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What clinical trials of ablation for atrial fibrillation tell us – and what they do not

  • Ram Amuthan
    Affiliations
    Department of Medicine, Jacobs School of Medicine & Biomedical Sciences, University at Buffalo, Buffalo, New York
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  • Anne B. Curtis
    Correspondence
    Address reprint requests and correspondence: Dr Anne B. Curtis, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, 100 High St, D2-76, Buffalo, NY 14203.
    Affiliations
    Department of Medicine, Jacobs School of Medicine & Biomedical Sciences, University at Buffalo, Buffalo, New York
    Search for articles by this author
Open AccessPublished:February 15, 2021DOI:https://doi.org/10.1016/j.hroo.2021.02.001
      Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia in clinical practice. Radiofrequency and cryoballoon catheter ablation are therapeutic options in addition to antiarrhythmic drug therapy for the treatment of AF. Ablation is effective at reducing recurrent atrial arrhythmias and also in the reduction of AF burden. Besides arrhythmia control, improvement in quality of life and clinical outcomes are also desirable goals with AF treatment. Randomized clinical trials have evaluated ablation in several patient populations, including symptomatic patients as first-line or second-line therapy, asymptomatic patients, and patients with heart failure. These trials clarify the durability of ablation in arrhythmia control, clarify quality-of-life improvement, and identify patient populations in whom ablation may be expected to improve clinical outcomes. In this review, we summarize the major clinical trials involving ablation; discuss the strengths, weakness, and clinical implications of these trials; and highlight the knowledge gaps in our current understanding of AF ablation for future clinical studies.

      Graphical abstract

      Keywords

      Key Findings
      • Catheter ablation for atrial fibrillation (AF) is effective in preventing recurrences and reducing AF burden both as first-line and second-line therapy.
      • Ablation improves quality of life in patients with symptomatic AF.
      • Ablation may improve clinical outcomes in patients with recent-onset AF and cardiovascular comorbidities when offered as part of an early rhythm control strategy.
      • Ablation reduces AF burden and improves clinical outcomes and cardiac function in patients with heart failure and reduced ejection fraction.

      Introduction

      Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major source of morbidity and mortality. Antiarrhythmic drugs (AADs) can suppress or delay recurrences of AF, but their efficacy is less than optimal in many patients. Haïssaguerre and colleagues
      • Haïssaguerre M.
      • Jaïs P.
      • Shah D.C.
      • et al.
      Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins.
      first identified pulmonary veins to be the main trigger source for AF. Pulmonary vein isolation (PVI) using either radiofrequency or cryoballoon ablation has since emerged as a safe and effective treatment modality in patients with AF, although patients with more advanced stages of AF often require adjunctive lesions in addition to PVI. The primary goal of AF ablation is to decrease or eliminate recurrences of AF, particularly those that are symptomatic and adversely affect quality of life (QOL). An important additional goal is to improve adverse clinical outcomes in patients with AF.
      The purpose of this review is to summarize the results of the major clinical trials of AF ablation, examine what we have learned, and understand what questions remain unanswered. We discuss the definition of a successful procedure, options for monitoring of recurrences, the definition of AF burden and how to assess it, techniques used for ablation, complications, and expected success rates. We then review clinical trials that addressed ablation to prevent recurrences of AF after failure of medical therapy, ablation as the initial approach to treatment of AF, the effect of ablation on QOL, and the results of clinical trials that examined clinical outcomes after ablation. We consider the interrelationship between AF and heart failure (HF) and the effect of ablation on AF burden and heart function. Finally, we conclude with the major knowledge gaps in ablation of AF.

      Atrial fibrillation ablation: Approaches, efficacy, and safety

      It is critical to have a consistent definition of what constitutes a successful procedure after AF ablation in order to evaluate the results of clinical trials. The 2017 expert consensus statement on catheter and surgical ablation of AF identified freedom from any atrial arrhythmia, defined as AF, atrial flutter, or atrial tachycardia, lasting for more than 30 seconds off AAD therapy, as the gold standard for reporting the efficacy of AF ablation.
      • Calkins H.
      • Hindricks G.
      • Cappato R.
      • et al.
      2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation.
      Options for monitoring for recurrences of atrial arrhythmias after ablation include Holter monitors, longer-term monitoring such as 30-day event monitors, intermittent rhythm recording using devices such as the Apple Watch or Kardia Mobile, or insertable loop recorders (ILRs).
      • Jeremiah W.
      • Cindy Y.
      • Ruchi P.
      • Alexander V.
      • David A.
      • Rod P.
      Smartwatch performance for the detection and quantification of atrial fibrillation.
      • Ajijola O.A.
      • Boyle N.G.
      • Shivkumar K.
      Detecting and monitoring arrhythmia recurrence following catheter ablation of atrial fibrillation.
      • Goldenthal I.L.
      • Sciacca R.R.
      • Riga T.
      • et al.
      Recurrent atrial fibrillation/flutter detection after ablation or cardioversion using the AliveCor KardiaMobile device: iHEART results.
      It is well recognized that symptoms alone are not sufficient to determine freedom from AF, as many patients have been demonstrated to have asymptomatic episodes after ablation. Major clinical trials will generally use either more extended monitoring or ILRs to detect recurrences of atrial arrhythmias.
      AF burden is another measure of the success of ablation, and it is defined as the total time in AF compared to the total duration of the monitoring period. It can be determined by continuous monitoring with an ILR or by an implanted cardiac device such as a pacemaker or an implantable cardioverter-defibrillator (ICD). AF burden is also recognized as an endpoint to assess the efficacy of ablation.
      The foundation of AF ablation is isolation of the pulmonary veins. Point-by-point radiofrequency energy delivered via transvenous electrodes and circumferential cryoenergy lesions delivered by balloon-based systems are the most common sources of energy utilized to achieve PVI. Both techniques have a similar efficacy and safety profile.
      • Kuck K.-H.
      • Brugada J.
      • Fürnkranz A.
      • et al.
      Cryoballoon or radiofrequency ablation for paroxysmal atrial fibrillation.
      Other energy sources that have been studied, but with limited clinical use, include a laser balloon ablation system, hot balloon ablation system using radiofrequency energy, and low-intensity collimated ultrasound ablation.
      AF ablation is a complex electrophysiological procedure which can lead to life threatening complications. In-hospital mortality following ablation varies between 0.6 and 4 per 1000 patients.
      • Aakriti G.
      • Tharani P.
      • Anand G.
      • et al.
      Complications of catheter ablation of atrial fibrillation.
      ,
      • Abhishek D.
      • Patel N.J.
      • Pant S.
      • et al.
      In-hospital complications associated with catheter ablation of atrial fibrillation in the United States between 2000 and 2010.
      Cardiac tamponade is the most frequent serious complication leading to death, while vascular complications are the most common adverse effect related to the procedure. Other complications include pulmonary vein stenosis, catheter entrapment, periprocedural embolic events, phrenic nerve injury, atrioesophageal fistula, vagal nerve injury, acute coronary artery injury, and pericarditis.
      PVI is sufficient to eliminate AF in approximately 60%–70% of patients with paroxysmal AF at 12–18 months of follow-up with a single procedure and after a 3-month blanking period.
      • Calkins H.
      • Hindricks G.
      • Cappato R.
      • et al.
      2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation.
      ,
      • Kuck K.-H.
      • Brugada J.
      • Fürnkranz A.
      • et al.
      Cryoballoon or radiofrequency ablation for paroxysmal atrial fibrillation.
      The success rate increases after repeat procedures, or with the addition of AADs, some of which may have previously been unsuccessful in controlling the arrhythmia. When repeat procedures are necessary, techniques such as left atrial roof lines, ablation of fractionated atrial electrograms, isolation of the left atrial appendage, and others are used, in addition to isolation of pulmonary veins that have reconnected. Success rates are lower in patients with enlarged atria or with HF with a reduced ejection fraction. Ablation is also performed in patients with persistent AF or even longstanding (>1 year) persistent AF, but success rates are progressively lower, typically around 50% after a single procedure for persistent AF and well below 50% with longstanding persistent AF.
      • Clarnette J.A.
      • Brooks A.G.
      • Mahajan R.
      • et al.
      Outcomes of persistent and long-standing persistent atrial fibrillation ablation: a systematic review and meta-analysis.
      • Verma A.
      • Jiang C.
      • Betts T.R.
      • et al.
      Approaches to catheter ablation for persistent atrial fibrillation.
      • Vogler J.
      • Willems S.
      • Sultan A.
      • et al.
      Pulmonary vein isolation versus defragmentation: the CHASE-AF Clinical Trial.
      In addition to reducing or eliminating recurrences of AF, it is essential to know whether AF ablation is effective in improving important clinical outcomes such as QOL, HF, and mortality. Recent data help to clarify the role of AF ablation in improving hard clinical outcomes in several subgroups of patients and the durability of ablation in controlling the arrhythmia and improving QOL.

