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Risk stratification for arrhythmic events in patients with asymptomatic pre-excitation: A systematic review for the 2015 ACC/AHA/HRS guideline for the management of adult patients with supraventricular tachycardia

A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society
Published:September 23, 2015DOI:https://doi.org/10.1016/j.hrthm.2015.09.017

      Objective

      To review the literature systematically to determine whether noninvasive or invasive risk stratification, such as with an electrophysiological study of patients with asymptomatic pre-excitation, reduces the risk of arrhythmic events and improves patient outcomes.

      Methods

      PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (all January 1, 1970, through August 31, 2014) were searched for randomized controlled trials and cohort studies examining noninvasive or invasive risk stratification in patients with asymptomatic pre-excitation. Studies were rejected for low-quality design or the lack of an outcome, population, intervention, or comparator of interest or if they were written in a language other than English.

      Results

      Of 778 citations found, 9 studies met all the eligibility criteria and were included in this paper. Of the 9 studies, 1 had a dual design–a randomized controlled trial of ablation versus no ablation in 76 patients and an uncontrolled prospective cohort of 148 additional patients–and 8 were uncontrolled prospective cohort studies (n=1,594). In studies reporting a mean age, the range was 32 to 50 years, and in studies reporting a median age, the range was 19 to 36 years. The majority of patients were male (range, 50% to 74%), and <10% had structural heart disease. In the randomized controlled trial component of the dual-design study, the 5-year Kaplan-Meier estimates of the incidence of arrhythmic events were 7% among patients who underwent ablation and 77% among patients who did not undergo ablation (relative risk reduction: 0.08; 95% confidence interval: 0.02 to 0.33; p<0.001). In the observational cohorts of asymptomatic patients who did not undergo catheter ablation (n=883, with follow-up ranging from 8 to 96 months), regular supraventricular tachycardia or benign atrial fibrillation (shortest RR interval >250 ms) developed in 0% to 16%, malignant atrial fibrillation (shortest RR interval ≤250 ms) in 0% to 9%, and ventricular fibrillation in 0% to 2%, most of whom were children in the last case.

      Conclusions

      The existing evidence suggests risk stratification with an electrophysiological study of patients with asymptomatic pre-excitation may be beneficial, along with consideration of accessory-pathway ablation in those deemed to be at high risk of future arrhythmias. Given the limitations of the existing data, well-designed and well-conducted studies are needed.

      Key Words

      ACC/AHA Task Force Members

      Jonathan L. Halperin, MD, FACC, FAHA, Chair
      Glenn N. Levine, MD, FACC, FAHA, Chair-Elect
      Jeffrey L. Anderson, MD, FACC, FAHA, Immediate Past Chair
      Former Task Force member; current member during this writing effort.
      Nancy M. Albert, PhD, RN, FAHA
      Former Task Force member; current member during this writing effort.
      Sana M. Al-Khatib, MD, MHS, FACC, FAHA
      Kim K. Birtcher, PharmD, AACC
      Biykem Bozkurt, MD, PhD, FACC, FAHA
      Ralph G. Brindis, MD, MPH, MACC
      Joaquin E. Cigarroa, MD, FACC
      Lesley H. Curtis, PhD, FAHA
      Lee A. Fleisher, MD, FACC, FAHA
      Federico Gentile, MD, FACC
      Samuel Gidding, MD, FAHA
      Mark A. Hlatky, MD, FACC
      John Ikonomidis, MD, PhD, FAHA
      José A. Joglar, MD, FACC, FAHA
      Richard J. Kovacs, MD, FACC, FAHA
      Former Task Force member; current member during this writing effort.
      E. Magnus Ohman, MD, FACC
      Former Task Force member; current member during this writing effort.
      Susan J. Pressler, PhD, RN, FAHA
      Frank W. Sellke, MD, FACC, FAHA
      Former Task Force member; current member during this writing effort.
      Win-Kuang Shen, MD, FACC, FAHA
      Former Task Force member; current member during this writing effort.
      Duminda N. Wijeysundera, MD, PhD

      Table of Contents

      • Abstract ▪
      • Introduction ▪
      • Methods ▪
        • Search Strategy ▪
        • Eligibility Criteria ▪
        • Methods of Review ▪
        • Statistical Analysis ▪
      • Results ▪
        • Study and Patient Characteristics ▪
        • Study Results ▪
        • Evidence Synthesis ▪
        • Quality of Included Studies ▪
      • Discussion ▪
        • Limitations ▪
        • Conclusions ▪
      • Tables and Figures ▪
        • Figure 1. Search Strategy QUORUM Diagram ▪
        • Table 1. Summary of Included Studies ▪
        • Table 2. Comparators and Outcomes ▪
        • Table 3. Quality Assessment of Included Studies ▪
      • References ▪
      • Appendix 1
        • Author Relationships With Industry and Other Entities (Relevant) ▪

      Introduction

      Electrocardiographic pre-excitation affects about 0.1% to 0.3% of the general population.
      • Hiss R.G.
      • Lamb L.E.
      Electrocardiographic findings in 122,043 individuals.
      When pre-excitation is accompanied by symptoms such as syncope or palpitations, the diagnosis of Wolff-Parkinson-White (WPW) syndrome is established.
      • Munger T.M.
      • Packer D.L.
      • Hammill S.C.
      • et al.
      A population study of the natural history of Wolff-Parkinson-White syndrome in Olmsted County, Minnesota, 1953-1989.
      Patients with WPW syndrome have an increased risk of sudden cardiac death (SCD) that may approach 4% over a lifetime.
      • Al-Khatib S.M.
      • Pritchett E.L.
      Clinical features of Wolff-Parkinson-White syndrome.
      Therefore, risk stratification of these symptomatic patients, particularly with an electrophysiological (EP) study, and catheter ablation of the accessory pathway are recommended;
      • Blomström-Lundqvist C.
      • Scheinman M.M.
      • Aliot E.M.
      • et al.
      ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias–executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Supraventricular Arrhythmias). Developed in collaboration with NASPE-Heart Rhythm Society.
      however, when patients with electrocardiographic pre-excitation have no symptoms, it is not clear how to risk-stratify them for arrhythmic events. In such patients, the first arrhythmic event may lead to SCD.
      • Klein G.J.
      • Bashore T.M.
      • Sellers T.D.
      • et al.
      Ventricular fibrillation in the Wolff-Parkinson-White syndrome.
      Therefore, how to accurately quantify the risk of SCD in asymptomatic patients has been debated for years, and management of such patients remains controversial.
      The “2003 ACC/AHA/ESC Guidelines for the Management of Patients With Supraventricular Arrhythmias” designated “no treatment” as a Class I recommendation and catheter ablation as a Class IIa recommendation in patients with asymptomatic pre-excitation.
      • Blomström-Lundqvist C.
      • Scheinman M.M.
      • Aliot E.M.
      • et al.
      ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias–executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Supraventricular Arrhythmias). Developed in collaboration with NASPE-Heart Rhythm Society.
      The guideline writing committee based these recommendations on the facts that the positive predictive value of the EP study is too low to justify routine use in asymptomatic patients
      • Priori S.G.
      • Aliot E.
      • Blomstrom-Lundqvist C.
      • et al.
      Task Force on Sudden Cardiac Death of the European Society of Cardiology.
      and that the potential value of EP study in identifying high-risk patients who may benefit from catheter ablation must be balanced against the approximately 2% risk of a major complication associated with catheter ablation.
      • Blomström-Lundqvist C.
      • Scheinman M.M.
      • Aliot E.M.
      • et al.
      ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias–executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Supraventricular Arrhythmias). Developed in collaboration with NASPE-Heart Rhythm Society.
      Although the guideline emphasized the importance of seeking medical expertise when patients with previously asymptomatic pre-excitation experience arrhythmia-related symptoms, it did not provide helpful information on the usefulness or comparative accuracy of invasive EP study and noninvasive EP study in predicting arrhythmic events or on the effectiveness of invasive EP study with catheter ablation of the accessory pathway, as appropriate, to prevent arrhythmic events, including SCD.
      • Blomström-Lundqvist C.
      • Scheinman M.M.
      • Aliot E.M.
      • et al.
      ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias–executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Supraventricular Arrhythmias). Developed in collaboration with NASPE-Heart Rhythm Society.
      On the basis of the “ACC/AHA Clinical Practice Guideline Methodology Summit Report”,
      • Jacobs A.K.
      • Kushner F.G.
      • Ettinger S.M.
      ACCF/AHA Clinical Practice Guideline Methodology Summit Report: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      the ACC/AHA Task Force on Practice Guidelines recognized the need for an objective review of the literature by an independent Evidence Review Committee (ERC) to inform recommendations about the evaluation and management of patients with asymptomatic pre-excitation in the “2015 ACC/AHA/HRS Guideline for the Management of Adults Patients With Supraventricular Tachycardia”.
      • Al-Khatib S.M.
      • Arshad A.
      • Balk E.M.
      • et al.
      Risk stratification for arrhythmic events in patients with asymptomatic pre-excitation: a systematic review for the 2015 ACC/AHA/HRS guideline for the management of adult patients with supraventricular tachycardia: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.

