the other studies (39 out of 53) were considered at low risk of bias (Supplemental Table 2).

      3.1 SCAF prevalence

      The overall prevalence of SCAF across the 54 included studies included was 28.1% (95% CI: 24.3-32.1%), with a high heterogeneity detected (I2=98.3%) (Fig. 1). According to the pre-specified ‘leave-one-out’ analysis reported in Supplemental Fig. 2, we did not find any significant influence of individual studies on pooled estimates or heterogeneity.
      Subgroup analyses for the prevalence of SCAF are reported in Table 2. We did not observe any significant differences across the subgroups explored, except for a non-significant trend for higher SCAF prevalence in patients with previous history of AF.
      Table 2Subgroup Analyses for SCAF Prevalence.
      SubgroupsN° StudiesPooled Prevalence95% CII2
      Geographical Location (p for subgroup differences=0.512)
      North America830.2%18.2-45.8%98.8%
      Europe1824.4%19.1-30.7%96.3%
      Asia1831.0%25.0-37.6%96.8%
      Other1028.0%20.3-37.2%99.3%
      Study Type (p for subgroup differences=0.115)
      Obs. Retrospective3031.8%27.1-36.8%96.7%
      Obs. Prospective1622.5%16.3-30.2%63.9%
      RCT826.5%18.0-37.2%98.8%
      Definition of SCAF (p for subgroup differences=0.837)
      Manual Confirm3127.1%22.1-32.7%97.8%
      Device-based1329.0%22.2-36.9%98.0%
      Other/Unclear1030.0%21.8-39.6%97.7%
      Type of Device (p for subgroup differences=0.233)
      Pacemaker2332.2%26.2-38.8%97.6%
      CRT728.8%21.5-37.3%91.3%
      ICD418.7%9.8-32.9%97.2%
      Mixed2025.5%19.9-32.0%98.9%
      Atrial Rate Cut-Off (p for subgroup differences=0.632)
      >200 bpm725.0%20.1-30.7%91.5%
      180-200 bpm2226.8%21.2-33.3%98.3%
      <180 bpm1030.7%23.6-38.8%97.7%
      Other/Unclear1529.6%21.1-39.8%98.2%
      Duration Cut-Off (p for subgroup differences=0.191)
      >6 min431.8%26.2-38.0%92.2%
      5-6 min3225.7%22.1-29.7%98.3%
      <5 min1334.3%25.3-44.6%97.7%
      Other/Unclear525.4%9.8-51.6%98.7%
      AF History (p for subgroup differences=0.066)
      Yes2232.2%25.2-40.1%98.4%
      No3124.6%20.9-28.6%97.6%
      Risk of Bias (p for subgroup differences=0.653)
      Low Risk3927.6%23.1-32.6%98.5%
      High Risk1529.4%23.2-36.5%96.9%
      Legend: AF= Atrial Fibrillation; BPM= beats per minute; CI= Confidence Interval; CRT= Cardiac Resynchronization Therapy; ICD=Implantable Cardiac Defibrillator; MIN=minute; SCAF= Subclinical Atrial Fibrillation.

      3.2 Meta-regression analysis

      A multivariable model comprised of cut-offs of SCAF duration and atrial rate, type of study, level of bias, the inclusion of patients with previous history of AF, and age and follow-up times (both modelled as restricted cubic splines) was able to explain a significant proportion of the heterogeneity observed (R2=61.9%, p<0.001; Supplementary Table 3). A graphical representation of the marginal relationship between follow-up times and age, modelled as restricted cubic splines, and the prevalence of AHRE is reported in Fig. 2, panel A and B, respectively. Prediction of SCAF prevalence according to the multivariable model, according to mean age and different follow-up times, is reported in Fig. 3.

