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Catheter ablation of atrial fibrillation with heart failure: An updated meta-analysis of randomized trials
Accepted Manuscript Catheter ablation of atrial fibrillation with heart failure: An updated meta-analysis of randomized trials
Babikir Kheiri, Mohammed Osman, Ahmed Abdalla, Tarek Haykal, Sahar Ahmed, Ghassan Bachuwa, Mustafa Hassan, Deepak L. Bhatt PII: DOI: Reference:
S0167-5273(18)32169-7 doi:10.1016/j.ijcard.2018.07.024 IJCA 26691
To appear in:
International Journal of Cardiology
Received date: Revised date: Accepted date:
2 April 2018 5 June 2018 3 July 2018
Please cite this article as: Babikir Kheiri, Mohammed Osman, Ahmed Abdalla, Tarek Haykal, Sahar Ahmed, Ghassan Bachuwa, Mustafa Hassan, Deepak L. Bhatt , Catheter ablation of atrial fibrillation with heart failure: An updated meta-analysis of randomized trials. Ijca (2018), doi:10.1016/j.ijcard.2018.07.024
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ACCEPTED MANUSCRIPT Catheter ablation of atrial fibrillation with heart failure: an updated meta-analysis of randomized trials Babikir Kheiri MDa,1, Mohammed Osman MDa,1, Ahmed Abdalla MDa,1, Tarek Haykal MDa,1, Sahar Ahmed MBBSa,1, Ghassan Bachuwa MDa,1, Mustafa Hassan MDa,1, Deepak L. Bhatt MD,
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Department of Internal Medicine, Hurley Medical Center/Michigan State University, Flint, MI
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a
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MPHb,1,*.
48503.
Brigham and Women’s Hospital Heart & Vascular Center, Harvard Medical School, Boston,
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b
1
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MA 02115.
This author takes responsibility for all aspects of the reliability and freedom from bias of the
Corresponding author:
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Deepak L. Bhatt, MD, MPH
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data presented and their discussed interpretation.
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Brigham and Women’s Hospital Heart & Vascular Center Harvard Medical School
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75 Francis Street
Boston, MA 02115, USA Tel: +1 (857) 307-1992 E-mail: [email protected] Acknowledgment of grant support None
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ACCEPTED MANUSCRIPT Conflicts of interest: Dr. Mustafa Hassan has received a research grant from Abbott. Dr. Deepak L. Bhatt discloses the following relationships - Advisory Board: Cardax, Elsevier
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Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; Board of Directors:
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Boston VA Research Institute, Society of Cardiovascular Patient Care; Chair: American Heart
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Association Quality Oversight Committee; Data Monitoring Committees: Cleveland Clinic, Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Mount Sinai
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School of Medicine, Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC
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Accreditation Committee), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke
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Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research
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Institute (clinical trial steering committee), HMP Communications (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate
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Editor), Population Health Research Institute (clinical trial steering committee), Slack
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Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical
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Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, St. Jude Medical
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ACCEPTED MANUSCRIPT (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, PLx Pharma, Takeda. The remaining authors report no relationships that could be construed as a conflict of interest. atrial fibrillation; catheter ablation; heart failure; systolic dysfunction; meta-
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Keywords:
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analysis.
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ACCEPTED MANUSCRIPT Abstract: Introduction: Atrial fibrillation (AF) and heart failure (HF) often coexist. We conducted this meta-analysis to assess the efficacy and safety of catheter ablation in this population.
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Methods: Electronic databases were searched for all randomized clinical trials (RCTs) that
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evaluated catheter ablation in patients with left ventricular systolic dysfunction (LVSD). We
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calculated the weighted mean differences (MDs) and risk ratios (RRs) using a random-effects model.
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Results: We included 7 RCTs with 851 patients (mean follow-up was 18 months). Catheter
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ablation in patients with LVSD was associated with significantly lower HF hospitalization rates (RR 0.57; 95% CI: 0.45–0.72; P<0.01), reduced all-cause mortality (RR 0.52; 95% CI: 0.35–
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0.76; P<0.01), improved left ventricular ejection fraction (MD 7.40; 95% CI: 3.37–11.43;
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P<0.01), increased 6-minute walk test (MD 26.96; 95% CI: 6.39–47.54; P=0.01), and improved peak oxygen consumption (VO2) (MD 3.17; 95% CI: 1.05-5.28; P<0.01; I2=0%), without
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significant increased risks of serious adverse events (RR 1.05; 95% CI: 0.96–1.16; P=0.30)
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compared with medical treatment.