      Methods

      The ERC conducted this systematic review to address the following specific clinical questions posed by the guideline writing committee for this clinical practice guideline (with input from the ERC):
      • 1.
        What is the comparative accuracy of invasive EP study (without catheter ablation of the accessory pathway) versus noninvasive testing for predicting arrhythmic events (including SCD) in patients with asymptomatic pre-excitation?;
      • 2.
        What is the usefulness of invasive EP study (without catheter ablation of the accessory pathway) versus no testing for predicting arrhythmic events (including SCD) in patients with asymptomatic pre-excitation?;
      • 3.
        What is the usefulness of invasive EP study (without catheter ablation of the accessory pathway) or noninvasive EP study for predicting arrhythmic events (including SCD) in patients with asymptomatic pre-excitation?
      • 4.
        What are the efficacy and effectiveness of invasive EP study with catheter ablation of the accessory pathway as appropriate versus noninvasive tests with treatment (including observation) or no testing/ablation as appropriate for preventing arrhythmic events (including SCD) and improving outcomes in patients with asymptomatic pre-excitation?
      This systematic review complied with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • et al.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      and with the recommendations of the “ACC/AHA Clinical Practice Guideline Methodology Summit Report”.
      • Jacobs A.K.
      • Kushner F.G.
      • Ettinger S.M.
      ACCF/AHA Clinical Practice Guideline Methodology Summit Report: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.

      Search Strategy

      Eligible studies were identified by using PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (all January 1, 1970, through August 31, 2014). The following search terms were used: “asymptomatic or incidental” and “pre-excitation or “Wolff-Parkinson-White or WPW” or “delta wave” or “accessory pathway.” The ERC also searched bibliographies of previous relevant systematic reviews.
      • Obeyesekere M.N.
      • Leong-Sit P.
      • Massel D.
      • et al.
      Incidence of atrial fibrillation and prevalence of intermittent pre-excitation in asymptomatic Wolff-Parkinson-White patients: a meta-analysis.
      • Chevalier P.
      • Cadi F.
      • Scridon A.
      • et al.
      Prophylactic radiofrequency ablation in asymptomatic patients with Wolff-Parkinson-White is not yet a good strategy: a decision analysis.
      • Obeyesekere M.N.
      • Leong-Sit P.
      • Massel D.
      • et al.
      Risk of arrhythmia and sudden death in patients with asymptomatic preexcitation: a meta-analysis.

      Eligibility Criteria

      Randomized controlled trials (RCTs) and nonrandomized comparative studies were included that compared invasive EP study with noninvasive testing, including resting ECG, stress testing, electrocardiographic monitoring, and esophageal pacing for predicting or preventing arrhythmic events in adults (≥18 years of age) with asymptomatic pre-excitation. Studies that allowed children were included only if the mean age of enrolled patients was ≥18 years of age. Studies were excluded if they enrolled only patients with WPW syndrome or if they enrolled patients with WPW syndrome and patients with asymptomatic pre-excitation but did not report results for the latter group separately. Case series and single-group (uncontrolled) observational studies were included if they had a minimum of 20 patients and follow-up of at least 80%. Eligible studies had to report on any of the following 7 prespecified outcomes: SCD or arrhythmic death, atrial fibrillation [AF], regular supraventricular tachycardia [SVT], all-cause mortality, quality of life, hospitalization or readmission for cardiovascular events, and ablation-related complications. The review was restricted to articles published in English. Unpublished studies were not sought.

      Methods of Review

      To determine the studies’ eligibility for inclusion in the systematic review, 2 members of the ERC independently reviewed each abstract and full citation. Disagreements were resolved by consensus or by involving a third reviewer (S.M. Al-Khatib). Abstracted data were entered into the Indico Clinical Guideline Platform (Indico Solutions Pty. Ltd., Melbourne, Victoria, Australia), a Web-based software platform. For each included study, the ERC members abstracted data on the study author; year of publication; sample size; inclusion and exclusion criteria; study design; setting (outpatient versus inpatient); participant characteristics (age, sex, presence of structural heart disease); the tests/procedures and their results or acute outcomes; long-term outcomes, including SCD or arrhythmic death, AF, regular SVT, all-cause mortality, quality of life, hospitalization/readmission for cardiovascular events, and ablation-related complications; duration of follow-up; and loss to follow-up. Overall study quality was assessed in terms of risk of bias, relevance to the study question, and fidelity of implementation.
      • Jacobs A.K.
      • Kushner F.G.
      • Ettinger S.M.
      ACCF/AHA Clinical Practice Guideline Methodology Summit Report: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      To evaluate risk of bias, the Cochrane Collaboration Risk of Bias Tool was used for RCTs,
      • Higgins J.P.
      • Altman D.G.
      • Gotzsche P.C.
      • et al.
      The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials.
      and the Newcastle-Ottawa Scale was used for cohort studies.

      Wells GA, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa, On:Ottawa Hospital Research Institute; 2013. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed September 30, 2015.

      An RCT was assigned an overall rating of low-to-intermediate risk of bias if the trial was not deemed to be at high risk of bias for any assessed domain of study quality.

      Statistical Analysis

      Given the major methodological differences between RCTs and cohort studies, the 2 study types were analyzed separately. For each outcome of interest, the feasibility of completing a quantitative synthesis (i.e., meta-analysis) was assessed. Meta-analyses were considered when at least 3 studies reported the same outcome in similar populations, but because of incomplete data, they were not feasible. Counts/percentages of arrhythmic events were pooled from the observational cohort studies.