      Ablation to prevent recurrent atrial arrhythmias

      Table 1 lists major trials evaluating the efficacy of ablation in patients with AF who had failed therapy with at least 1 AAD. The trials used different techniques for ablation, various definitions for recurrent atrial arrhythmias, and several monitoring methods to detect recurrences. Ablation has been shown to be more effective than AADs in preventing recurrences in patients with both paroxysmal and persistent AF during a follow-up period of up to 1 year. A meta-analysis of these trials confirmed the efficacy of ablation in reducing the burden of recurrent atrial arrhythmias as a second-line therapy, with a 63% reduction in the risk of recurrence compared to drug therapy (risk ratio 0.37; 95% confidence interval [CI] 0.29–0.48; P < .00001).
      • Khan A.R.
      • Khan S.
      • Sheikh M.A.
      • Khuder S.
      • Grubb B.
      • Moukarbel G.V.
      Catheter ablation and antiarrhythmic drug therapy as first- or second-line therapy in the management of atrial fibrillation.
      The Cryoballoon vs Irrigated Radiofrequency Catheter Ablation: Double Short vs Standard Exposure Duration (CIRCA-DOSE)
      • Andrade J.G.
      • Champagne J.
      • Dubuc M.
      • et al.
      Cryoballoon or radiofrequency ablation for atrial fibrillation assessed by continuous monitoring.
      trial was a multicenter, prospective, parallel-group, single-blinded randomized clinical trial designed to evaluate the comparative effectiveness of various ablation technologies in patients with drug-refractory paroxysmal AF. All patients had an ILR for continuous arrhythmia monitoring. Though the 1-year freedom from any atrial arrhythmia ranged from 51.7% to 53.9% depending on the ablation technology used, all the strategies were effective in lowering median AF burden by 98.40%–99.93% compared to the monitoring period prior to ablation. Thus, ablation has been shown to be significantly more effective than AADs in preventing recurrences of AF in patients who have failed medical therapy and also in drastically reducing AF burden. However, given that these trial designs generally randomized patients to either an approach that had already failed (AADs) or ablation, it is perhaps not surprising that ablation was superior.
      Table 1Clinical trials evaluating ablation in drug-refractory atrial fibrillation
      StudyMethodsDefinition of recurrent atrial arrhythmiaMonitoring methodsFreedom from recurrenceResults (primary outcomes)
      Stabile et al
      • Stabile G.
      • Bertaglia E.
      • Senatore G.
      • et al.
      Catheter ablation treatment in patients with drug-refractory atrial fibrillation: a prospective, multi-centre, randomized, controlled study (Catheter Ablation For The Cure Of Atrial Fibrillation Study).


      2006
      RFA with AADs vs AADs in pAF and persAF>30 seconds after 1-month blankingTranstelephonic and HolterAblation: 55.9%

      AADs: 8.7% (12-month follow-up)
      Ablation with AADs is superior in preventing recurrences (P < .001)
      Oral et al
      • Oral H.
      • Pappone C.
      • Chugh A.
      • et al.
      Circumferential pulmonary-vein ablation for chronic atrial fibrillation.


      2006
      Amiodarone with cardioversions during first 3 months alone or with RFA in chronic AF>3 seconds, no blankingTranstelephonicAblation: 74%

      Control: 58% (12-month follow-up)
      Ablation is more effective in maintaining sinus rhythm without AADs compared to control group (P = .05)
      Pappone et al (APAF)
      • Pappone C.
      • Augello G.
      • Sala S.
      • et al.
      A randomized trial of circumferential pulmonary vein ablation versus antiarrhythmic drug therapy in paroxysmal atrial fibrillation: the APAF Study.


      2006
      RFA vs AADs in pAF>30 seconds, 6-week blankingHolter and eventAblation: 86%

      AADs: 22% (12-month follow-up)
      Ablation is more effective than AADs at preventing recurrences (P < .001)
      Jaïs et al (A4)
      • Jaïs P.
      • Cauchemez B.
      • MAcle L.
      • et al.
      Catheter ablation versus antiarrhythmic drugs for atrial fibrillation.


