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
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=1594). 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.
- AHA Scientific Statements
- accessory atrioventricular bundle
- cardiac arrhythmias
- pre-excitation syndromes
- risk assessment
- sudden cardiac death
- Wolff–Parkinson-White Syndrome
Table of Contents
Search Strategy e577
Eligibility Criteria e579
Methods of Review e579
Statistical Analysis e582
Study and Patient Characteristics e582
Study Results e582
Evidence Synthesis e584
Quality of Included Studies e584
Tables and Figures
Author Relationships With Industry and Other Entities (Relevant) e586
Electrocardiographic pre-excitation affects about 0.1% to 0.3% of the general population.1 When pre-excitation is accompanied by symptoms such as syncope or palpitations, the diagnosis of Wolff-Parkinson-White (WPW) syndrome is established.2 Patients with WPW syndrome have an increased risk of sudden cardiac death (SCD) that may approach 4% over a lifetime.3 Therefore, risk stratification of these symptomatic patients, particularly with an electrophysiological (EP) study, and catheter ablation of the accessory pathway are recommended4; 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.5 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.4 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 patients6 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.4 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.4
On the basis of the “ACC/AHA Clinical Practice Guideline Methodology Summit Report”,7 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”.8
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):
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?;
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?;
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?
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 statement9 and with the recommendations of the “ACC/AHA Clinical Practice Guideline Methodology Summit Report”.7
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.10–12
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.7 To evaluate risk of bias, the Cochrane Collaboration Risk of Bias Tool was used for RCTs,13 and the Newcastle-Ottawa Scale was used for cohort studies.14 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.
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 (ie, 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.
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.15 A search of the bibliography of this article15 resulted in 1 additional paper16 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 patients17—and 8 were uncontrolled prospective observational cohort studies.15, 16, 18–23 These 9 studies contributed data from 1818 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.17–23 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.15–23 The RCT17 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,17–20,22,23 and in studies reporting a median age, the range was 19 to 36 years.15–17 The majority of patients were male (range 50% to 74%). Structural heart disease was reported to be present in a minority of patients (<10%).15,17,18,20,21,23 Intermittent pre-excitation was an exclusion criterion in 1 study20 and was reported to be present in 23% of patients in another study.23 The remaining studies did not report on whether pre-excitation was intermittent or persistent.
Study comparators and outcomes are presented in Table 2. In the 2003 RCT component of the dual-design study by Pappone et al,17 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.17 In the associated observational cohort, symptoms of SVT developed in 6 (4%) of 148 patients.17
In the 1986 study by Milstein et al,22 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,19 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,23 no events occurred during a mean follow-up of 15 months.
In the 1990 study by Leitch et al,20 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,18 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,21 129 (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,16 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,15 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,17 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,15 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.
Because 4 15–17, 21 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.15 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).17 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,15, 18–20,23 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 al18 and 2 in Pappone et al, 200321/Pappone et al, 201415), were all children (n=11, all in Pappone et al, 201415). None of the patients who died suddenly had undergone accessory-pathway ablation. In 2 studies,20,22 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.15–23 The degree to which the enrolled population was representative of patients seen in clinical practice was questionable in 5 studies.15–17, 20, 21 The RCT by Pappone et al17 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.15,16,18–23
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.15 Importantly, malignant arrhythmias correlated more with the EP properties of the accessory pathway than with the presence or absence of symptoms.15 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 2169 patients.15
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.17 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 al15 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-up15; 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 al15 provided detailed information on complications in 1168 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.
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 study15–17,21 made it impossible to examine collective data from all available studies, so the most recent and inclusive study from that group was used.15 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 US 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.24 Given the highly selected study population, however, excluding this study likely did not have a major effect on our findings.
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
↵* These members of the Evidence Review Committee are listed alphabetically, and all participated equally in the process.
†Former Task Force member; current member during this writing effort.
This document was approved by the American College of Cardiology Board of Trustees and Executive Committee, the American Heart Association Science Advisory and Coordinating Committee, and the Heart Rhythm Society Board of Trustees in August 2015 and the American Heart Association Executive Committee in September 2015.
The Executive Review Committee Comprehensive Relationships Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIR.0000000000000309/-/DC1.
The American Heart Association requests that this document be cited as follows: Al-Khatib SM, Arshad A, Balk EM, Das SR, Hsu JC, Joglar JA, Page RL. 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. Circulation. 2016;133:e575-e586. doi: 10.1161/CIR.0000000000000309.
This article is copublished in Journal of the American College of Cardiology and HeartRhythm Journal.
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