      Results

      Study and Patient Characteristics

      We screened 778 abstracts, evaluated 31 full-text articles, and included 7 articles. In addition, 1 paper known to the ERC was published after the search was completed and was added to the review.
      • Pappone C.
      • Vicedomini G.
      • Manguso F.
      • et al.
      Wolff-Parkinson-white syndrome in the era of catheter ablation: insights from a registry study of 2169 patients.
      A search of the bibliography of this article
      • Pappone C.
      • Vicedomini G.
      • Manguso F.
      • et al.
      Wolff-Parkinson-white syndrome in the era of catheter ablation: insights from a registry study of 2169 patients.
      resulted in 1 additional paper
      • Santinelli V.
      • Radinovic A.
      • Manguso F.
      • et al.
      Asymptomatic ventricular preexcitation: a long-term prospective follow-up study of 293 adult patients.
      that was also included. The search strategy used is shown in Figure 1.
      Of the 9 eligible studies that were identified, 1 had a dual-study design–encompassing both an RCT of ablation versus no ablation in 76 patients and a separate, uncontrolled prospective cohort of 148 additional patients
      • Pappone C.
      • Santinelli V.
      • Manguso F.
      • et al.
      A randomized study of prophylactic catheter ablation in asymptomatic patients with the Wolff-Parkinson-White syndrome.
      –and 8 were uncontrolled prospective observational cohort studies.
      • Pappone C.
      • Vicedomini G.
      • Manguso F.
      • et al.
      Wolff-Parkinson-white syndrome in the era of catheter ablation: insights from a registry study of 2169 patients.
      • Santinelli V.
      • Radinovic A.
      • Manguso F.
      • et al.
      Asymptomatic ventricular preexcitation: a long-term prospective follow-up study of 293 adult patients.
      • Brembilla-Perrot B.
      • Holban I.
      • Houriez P.
      • et al.
      Influence of age on the potential risk of sudden death in asymptomatic Wolff-Parkinson-White syndrome.
      • Klein G.J.
      • Yee R.
      • Sharma A.D.
      Longitudinal electrophysiologic assessment of asymptomatic patients with the Wolff-Parkinson-White electrocardiographic pattern.
      • Leitch J.W.
      • Klein G.J.
      • Yee R.
      • et al.
      Prognostic value of electrophysiology testing in asymptomatic patients with Wolff-Parkinson-White pattern.
      • Pappone C.
      • Santinelli V.
      • Rosanio S.
      • et al.
      Usefulness of invasive electrophysiologic testing to stratify the risk of arrhythmic events in asymptomatic patients with Wolff-Parkinson-White pattern: results from a large prospective long-term follow-up study.
      • Milstein S.
      • Sharma A.D.
      • Klein G.J.
      Electrophysiologic profile of asymptomatic Wolff-Parkinson-White pattern.
      • Satoh M.
      • Aizawa Y.
      • Funazaki T.
      • et al.
      Electrophysiologic evaluation of asymptomatic patients with the Wolff-Parkinson-White pattern.
      These 9 studies contributed data from 1,818 participants (although some patients were included in >1 study), with sample sizes ranging from 29 to 550 asymptomatic patients with no ablation of the accessory pathway and from 37 to 206 asymptomatic patients with ablation of the accessory pathway.
      • Pappone C.
      • Santinelli V.
      • Manguso F.
      • et al.
      A randomized study of prophylactic catheter ablation in asymptomatic patients with the Wolff-Parkinson-White syndrome.
      • Brembilla-Perrot B.
      • Holban I.
      • Houriez P.
      • et al.
      Influence of age on the potential risk of sudden death in asymptomatic Wolff-Parkinson-White syndrome.
      • Klein G.J.
      • Yee R.
      • Sharma A.D.
      Longitudinal electrophysiologic assessment of asymptomatic patients with the Wolff-Parkinson-White electrocardiographic pattern.
      • Leitch J.W.
      • Klein G.J.
      • Yee R.
      • et al.
      Prognostic value of electrophysiology testing in asymptomatic patients with Wolff-Parkinson-White pattern.
      • Pappone C.
      • Santinelli V.
      • Rosanio S.
      • et al.
      Usefulness of invasive electrophysiologic testing to stratify the risk of arrhythmic events in asymptomatic patients with Wolff-Parkinson-White pattern: results from a large prospective long-term follow-up study.
      • Milstein S.
      • Sharma A.D.
      • Klein G.J.
      Electrophysiologic profile of asymptomatic Wolff-Parkinson-White pattern.
      • Satoh M.
      • Aizawa Y.
      • Funazaki T.
      • et al.
      Electrophysiologic evaluation of asymptomatic patients with the Wolff-Parkinson-White pattern.
      All 9 studies addressed question 3, which examined the usefulness of either invasive EP study without catheter ablation of the accessory pathway or noninvasive EP study for predicting arrhythmic events in patients with asymptomatic pre-excitation.
      • Pappone C.
      • Vicedomini G.
      • Manguso F.
      • et al.
      Wolff-Parkinson-white syndrome in the era of catheter ablation: insights from a registry study of 2169 patients.
      • Santinelli V.
      • Radinovic A.
      • Manguso F.
      • et al.
      Asymptomatic ventricular preexcitation: a long-term prospective follow-up study of 293 adult patients.
      • Pappone C.
      • Santinelli V.
      • Manguso F.
      • et al.
      A randomized study of prophylactic catheter ablation in asymptomatic patients with the Wolff-Parkinson-White syndrome.
      • Brembilla-Perrot B.
      • Holban I.
      • Houriez P.
      • et al.
      Influence of age on the potential risk of sudden death in asymptomatic Wolff-Parkinson-White syndrome.
      • Klein G.J.
      • Yee R.
      • Sharma A.D.
      Longitudinal electrophysiologic assessment of asymptomatic patients with the Wolff-Parkinson-White electrocardiographic pattern.
      • Leitch J.W.
      • Klein G.J.
      • Yee R.
      • et al.
      Prognostic value of electrophysiology testing in asymptomatic patients with Wolff-Parkinson-White pattern.
      • Pappone C.
      • Santinelli V.
      • Rosanio S.
      • et al.
      Usefulness of invasive electrophysiologic testing to stratify the risk of arrhythmic events in asymptomatic patients with Wolff-Parkinson-White pattern: results from a large prospective long-term follow-up study.
      • Milstein S.
      • Sharma A.D.
      • Klein G.J.
      Electrophysiologic profile of asymptomatic Wolff-Parkinson-White pattern.
      • Satoh M.
      • Aizawa Y.
      • Funazaki T.
      • et al.
      Electrophysiologic evaluation of asymptomatic patients with the Wolff-Parkinson-White pattern.
      The RCT
      • Pappone C.
      • Santinelli V.
      • Manguso F.
      • et al.
      A randomized study of prophylactic catheter ablation in asymptomatic patients with the Wolff-Parkinson-White syndrome.
      component of the dual-design study also addressed question 4, which examined the efficacy of invasive EP study with catheter ablation of the accessory pathway as appropriate versus noninvasive tests with treatment or no testing/ablation as appropriate for preventing arrhythmic events and improving outcomes in patients with asymptomatic pre-excitation.
      The characteristics of the studies and the participants are presented in Table 1. In studies reporting a mean age, the range was 32 to 50 years,
      • Pappone C.
      • Santinelli V.
      • Manguso F.
      • et al.
      A randomized study of prophylactic catheter ablation in asymptomatic patients with the Wolff-Parkinson-White syndrome.
      • Brembilla-Perrot B.
      • Holban I.
      • Houriez P.
      • et al.
      Influence of age on the potential risk of sudden death in asymptomatic Wolff-Parkinson-White syndrome.
      • Klein G.J.
      • Yee R.
      • Sharma A.D.
      Longitudinal electrophysiologic assessment of asymptomatic patients with the Wolff-Parkinson-White electrocardiographic pattern.
      • Leitch J.W.
      • Klein G.J.
      • Yee R.
      • et al.
      Prognostic value of electrophysiology testing in asymptomatic patients with Wolff-Parkinson-White pattern.
      • Milstein S.
      • Sharma A.D.
      • Klein G.J.
      Electrophysiologic profile of asymptomatic Wolff-Parkinson-White pattern.
      • Satoh M.
      • Aizawa Y.
      • Funazaki T.
      • et al.
      Electrophysiologic evaluation of asymptomatic patients with the Wolff-Parkinson-White pattern.
      and in studies reporting a median age, the range was 19 to 36 years.
      • Pappone C.
      • Vicedomini G.
      • Manguso F.
      • et al.
      Wolff-Parkinson-white syndrome in the era of catheter ablation: insights from a registry study of 2169 patients.
      • Santinelli V.
      • Radinovic A.
      • Manguso F.
      • et al.
      Asymptomatic ventricular preexcitation: a long-term prospective follow-up study of 293 adult patients.
      • Pappone C.
      • Santinelli V.
      • Manguso F.
      • et al.
      A randomized study of prophylactic catheter ablation in asymptomatic patients with the Wolff-Parkinson-White syndrome.
      The majority of patients were male (range 50% to 74%). Structural heart disease was reported to be present in a minority of patients (<10%).
      • Pappone C.
      • Vicedomini G.
      • Manguso F.
      • et al.
      Wolff-Parkinson-white syndrome in the era of catheter ablation: insights from a registry study of 2169 patients.
      • Pappone C.
      • Santinelli V.
      • Manguso F.
      • et al.
      A randomized study of prophylactic catheter ablation in asymptomatic patients with the Wolff-Parkinson-White syndrome.
      • Brembilla-Perrot B.
      • Holban I.
      • Houriez P.
      • et al.
      Influence of age on the potential risk of sudden death in asymptomatic Wolff-Parkinson-White syndrome.
      • Leitch J.W.
      • Klein G.J.
      • Yee R.
      • et al.
      Prognostic value of electrophysiology testing in asymptomatic patients with Wolff-Parkinson-White pattern.
      • Pappone C.
      • Santinelli V.
      • Rosanio S.
      • et al.
      Usefulness of invasive electrophysiologic testing to stratify the risk of arrhythmic events in asymptomatic patients with Wolff-Parkinson-White pattern: results from a large prospective long-term follow-up study.
      • Satoh M.
      • Aizawa Y.
      • Funazaki T.
      • et al.
      Electrophysiologic evaluation of asymptomatic patients with the Wolff-Parkinson-White pattern.
      Intermittent pre-excitation was an exclusion criterion in 1 study
      • Leitch J.W.
      • Klein G.J.
      • Yee R.
      • et al.
      Prognostic value of electrophysiology testing in asymptomatic patients with Wolff-Parkinson-White pattern.
      and was reported to be present in 23% of patients in another study.
      • Satoh M.
      • Aizawa Y.
      • Funazaki T.
      • et al.
      Electrophysiologic evaluation of asymptomatic patients with the Wolff-Parkinson-White pattern.
      The remaining studies did not report on whether pre-excitation was intermittent or persistent.
      Table 1Summary of Included Studies
      Study (Author, Year)Study DesignSample Size (N)Participant CharacteristicsInclusion CriteriaExclusion Criteria
      Pappone C, et al., 2003
      • Pappone C.
      • Santinelli V.
      • Manguso F.
      • et al.
      A randomized study of prophylactic catheter ablation in asymptomatic patients with the Wolff-Parkinson-White syndrome.
      14602878
      Combined RCT and prospective observational cohort study. All pts underwent EP study. Pts with inducible arrhythmia on EP study who were ≤35 y were randomized to ablation vs. no ablation. The remaining pts were followed as an observational cohort.224 (EP study identified 76 high-risk pts who were then enrolled in an RCT and 148 low-risk pts enrolled in a prospective observational cohort study)
      • Median (IQR) age 23 y (15-30 y) for ablation group and 22 y (15-30 y) for no-ablation group. Male sex 53% in ablation arm and 47% in no-ablation group. No structural heart disease in either group.
      • Median (IQR) age for observational cohort 36 y (27-48 y). Male sex 59% in this cohort. Structural heart disease 7%.
      • Ventricular pre-excitation documented by 12-lead ECG
      • Absence of arrhythmia-related symptoms
      • Participation in other investigational protocols
      • Age <13 y
      • Pregnancy
      • Concomitant medical conditions
      Brembilla-Perrot B, et al., 2001
      • Brembilla-Perrot B.
      • Holban I.
      • Houriez P.
      • et al.
      Influence of age on the potential risk of sudden death in asymptomatic Wolff-Parkinson-White syndrome.


      11707045
      Uncontrolled prospective observational study. All pts underwent testing with transesophageal stimulation.92
      • Mean age (±SD): 34 y (±15 y), age range 11-69 y
      • 68 men, 24 women
      • No structural heart disease
      • Asymptomatic WPW pattern on the ECG
      • No documented tachycardia and no history of sustained tachycardia
      • Documentation of SVT at any time
      Klein GJ, et al., 1989
      • Klein G.J.
      • Yee R.
      • Sharma A.D.
      Longitudinal electrophysiologic assessment of asymptomatic patients with the Wolff-Parkinson-White electrocardiographic pattern.


      2710202
      Uncontrolled prospective observational study. All pts underwent an EP study.29
      • Age (±SD): 50 y (±18 y) in the pre-excitation–lost subgroup
        39 y (±11 y) in the pre-excitation–persistent subgroup
      • Sex: 17/29 (58.6%) men, 12/29 (41.4%) women
      • Structural heart disease: –
      • Asymptomatic WPW pattern on the ECG
      • No documented tachycardia and no history of sustained tachycardia
      Leitch JW, et al., 1990
      • Leitch J.W.
      • Klein G.J.
      • Yee R.
      • et al.
      Prognostic value of electrophysiology testing in asymptomatic patients with Wolff-Parkinson-White pattern.