      2008
      RFA vs AADs in pAF>3 minutes, 3-month blankingHolterAblation: 89%

      AADs: 23% (12-month follow-up)
      Ablation is superior to AADs at maintaining sinus rhythm (P < .0001)
      Forleo et al
      • Forleo G.B.
      • Mantica M.
      • De Luca L.
      • et al.
      Catheter ablation of atrial fibrillation in patients with diabetes mellitus type 2: results from a randomized study comparing pulmonary vein isolation versus antiarrhythmic drug therapy.


      2009
      RFA vs AADs in diabetic patients with symptomatic AF>30 seconds, 5-week blankingHolterAblation: 80%

      AADs: 42.9% (12-month follow-up)
      Ablation is more effective than AADs at preventing recurrences in diabetic subjects (P = .001)
      Wilber et al (ThermoCool AF)
      • Wilber D.J.
      • Pappone C.
      • Neuzil P.
      • et al.
      Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial.


      2009
      RFA vs AADs in pAFNo clear definition, 3-month blankingTranstelephonic and HolterAblation: 63%

      AADs: 17% (9-month effectiveness period)
      Ablation resulted in a longer time to treatment failure compared to AADs (P < .01)
      Packer et al (STOP AF)
      • Packer D.L.
      • Kowal R.C.
      • Wheelan K.R.
      • et al.
      Cryoballoon ablation of pulmonary veins for paroxysmal atrial fibrillation: first results of the North American Arctic Front (STOP AF) pivotal trial.


      2013
      Cryoballoon vs AADs in pAF and persAFAny detectable AF, 3-month blankingTranstelephonic and HolterAblation: 69.9%

      AADs: 7.3% (12-month follow-up)
      Ablation is more effective than AADs at preventing recurrences (P < .001)
      Mont et al (SARA)
      • Mont L.
      • Bisbal F.
      • Hernández-Madrid A.
      • et al.
      Catheter ablation vs. antiarrhythmic drug treatment of persistent atrial fibrillation: a multicentre, randomized, controlled trial (SARA study).


      2014
      RFA vs AADs in persAF>24 hours for primary outcome measure and >30 seconds for secondary outcomes, 3-month blankingHolterAblation: 60.2%

      AADs: 29.2% (12-month follow-up, based on secondary outcome definition)
      Ablation is superior to AADs for sinus rhythm maintenance (P = .002)
      Hummel et al (TTOP-AF)
      • Hummel J.
      • Michaud G.
      • Hoyt R.
      • et al.
      Phased RF ablation in persistent atrial fibrillation.


      2014
      Phased RFA system vs AADs in persAF and longstanding persAF≥10 minutes on Holter, blanking not specifiedHolterNot reported

      Effectiveness defined as ≥90% reduction in time of recurrent arrhythmia episodes

      Ablation: 55.8%

      AADs: 26.4% (6-month follow-up)
      Ablation is more effective than AADs in reduction of atrial arrhythmias (P < .0001)
      Natale et al (SMART-AF)
      • Natale A.
      • Reddy V.Y.
      • Monir G.
      • et al.
      Paroxysmal AF catheter ablation with a contact force sensing catheter: results of the prospective, multicenter SMART-AF trial.


      2014
      RFA using contact force–sensing catheter in pAF, nonrandomized trial comparing to performance goals>30 seconds, 3-month blankingTranstelephonic and HolterAblation: 72.5% (12-month follow-up)Ablation with contact force–sensing catheter is safe and effective
      Verma et al (STAR AF II)
      • Verma A.
      • Jiang C.
      • Betts T.R.
      • et al.
      Approaches to catheter ablation for persistent atrial fibrillation.


      2015
      RFA using PVI alone vs PVI and ablation of complex fractionated activity vs PVI and linear ablation of left atrial roof and mitral valve isthmus in persAF>30 seconds, 3-month blankingTranstelephonic and HolterPVI alone: 59%

      PVI with complex electrogram ablation: 49%

      PVI with linear ablation: 46% (18-month follow-up)
      No reduction in recurrent arrhythmias with additional ablation (P = .15)
      Reddy et al (TOCCASTAR)
      • Reddy V.Y.
      • Dukkipati S.R.
      • Neuzil P.
      • et al.
      Randomized, controlled trial of the safety and effectiveness of a contact force–sensing irrigated catheter for ablation of paroxysmal atrial fibrillation.


      2015
      RFA using contact force catheter vs non–contact force catheter in pAF>30 seconds, 3-month blankingTranstelephonic and HolterContact force catheter: 67.8%

      Non–contact force catheter: 69.4% (Effectiveness evaluation at 12-month follow-up)
      Ablation using the contact force catheter is noninferior to non–contact force catheter with respect to efficacy (P = .0073) and safety (P = .0004)
      Dukkipati et al (HeartLight)
      • Dukkipati S.R.
      • Cuoco F.
      • Kutinsky I.
      • et al.
      Pulmonary vein isolation using the visually guided laser balloon: a prospective, multicenter, and randomized comparison to standard radiofrequency ablation.


      2015
      RFA vs visually guided laser balloonSymptomatic AF ≥1 minute or atypical flutter or atrial tachycardia, 3-month blankingTranstelephonic and HolterRFA: 63.9%

      Visually guided laser balloon: 63.5% (12-month follow-up)
      Visually guided laser balloon is noninferior to RFA with respect to efficacy (P = .003) and safety (P = .002)
      Kuck et al (FIRE AND ICE)
      • Kuck K.-H.
      • Brugada J.
      • Fürnkranz A.
      • et al.
      Cryoballoon or radiofrequency ablation for paroxysmal atrial fibrillation.


      2016
      RFA vs cryoballoon in pAF>30 seconds, 3-month blankingTranstelephonic and HolterRFA: 76.9%

      Cryoballoon: 78.7% (12-month follow-up)
      Cryoballoon is noninferior to RFA with similar safety profiles (P < .001)
      Sohara et al
      • Sohara H.
      • Ohe T.
      • Okumura K.
      • et al.
      HotBalloon ablation of the pulmonary veins for paroxysmal AF: a multicenter randomized trial in Japan.


      2016
      RFA using HotBalloon system vs AADs in pAF>30 seconds, 84-day blankingHolterRFA: 59%

      AADs: 5% (9-month effectiveness period)
      Ablation using the HotBalloon system is superior to AADs (P < .001)
      Andrade et al (CIRCA-DOSE)
      • Andrade J.G.
      • Champagne J.
      • Dubuc M.
      • et al.
      Cryoballoon or radiofrequency ablation for atrial fibrillation assessed by continuous monitoring.