      3.3 Clinical variables associated with SCAF

      We calculated pooled estimates for several characteristics comparing patients with SCAF vs. patients without SCAF (Table 3). The occurrence of SCAF was significantly associated with older age, higher CHA2DS2-VASc score, and clinical history of atrial fibrillation, hypertension, heart failure, and history of stroke/transient ischemic attack; however, male sex, body mass index, diabetes and coronary artery disease were not associated with SCAF. We did not observe any significant association between SCAF and pharmacological treatments.
      Table 3Association between clinical characteristics and SCAF Presence.
      Categorical VariableNumber of studiesORLower 95%CIUpper 95%CII2
      AF History154.392.737.0785%
      Male Sex391.080.951.2363%
      Hypertension351.141.041.2523%
      Diabetes330.960.861.0639%
      CHF181.391.061.8362%
      CAD291.010.891.1430%
      History of Stroke/TIA231.171.031.330%
      Treatments
      Beta-Blockers271.120.921.3769%
      Statins140.930.811.062%
      Amiodarone81.260.712.2579%
      ACEi/ARBs251.110.981.2737%
      Continuous VariablesNumber of studiesMDLower 95%CIUpper 95%CII2
      Age351.360.402.3285%
      CHA2DS2-VASc150.230.140.3239%
      LVEF23-0.70-1.450.0561%
      BMI120.31-0.140.7548%
      Legend: ACEi= Angiotensin Converting Enzime Inhibitors; AF= Atrial Fibrillation; ARB= Angiotensin II Receptor Blocker; BMI= Body Mass Index; CAD= Coronary Artery Disease; CHF= Congestive Heart Failure CI= Confidence Interval; LVEF= Left Ventricular Ejection Fraction; MD= Mean Difference; OR= Odds Ratio; TIA= Transient Ischemic Attack.