      2225373
      Uncontrolled prospective observational study. All pts underwent an EP study.75
      • Mean age (±SD) 34 y (±13 y), age range 7-77 y
      • Male pts 44 (59%)
      • Structural heart disease 5/75 (7%): (1 with CAD, 2 with cardiomyopathy, 1 with valvular heart disease, 1 with Ebstein anomaly)
      • Asymptomatic with WPW pattern on the ECG
      • All pts underwent symptom-limited exercise stress testing and 24-h Holter monitoring and were excluded from the study if SVT was documented at any time.
      • Other specific exclusions were intermittent pre-excitation either at rest or during exercise testing and EP study.
      Milstein S, et al., 1986
      • Milstein S.
      • Sharma A.D.
      • Klein G.J.
      Electrophysiologic profile of asymptomatic Wolff-Parkinson-White pattern.


      3706161
      Uncontrolled prospective cohort study. All pts underwent an EP study.42
      • Mean age (±SD) 36 y (±12 y); age range 7-77 y
      • Sex: 21 (50%) men and 21 (50%) women
      • Structural heart disease: –
      • WPW pattern seen on a routine ECG. These pts were considered asymptomatic because they had neither documented arrhythmias nor a history of sustained palpitations
      Pappone C, et al., 2003
      • Pappone C.
      • Santinelli V.
      • Rosanio S.
      • et al.
      Usefulness of invasive electrophysiologic testing to stratify the risk of arrhythmic events in asymptomatic patients with Wolff-Parkinson-White pattern: results from a large prospective long-term follow-up study.


      12535816
      Uncontrolled prospective observational study. All pts underwent an EP study.212
      • Mean age of overall population (±SD): 35.8 y (±20.5 y), age range 7-63 y. Sex in overall population: N/A. Structural heart disease in overall population was present in 10/212 (5%) (5 with MVP, 2 with HCM, 3 with hypertension)
      • Mean age (±SD) of the 162 patients with complete f/u 33.6 y (±14.3 y), age range 7-63 y. Male 105/162 (65%). Structural heart disease was present in 4/162 (3 with MVP, 1 with HCM)
      • Asymptomatic WPW pattern was found either incidentally at routine examination or during a medical check-up before admission to a competitive sport or a high-risk occupation
      Satoh M, et al., 1989
      • Satoh M.
      • Aizawa Y.
      • Funazaki T.
      • et al.
      Electrophysiologic evaluation of asymptomatic patients with the Wolff-Parkinson-White pattern.


      2466266
      Uncontrolled observational cohort study. All pts underwent an EP study.95 (34 asymptomatic and 61 symptomatic pts)
      • Mean age (±SD) 32 y (±19 y)
      • Male 73%
      • Structural heart disease 13%
      • Intermittent pre-excitation 23%
      • WPW pattern
      • Asymptomatic (neither documented tachycardia, nor a history of palpitations suggestive of paroxysmal tachycardia)
      Santinelli V, et al., 2009
      • Santinelli V.
      • Radinovic A.
      • Manguso F.
      • et al.
      Asymptomatic ventricular preexcitation: a long-term prospective follow-up study of 293 adult patients.


      19808453
      Uncontrolled prospective observational study. All pts underwent an EP study293
      • Median age (IQR) 36 y (28-48 y)
      • Male 61%
      • Incidental WPW pattern on the ECG
      • Asymptomatic based on an accurate history
      • Participation in other research studies
      Pappone C, et al., 2014
      • Pappone C.
      • Vicedomini G.
      • Manguso F.
      • et al.
      Wolff-Parkinson-white syndrome in the era of catheter ablation: insights from a registry study of 2169 patients.


      25052405
      Uncontrolled prospective observational study. All pts underwent an EP study. They reported data by treatment with catheter ablation.2169 (756 asymptomatic, 550 asymptomatic and with no ablation, and 1413 symptomatic pts)
      • Median age 19 y, male preponderance among asymptomatic pts (63%).
      • Structural heart diseases were found in 1.5% of asymptomatic pts
      • Asymptomatic and symptomatic pts without prior ablation or documented life-threatening arrhythmias who consented to undergo a baseline EP study
      CAD indicates coronary artery disease; ECG, electrocardiogram; EP, electrophysiological; HCM, hypertrophic cardiomyopathy; IQR, interquartile range; MVP, mitral valve prolapse; pt, patient; RCT, randomized controlled trial; SD, standard deviation; SVT, supraventricular tachycardia; WPW, Wolff-Parkinson-White; and –, not available.