      2019
      Contact force RFA vs 4-minute cryoballoon vs 2-minute cryoballoon in pAF>30 seconds, 84-day blankingImplantable loop monitorRFA: 53.9%

      4-minute cryoballoon: 52.2%

      2-minute cryoballoon: 51.7% (12-month follow-up)
      No significant differences between ablation strategies in reducing recurrences
      AADs = antiarrhythmic drugs; pAF = paroxysmal atrial fibrillation; persAF = persistent atrial fibrillation; PVI = pulmonary vein isolation; RFA = radiofrequency ablation.

      Ablation as first-line management for atrial fibrillation

      Given that many patients progress over time from paroxysmal to persistent to permanent AF, and that remodeling of the atria in AF may make restoration of sinus rhythm more and more difficult, there has been interest in exploring ablation as a first-line strategy for the management of AF. In addition, an early approach when no therapy has been tried already allows for a fairer comparison of AADs vs ablation.
      The Radiofrequency Ablation vs Antiarrhythmic Drugs as First-line Treatment of Symptomatic Atrial Fibrillation (RAAFT-1),
      • Wazni O.M.
      • Marrouche N.F.
      • Martin D.O.
      • et al.
      Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial.
      Medical Antiarrhythmic Treatment or Radiofrequency Ablation in Paroxysmal Atrial Fibrillation (MANTRA-PAF),
      • Cosedis Nielsen J.
      • Johannessen A.
      • Raatikainen P.
      • et al.
      Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation.
      and Radiofrequency Ablation vs Antiarrhythmic Drugs for Atrial Fibrillation Treatment (RAAFT-2)
      • Morillo C.A.
      • Verma A.
      • Connolly S.J.
      • et al.
      Radiofrequency Ablation vs Antiarrhythmic Drugs as First-Line Treatment of Paroxysmal Atrial Fibrillation (RAAFT-2): a randomized trial.
      randomized trials compared radiofrequency ablation as first-line therapy against AAD therapy for symptomatic AF. Table 2 depicts the essential features of these studies. A meta-analysis
      • Hakalahti A.
      • Biancari F.
      • Nielsen J.C.
      • Raatikainen M.J.P.
      Radiofrequency ablation vs. antiarrhythmic drug therapy as first line treatment of symptomatic atrial fibrillation: systematic review and meta-analysis.
      of these studies showed that radiofrequency ablation was associated with a greater freedom from recurrent AF, defined as episodes lasting 15 seconds to 1 minute in the various studies, as detected by Holter or event monitoring (risk ratio 0.63, 95% CI 0.44–0.92, P = .02). The analysis also concluded that radiofrequency ablation caused more severe adverse effects than AAD therapy.
      Table 2Clinical trials evaluating ablation as first-line therapy for symptomatic paroxysmal atrial fibrillation


      Study
      MethodsKey inclusion and exclusion criteriaDefinition of recurrent atrial arrhythmiaMonitoring methodsPrimary endpoints
      Wazni et al (RAAFT-1)
      • Wazni O.M.
      • Marrouche N.F.
      • Martin D.O.
      • et al.
      Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial.


      2005
      RFA vs AADs as initial therapy in symptomatic AFInclusion: age 18–75 years, symptomatic AF >3 months

      Exclusion: previous ablation or use of AADs
      >15 seconds, 2-month blankingHolter and eventAtrial tachyarrhythmia recurrence in 13% in ablation arm compared to 63% in drug arm (P < .001) at 12 months
      Nielsen et al (MANTRA-PAF)
      • Cosedis Nielsen J.
      • Johannessen A.
      • Raatikainen P.
      • et al.
      Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation.


      2012
      RFA vs AADs as initial therapy in paroxysmal AFInclusion: symptomatic AF for at least 6 months

      Exclusion: age >70 years, previous ablation or use of AADs, LA diameter > 5 cm
      >1 minute, 3-month blankingHolterNo significant difference in cumulative AF burden between the ablation and drug therapy arm (P = .10) over a period of 2 years
      Morillo et al (RAAFT-2)
      • Morillo C.A.
      • Verma A.
      • Connolly S.J.
      • et al.
      Radiofrequency Ablation vs Antiarrhythmic Drugs as First-Line Treatment of Paroxysmal Atrial Fibrillation (RAAFT-2): a randomized trial.


      2014
      RFA vs AADs as initial therapy in paroxysmal AFInclusion: symptomatic AF for at least 6 months

      Exclusion: age <18 or >75 years, previous ablation or use of AADs, LA diameter > 5.5 cm
      >30 seconds, 3-month blankingTranstelephonic and HolterAtrial tachyarrhythmia recurrence in 54.5% in ablation arm compared to 72.1% in drug arm (P < .001) at 24 months
      Wazni et al (STOP AF First)
      • Wazni O.M.
      • Dandamudi G.
      • Sood N.
      • et al.
      Cryoballoon ablation as initial therapy for atrial fibrillation.


      2020
      Cryoballoon vs AADs as initial therapy in paroxysmal AFInclusion: age 18–80 years

      Exclusion: treatment with AADs, left atrial size > 5 cm, previous LA procedure
      ≥30 seconds during ambulatory monitoring or ≥10 seconds on 12-lead ECG, three-month blankingTranstelephonic and 24-hour HolterTreatment success was 74.6% in the ablation arm compared to 45% in the drug therapy arm (P < .001) at 12 months

      No difference in serious events between groups
      Andrade et al (Early AF)
      • Andrade J.G.
      • Wells G.A.
      • Deyell M.W.
      • et al.
      Cryoablation or drug therapy for initial treatment of atrial fibrillation.