      4. Discussion

      This systematic review and meta-regression analysis about the epidemiology of SCAF in patients with CIEDs found an overall prevalence of 28.1% of patients presenting AHREs among the over 72000 patients with CIEDs. While no significant differences were found in prevalence among the subgroups examined, meta-regression analysis found that both patients’ age and length of follow-up were significantly, independently and non-linearly associated with SCAF prevalence. Furthermore, the analysis of clinical characteristics revealed that patients presenting SCAF, beyond having a more frequent AF history, were older, more likely hypertensive, affected with congestive heart failure and with an history of stroke/transient ischemic attack. Accordingly, SCAF patients had an overall higher CHA2DS2-VASc score [Central Illustration].
      Central Illustration:
      Central IllustrationEpidemiology of Subclinical Atrial Fibrillation in Patients with CIEDs: A Systematic Review and Meta-RegressionLegend: CIEDs= Cardiac Implanted Electronic Devices; IR= Incidence Rate; SCAF= Subclinical Atrial Fibrillation.
      Our findings have important epidemiological and clinical implications. First, the pooled estimate we provided adds an important piece of information in understanding the natural course of this condition. Thus far, no accurate evaluation of SCAF epidemiology has been provided by any study. Available studies have shown large variability in reporting the occurrence of SCAF [
      • Hindricks G
      • Potpara T
      • Dagres N
      • Arbelo E
      • Bax JJ
      • Blomström-Lundqvist C
      • et al.
      2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European association for cardio-thoracic surgery (EACTS).
      ] and differences in studies design, patients’ characteristics and follow-up duration limit the generalizability of any of the previous studies to the general population of patients receiving a CIED implant.
      The finding that 28% of patients receiving a CIED report SCAF after receiving the device is highly relevant. First, it gives us a reliable appraisal of the real “size of the problem”. Second, it allows us to make some considerations in terms of patients’ care. Indeed, the presence of SCAF significantly increases the risk of developing incident clinical AF. Some recent estimates showed that presence of SCAF entails more than 3-fold higher risk of clinical AF [
      • Vitolo M
      • Imberti JF
      • Maisano A
      • Albini A
      • Bonini N
      • Valenti AC
      • et al.
      Device-detected atrial high rate episodes and the risk of stroke/thrombo-embolism and atrial fibrillation incidence: a systematic review and meta-analysis.
      ]. Overall, the findings that almost 1 in every 3 patients receiving a CIED could be at high risk for developing clinical AF clearly underlines the importance of performing more accurate monitoring for this condition and the need for proper dissemination of information about its impact on patients.
      Furthermore, as shown in the ASSERT trial and further underlined by other studies and meta-analyses, the presence of SCAF increases the risk of stroke by more than 2 fold and the risk of all-cause death and other outcomes, particularly in those patients with a high baseline thromboembolic risk [
      • Freedman B
      • Boriani G
      • Glotzer TV
      • Healey JS
      • Kirchhof P
      • Potpara TS
      Management of atrial high-rate episodes detected by cardiac implanted electronic devices.
      ,
      • Vitolo M
      • Imberti JF
      • Maisano A
      • Albini A
      • Bonini N
      • Valenti AC
      • et al.
      Device-detected atrial high rate episodes and the risk of stroke/thrombo-embolism and atrial fibrillation incidence: a systematic review and meta-analysis.
      ,
      • Boriani G
      • Glotzer TV
      • Santini M
      • West TM
      • De Melis M
      • Sepsi M
      • et al.
      Device-detected atrial fibrillation and risk for stroke: an analysis of >10 000 patients from the SOS AF project (stroke prevention strategies based on atrial fibrillation information from implanted devices).
      ,
      • Healey JS
      • Connolly SJ
      • Gold MR
      • Israel CW
      • Van Gelder IC
      • Capucci A
      • et al.
      Subclinical atrial fibrillation and the risk of stroke.
      ,
      • Mahajan R
      • Perera T
      • Elliott AD
      • Twomey DJ
      • Kumar S
      • Munwar DA
      • et al.
      Subclinical device-detected atrial fibrillation and stroke risk: a systematic review and meta-analysis.
      ]. Data from European Society of Cardiology countries reported that almost 750,000 patients received a CIED [
      • Raatikainen MJP
      • Arnar DO
      • Merkely B
      • Nielsen JC
      • Hindricks G
      • Heidbuchel H
      • et al.
      A decade of information on the use of cardiac implantable electronic devices and interventional electrophysiological procedures in the European society of cardiology countries: 2017 report from the European heart rhythm association.
      ], extrapolating our findings suggests that more than 210,000 patients would report SCAF and consequently have such a higher risk for clinical AF and stroke, also progressively increasing with age and throughout time, with important implications for patients’ management and health-care services resources use. These numbers highlight the need for further data regarding the use of oral anticoagulants in patients with SCAF. While not all the guidelines discuss this issue, use of oral anticoagulant is recommended only in patients with high stroke risk and longer (≥24 h) episodes of AHRE [
      • Hindricks G
      • Potpara T
      • Dagres N
      • Arbelo E
      • Bax JJ
      • Blomström-Lundqvist C
      • et al.
      2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European association for cardio-thoracic surgery (EACTS).
      ,
      • Proietti M
      • Lane DA
      • Boriani G
      • Lip GYH.
      Stroke prevention, evaluation of bleeding risk, and anticoagulant treatment management in atrial fibrillation contemporary international guidelines.
      ,
      • Andrade JG
      • Aguilar M
      • Atzema C
      • Bell A
      • Cairns JA
      • Cheung CC
      • et al.
      The 2020 Canadian cardiovascular society/Canadian heart rhythm society comprehensive guidelines for the management of atrial fibrillation.
      ]. Uncertainty still exists in patients with shorter AHRE episodes. Two currently ongoing randomized trials will provide important evidence to elucidate this important issue [
      • Lopes RD
      • Alings M
      • Connolly SJ
      • Beresh H
      • Granger CB
      • Mazuecos JB
      • et al.
      Rationale and design of the apixaban for the reduction of thrombo-embolism in patients with device-detected sub-clinical atrial fibrillation (ARTESiA) trial.