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Conclusions: In this meta-analysis of RCTs, catheter ablation was associated with significant improvements in the clinical, structural, and functional capacity of patients with AF and coexisting HF compared with medical treatment. Keywords: atrial fibrillation; catheter ablation; heart failure; systolic dysfunction; metaanalysis.
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ACCEPTED MANUSCRIPT 1. Introduction: As a cause or a consequence, atrial fibrillation (AF) and heart failure (HF) often coexist. Studies have shown an increased risk of stroke, HF hospitalization, and all-cause mortality in patients with new-onset AF [1]. In a previous meta-analysis of 4 randomized clinical trials
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(RCTs) [2], catheter ablation in AF and HF was shown to be superior to rate-control in improving left ventricular ejection fraction (LVEF), functional capacity, and quality-of-life
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(QoL). Recently, 3 RCTs have been published with promising findings [3–5]. Hence, we
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conducted a comprehensive search of electronic databases for all RCTs to evaluate the efficacy and safety of catheter ablation in AF and coexisting HF with reduced ejection fraction (HFrEF).
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2. Methods:
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2.1. Data sources
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We registered our prespecified study protocol with PROSPERO (CRD42018088003). We conducted our meta-analysis according to the Preferred Reporting Items for Systematic Reviews
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and Meta-Analyses Protocols (PRISMA-P) Statement 2015 [6]. Two authors (BK, AA)
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independently performed a literature search of PubMed, Embase, and the Cochrane Collaboration Central Register of Controlled Trials from inception to February 2018 and any
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discrepancies were resolved by a third author (MO). 2.2. Selection criteria and data extraction We included only RCTs that evaluated catheter ablation in patients with left ventricular systolic dysfunction (LVSD). Three authors (BK, MO, TH) extracted the data independently and any discrepancies were resolved via a third author (AA). 2.3. Outcomes: 5
ACCEPTED MANUSCRIPT The outcomes were categorized as follows: clinical (HF hospitalization, all-cause mortality, serious adverse events), structural (LVEF improvement), functional capacity (6-minute walk test [6-MWT] and peak oxygen consumption [VO2]), and quality of life (36-item Short-Form Health Survey physical component scores [SF-36 PCS]) outcomes. Serious adverse events were defined
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as by each study (procedural-, ablation-, non- procedural major complications).
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2.4. Statistical Analysis
We calculated the weighted mean difference (MD) and 95% CI using the inverse variance
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(IV) method for continuous data. In addition, we calculated aggregated risk ratios (RRs) and 95% confidence intervals (CIs) using the Mantel-Haenszel method for dichotomous data. We
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used a random-effects model to account for the between-study heterogeneity and we measured
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the heterogeneity using I2 statistics. We used Review Manager (RevMan), version 5.3 Windows
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(Cochrane Collaboration, Oxford, UK) for analysis. Furthermore, subgroup analysis was conducted to evaluate the interaction of the AF type (paroxysmal vs persistent) and the absolute
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change in LVEF.
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3. Results:
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We included 7 RCTs [3–5,7–10] with 856 patients; 429 underwent catheter ablation and 427 were assigned for rate control and/or antiarrhythmic medications (AAD) or atrioventricular (AV) node ablation with biventricular pacing. Mean follow-up was 18 months. Online Figure 1 shows the study selection process. Clinical trials and baseline patient characteristics are shown in online Tables 1-2. All RCTs included patients with persistent AF. In addition, 2 trials also included patients with paroxysmal AF (n=160) [3,10]. Most trials (6) were multicenter [3–5,8–10]. The included clinical trials 6
ACCEPTED MANUSCRIPT compared catheter ablation with either rate control only (4 trials) [4,7–9], rate control and AAD (1 trial) [3], AAD only (1 trial) [5], and AV node ablation (1 trial) [10]. All patients assigned to catheter ablation underwent radiofrequency ablation. The average arrhythmia-free survival in the catheter ablation group ranged between 50% and 100%. The catheter ablation characteristics are
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shown in online Table 3. The results showed that catheter ablation in comparison with the control group was
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associated with significantly lower HF-hospitalization rates (17.7% versus 31.3%; RR 0.57; 95%
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CI: 0.45–0.72; P<0.01; I2 0%) and reduced all-cause mortality (8.1% versus 15.9%; RR 0.52; 95% CI: 0.35–0.76; P<0.01; I2 0%) without significantly increased risk of serious adverse events
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(49.5% versus 47.1%; RR 1.05; 95% CI: 0.96–1.16; P=0.30; I2 0%) (Figure 1). Furthermore, ablation was associated with improved LVEF (MD 7.40; 95% CI: 3.37–11.43; P<0.01; I2 86%),
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increased 6-MWT (MD 26.96; 95% CI: 6.39–47.54; P=0.01; I2 45%), and improved peak VO2
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(MD 3.17; 95% CI: 1.05-5.28; P<0.01; I2=0%). Although nonsignificant, ablation was associated
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with higher SF-36 PCS (MD 3.35; 95% CI: -0.26–6.95; P=0.07; I2 8%) (Figure 2).