      2020
      Cryoballoon vs AADs in untreated symptomatic AFInclusion: age >18 years

      Exclusion: regular use of AADs
      ≥30 seconds, 3-month blankingImplantable cardiac monitorsAtrial tachyarrhythmia recurrence in 42.9% in ablation arm compared to 67.8% in drug arm (P < .001) at 12 months
      AF = atrial fibrillation; AADs = antiarrhythmic drugs; ECG = electrocardiogram; LA = left atrium; RFA = radiofrequency ablation.
      Patients in the MANTRA-PAF trial were subjected to 7-day Holter monitoring at 3, 6, 12, 18, and 24 months during clinical follow-up. Although AF burden during each follow-up was lower than at baseline for both treatment groups (P < .001), there was no significant difference in the cumulative burden of AF between the groups over a period of 18 months of follow-up. However, at 24 months, AF burden was lower in the ablation group than in the drug therapy group (90th percentile, 9% vs 19%, P = .007) and more patients in the ablation group were free from any AF (85% vs 71%, P = .004), suggesting the durability of ablation in controlling the arrhythmia.
      The Cryoballoon Catheter Ablation in Antiarrhythmic Drug Naive Paroxysmal Atrial Fibrillation (STOP AF First)
      • Wazni O.M.
      • Dandamudi G.
      • Sood N.
      • et al.
      Cryoballoon ablation as initial therapy for atrial fibrillation.
      and Early Aggressive Invasive Intervention for Atrial Fibrillation (EARLY-AF)
      • Andrade J.G.
      • Wells G.A.
      • Deyell M.W.
      • et al.
      Cryoablation or drug therapy for initial treatment of atrial fibrillation.
      trials were designed to evaluate cryoballoon ablation against AAD therapy as initial treatment for patients with symptomatic paroxysmal AF. Table 2 demonstrates the key features of both trials. The STOP AF First trial evaluated treatment success using patient-activated telephone monitoring and 24-hour Holter monitoring during follow-up, while the EARLY-AF trial used ILRs. Both trials demonstrated the superiority of cryoballoon ablation in preventing atrial arrhythmia recurrences at 1 year with a low risk of serious adverse effects. The EARLY-AF trial also demonstrated that mean AF burden was 3.3% lower in the ablation arm, although the median AF burden was extremely low, 0% in the ablation arm and 0.13% in the AAD arm. Both trials were underpowered to assess for cardiovascular outcomes and had follow-up data only for a year. Ablation is thus effective in reducing recurrences of atrial arrhythmias and in reducing AF burden when offered as first-line therapy in symptomatic patients. However, there is a similar reduction in AF burden with both ablation and AADs from baseline and no clinically meaningful difference in AF burden between groups up to 2 years of follow-up.

      Ablation to improve quality of life

      Table 3 summarizes the major randomized trials of catheter ablation that evaluated QOL in patients with symptomatic AF. Generic questionnaires such as the Short Form-36 health survey, EQ-5D from the EuroQol group, or AF-specific questionnaires like the AF symptom frequency and severity checklist were utilized. There was a significant improvement in QOL scores when ablation was offered as first-line therapy for paroxysmal AF
      • Wazni O.M.
      • Marrouche N.F.
      • Martin D.O.
      • et al.
      Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial.
      ,
      • Cosedis Nielsen J.
      • Johannessen A.
      • Raatikainen P.
      • et al.
      Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation.
      ,
      • Wilber D.J.
      • Pappone C.
      • Neuzil P.
      • et al.
      Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial.
      and also in patients with paroxysmal AF who had failed therapy with at least 1 AAD.
      • Jaïs P.
      • Cauchemez B.
      • MAcle L.
      • et al.
      Catheter ablation versus antiarrhythmic drugs for atrial fibrillation.
      The benefit was seen up to 24 months of follow-up. However, in the Catheter Ablation vs Antiarrhythmic Drug Treatment of Persistent Atrial Fibrillation (SARA) study, no significant differences in QOL outcomes were detected in patients with drug-refractory persistent AF between the ablation and AAD therapy arms at 12 months of follow-up.
      • Mont L.
      • Bisbal F.
      • Hernández-Madrid A.
      • et al.
      Catheter ablation vs. antiarrhythmic drug treatment of persistent atrial fibrillation: a multicentre, randomized, controlled trial (SARA study).
      This finding was attributed to a lack of power to detect a statistically significant difference in the secondary outcome of QOL. Wokhlu and colleagues
      • Wokhlu A.
      • Monahan K.H.
      • Hodge D.O.
      • et al.
      Long-term quality of life after ablation of atrial fibrillation: the impact of recurrence, symptom relief, and placebo effect.
      prospectively studied the effect of AF ablation on QOL in 502 symptomatic patients. QOL was assessed using the Short Form-36 health survey. At 2 years of follow-up, ablation was associated with higher QOL scores in patients both with and without recurrence of atrial arrhythmias. Ablation is thus an effective tool in improving QOL in patients with symptomatic AF during a follow-up period of up to 2 years, as shown by both prospective observational and randomized trial data.
      Table 3Clinical trials evaluating ablation and quality-of-life outcomes
      StudyMethods and patient populationQOL measureFollow-upQOL outcome
      Wazni et al (RAAFT-1)
      • Wazni O.M.
      • Marrouche N.F.
      • Martin D.O.
      • et al.
      Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial.


      2005
      Ablation vs AADs as first-line therapy in symptomatic AFShort Form-36 health survey6 monthsImprovement in QOL in the ablation arm compared to AAD therapy (P < .001)
      Oral et al
      • Oral H.
      • Pappone C.
      • Chugh A.
      • et al.
      Circumferential pulmonary-vein ablation for chronic atrial fibrillation.


      2006
      Amiodarone with cardioversions during first 3 months alone or with ablation in chronic AFSymptom severity score12 monthsReduction in severity of symptoms following maintenance of sinus after ablation (P < .001)
      Jaïs et al (A4)
      • Jaïs P.
      • Cauchemez B.
      • MAcle L.
      • et al.
      Catheter ablation versus antiarrhythmic drugs for atrial fibrillation.


      2008
      Ablation vs AAD in drug-refractory pAFShort Form-36 health survey12 monthsHigher QOL score in the ablation arm compared to AAD therapy (P = .01)
      Forleo et al
      • Forleo G.B.
      • Mantica M.
      • De Luca L.
      • et al.
      Catheter ablation of atrial fibrillation in patients with diabetes mellitus type 2: results from a randomized study comparing pulmonary vein isolation versus antiarrhythmic drug therapy.


      2009
      Ablation vs AADs in diabetic patients with symptomatic drug-refractory AFShort Form-36 health survey12 monthsHigher improvement in QOL score with ablation (P < .05)
      Wilber et al (ThermoCool AF)
      • Wilber D.J.
      • Pappone C.
      • Neuzil P.
      • et al.
      Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial.


      2009
      Ablation vs AADs in drug-refractory pAFShort Form-36 health survey

      AF symptom frequency and severity checklist
      3 monthsHigher QOL score and lower symptom frequency and severity scores compared to AAD therapy (P < .001)
      Nielsen et al (MANTRA-PAF)
      • Cosedis Nielsen J.
      • Johannessen A.
      • Raatikainen P.
      • et al.
      Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation.