      ,
      • Kirchhof P
      • Blank BF
      • Calvert M
      • Camm AJ
      • Chlouverakis G
      • Diener H-C
      • et al.
      Probing oral anticoagulation in patients with atrial high rate episodes: rationale and design of the non-vitamin k antagonist oral anticoagulants in patients with atrial high rate episodes (NOAH-AFNET 6) trial.
      ].
      Our findings regarding the relationship between increasing age and SCAF occurrence underlines how SCAF shares similar risk factors with clinical AF, and extends our knowledge on SCAF epidemiology beyond the estimate of prevalence per se. Indeed, is well-known that increasing older age is a pivotal risk factor for AF [
      • Boriani G
      • Vitolo M
      • Diemberger I
      • Proietti M
      • Valenti AC
      • Malavasi VL
      • et al.
      Optimizing indices of atrial fibrillation susceptibility and burden to evaluate atrial fibrillation severity, risk and outcomes.
      ], and our multivariate analysis elucidates that the contribution of increasing age to the risk of developing SCAF is pivotal. Also, the non-linear association between follow-up time and SCAF prevalence suggests that the observation period is likely to play a role in determining the prevalence observed in CIED recipients. The combination of increasing age and longer follow-up, concurrently with the higher prevalence of comorbidities, which we found associated with presence of SCAF, could underline how these factors combine together to determine the development of an atrial arrhythmogenic substrate [
      • Boriani G
      • Vitolo M
      • Diemberger I
      • Proietti M
      • Valenti AC
      • Malavasi VL
      • et al.
      Optimizing indices of atrial fibrillation susceptibility and burden to evaluate atrial fibrillation severity, risk and outcomes.
      ]. Indeed, also the association with increasing age could be a proxy of a generally more complex and impaired clinical situation with no specific risk factor driving the occurrence of SCAF (as underlined by the results of meta-regression analysis), but with the overall progressively higher amount of exposure to risk factors determining the arrhythmogenic substrate. As the occurrence of clinical AF is multifactorial and related to various risk factors [
      • Allan V
      • Honarbakhsh S
      • Casas J-P
      • Wallace J
      • Hunter R
      • Schilling R
      • et al.
      Are cardiovascular risk factors also associated with the incidence of atrial fibrillation?.
      ], the relationship between age, exposure and comorbidities together lead to SCAF, through the mechanism of developing atrial cardiomyopathy and further strengthening the relationship between SCAF, clinical AF and higher risk of thromboembolic events [
      • Boriani G
      • Vitolo M
      • Diemberger I
      • Proietti M
      • Valenti AC
      • Malavasi VL
      • et al.
      Optimizing indices of atrial fibrillation susceptibility and burden to evaluate atrial fibrillation severity, risk and outcomes.
      ,
      • Hirsh BJ
      • Copeland-Halperin RS
      • Halperin JL.
      Fibrotic atrial cardiomyopathy, atrial fibrillation, and thromboembolism: mechanistic links and clinical inferences.
      ,
      • Guichard JB
      • Nattel S.
      Atrial cardiomyopathy: a useful notion in cardiac disease management or a passing fad?.
      ,
      • Coats AJS
      • Heymans S
      • Farmakis D
      • Anker SD
      • Backs J
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      • et al.
      Atrial disease and heart failure: the common soil hypothesis proposed by the heart failure association of the European society of cardiology.
      ].
      These findings may have significant implications in the management of patients receiving CIEDs, underlining the importance of close observation for SCAF occurrence. Further studies are required to expand and corroborate these hypotheses, and to clarify whether specific subgroups of patients may have a different risk(s) of SCAF. Indeed, it should be noted that few studies focused on very elderly CIED recipients, and therefore our estimates for this group of patients were broad, underlining the need for specific studies aiming at evaluating the epidemiology of SCAF in elderly patients, as well as other high-risk subgroups which may experience a different burden of SCAF.
      We also observed that patients presenting with SCAF were found to have a higher burden of risk factors and comorbidities, eventually resulting in a higher CHA2DS2-VASc score, conferring greater thromboembolic risk compared to patients without SCAF. This evidence supports the current knowledge about the increased risk of stroke and thromboembolic events in patients with SCAF, underlining the need for more data about oral anticoagulant and supporting current recommendations on prescribing oral anticoagulant drugs in SCAF patients with very high thromboembolic risk [
      • Hindricks G
      • Potpara T
      • Dagres N
      • Arbelo E
      • Bax JJ
      • Blomström-Lundqvist C
      • et al.
      2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European association for cardio-thoracic surgery (EACTS).
      ].
      In the latest European Society of Cardiology clinical guidelines on the management of patients with AF, the nosological entity of SCAF is by definition identifiable only in patients who have no previous history of AF [
      • Hindricks G
      • Potpara T
      • Dagres N
      • Arbelo E
      • Bax JJ
      • Blomström-Lundqvist C
      • et al.
      2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European association for cardio-thoracic surgery (EACTS).
      ]. In our meta-analysis we also included patients with previous history of AF. While also other meta-analyses about SCAF included patients with previous history of AF [
      • Vitolo M
      • Imberti JF
      • Maisano A
      • Albini A
      • Bonini N
      • Valenti AC
      • et al.
      Device-detected atrial high rate episodes and the risk of stroke/thrombo-embolism and atrial fibrillation incidence: a systematic review and meta-analysis.
      ], the approach of excluding patients with history of AF has been only recently adopted, hence excluding all studies with such patients would have excluded large part of previous evidence about SCAF. While overall 22/54 studies (41%) included patients with previous history of AF, only 10/54 studies (19%) included more than 25% of patients with previous history of AF, thus with a limited contribution of the group of previously diagnosed AF patients in most of these cohorts. While the subgroup analysis reported a non-significant trend in higher SCAF prevalence in those patients with previous history of AF, the presence of SCAF was clinically more associated with the previous history of AF.