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Subgroup analysis to evaluate the heterogeneity of the absolute LVEF changes based on the type of AF showed a significant interaction (P=0.03) (online Table 4).
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4. Discussion:
In this meta-analysis of all RCTs, catheter ablation was associated with significant improvements in the clinical, structural, functional, and quality of life (QOL) outcomes in patients with AF and coexisting HF compared with medical treatment. We should note that the high heterogeneity among the clinical outcomes is likely attributed to several factors, including the differences in measuring LVEF (echocardiogram versus cardiac magnetic resonance),
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ACCEPTED MANUSCRIPT subjective nature of the SF-36 questionnaire, varied ablation strategies, multiple treatment modalities among the control groups, and different follow-up durations. Nevertheless, our results are consistent with the current expert consensus recommendations regarding catheter ablation of AF as a safe, effective, and clinically acceptable therapeutic option in patients with HF and
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reduced cardiac function [11]. In recent analyses of the PARADIGM-HF (Prospective
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comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in
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Heart Failure) and ATMOSPHERE (Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure) trials [12,13], patients with paroxysmal AF were found to have a greater risk of
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HF hospitalization and stroke [1]. Furthermore, new-onset AF was associated with increased
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risks of cardiovascular death, HF hospitalization, and stroke. The underlying cause of reduced LVEF in the context of AF has been postulated to be the rapid ventricular rate, so-called
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“tachycardia-mediated cardiomyopathy.” However, LVEF improvement was found to be modest
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in this situation, despite adequate rate control. These findings support the role of other mechanisms of AF-driven reduced LVEF which can be related to loss of atrial contraction,
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irregular ventricular activity, neurohormonal activation, and pro-fibrotic pathways [4].
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Therefore, an “arrhythmia-mediated cardiomyopathy” has been suggested to describe ventricular
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systolic dysfunction attributable to AF. In our analysis, we found a significant improvement of 7.40% in the LVEF with catheter ablation. However, there was high heterogeneity among the included studies (I2=86%). This finding could be explained by the fact that some of the included trials used different cardiac imaging modalities such as cardiac magnetic resonance (CMR) to assess LVEF. Nevertheless, it is well known that visual estimation of the LVEF is observer-dependent and thus variation in the
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ACCEPTED MANUSCRIPT estimates could have affected our results [14]. A sensitivity analysis by excluding each RCT sequentially did not change the significant results of the summary estimate. To evaluate the heterogeneity of the absolute change in LVEF, we conducted a subgroup analysis based on the type of AF. The result showed a significant interaction between persistent
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and paroxysmal AF (MD 7.2 vs 1.0), which implies that patients with persistent AF are more likely to have a greater benefit from catheter ablation than those with paroxysmal AF. However,
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the current expert consensus document recommends catheter ablation of AF in patients with HF
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without specification of AF types [11]. In both the AF-CHF (Atrial Fibrillation and Congestive Heart Failure) and the DIAMOND-CHF (Danish Investigators of Arrhythmia and Mortality on
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Dofetilide in Congestive Heart Failure) trials [15,16], antiarrhythmic drugs were not associated
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with lower mortality in AF patients with coexisting HF despite a lower burden of AF compared with rate control. In contrast, in our meta-analysis, we found that catheter ablation in this
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situation was associated with significant reduction of all-cause mortality compared with drug
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therapy (8.1% versus 15.9%; P<0.01). This finding supports the beneficial strategy of sinus
population.