      Study Results

      Study comparators and outcomes are presented in Table 2. In the 2003 RCT component of the dual-design study by Pappone et al.,
      • Pappone C.
      • Santinelli V.
      • Manguso F.
      • et al.
      A randomized study of prophylactic catheter ablation in asymptomatic patients with the Wolff-Parkinson-White syndrome.
      during a median follow-up of 27 months, 2 (5%) of 37 patients in the ablation group had regular SVT, versus 21 (60%) of 35 patients in the no-ablation group (regular SVT in 15 patients, AF in 5 patients, and ventricular fibrillation [VF] in 1 patient). In the randomized comparison of ablation versus no ablation, the 5-year Kaplan-Meier estimates of the incidence of arrhythmic events were 7% among patients who underwent ablation and 77% among those who did not (relative risk reduction: 0.08; 95% confidence interval: 0.02 to 0.33; p<0.001). The rates of different types of arrhythmic events occurring within 5 years were not reported in this paper.
      • Pappone C.
      • Santinelli V.
      • Manguso F.
      • et al.
      A randomized study of prophylactic catheter ablation in asymptomatic patients with the Wolff-Parkinson-White syndrome.
      In the associated observational cohort, symptoms of SVT developed in 6 (4%) of 148 patients.
      • Pappone C.
      • Santinelli V.
      • Manguso F.
      • et al.
      A randomized study of prophylactic catheter ablation in asymptomatic patients with the Wolff-Parkinson-White syndrome.
      Table 2Comparators and Outcomes
      Study (Author, Year)Study GroupsResults of Noninvasive TestingResults of Invasive EP StudyAcute Outcome of Catheter AblationClinical Outcomes of InterestDuration of Follow-UpLoss to Follow-Up
      Pappone C, et al., 2003
      • Pappone C.
      • Santinelli V.
      • Manguso F.
      • et al.
      A randomized study of prophylactic catheter ablation in asymptomatic patients with the Wolff-Parkinson-White syndrome.
      14602878
      Group 1: Ablation Group 2: No ablation Group 3: Low-risk group followed as an observational cohortN/A15/37 (41%) pts in the ablation group had inducible AVRT. In 8 additional pts, AVRT degenerated into sustained AF. The median number of radiofrequency applications was 9 (range, 5-22).Ablation was acutely successful in all pts. Complications related to EP study (2 pneumothoraxes and 1 large femoral hematoma) developed in 3 (1%) pts. An ablation-related complication (permanent right bundle-branch block) developed in 1/37 (3%) pt with an anteroseptal accessory pathway.2/37 (5%) pts in the ablation group had an arrhythmic event, found on EP study to be due to AVNRT in both pts. Within a mean of 15 mo, 21/35 (60%) pts in the no-ablation group had an arrhythmic event, which was SVT in 15 pts, AF in 5 pts, and VF (not preceded by symptoms) in 1 pt. Among the high-risk controls (group 2), the 5-y rate of arrhythmic events was 77% vs. 7% in the ablation group. In the observational cohort, symptoms of SVT developed in 6 pts and 20 pts lost ventricular pre-excitation.Ablation group median f/u 27 mo, range 9-60 mo. Control group median f/u 21 mo, range 8-60 mo.None
      Brembilla-Perrot B, et al., 2001
      • Brembilla-Perrot B.
      • Holban I.
      • Houriez P.
      • et al.
      Influence of age on the potential risk of sudden death in asymptomatic Wolff-Parkinson-White syndrome.
      11707045
      Group 1: Transesophageal stimulationAll patients had 24-h Holter and stress test performed before study entry and only those without supraventricular arrhythmia were includedThe number of accessory pathways found was not reported. The ERPs of pathway(s) at baseline and during isoproterenol infusion were not reported. Shortest RR interval (<250 ms) during induced AF was present in 20/92 (22%) patients. Atrial tachyarrhythmia was induced in 27% of pts.No ablation3/92 (3%) pts developed symptomatic AF several years later. Of these 3 pts, 1 presented with AF and then VF 1 d after an aortic aneursymectomy. Among the 42 pts considered to have a benign form of WPW syndrome, there was no clinical event, except a death related to an accident.
      Klein GJ, et al., 1989
      • Klein G.J.
      • Yee R.
      • Sharma A.D.
      Longitudinal electrophysiologic assessment of asymptomatic patients with the Wolff-Parkinson-White electrocardiographic pattern.
      2710202
      Group 1: Invasive EP study without catheter ablationN/A28/29 (97%) pts had only 1 accessory pathway, and 1/29 (3%) pts had >1 accessory pathway. The mean (±SD) ERP of pathway(s) at baseline was 334 ms (±105 ms) on the initial study and 301 ms (±78 ms) on the f/u study. The shortest RR interval (±SD) during induced AF was 266 ms (±39 ms). Sustained AF was induced in 2/29 (7%) pts on the initial study and 11/29 (38%) pts on the f/u study.No ablationSustained paroxysmal SVT 2/29 (7%) (during 36-79 mo); 27/29 (93%) remained asymptomatic; 9/29 (31%) lost WPW pattern on the ECG.36-79 moNone
      Leitch JW, et al., 1990
      • Leitch J.W.
      • Klein G.J.
      • Yee R.
      • et al.
      Prognostic value of electrophysiology testing in asymptomatic patients with Wolff-Parkinson-White pattern.
      2225373
      Group 1: Invasive EP study without catheter ablationN/AAt baseline, the median ERP of the accessory pathway was 293 ms (IQR 280-310 ms), and the median retrograde ERP of the accessory pathway was 288 ms (IQR 240-320 ms). The median shortest RR interval during preexcited AF was 274 ms (IQR 240-325 ms) in 72 pts, was ≤250 ms in 23 pts, and was ≤200 ms in 8 pts. AVRT was induced in 12/75 (16%), and sustained AF was induced in 23/75 (31%).No ablation3/75 (4%) died of noncardiac causes, and 1/75 (1%) pt died suddenly after initial consultation but before EP study was done. 5/75 (7%) developed symptomatic AVRT. 1/75 (1%) developed symptomatic AF. The presence of sustained AVRT at EP study did not differentiate pts who remained asymptomatic from pts who became symptomatic. Only 1 (4%) pt developed clinical AF of the 23 pts in whom AF was induced at EP study.Median 4.3 y (range 1-9 y)None
      Milstein S, et al., 1986
      • Milstein S.
      • Sharma A.D.
      • Klein G.J.
      Electrophysiologic profile of asymptomatic Wolff-Parkinson-White pattern.
      3706161
      Group 1: Asymptomatic WPW patternN/A43 accessory pathways in 42 asymptomatic pts. Mean (±SD) ERP of accessory pathway was 333±106 ms in asymptomatic pts vs. 298±42 ms in asymptomatic pts (p<0.025). Mean shortest RR interval during AF was 277±48 ms in the asymptomatic groups vs. 247±51 ms in the symptomatic group (p<0.025). Sustained AVRT could be induced in only 1 pt.No ablation1 pt died of metastatic carcinoma after 43 mo, and 1 pt died suddenly after he had agreed to participate in the study but before EP study could be performed. 4 pts received propranolol because of undocumented “skipped beats.” All other pts remained asymptomatic.29±18 moNone
      Pappone C, et al., 2003
      • Pappone C.
      • Santinelli V.
      • Rosanio S.
      • et al.
      Usefulness of invasive electrophysiologic testing to stratify the risk of arrhythmic events in asymptomatic patients with Wolff-Parkinson-White pattern: results from a large prospective long-term follow-up study.
      12535816
      Group 1: Invasive EP study without catheter ablationN/A17/162 (10%) had multiple accessory pathways. Baseline mean (±SD) ERP was 275.2 ms (±33.8 ms). Isoproterenol mean (±SD) ERP was 246.1 ms (±30.5 ms). Shortest RR in AF was not reported. 47/162 (29%) had inducible arrhythmia: nonsustained AF in 17, sustained AF in 19, and inducible AVRT that degenerated into totally pre-excited sustained AF in 11.No ablation129/209 (62%) remained asymptomatic at the end of f/u, whereas 33 (16%) developed arrhythmic events: SVT in 25, AF in 8, documented VF in 3/209 (aborted sudden death in 2, both of whom had developed symptoms due to AF), and sudden death in 1/20937.7±16.1 mo; range 14 to 60 mo3/212 (1.4%); 47/212 who refused the 5-y EP study were excluded from the analysis.
      Satoh M, et al., 1989
      • Satoh M.
      • Aizawa Y.
      • Funazaki T.
      • et al.
      Electrophysiologic evaluation of asymptomatic patients with the Wolff-Parkinson-White pattern.
      2466266
      Group 1: Asymptomatic pts with WPW patternIntermittent pre-excitation on ECG recording 23%Number of pts with multiple accessory pathways not reported. Baseline mean ERP of accessory pathway was 288±29 ms in asymptomatic pts. Shortest RR in AF not reported. AVRT was induced in 6/34 (18%) pts in the asymptomatic group, and sustained AF was induced in 2/34 (6%) of asymptomatic pts.No ablationGroup 1: no eventsMean 15 mo (range 2 to 47 mo)
      Santinelli V, et al., 2009
      • Santinelli V.
      • Radinovic A.
      • Manguso F.
      • et al.
      Asymptomatic ventricular preexcitation: a long-term prospective follow-up study of 293 adult patients.
      19808453
      Group 1: Invasive EP study without catheter ablationN/AAnterograde ERP of accessory pathway ≤250 ms was present in 39/293 (13%) pts. Multiple accessory pathways were found in 13 (4%) pts. Inducible arrhythmia was found in 47 (16%) pts.No ablation262/293 (89%) pts did not experience arrhythmic events, remaining totally asymptomatic, whereas 31/293 (11%) pts had an arrhythmic event, which was potentially life threatening in 17 of them. Potentially life-threatening tachyarrhythmias resulted in resuscitated cardiac arrest (1 pt), presyncope (7 pts), syncope (4 pts), or dizziness (5 pts).Median duration of f/u after EP study was 67 mo (range 8 to 90)
      Pappone C, et al., 2014
      • Pappone C.
      • Vicedomini G.
      • Manguso F.
      • et al.
      Wolff-Parkinson-white syndrome in the era of catheter ablation: insights from a registry study of 2169 patients.
      25052405
      Group 1: Asymptomatic pts with WPW pattern (they presented data on symptomatic pts and by whether catheter ablation of the accessory pathway was done, but the groups were not matched and selection bias was not adjusted for)No ablation: Multiple accessory pathways in 59 (6%), median (IQR) ERP of accessory pathway 280 ms (250-300 ms). Inducible AVRT triggering AF on EP study was found in 47 (5%) of pts. With ablation: Multiple accessory pathways in 80 (7%), median ERP (IQR) of accessory pathway 280 ms (250-300 ms). Inducible AVRT triggering AF on EP study was found in 73 (6%) of pts.206/756 asymptomatic pts were treated with ablation; ablation was successful in 98.5%.No ablation: during a median f/u of 22 mo, VF occurred in 13/550 (2%) asymptomatic pts (almost exclusively in children). During a median f/u of 46.5 mo, 48/550 (9%) additional asymptomatic pts experienced malignant arrhythmias, and 86/756 (11%) of the asymptomatic pts developed benign arrhythmias (AVRT and AF). With ablation: no pt developed malignant arrhythmias or VF over the 8 y of f/u.Median 96 moNo ablation: completeness of f/u was 99.8% at 1 y and 92.3% at the end of the study With ablation: completeness of f/u was 95.5% at 1 y and 90.2% at the end of the study
      AF indicates atrial fibrillation; AVNRT, atrioventricular nodal reentrant tachycardia; AVRT, atrioventricular reciprocating tachycardia; ECG, electrocardiogram/electrocardiographic; EP, electrophysiological; ERP, effective refractory period; f/u, follow-up; IQR, interquartile range; N/A, not applicable; pt, patient; SD, standard deviation; SVT, supraventricular tachycardia; VF, ventricular fibrillation; WPW, Wolf-Parkinson-White; and –, not available.
      In the 1986 study by Milstein et al.,
      • Milstein S.
      • Sharma A.D.
      • Klein G.J.
      Electrophysiologic profile of asymptomatic Wolff-Parkinson-White pattern.
      4 (10%) of 42 patients started receiving propranolol because of palpitations of unclear etiology, whereas all other patients remained asymptomatic during a mean follow-up of 29 months.
      In the 1989 study by Klein et al.,
      • Klein G.J.
      • Yee R.
      • Sharma A.D.
      Longitudinal electrophysiologic assessment of asymptomatic patients with the Wolff-Parkinson-White electrocardiographic pattern.
      sustained SVT occurred in 2 (7%) of 29 patients during 36 to 79 months of follow-up, with the other 27 (93%) patients remaining asymptomatic.
      In the 1989 study by Satoh et al.,
      • Satoh M.
      • Aizawa Y.
      • Funazaki T.
      • et al.
      Electrophysiologic evaluation of asymptomatic patients with the Wolff-Parkinson-White pattern.
      no events occurred during a mean follow-up of 15 months.
      In the 1990 study by Leitch et al.,
      • Leitch J.W.
      • Klein G.J.
      • Yee R.
      • et al.
      Prognostic value of electrophysiology testing in asymptomatic patients with Wolff-Parkinson-White pattern.
      5 (7%) of 75 patients developed symptomatic atrioventricular reentrant tachycardia, and 1 (1%) of 75 developed symptomatic AF over a median follow-up of 4.3 years. The presence of sustained atrioventricular reentrant tachycardia at EP study did not differentiate patients who remained asymptomatic from patients who became symptomatic during follow-up.
      In the 2001 study by Brembilla-Perrot et al.,
      • Brembilla-Perrot B.
      • Holban I.
      • Houriez P.
      • et al.
      Influence of age on the potential risk of sudden death in asymptomatic Wolff-Parkinson-White syndrome.
      which did not report duration of follow-up, 3 (3%) of 92 patients developed a clinically significant atrial arrhythmia several years after initial enrollment. Of these 3 patients, 1 adult presented with AF and then VF 1 day after an aortic aneursymectomy.
      In another 2003 study by Pappone et al.,
      • Pappone C.
      • Santinelli V.
      • Rosanio S.
      • et al.
      Usefulness of invasive electrophysiologic testing to stratify the risk of arrhythmic events in asymptomatic patients with Wolff-Parkinson-White pattern: results from a large prospective long-term follow-up study.
      129 (62%) of 209 patients remained asymptomatic at the end of follow-up (mean follow-up, 38 months), whereas 33 (16%) experienced arrhythmic events. Of these 33 patients, 25 developed regular SVT, 8 developed AF, and 3 had documented VF (aborted SCD in 2, both of whom had AF, and death in 1 of 209).
      In the 2009 study by Santinelli et al.,
      • Santinelli V.
      • Radinovic A.
      • Manguso F.
      • et al.
      Asymptomatic ventricular preexcitation: a long-term prospective follow-up study of 293 adult patients.
      during a median follow-up of 67 months (range, 8 to 90 months), 262 (89%) of 293 patients did not experience arrhythmic events, remaining totally asymptomatic, whereas 31 (11%) of 293 patients had an arrhythmic event, which was potentially life threatening in 17 patients (6%). Potentially life-threatening tachyarrhythmias resulted in resuscitated cardiac arrest (1 patient), presyncope (7 patients), syncope (4 patients), or dizziness (5 patients).
      In a 2014 study by Pappone et al.,
      • Pappone C.
      • Vicedomini G.
      • Manguso F.
      • et al.
      Wolff-Parkinson-white syndrome in the era of catheter ablation: insights from a registry study of 2169 patients.
      during a median follow-up of 22 months (range, 15 to 41 months), VF occurred in 13 (2%) of 550 asymptomatic patients with no ablation, almost all of whom were children. During a median follow-up of 46.5 months (range, 36 to 58.5 months), 48 (9%) additional previously asymptomatic patients experienced malignant arrhythmias. In all patients, VF developed a few minutes after warning symptoms and resulted in a resuscitated cardiac arrest without neurological sequelae. These malignant arrhythmic events correlated with the electrophysiological properties of the accessory pathway. Eighty-six of the 756 (550 asymptomatic patients with no ablation plus 206 asymptomatic patients who underwent ablation) asymptomatic patients (11%) developed benign arrhythmias (atrioventricular reentrant tachycardia and AF). Ablation was reported to be successful in 98.5% of cases; after radiofrequency ablation, no patient developed malignant AF (shortest RR ≤250 ms) or VF over the 8 years of follow-up.
      Two studies reported on EP study– and ablation-related complications. In the first 2003 study by Pappone et al.,
      • Pappone C.
      • Santinelli V.
      • Manguso F.
      • et al.
      A randomized study of prophylactic catheter ablation in asymptomatic patients with the Wolff-Parkinson-White syndrome.
      complications related to EP study developed in 3 patients (1%) (2 pneumothoraxes and 1 large femoral hematoma). An ablation-related complication (permanent right bundle-branch block) developed in 1 (3%) of 37 patients. In the 2014 study by Pappone et al.,
      • Pappone C.
      • Vicedomini G.
      • Manguso F.
      • et al.
      Wolff-Parkinson-white syndrome in the era of catheter ablation: insights from a registry study of 2169 patients.
      complications of EP study consisted of pneumothorax in 5 patients (0.2%), femoral hematomas at the catheter entry site in 25 patients (1%), and fistulas in 2 patients (0.09%). Ablation-related complications included right bundle-branch block in 10 patients (0.9%); left bundle-branch block in 3 patients (0.3%) with anteroseptal accessory pathways; and a small, asymptomatic pericardial effusion requiring prolongation of hospital stay in 2 children (0.2%) with left and right accessory pathways. Serious complications included third-degree atrioventricular block in 1 patient (0.1%). No deaths occurred after ablation.