      2012
      Ablation vs AADs as first-line therapy in pAFShort Form-36 health survey24 monthsHigher improvement in the physical component of QOL score in the ablation arm compared to AAD therapy (P = .01)
      Packer et al (STOP AF)
      • Packer D.L.
      • Kowal R.C.
      • Wheelan K.R.
      • et al.
      Cryoballoon ablation of pulmonary veins for paroxysmal atrial fibrillation: first results of the North American Arctic Front (STOP AF) pivotal trial.


      2013
      Cryoballoon vs AADs in drug-refractory pAF and persAFShort Form-36 health survey12 monthsSignificantly improved symptoms and QOL score with ablation
      Mont et al (SARA)
      • Mont L.
      • Bisbal F.
      • Hernández-Madrid A.
      • et al.
      Catheter ablation vs. antiarrhythmic drug treatment of persistent atrial fibrillation: a multicentre, randomized, controlled trial (SARA study).


      2014
      Ablation vs AADs in drug refractory persAFAF QOL questionnaire12 monthsNo significant differences in QOL between groups
      Morillo et al (RAAFT-2)
      • Morillo C.A.
      • Verma A.
      • Connolly S.J.
      • et al.
      Radiofrequency Ablation vs Antiarrhythmic Drugs as First-Line Treatment of Paroxysmal Atrial Fibrillation (RAAFT-2): a randomized trial.


      2014

      Ablation vs AADs as first-line therapy in pAFEQ-5D (generic tool from EuroQol group)12 monthsHigher score change from baseline in the ablation group (P = .03) compared to AAD therapy
      Hummel et al (TTOP-AF)
      • Hummel J.
      • Michaud G.
      • Hoyt R.
      • et al.
      Phased RF ablation in persistent atrial fibrillation.


      2014
      Phased RFA system vs AADs in drug-refractory persAF and longstanding persAFAF symptom severity and QOL survey6 monthsHigher QOL score in the ablation arm (P = .0052)
      Reddy et al (TOCCASTAR)
      • Reddy V.Y.
      • Dukkipati S.R.
      • Neuzil P.
      • et al.
      Randomized, controlled trial of the safety and effectiveness of a contact force–sensing irrigated catheter for ablation of paroxysmal atrial fibrillation.


      2015
      Ablation using contact force catheter vs non–contact force catheter in drug-refractory pAFAF effect on QOL questionnaire12 monthsSignificant improvement in QOL in both the ablation arms
      Sohara et al
      • Sohara H.
      • Ohe T.
      • Okumura K.
      • et al.
      HotBalloon ablation of the pulmonary veins for paroxysmal AF: a multicenter randomized trial in Japan.


      2016
      Ablation using HotBalloon system vs AADs in drug-refractory pAFShort Form-36 health survey, version Japan12 monthsSignificant improvement from baseline in most components of the QOL metric with ablation
      AADs = antiarrhythmic drugs; AF = atrial fibrillation; pAF = paroxysmal atrial fibrillation; persAF = persistent atrial fibrillation; QOL = quality of life; RFA = radiofrequency ablation.

      Rhythm control management and clinical outcomes in atrial fibrillation

      The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial investigated the impact of a rate vs a rhythm control strategy on mortality in patients with AF, with no significant difference found.
      A comparison of rate control and rhythm control in patients with atrial fibrillation.
      However, a sub-analysis showed that although maintenance of sinus rhythm led to better outcomes than AF, this improvement appeared to be offset by the adverse effects of AADs.
      • Corley S.D.
      • Epstein A.E.
      • DiMarco J.P.
      • et al.
      Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study.
      This finding engendered interest in exploring whether ablation could improve outcomes and control AF as well as if not better than AADs, while also avoiding the adverse effects of medical therapy.
      It is clear from previous clinical trials that catheter ablation can reduce or eliminate recurrences of AF in many patients, greatly reducing symptoms and improving QOL. The impact of ablation on clinical outcomes such are HF or mortality has been investigated in the Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA)
      • Packer D.L.
      • Mark D.B.
      • Robb R.A.
      • et al.
      Effect of catheter ablation vs antiarrhythmic drug therapy on mortality, stroke, bleeding, and cardiac arrest among patients with atrial fibrillation: the CABANA randomized clinical trial.
      trial and the Early Treatment of Atrial Fibrillation for Stroke Prevention Trial (EAST-AFNET 4).
      • Kirchhof P.
      • Camm A.J.
      • Goette A.
      • et al.
      Early rhythm-control therapy in patients with atrial fibrillation.
      Both were specifically designed to test contemporary rhythm control strategies (including ablation) on clinical outcomes such as morbidity and mortality. Table 4 summarizes the major differences between these trials.
      Table 4Clinical trials evaluating the effect of ablation on clinical outcomes of morbidity and mortality
      StudyMethodsKey inclusion and exclusion criteriaMedian time since AF diagnosisPrevious treatment for AFInterventions utilizedPrimary outcome
      Packer et al (CABANA)
      • Packer D.L.
      • Mark D.B.
      • Robb R.A.
      • et al.
      Effect of catheter ablation vs antiarrhythmic drug therapy on mortality, stroke, bleeding, and cardiac arrest among patients with atrial fibrillation: the CABANA randomized clinical trial.


      2019
      Ablation vs AAD therapy in patients with symptomatic AFInclusion: age ≥65 years or <65 years with at least 1 risk factor for stroke

      Exclusion: prior ablation, failed more than 2 AADs

      Number of patients randomized: 2204
      1.1 yearsAblation arm: 81.6% with 1 AAD

      AAD therapy arm: 82.2% with 1 AAD
      Ablation arm: 90.8% underwent ablation

      AAD therapy arm: 88.4% received AAD therapy;27.5% crossed over to undergo ablation
      No significant reduction in the composite of death, disabling stroke, serious bleeding, or cardiac arrest with ablation (hazard ratio 0.86, P = .30) over a median follow-up of 48.5 months
      Kirchhof et al (EAST-AFNET 4)
      • Kirchhof P.
      • Camm A.J.
      • Goette A.
      • et al.
      Early rhythm-control therapy in patients with atrial fibrillation.


      2020
      Early rhythm control therapy vs usual care in patients with recent-onset AFInclusion: age >75 years or history of stroke or age >65 years with at least 1 additional risk factor for stroke

      Exclusion: prior ablation, therapy failure with amiodarone

      Number of patients randomized: 2789
      36 daysNo prior treatment with AADs (around 40% in both arms had previous cardioversion)Early rhythm control arm: 19.4% underwent ablation and 45.7% received AAD

      Usual care arm: 7% underwent ablation and 7.6% received AAD

      (at 2 years of follow-up)
      Significant reduction in the composite of death from cardiovascular causes, stroke, or hospitalization with worsening heart failure or acute coronary syndrome with early rhythm control therapy (hazard ratio 0.79, P = .005) over a median follow-up of 5.1 years
      AAD = anti arrhythmic drug; AF = atrial fibrillation.