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rhythm maintenance with catheter ablation instead of antiarrhythmic medication use alone in this
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In patients with HF, the change in the 6-MWT after an intervention has been established as an independent survival predictor [17]. Our results showed a significant improvement of 26.96 meters in the 6-MWT compared with medical treatment (P=0.01). The high heterogeneity of the 6-MWT in our result (I2=45%) could be explained by the inherent variability between and within individuals in performing the test, which could be influenced by various physiological (e.g., walking style) and psychological (e.g., encouragement) factors. However, we found no heterogeneity in the peak oxygen consumption (VO2) (I2=0%) when assessing functional 9
ACCEPTED MANUSCRIPT capacity with more objective cardiopulmonary exercise testing, yet significant improvements favoring the catheter ablation group were obtained (MD +3.17 mL/kg/minute). Despite the well-known associated complications of AF catheter ablation such as bleeding, stroke, pericardial tamponade, and even death [2], our results did not show a significant increase
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in serious adverse events compared with medical management (49.5% versus 47.1%; P=0.30) in
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the skilled centers participating in these randomized trials.
Future adequately powered trials should incorporate more reliable and accurate imaging
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techniques for assessing LV volumes and function, such as three-dimensional speckle tracking echocardiography [18]. In addition, trials are needed to examine the clinical, structural,
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functional, and QOL outcomes of catheter ablation in AF with HF in patients with paroxysmal
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AF and those not well represented in clinical trials, such as older (≥75) and young (<45) patients.
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In conclusion, our updated meta-analysis supports the growing evidence of the superiority of catheter ablation in improving the structural (LVEF) and functional capacity as well as the QoL
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of patients with AF and coexisting HF, with no apparent significant increase in the risk of
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complications in carefully selected patients. However, further adequately powered, shamcontrolled trials with a consistent ablation strategy, especially at earlier disease stages, and with a
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standardized control group are warranted. We hope the ongoing CATCH-AF (Catheter Ablation vs Medical Therapy in Congested Hearts with AF; ID-NCT02686749) trial may shed some light on the use of ablation in HF at earlier stages. Acknowledgment We would like to thank Katherine Negele, editorial assistant, research department, Hurley Medical Center, for assistance with manuscript editing. 10
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ACCEPTED MANUSCRIPT echocardiography, Eur Hear. J Cardiovasc Imaging. 13 (2012) 159–168. Figure legends: Figure 1. Forest plot of the clinical outcomes.
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Abbreviations: AATAC: Ablation Versus Amiodarone for Treatment of Persistent Atrial
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Fibrillation in Patients With Congestive Heart Failure and an Implanted Device; ARC-HF: A Randomized Trial to Assess Catheter Ablation Versus Rate Control in the Management of
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Persistent Atrial Fibrillation in Chronic Heart Failure; CAMERA-MRI: Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction; CAMTAF: Catheter
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Ablation Versus Medical Treatment of Atrial Fibrillation in Heart Failure; CASTLE-AF: Catheter Ablation vs. Standard Conventional Treatment in Patients With LV Dysfunction and
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AF; CI: confidence interval; IV: inverse variance; PABA-CHF: Pulmonary Vein Antrum Isolation versus AV Node Ablation with Bi-Ventricular Pacing for Treatment of Atrial
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Fibrillation in Patients with Congestive Heart Failure study; SD: standard deviation.
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Figure 2. Forest plot of the structural (A), functional capacity (B-C), and quality of life outcomes (D).
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Abbreviations: AATAC: Ablation Versus Amiodarone for Treatment of Persistent Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted Device; ARC-HF: A
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Randomized Trial to Assess Catheter Ablation Versus Rate Control in the Management of Persistent Atrial Fibrillation in Chronic Heart Failure; CAMERA-MRI: Catheter Ablation Versus
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Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction; CAMTAF: Catheter Ablation Versus Medical Treatment of Atrial Fibrillation in Heart Failure; CASTLE-AF: Catheter Ablation vs. Standard Conventional Treatment in Patients With LV Dysfunction and AF; CI: confidence interval; IV: inverse variance; PABA-CHF: Pulmonary Vein Antrum Isolation versus AV Node Ablation with Bi-Ventricular Pacing for Treatment of Atrial Fibrillation in Patients with Congestive Heart Failure study; SD: standard deviation.
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ACCEPTED MANUSCRIPT Highlights: Catheter ablation was associated with lower heart failure hospitalization rates.
Improved left ventricular ejection fraction was observed with catheter ablation.