      5. Limitations

      The main limitation is the high heterogeneity reported in our pooled estimates. However, high heterogeneity is a common concern in epidemiological meta-analysis exploring the prevalence of several conditions, in which we expect the results to vary consistently in each study [
      • Odutayo A
      • Wong CX
      • Hsiao AJ
      • Hopewell S
      • Altman DG
      • Emdin CA.
      Atrial fibrillation and risks of cardiovascular disease, renal disease, and death: systematic review and meta-analysis.
      ,
      • Colditz GA
      • Burdick E
      • Mosteller F.
      Heterogeneity in meta-analysis of data from epidemiologic studies: a commentary.
      ,
      • Romiti GF
      • Corica B
      • Pipitone E
      • Vitolo M
      • Raparelli V
      • Basili S
      • et al.
      Prevalence, management and impact of chronic obstructive pulmonary disease in atrial fibrillation: a systematic review and meta-analysis of 4,200,000 patients.
      ]. This also reflect the clinical heterogeneity found in clinical practice, with SCAF prevalence highly likely to be influenced by several determinants. Furthermore, we performed additional analyses to account for heterogeneity, including the multivariable meta-regression which allows us to account for roughly 60% of the observed heterogeneity in the pooled estimate for SCAF prevalence. Although we cannot exclude the contribution of other, unaccounted confounders in influencing our findings, the results of the meta-regression clearly underline the impact of age and follow-up time in determining the occurrence of SCAF, representing, together with the epidemiological data about the clinical profile of SCAF patients, the most relevant evidence provided by our work.

      6. Conclusions

      In this systematic review and meta-regression analysis, SCAF increased with age and decreased over longer follow-up times, both being independently associated with its prevalence. The presence of SCAF is associated with higher age, more prevalent comorbidities, and higher thromboembolic risk.

      Funding

      No funding was received by any authors for the development of this project.
      Fig. 1
      Fig. 1Pooled Prevalence of SCAF across the Included Studies.
      CI= Confidence Interval; GLMM= General Linear Mixed Model.
      Fig. 2
      Fig. 2Marginal Relationship between Follow-up times and Mean Age of the included studies and SCAF prevalence.
      Panel A) Years of Follow-Up; Panel B) Age.
      Fig. 3
      Fig. 3Prevalence of SCAF according to mean age at different follow-up times.
      Each curve is a graphical representation of SCAF incidence rate at each year of follow-up according to patients’ age.

      Declaration of Competing Interest

      JSH reports research grants and speaking fees from Boehringer-Ingelheim, Bayer, BMS/Pfizer and Servier; DL has received investigator-initiated educational grants from Bristol-Myers Squibb (BMS), has been a speaker for Boehringer Ingelheim, and BMS/Pfizer and has consulted for BMS, Boehringer Ingelheim, and Daiichi-Sankyo; GB received small speaker's fees from Medtronic, Boston, Boehringer Ingelheim and Bayer; SB reports esearch grant from MSD not relevant to the manuscript; GYHL has been consultant and speaker for BMS/Pfizer, Boehringer Ingelheim and Daiichi-Sankyo. No fees are directly received personally. All other authors have nothing to declare.

      Acknowledgments

      None.

      Appendix. Supplementary materials

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