      CABANA trial

      The CABANA trial was a multicenter, international, open-label, controlled trial that randomized recently diagnosed symptomatic and inadequately treated patients with AF either to catheter ablation or to medical therapy. Key inclusion criteria included patients aged ≥65 years or <65 years with additional risk factors for stroke with paroxysmal or persistent AF deemed to warrant active therapy and eligible for catheter ablation and therapy with ≥2 rate and rhythm control drugs. Key exclusion criteria included AF in the setting of reversible causes, recent cardiac events, class IV angina or HF, failure to tolerate >2 AADs, prior catheter-based/surgical interventions for AF, and renal failure requiring dialysis. There were 1108 patients randomized to the ablation arm, of whom 1006 (90.8%) underwent ablation, and 1096 patients to the drug therapy arm, of whom 1092 (99.6%) received drug therapy, which was predominantly rhythm control therapy (969 patients, 88.4%). Both groups had approximately 14% of patients over the age of 75 years and 3.5% nonwhite, both populations not well represented in prior ablation trials. The median time since onset of AF was 1.1 years in both the groups. At the time of enrollment, 81.6% of patients in the ablation arm and 82.2% of patients in the drug therapy arm had current or past use of at least 1 AAD. Over a median follow-up of 48.5 months, the primary composite endpoint of death, disabling stroke, serious bleeding, or cardiac arrest occurred in 8% of the patients in the ablation arm vs 9.2% in the medical therapy arm (hazard ratio [HR] 0.85; P = .3), thus not meeting statistical significance in the intention-to-treat analysis. However, 301 (27.5%) patients in the drug therapy arm crossed over to the ablation arm during the follow-up period, potentially affecting the results. In the prespecified treatment-received analysis and per-protocol treatment comparisons, there was a suggestion of a statistically significant benefit with ablation with respect to the primary endpoint.
      QOL outcomes were measured using the Atrial Fibrillation Effect on Quality of Life (AFEQT) questionnaire and the Mayo AF-Specific Symptom Inventory (MAFSI).
      • Mark D.B.
      • Anstrom K.J.
      • Sheng S.
      • et al.
      Effect of catheter ablation vs medical therapy on quality of life among patients with atrial fibrillation: the CABANA randomized clinical trial.
      At the 5-year follow-up, the mean AFEQT score was 3.4 points higher in the ablation arm compared to the drug therapy arm (95% CI 2.1–4.8; P < .001), with benefits across all the component scores of symptoms, daily activities, and treatment concerns. The mean difference in both the MAFSI frequency and severity score among all follow-up intervals was -1.4 (95% CI -1.9 to -0.9; P < .001) and -1.1 (95% CI -1.5 to -0.8), respectively, favoring catheter ablation. The benefits of catheter ablation on QOL assessed by the AFEQT and MAFSI summary scores were maximal at 12 months of follow-up, after which there was some reduction in benefit.
      A subset of 1240 patients (56% of the CABANA population) was prospectively studied using a proprietary electrocardiographic monitoring system.
      • Poole J.E.
      • Bahnson T.D.
      • Monahan K.H.
      • et al.
      Recurrence of atrial fibrillation after catheter ablation or antiarrhythmic drug therapy in the CABANA trial.
      Symptom-driven 2-minute recordings, 24-hour autodetect triggered recordings for atrial tachyarrhythmias once per month in the first year followed by quarterly recordings, and biannual 96-hour Holter recordings for the period of the trial were used to determine AF recurrence and burden. Catheter ablation was associated with a significant reduction in the recurrence of symptomatic AF (HR 0.49; 95% CI 0.39–0.61; P < .001), any AF (HR 0.52; 95% CI 0.45–0.60; P < .001), and a composite of AF, atrial flutter, or atrial tachycardia (HR 0.53; 95% CI 0.46–0.62; P < .001) over a follow-up of 5 years. AF burden was significantly reduced in both randomized arms. However, AF burden was lower at 14.7% in the ablation arm compared to 20.8% in the medical therapy arm (P ≤ .01). AF burden was significantly reduced in the ablation arm for both paroxysmal and persistent AF. The relationship between reduction in AF burden and improvement in QOL and other clinical outcomes was not reported. Thus, in symptomatic patients with AF and risk factors for stroke, catheter ablation was not associated with an improvement in clinical outcomes as compared to AAD therapy. However, ablation resulted in a durable improvement in QOL and reduction in atrial arrhythmia recurrence and AF burden over a follow-up period of 5 years.

      EAST-AFNET 4 trial

      The EAST-AFNET 4 study was an international, open-label, randomized trial with blinded outcome assessment that assigned patients with early AF (diagnosed within a year of enrollment) to early rhythm control or usual care. Patients at risk for cardiovascular events were enrolled, which included patients >75 years of age or with a prior history of stroke or transient ischemic attack and patients with 2 or more of the following features of age >65 years, female sex, HF, hypertension, diabetes, chronic kidney disease stage 3 and 4, and left ventricular hypertrophy. Key exclusion criteria included limited life expectancy, severe renal disease, prior AF ablation, and previous therapy failure with amiodarone. A total of 2789 patients were enrolled a median of 36 days after the first diagnosis of AF and underwent randomization. About 30% of patients in both the groups did not have any symptoms attributable to AF at baseline. The trial was stopped for efficacy after a median of 5 years of follow-up. Patients in the rhythm control arm had received therapy with ablation (19.4%) or AAD therapy (45.7%) by 2 years of follow-up. Patients in the usual care arm mostly received rate control therapy (85.4% of patients at 2 years). The first primary composite endpoint of death from cardiovascular causes, stroke, or hospitalization with worsening of HF or acute coronary syndrome occurred less often in the early rhythm control arm (HR 0.79, 95% CI 0.66–0.94; P = .005). The second primary endpoint of nights spent in the hospital was not significantly different between the groups, and the primary safety endpoint event rate also did not differ significantly. Patients in the rhythm control arm were more often in sinus rhythm (82%) compared to the usual care arm (60.5%), as determined by electrocardiograms during follow-up visits. At 2 years of follow-up, most patients in both the groups (>70%) were asymptomatic.
      EAST-AFNET 4 likely excluded patients very symptomatic from AF, as they could have had a perceived benefit from a rhythm management strategy. Only patients in the rhythm control arm were required to transmit a single-lead electrocardiogram twice per week and also when symptomatic. Recurrent AF triggered an in-person visit (15.4% of patients in the rhythm control arm) to escalate therapy as clinically indicated. The trial did not include detailed information on recurrent AF or AF burden.
      Rhythm control therapy (including ablation) offered early in the course of AF to symptomatic and asymptomatic patients with concomitant cardiovascular conditions is therefore associated with improved clinical outcomes. It does not appear to matter whether sinus rhythm is maintained by ablation or AADs, as long as rhythm is monitored and changes in therapy are made if AF recurs. It remains to be seen if the improvement in outcomes is related to a decrease in recurrence of AF or a reduction in AF burden.