Catheter ablation was associated with improved 6-minute walk test.
No increased serious adverse events were observed with catheter ablation.
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Babikir Kheiri, Mohammed Osman, Ahmed Abdalla, Tarek Haykal, Sahar Ahmed, Ghassan Bachuwa, Mustafa Hassan, Deepak L. Bhatt PII: DOI: Reference:
S0167-5273(18)32169-7 doi:10.1016/j.ijcard.2018.07.024 IJCA 26691
To appear in:
International Journal of Cardiology
Received date: Revised date: Accepted date:
2 April 2018 5 June 2018 3 July 2018
Please cite this article as: Babikir Kheiri, Mohammed Osman, Ahmed Abdalla, Tarek Haykal, Sahar Ahmed, Ghassan Bachuwa, Mustafa Hassan, Deepak L. Bhatt , Catheter ablation of atrial fibrillation with heart failure: An updated meta-analysis of randomized trials. Ijca (2018), doi:10.1016/j.ijcard.2018.07.024
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Catheter ablation of atrial fibrillation with heart failure: an updated meta-analysis of randomized trials Babikir Kheiri MDa,1, Mohammed Osman MDa,1, Ahmed Abdalla MDa,1, Tarek Haykal MDa,1, Sahar Ahmed MBBSa,1, Ghassan Bachuwa MDa,1, Mustafa Hassan MDa,1, Deepak L. Bhatt MD,
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Department of Internal Medicine, Hurley Medical Center/Michigan State University, Flint, MI
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a
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MPHb,1,*.
48503.
Brigham and Women’s Hospital Heart & Vascular Center, Harvard Medical School, Boston,
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b
1
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MA 02115.
This author takes responsibility for all aspects of the reliability and freedom from bias of the
Corresponding author:
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Deepak L. Bhatt, MD, MPH
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data presented and their discussed interpretation.
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Brigham and Women’s Hospital Heart & Vascular Center Harvard Medical School
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75 Francis Street
Boston, MA 02115, USA Tel: +1 (857) 307-1992 E-mail: [email protected] Acknowledgment of grant support None
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ACCEPTED MANUSCRIPT Conflicts of interest: Dr. Mustafa Hassan has received a research grant from Abbott. Dr. Deepak L. Bhatt discloses the following relationships - Advisory Board: Cardax, Elsevier
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Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; Board of Directors:
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Boston VA Research Institute, Society of Cardiovascular Patient Care; Chair: American Heart
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Association Quality Oversight Committee; Data Monitoring Committees: Cleveland Clinic, Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Mount Sinai
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School of Medicine, Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC
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Accreditation Committee), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke
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Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research
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Institute (clinical trial steering committee), HMP Communications (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate
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Editor), Population Health Research Institute (clinical trial steering committee), Slack
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Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical
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Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, St. Jude Medical
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ACCEPTED MANUSCRIPT (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, PLx Pharma, Takeda. The remaining authors report no relationships that could be construed as a conflict of interest. atrial fibrillation; catheter ablation; heart failure; systolic dysfunction; meta-
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Keywords:
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analysis.
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ACCEPTED MANUSCRIPT Abstract: Introduction: Atrial fibrillation (AF) and heart failure (HF) often coexist. We conducted this meta-analysis to assess the efficacy and safety of catheter ablation in this population.
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Methods: Electronic databases were searched for all randomized clinical trials (RCTs) that
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evaluated catheter ablation in patients with left ventricular systolic dysfunction (LVSD). We
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calculated the weighted mean differences (MDs) and risk ratios (RRs) using a random-effects model.
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Results: We included 7 RCTs with 851 patients (mean follow-up was 18 months). Catheter
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ablation in patients with LVSD was associated with significantly lower HF hospitalization rates (RR 0.57; 95% CI: 0.45–0.72; P<0.01), reduced all-cause mortality (RR 0.52; 95% CI: 0.35–
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0.76; P<0.01), improved left ventricular ejection fraction (MD 7.40; 95% CI: 3.37–11.43;
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P<0.01), increased 6-minute walk test (MD 26.96; 95% CI: 6.39–47.54; P=0.01), and improved peak oxygen consumption (VO2) (MD 3.17; 95% CI: 1.05-5.28; P<0.01; I2=0%), without
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significant increased risks of serious adverse events (RR 1.05; 95% CI: 0.96–1.16; P=0.30)
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compared with medical treatment.