      Evidence Synthesis

      Because 4
      • Pappone C.
      • Vicedomini G.
      • Manguso F.
      • et al.
      Wolff-Parkinson-white syndrome in the era of catheter ablation: insights from a registry study of 2169 patients.
      • Santinelli V.
      • Radinovic A.
      • Manguso F.
      • et al.
      Asymptomatic ventricular preexcitation: a long-term prospective follow-up study of 293 adult patients.
      • Pappone C.
      • Santinelli V.
      • Manguso F.
      • et al.
      A randomized study of prophylactic catheter ablation in asymptomatic patients with the Wolff-Parkinson-White syndrome.
      • Pappone C.
      • Santinelli V.
      • Rosanio S.
      • et al.
      Usefulness of invasive electrophysiologic testing to stratify the risk of arrhythmic events in asymptomatic patients with Wolff-Parkinson-White pattern: results from a large prospective long-term follow-up study.
      of the 9 included papers were published by the same group and some of their patients were included in >1 study, only the most recent and inclusive study by that group was included in this part of the analysis.
      • Pappone C.
      • Vicedomini G.
      • Manguso F.
      • et al.
      Wolff-Parkinson-white syndrome in the era of catheter ablation: insights from a registry study of 2169 patients.
      In the RCT component of the dual-design study (n=76), estimates of the incidence of arrhythmic events were 7% among patients who underwent ablation and 77% among the controls (p<0.001).
      • Pappone C.
      • Santinelli V.
      • Manguso F.
      • et al.
      A randomized study of prophylactic catheter ablation in asymptomatic patients with the Wolff-Parkinson-White syndrome.
      In the observational cohorts of asymptomatic patients who did not undergo catheter ablation (n=883) during follow-up that ranged from 8 to 96 months,
      • Pappone C.
      • Vicedomini G.
      • Manguso F.
      • et al.
      Wolff-Parkinson-white syndrome in the era of catheter ablation: insights from a registry study of 2169 patients.
      • Brembilla-Perrot B.
      • Holban I.
      • Houriez P.
      • et al.
      Influence of age on the potential risk of sudden death in asymptomatic Wolff-Parkinson-White syndrome.
      • Klein G.J.
      • Yee R.
      • Sharma A.D.
      Longitudinal electrophysiologic assessment of asymptomatic patients with the Wolff-Parkinson-White electrocardiographic pattern.
      • Leitch J.W.
      • Klein G.J.
      • Yee R.
      • et al.
      Prognostic value of electrophysiology testing in asymptomatic patients with Wolff-Parkinson-White pattern.
      • Satoh M.
      • Aizawa Y.
      • Funazaki T.
      • et al.
      Electrophysiologic evaluation of asymptomatic patients with the Wolff-Parkinson-White pattern.
      regular SVT or benign AF (shortest RR >250 ms) developed in 0% to 16%, and malignant AF (shortest RR ≤250 ms) developed in 0% to 9%. VF developed in 0 to 14 (2%) of 883 patients who, except for 3 (1 in the study by Brembilla-Perrot et al.
      • Brembilla-Perrot B.
      • Holban I.
      • Houriez P.
      • et al.
      Influence of age on the potential risk of sudden death in asymptomatic Wolff-Parkinson-White syndrome.
      and 2 in Pappone et al., 2003
      • Pappone C.
      • Santinelli V.
      • Rosanio S.
      • et al.
      Usefulness of invasive electrophysiologic testing to stratify the risk of arrhythmic events in asymptomatic patients with Wolff-Parkinson-White pattern: results from a large prospective long-term follow-up study.
      /Pappone et al., 2014,
      • Pappone C.
      • Vicedomini G.
      • Manguso F.
      • et al.
      Wolff-Parkinson-white syndrome in the era of catheter ablation: insights from a registry study of 2169 patients.
      ) were all children (n=11, all in Pappone et al., 2014.
      • Pappone C.
      • Vicedomini G.
      • Manguso F.
      • et al.
      Wolff-Parkinson-white syndrome in the era of catheter ablation: insights from a registry study of 2169 patients.
      ) None of the patients who died suddenly had undergone accessory-pathway ablation. In 2 studies,
      • Leitch J.W.
      • Klein G.J.
      • Yee R.
      • et al.
      Prognostic value of electrophysiology testing in asymptomatic patients with Wolff-Parkinson-White pattern.
      • Milstein S.
      • Sharma A.D.
      • Klein G.J.
      Electrophysiologic profile of asymptomatic Wolff-Parkinson-White pattern.
      1 patient was reported to have died suddenly after consenting to undergo an EP study but before the EP study was performed. Given the ambiguity of these 2 deaths, they were not included in the estimates of VF.