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Conclusions: In this meta-analysis of RCTs, catheter ablation was associated with significant improvements in the clinical, structural, and functional capacity of patients with AF and coexisting HF compared with medical treatment. Keywords: atrial fibrillation; catheter ablation; heart failure; systolic dysfunction; metaanalysis.
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ACCEPTED MANUSCRIPT 1. Introduction: As a cause or a consequence, atrial fibrillation (AF) and heart failure (HF) often coexist. Studies have shown an increased risk of stroke, HF hospitalization, and all-cause mortality in patients with new-onset AF [1]. In a previous meta-analysis of 4 randomized clinical trials
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(RCTs) [2], catheter ablation in AF and HF was shown to be superior to rate-control in improving left ventricular ejection fraction (LVEF), functional capacity, and quality-of-life
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(QoL). Recently, 3 RCTs have been published with promising findings [3–5]. Hence, we
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conducted a comprehensive search of electronic databases for all RCTs to evaluate the efficacy and safety of catheter ablation in AF and coexisting HF with reduced ejection fraction (HFrEF).
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2. Methods:
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2.1. Data sources
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We registered our prespecified study protocol with PROSPERO (CRD42018088003). We conducted our meta-analysis according to the Preferred Reporting Items for Systematic Reviews
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and Meta-Analyses Protocols (PRISMA-P) Statement 2015 [6]. Two authors (BK, AA)
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independently performed a literature search of PubMed, Embase, and the Cochrane Collaboration Central Register of Controlled Trials from inception to February 2018 and any
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discrepancies were resolved by a third author (MO). 2.2. Selection criteria and data extraction We included only RCTs that evaluated catheter ablation in patients with left ventricular systolic dysfunction (LVSD). Three authors (BK, MO, TH) extracted the data independently and any discrepancies were resolved via a third author (AA). 2.3. Outcomes: 5
ACCEPTED MANUSCRIPT The outcomes were categorized as follows: clinical (HF hospitalization, all-cause mortality, serious adverse events), structural (LVEF improvement), functional capacity (6-minute walk test [6-MWT] and peak oxygen consumption [VO2]), and quality of life (36-item Short-Form Health Survey physical component scores [SF-36 PCS]) outcomes. Serious adverse events were defined
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as by each study (procedural-, ablation-, non- procedural major complications).
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2.4. Statistical Analysis
We calculated the weighted mean difference (MD) and 95% CI using the inverse variance
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(IV) method for continuous data. In addition, we calculated aggregated risk ratios (RRs) and 95% confidence intervals (CIs) using the Mantel-Haenszel method for dichotomous data. We
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used a random-effects model to account for the between-study heterogeneity and we measured
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the heterogeneity using I2 statistics. We used Review Manager (RevMan), version 5.3 Windows
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(Cochrane Collaboration, Oxford, UK) for analysis. Furthermore, subgroup analysis was conducted to evaluate the interaction of the AF type (paroxysmal vs persistent) and the absolute
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change in LVEF.
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3. Results:
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We included 7 RCTs [3–5,7–10] with 856 patients; 429 underwent catheter ablation and 427 were assigned for rate control and/or antiarrhythmic medications (AAD) or atrioventricular (AV) node ablation with biventricular pacing. Mean follow-up was 18 months. Online Figure 1 shows the study selection process. Clinical trials and baseline patient characteristics are shown in online Tables 1-2. All RCTs included patients with persistent AF. In addition, 2 trials also included patients with paroxysmal AF (n=160) [3,10]. Most trials (6) were multicenter [3–5,8–10]. The included clinical trials 6
ACCEPTED MANUSCRIPT compared catheter ablation with either rate control only (4 trials) [4,7–9], rate control and AAD (1 trial) [3], AAD only (1 trial) [5], and AV node ablation (1 trial) [10]. All patients assigned to catheter ablation underwent radiofrequency ablation. The average arrhythmia-free survival in the catheter ablation group ranged between 50% and 100%. The catheter ablation characteristics are
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shown in online Table 3. The results showed that catheter ablation in comparison with the control group was
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associated with significantly lower HF-hospitalization rates (17.7% versus 31.3%; RR 0.57; 95%
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CI: 0.45–0.72; P<0.01; I2 0%) and reduced all-cause mortality (8.1% versus 15.9%; RR 0.52; 95% CI: 0.35–0.76; P<0.01; I2 0%) without significantly increased risk of serious adverse events
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(49.5% versus 47.1%; RR 1.05; 95% CI: 0.96–1.16; P=0.30; I2 0%) (Figure 1). Furthermore, ablation was associated with improved LVEF (MD 7.40; 95% CI: 3.37–11.43; P<0.01; I2 86%),
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increased 6-MWT (MD 26.96; 95% CI: 6.39–47.54; P=0.01; I2 45%), and improved peak VO2
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(MD 3.17; 95% CI: 1.05-5.28; P<0.01; I2=0%). Although nonsignificant, ablation was associated
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with higher SF-36 PCS (MD 3.35; 95% CI: -0.26–6.95; P=0.07; I2 8%) (Figure 2).
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Subgroup analysis to evaluate the heterogeneity of the absolute LVEF changes based on the type of AF showed a significant interaction (P=0.03) (online Table 4).
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4. Discussion:
In this meta-analysis of all RCTs, catheter ablation was associated with significant improvements in the clinical, structural, functional, and quality of life (QOL) outcomes in patients with AF and coexisting HF compared with medical treatment. We should note that the high heterogeneity among the clinical outcomes is likely attributed to several factors, including the differences in measuring LVEF (echocardiogram versus cardiac magnetic resonance),
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ACCEPTED MANUSCRIPT subjective nature of the SF-36 questionnaire, varied ablation strategies, multiple treatment modalities among the control groups, and different follow-up durations. Nevertheless, our results are consistent with the current expert consensus recommendations regarding catheter ablation of AF as a safe, effective, and clinically acceptable therapeutic option in patients with HF and
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reduced cardiac function [11]. In recent analyses of the PARADIGM-HF (Prospective
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comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in
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Heart Failure) and ATMOSPHERE (Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure) trials [12,13], patients with paroxysmal AF were found to have a greater risk of
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HF hospitalization and stroke [1]. Furthermore, new-onset AF was associated with increased
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risks of cardiovascular death, HF hospitalization, and stroke. The underlying cause of reduced LVEF in the context of AF has been postulated to be the rapid ventricular rate, so-called
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“tachycardia-mediated cardiomyopathy.” However, LVEF improvement was found to be modest
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in this situation, despite adequate rate control. These findings support the role of other mechanisms of AF-driven reduced LVEF which can be related to loss of atrial contraction,
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irregular ventricular activity, neurohormonal activation, and pro-fibrotic pathways [4].
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Therefore, an “arrhythmia-mediated cardiomyopathy” has been suggested to describe ventricular
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systolic dysfunction attributable to AF. In our analysis, we found a significant improvement of 7.40% in the LVEF with catheter ablation. However, there was high heterogeneity among the included studies (I2=86%). This finding could be explained by the fact that some of the included trials used different cardiac imaging modalities such as cardiac magnetic resonance (CMR) to assess LVEF. Nevertheless, it is well known that visual estimation of the LVEF is observer-dependent and thus variation in the
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ACCEPTED MANUSCRIPT estimates could have affected our results [14]. A sensitivity analysis by excluding each RCT sequentially did not change the significant results of the summary estimate. To evaluate the heterogeneity of the absolute change in LVEF, we conducted a subgroup analysis based on the type of AF. The result showed a significant interaction between persistent
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and paroxysmal AF (MD 7.2 vs 1.0), which implies that patients with persistent AF are more likely to have a greater benefit from catheter ablation than those with paroxysmal AF. However,
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the current expert consensus document recommends catheter ablation of AF in patients with HF
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without specification of AF types [11]. In both the AF-CHF (Atrial Fibrillation and Congestive Heart Failure) and the DIAMOND-CHF (Danish Investigators of Arrhythmia and Mortality on
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Dofetilide in Congestive Heart Failure) trials [15,16], antiarrhythmic drugs were not associated
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with lower mortality in AF patients with coexisting HF despite a lower burden of AF compared with rate control. In contrast, in our meta-analysis, we found that catheter ablation in this
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situation was associated with significant reduction of all-cause mortality compared with drug
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therapy (8.1% versus 15.9%; P<0.01). This finding supports the beneficial strategy of sinus
population.