      Quality of Included Studies

      Quality assessment of included studies is shown in Table 3. All studies showed intermediate-to-high relevance with regard to their study population, testing, intervention, and outcome measures.
      • Pappone C.
      • Vicedomini G.
      • Manguso F.
      • et al.
      Wolff-Parkinson-white syndrome in the era of catheter ablation: insights from a registry study of 2169 patients.
      • Santinelli V.
      • Radinovic A.
      • Manguso F.
      • et al.
      Asymptomatic ventricular preexcitation: a long-term prospective follow-up study of 293 adult patients.
      • Pappone C.
      • Santinelli V.
      • Manguso F.
      • et al.
      A randomized study of prophylactic catheter ablation in asymptomatic patients with the Wolff-Parkinson-White syndrome.
      • Brembilla-Perrot B.
      • Holban I.
      • Houriez P.
      • et al.
      Influence of age on the potential risk of sudden death in asymptomatic Wolff-Parkinson-White syndrome.
      • Klein G.J.
      • Yee R.
      • Sharma A.D.
      Longitudinal electrophysiologic assessment of asymptomatic patients with the Wolff-Parkinson-White electrocardiographic pattern.
      • Leitch J.W.
      • Klein G.J.
      • Yee R.
      • et al.
      Prognostic value of electrophysiology testing in asymptomatic patients with Wolff-Parkinson-White pattern.
      • Pappone C.
      • Santinelli V.
      • Rosanio S.
      • et al.
      Usefulness of invasive electrophysiologic testing to stratify the risk of arrhythmic events in asymptomatic patients with Wolff-Parkinson-White pattern: results from a large prospective long-term follow-up study.
      • Milstein S.
      • Sharma A.D.
      • Klein G.J.
      Electrophysiologic profile of asymptomatic Wolff-Parkinson-White pattern.
      • Satoh M.
      • Aizawa Y.
      • Funazaki T.
      • et al.
      Electrophysiologic evaluation of asymptomatic patients with the Wolff-Parkinson-White pattern.
      The degree to which the enrolled population was representative of patients seen in clinical practice was questionable in 5 studies.
      • Pappone C.
      • Vicedomini G.
      • Manguso F.
      • et al.
      Wolff-Parkinson-white syndrome in the era of catheter ablation: insights from a registry study of 2169 patients.
      • Santinelli V.
      • Radinovic A.
      • Manguso F.
      • et al.
      Asymptomatic ventricular preexcitation: a long-term prospective follow-up study of 293 adult patients.
      • Pappone C.
      • Santinelli V.
      • Manguso F.
      • et al.
      A randomized study of prophylactic catheter ablation in asymptomatic patients with the Wolff-Parkinson-White syndrome.
      • Leitch J.W.
      • Klein G.J.
      • Yee R.
      • et al.
      Prognostic value of electrophysiology testing in asymptomatic patients with Wolff-Parkinson-White pattern.
      • Pappone C.
      • Santinelli V.
      • Rosanio S.
      • et al.
      Usefulness of invasive electrophysiologic testing to stratify the risk of arrhythmic events in asymptomatic patients with Wolff-Parkinson-White pattern: results from a large prospective long-term follow-up study.
      The RCT by Pappone et al.
      • Pappone C.
      • Santinelli V.
      • Manguso F.
      • et al.
      A randomized study of prophylactic catheter ablation in asymptomatic patients with the Wolff-Parkinson-White syndrome.
      had low risk of bias because, among other measures, it implemented independent blind assessment of outcomes. All other studies had intermediate overall risk of bias because they had not implemented blind assessment of outcomes.
      • Pappone C.
      • Vicedomini G.
      • Manguso F.
      • et al.
      Wolff-Parkinson-white syndrome in the era of catheter ablation: insights from a registry study of 2169 patients.
      • Santinelli V.
      • Radinovic A.
      • Manguso F.
      • et al.
      Asymptomatic ventricular preexcitation: a long-term prospective follow-up study of 293 adult patients.
      • Brembilla-Perrot B.
      • Holban I.
      • Houriez P.
      • et al.
      Influence of age on the potential risk of sudden death in asymptomatic Wolff-Parkinson-White syndrome.
      • Klein G.J.
      • Yee R.
      • Sharma A.D.
      Longitudinal electrophysiologic assessment of asymptomatic patients with the Wolff-Parkinson-White electrocardiographic pattern.
      • Leitch J.W.
      • Klein G.J.
      • Yee R.
      • et al.
      Prognostic value of electrophysiology testing in asymptomatic patients with Wolff-Parkinson-White pattern.
      • Pappone C.
      • Santinelli V.
      • Rosanio S.
      • et al.
      Usefulness of invasive electrophysiologic testing to stratify the risk of arrhythmic events in asymptomatic patients with Wolff-Parkinson-White pattern: results from a large prospective long-term follow-up study.
      • Milstein S.
      • Sharma A.D.
      • Klein G.J.
      Electrophysiologic profile of asymptomatic Wolff-Parkinson-White pattern.
      • Satoh M.
      • Aizawa Y.
      • Funazaki T.
      • et al.
      Electrophysiologic evaluation of asymptomatic patients with the Wolff-Parkinson-White pattern.
      Table 3Quality Assessment of Included Studies
      Study (Author, Year)Representativeness of the CohortSelection of a Nonexposed CohortAscertainment of ExposureDemonstration That Outcome of Interest Was Not Present at EnrollmentIndependent Blind Assessment of OutcomesWas Follow-Up Long Enough for Outcomes to Occur?Adequacy of Cohort Follow-Up (Including Loss to Follow-Up)Precision of Findings
      Pappone C, et al., 2003
      • Pappone C.
      • Santinelli V.
      • Manguso F.
      • et al.
      A randomized study of prophylactic catheter ablation in asymptomatic patients with the Wolff-Parkinson-White syndrome.


      14602878
      QuestionableYesYesReasonable, based on the absence of symptomsThe events were reviewed by an independent committee whose members were unaware of the pts’ treatment assignmentsYesYesFairly precise with CI 0.02-0.33 for arrhythmic events and 0.002-0.104 for event-free survival
      Brembilla-Perrot B, et al., 2001
      • Brembilla-Perrot B.
      • Holban I.
      • Houriez P.
      • et al.
      Influence of age on the potential risk of sudden death in asymptomatic Wolff-Parkinson-White syndrome.


      11707045
      YesN/A (no comparator group)All pts underwent EP studyReasonable, based on the absence of symptoms. Pts had to have a normal ECG, exercise stress test, and 24-h Holter monitorUncertain because duration of f/u was not reportedF/u and loss to f/u were not reportedN/A (no comparator group)
      Klein GJ, et al., 1989
      • Klein G.J.
      • Yee R.
      • Sharma A.D.
      Longitudinal electrophysiologic assessment of asymptomatic patients with the Wolff-Parkinson-White electrocardiographic pattern.


      2710202
      YesN/A (no comparator group)All pts underwent EP study2/29 had SVT between scheduling EP study and when EP study was performedYesYesN/A (no comparator group)
      Leitch JW, et al., 1990
      • Leitch J.W.
      • Klein G.J.
      • Yee R.
      • et al.
      Prognostic value of electrophysiology testing in asymptomatic patients with Wolff-Parkinson-White pattern.


      2225373
      QuestionableN/A (no comparator group)All pts underwent EP studyYesYesYesN/A (no comparator group)
      Milstein S, et al., 1986
      • Milstein S.
      • Sharma A.D.
      • Klein G.J.
      Electrophysiologic profile of asymptomatic Wolff-Parkinson-White pattern.


      3706161
      YesN/A (all pts underwent EP study)All pts underwent EP studyYesYesYesImprecise due to small sample size
      Pappone C, et al., 2003
      • Pappone C.
      • Santinelli V.
      • Rosanio S.
      • et al.
      Usefulness of invasive electrophysiologic testing to stratify the risk of arrhythmic events in asymptomatic patients with Wolff-Parkinson-White pattern: results from a large prospective long-term follow-up study.


      12535816
      QuestionableN/A (no comparator group)All pts underwent EP studyYesYesQuestionableN/A (no comparator group)
      Satoh M, et al., 1989
      • Satoh M.
      • Aizawa Y.
      • Funazaki T.
      • et al.
      Electrophysiologic evaluation of asymptomatic patients with the Wolff-Parkinson-White pattern.


      2466266
      YesN/A (all pts underwent EP study)All pts underwent EP studyYesYesImprecise (no events)
      Santinelli V, et al., 2009
      • Santinelli V.
      • Radinovic A.
      • Manguso F.
      • et al.
      Asymptomatic ventricular preexcitation: a long-term prospective follow-up study of 293 adult patients.


      19808453
      QuestionableN/A (no comparator group)All pts underwent EP studyYesYesN/A (no comparator group)
      Pappone C, et al., 2014
      • Pappone C.
      • Vicedomini G.
      • Manguso F.
      • et al.
      Wolff-Parkinson-white syndrome in the era of catheter ablation: insights from a registry study of 2169 patients.


      25052405
      QuestionableN/A (no comparator group)All pts underwent EP studyYesYesN/A (no comparator group)
      CI indicates confidence interval; ECG, echocardiogram; EP, electrophysiological; f/u, follow-up; N/A, not applicable; pt, patient; SVT, supraventricular tachycardia; and –, not available.