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rhythm maintenance with catheter ablation instead of antiarrhythmic medication use alone in this
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In patients with HF, the change in the 6-MWT after an intervention has been established as an independent survival predictor [17]. Our results showed a significant improvement of 26.96 meters in the 6-MWT compared with medical treatment (P=0.01). The high heterogeneity of the 6-MWT in our result (I2=45%) could be explained by the inherent variability between and within individuals in performing the test, which could be influenced by various physiological (e.g., walking style) and psychological (e.g., encouragement) factors. However, we found no heterogeneity in the peak oxygen consumption (VO2) (I2=0%) when assessing functional 9
ACCEPTED MANUSCRIPT capacity with more objective cardiopulmonary exercise testing, yet significant improvements favoring the catheter ablation group were obtained (MD +3.17 mL/kg/minute). Despite the well-known associated complications of AF catheter ablation such as bleeding, stroke, pericardial tamponade, and even death [2], our results did not show a significant increase
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in serious adverse events compared with medical management (49.5% versus 47.1%; P=0.30) in
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the skilled centers participating in these randomized trials.
Future adequately powered trials should incorporate more reliable and accurate imaging
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techniques for assessing LV volumes and function, such as three-dimensional speckle tracking echocardiography [18]. In addition, trials are needed to examine the clinical, structural,
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functional, and QOL outcomes of catheter ablation in AF with HF in patients with paroxysmal
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AF and those not well represented in clinical trials, such as older (≥75) and young (<45) patients.
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In conclusion, our updated meta-analysis supports the growing evidence of the superiority of catheter ablation in improving the structural (LVEF) and functional capacity as well as the QoL
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of patients with AF and coexisting HF, with no apparent significant increase in the risk of
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complications in carefully selected patients. However, further adequately powered, shamcontrolled trials with a consistent ablation strategy, especially at earlier disease stages, and with a
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standardized control group are warranted. We hope the ongoing CATCH-AF (Catheter Ablation vs Medical Therapy in Congested Hearts with AF; ID-NCT02686749) trial may shed some light on the use of ablation in HF at earlier stages. Acknowledgment We would like to thank Katherine Negele, editorial assistant, research department, Hurley Medical Center, for assistance with manuscript editing. 10
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ACCEPTED MANUSCRIPT echocardiography, Eur Hear. J Cardiovasc Imaging. 13 (2012) 159–168. Figure legends: Figure 1. Forest plot of the clinical outcomes.
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Abbreviations: AATAC: Ablation Versus Amiodarone for Treatment of Persistent Atrial
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Fibrillation in Patients With Congestive Heart Failure and an Implanted Device; ARC-HF: A Randomized Trial to Assess Catheter Ablation Versus Rate Control in the Management of
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Persistent Atrial Fibrillation in Chronic Heart Failure; CAMERA-MRI: Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction; CAMTAF: Catheter
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Ablation Versus Medical Treatment of Atrial Fibrillation in Heart Failure; CASTLE-AF: Catheter Ablation vs. Standard Conventional Treatment in Patients With LV Dysfunction and
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AF; CI: confidence interval; IV: inverse variance; PABA-CHF: Pulmonary Vein Antrum Isolation versus AV Node Ablation with Bi-Ventricular Pacing for Treatment of Atrial
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Fibrillation in Patients with Congestive Heart Failure study; SD: standard deviation.
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Figure 2. Forest plot of the structural (A), functional capacity (B-C), and quality of life outcomes (D).
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Abbreviations: AATAC: Ablation Versus Amiodarone for Treatment of Persistent Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted Device; ARC-HF: A
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Randomized Trial to Assess Catheter Ablation Versus Rate Control in the Management of Persistent Atrial Fibrillation in Chronic Heart Failure; CAMERA-MRI: Catheter Ablation Versus
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Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction; CAMTAF: Catheter Ablation Versus Medical Treatment of Atrial Fibrillation in Heart Failure; CASTLE-AF: Catheter Ablation vs. Standard Conventional Treatment in Patients With LV Dysfunction and AF; CI: confidence interval; IV: inverse variance; PABA-CHF: Pulmonary Vein Antrum Isolation versus AV Node Ablation with Bi-Ventricular Pacing for Treatment of Atrial Fibrillation in Patients with Congestive Heart Failure study; SD: standard deviation.
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ACCEPTED MANUSCRIPT Highlights: Catheter ablation was associated with lower heart failure hospitalization rates.
Improved left ventricular ejection fraction was observed with catheter ablation.
Catheter ablation was associated with improved 6-minute walk test.
No increased serious adverse events were observed with catheter ablation.
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Figure 1
Figure 2