      Discussion

      In this systematic review, only a single RCT was found that addressed the best management strategy for patients with asymptomatic pre-excitation. Although data from observational cohorts of asymptomatic patients who did not undergo catheter ablation (n=883) suggest that most of these patients have a benign course, with few clinically significant arrhythmic events during follow-up that ranged from 8 to 96 months, malignant AF (shortest RR ≤250 ms) developed in up to 9% of patients, and VF developed in up to 2% of patients. These percentages are not trivial, given the potential fatality of these events.
      • Pappone C.
      • Vicedomini G.
      • Manguso F.
      • et al.
      Wolff-Parkinson-white syndrome in the era of catheter ablation: insights from a registry study of 2169 patients.
      Importantly, malignant arrhythmias correlated more with the EP properties of the accessory pathway than with the presence or absence of symptoms.
      • Pappone C.
      • Vicedomini G.
      • Manguso F.
      • et al.
      Wolff-Parkinson-white syndrome in the era of catheter ablation: insights from a registry study of 2169 patients.
      Notably, in the RCT of ablation versus no ablation, the 5-year estimates of the incidence of arrhythmic events were 7% among patients who underwent ablation and 77% among the controls. Therefore, risk stratification with an EP study of patients with asymptomatic pre-excitation may be beneficial, along with consideration of accessory-pathway ablation in those deemed to be at high risk of future arrhythmias. This approach is further supported by the low risk of complications: Complication rates ranged from 0.09% to 1% and included pneumothorax and access site complications in a registry study of EP that included 2,169 patients.
      • Pappone C.
      • Vicedomini G.
      • Manguso F.
      • et al.
      Wolff-Parkinson-white syndrome in the era of catheter ablation: insights from a registry study of 2169 patients.
      The question of whether to ablate the accessory pathway(s) in EP study–identified high-risk patients was examined in only 1 RCT, which enrolled 76 patients. In that trial, estimates of the incidence of arrhythmic events were 7% in patients who underwent ablation versus 77% in patients who did not undergo ablation.
      • Pappone C.
      • Santinelli V.
      • Manguso F.
      • et al.
      A randomized study of prophylactic catheter ablation in asymptomatic patients with the Wolff-Parkinson-White syndrome.
      The 1 other study that examined patients on the basis of whether an ablation was performed was the largest and longest prospective cohort study by Pappone et al.
      • Pappone C.
      • Vicedomini G.
      • Manguso F.
      • et al.
      Wolff-Parkinson-white syndrome in the era of catheter ablation: insights from a registry study of 2169 patients.
      In that study, none of the asymptomatic patients who had undergone ablation of the accessory pathway developed malignant arrhythmia or VF during 8 years of follow-up;
      • Pappone C.
      • Vicedomini G.
      • Manguso F.
      • et al.
      Wolff-Parkinson-white syndrome in the era of catheter ablation: insights from a registry study of 2169 patients.
      however, the ablation and no-ablation groups were not matched, and researchers did not adjust for selection bias. Given the small number of patients in the 1 RCT published to date and the observational studies’ methodological limitations, including the relatively small sample size of patients included in most of those studies, well-designed and conducted prospective studies, especially RCTs of ablation versus no ablation, are needed.
      The decision to ablate the accessory pathway should be informed not only by data on the effectiveness of the procedure, but also by data on the risk of complications. Although 7 of the 9 included studies did not report on complications, 1 study by Pappone et al.
      • Pappone C.
      • Vicedomini G.
      • Manguso F.
      • et al.
      Wolff-Parkinson-white syndrome in the era of catheter ablation: insights from a registry study of 2169 patients.
      provided detailed information on complications in 1,168 patients who underwent an ablation. The risk of complications ranged from 0.1% (complete heart block) to 0.9% (ablation-induced right bundle-branch block). No ablation-related deaths occurred.

      Limitations

      This systematic review has several important limitations. First, because of the lack of data from RCTs and controlled prospective studies, the selection bias inherent to observational studies could not be avoided, and the evidence could not be quantitatively synthesized. Second, the inclusion of some patients in >1 study
      • Pappone C.
      • Vicedomini G.
      • Manguso F.
      • et al.
      Wolff-Parkinson-white syndrome in the era of catheter ablation: insights from a registry study of 2169 patients.
      • Santinelli V.
      • Radinovic A.
      • Manguso F.
      • et al.
      Asymptomatic ventricular preexcitation: a long-term prospective follow-up study of 293 adult patients.
      • Pappone C.
      • Santinelli V.
      • Manguso F.
      • et al.
      A randomized study of prophylactic catheter ablation in asymptomatic patients with the Wolff-Parkinson-White syndrome.
      • Pappone C.
      • Santinelli V.
      • Rosanio S.
      • et al.
      Usefulness of invasive electrophysiologic testing to stratify the risk of arrhythmic events in asymptomatic patients with Wolff-Parkinson-White pattern: results from a large prospective long-term follow-up study.
      made it impossible to examine collective data from all available studies, so the most recent and inclusive study from that group was used
      • Pappone C.
      • Vicedomini G.
      • Manguso F.
      • et al.
      Wolff-Parkinson-white syndrome in the era of catheter ablation: insights from a registry study of 2169 patients.
      . Third, as is generally the case with systematic reviews, this review is limited by the possibility of publication and reporting biases and the inconsistency of outcome definitions across the studies. Fourth, several of the potentially eligible studies had to be excluded because they enrolled asymptomatic and symptomatic patients with pre-excitation and did not report on the characteristics and outcomes of these groups separately. Fifth, allowing studies that included children may have affected the generalizability of the findings to an adult population. Sixth, by limiting the search to studies published since 1970, an important study published in 1968 and conducted in 128 healthy U.S. Air Force men followed for 5 to 28 years was excluded. That study showed that in the absence of cardiac disease and arrhythmias, asymptomatic pre-excitation did not affect the prognosis; although 3 deaths were observed, no known death was attributable to a cardiac cause.
      • Berkman N.L.
      • Lamb L.E.
      The Wolff-Parkinson-White electrocardiogram. A follow-up study of five to twenty-eight years.
      Given the highly selected study population, however, excluding this study likely did not have a major effect on our findings.

      Conclusions

      In this systematic review, little evidence was found from RCTs with regard to the best management strategy for patients with asymptomatic pre-excitation. Data from observational studies on 883 patients who did not undergo ablation showed that up to 9% of patients developed malignant arrhythmias, and up to 2% developed VF during follow-up. These observations, coupled with the very low risk of complications resulting from an EP study, suggest that risk stratification of patients with asymptomatic pre-excitation using an EP study may be beneficial, with consideration of accessory-pathway ablation in those deemed to be at high risk of future arrhythmias. Given the limitations of the existing data, well-designed and well-conducted studies are needed.

      Presidents and Staff

      American College of Cardiology
      Kim A. Williams, Sr, MD, FACC, FAHA, President
      Shalom Jacobovitz, Chief Executive Officer
      William J. Oetgen, MD, MBA, FACC, Executive Vice President, Science, Education, and Quality
      Amelia Scholtz, PhD, Publications Manager, Science, Education, and Quality
      American College of Cardiology/American Heart Association
      Lisa Bradfield, CAE, Director, Science and Clinical Policy
      Abdul R. Abdullah, MD, Associate Science and Medicine Advisor
      Alexa B. Papaila, Project Manager, Science and Clinical Policy
      American Heart Association
      Mark A. Creager, MD, FACC, FAHA, President
      Nancy Brown, Chief Executive Officer
      Rose Marie Robertson, MD, FAHA, Chief Science and Medical Officer
      Gayle R. Whitman, PhD, RN, FAHA, FAAN, Senior Vice President, Office of Science Operations
      Marco Di Buono, PhD, Vice President, Science, Research, and Professional Education
      Jody Hundley, Production Manager, Scientific Publications, Office of Science Operations
      Appendix 1Author Relationships With Industry and Other Entities (Relevant)
      For transparency, the ERC members’ comprehensive disclosure information is available as an online supplement.
      –Risk Stratification for Arrhythmic Events in Patients With Asymptomatic Pre-Excitation: A Systematic Review for the 2015 ACC/AHA/HRS Guideline for the Management of Adult Patients With Supraventricular Tachycardia (May 2014)
      Committee MemberEmploymentConsultantSpeakers BureauOwnership/Partnership/PrincipalPersonal ResearchInstitutional, Organizational, or Other Financial BenefitExpert Witness
      Sana M. Al-Khatib (Chair)Duke Clinical Research Institute–Associate Professor of MedicineNoneNoneNoneNoneNoneNone
      Aysha ArshadValley Health System–Director Lead ExtractionNoneNoneNoneNoneNoneNone
      Ethan M. BalkTufts Center for Clinical Evidence Synthesis, Institute for Clinical Research and Health Policy Studies–Associate Professor of MedicineNoneNoneNoneNoneNoneNone
      Sandeep DasUT Southwestern Medical Center–Associate ProfessorNoneNoneNoneNoneNoneNone
      Jonathan HsuUniversity of California San Diego–Assistant ProfessorNoneNoneNoneNoneNoneNone
      José A. Joglar

      (SVT Guideline Vice Chair)
      UT Southwestern Medical Center–Professor of Internal Medicine; Program Director, Clinical Cardiac ElectrophysiologyNoneNoneNoneNoneNoneNone
      Richard L. Page

      (SVT Guideline Chair)
      University of Wisconsin School of Medicine and Public Health–Chair, Department of MedicineNoneNoneNoneNoneNoneNone
      This table represents the relationships of Evidence Review Committee members with industry and other entities that were determined to be relevant to this document. These relationships were reviewed and updated in conjunction with all conference calls of the committee during the evidence review process. The table does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interest represents ownership of ≥5% of the voting stock or share of the business entity, or ownership of ≥$5,000 of the fair market value of the business entity; or if funds received by the person from the business entity exceed 5% of the person’s gross income for the previous year. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted.
      ACC indicates American College of Cardiology; AHA, American Heart Association; HRS, Heart Rhythm Society; SVT, supraventricular tachycardia; and UT, University of Texas.
      low asterisk For transparency, the ERC members’ comprehensive disclosure information is available as an online supplement.

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