      Atrial fibrillation and heart failure

      In the Framingham Heart Study, HF was associated with a markedly increased risk (odds ratio 4.5 for men and 5.9 for women) for developing AF during a 38-year period of follow-up.
      • Benjamin E.J.
      • Levy D.
      • Vaziri S.M.
      • D’Agostino R.B.
      • Belanger A.J.
      • Wolf P.A.
      Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study.
      Analysis of the Framingham cohort has confirmed the complex relationship between HF and AF. It has been established that new-onset/incident AF is associated with higher all-cause mortality in patients with both prevalent HF with a reduced ejection fraction and HF with a preserved ejection fraction as compared with a population with no HF.
      • Santhanakrishnan R.
      • Wang N.
      • Larson M.G.
      • et al.
      Atrial fibrillation begets heart failure and vice versa.
      AF has been shown to have an unfavorable effect on patients with chronic HF, with lower peak workload and peak oxygen uptake as assessed by graded bicycle ergometry.
      • Pardaens K.
      • Van Cleemput J.
      • Vanhaecke J.
      • Fagard R.H.
      Atrial fibrillation is associated with a lower exercise capacity in male chronic heart failure patients.
      The onset of AF in patients with HF is associated with worsening NYHA functional class, decrease in peak oxygen consumption and cardiac index, and an increase in the severity of mitral and tricuspid regurgitation.
      • Pozzoli M.
      • Cioffi G.
      • Traversi E.
      • Pinna G.D.
      • Cobelli F.
      • Tavazzi L.
      Predictors of primary atrial fibrillation and concomitant clinical and hemodynamic changes in patients with chronic heart failure: a prospective study in 344 patients with baseline sinus rhythm.
      Table 5 lists randomized controlled trials assessing the efficacy of ablation for AF in patients with HF, the definition of AF recurrences, the methods used to detect recurrent AF and AF burden, and the primary outcomes of the trials.
      Table 5Clinical trials evaluating ablation in patients with atrial fibrillation and heart failure
      StudyMethodsDefinition of recurrent atrial arrhythmiaMonitoring methodsFreedom from recurrenceResults (primary outcomes)
      Khan et al (PABA CHF)
      • Khan M.N.
      • Jaïs P.
      • Cummings J.
      • et al.
      Pulmonary-vein isolation for atrial fibrillation in patients with heart failure.


      2008
      PVI vs AVN ablation and BIV pacing in symptomatic, drug-resistant AF>30 seconds, 2-month blankingLoop event monitorsPVI: 88%

      BIV pacing arm: 0% (6-month follow-up)
      Composite primary endpoint of improved HF questionnaire score, longer 6-minute walk distance, and higher EF favoring the PVI arm (P < .017)
      Jones et al.
      • Jones D.G.
      • Haldar S.K.
      • Hussain W.
      • et al.
      A randomized trial to assess catheter ablation versus rate control in the management of persistent atrial fibrillation in heart failure.


      2013
      Ablation vs rate control in persAF>30 seconds, 2-month blankingHolterAblation: 88%

      Rate control: NA on account of persAF (12-month follow-up)
      Improvement in peak oxygen consumption in ablation arm (difference +3.07 mL/kg/min, P = .018)
      Hunter et al (CAMTAF)
      • Hunter R.J.
      • Berriman T.J.
      • Diab I.
      • et al.
      A randomized controlled trial of catheter ablation versus medical treatment of atrial fibrillation in heart failure (the CAMTAF trial).


      2014
      Ablation vs rate control in persAF>30 seconds, 3-month blankingHolterAblation: 73%

      Rate control: 0% (12-month follow-up)
      Absolute increase in EF of 8% in the ablation arm at 6 months (P < .001)
      Di Biase et al (AATAC)
      • Di Biase L.
      • Mohanty P.
      • Mohanty S.
      • et al.
      Ablation versus amiodarone for treatment of persistent atrial fibrillation in patients with congestive heart failure and an implanted device: results from the AATAC Multicenter Randomized Trial.


      2016
      Ablation vs amiodarone in persAF>30 seconds, 3-month blankingRemote interrogation of ICD or CRT-D devicesAblation: 70%

      Amiodarone: 34% (24-month follow-up)
      Reduction in recurrent AF in the ablation arm (P < .001)
      Prabhu et al (CAMERA MRI)
      • Prabhu S.
      • Taylor A.J.
      • Costello B.T.
      • et al.
      Catheter ablation versus medical rate control in atrial fibrillation and systolic dysfunction.


      2017
      Ablation vs rate control in persAF>30 seconds, 1-month blankingImplanted loop recorder in ablation group and Holter in the rate control groupAblation: 76%

      Rate control: 0% (6-month follow-up)
      Improvement in LVEF by 18.3% in ablation arm vs 4.4% in the rate control arm (P < .0001)
      Marrouche et al (CASTLE-AF)
      • Marrouche N.F.
      • Brachmann J.
      • Andresen D.
      • et al.
      Catheter ablation for atrial fibrillation with heart failure.


      2018
      Ablation vs medical therapy (rate or rhythm control) in symptomatic AF>30 seconds, 3-month blankingRemote interrogation of ICD or CRT-D devicesAblation: 63.1%

      Medical therapy: 21.7% (60-month follow-up)
      Composite primary endpoint of death or HF hospitalization occurred less frequently in the ablation arm (hazard ratio 0.62, P = .007)
      AF = atrial fibrillation; AVN = atrioventricular node; BIV = biventricular; CRT-D = cardiac resynchronization therapy defibrillator; EF = ejection fraction; HF = heart failure; ICD = implantable cardioverter-defibrillator; NA = not applicable; persAF = persistent atrial fibrillation; PVI = pulmonary vein isolation.

      Effect of ablation on atrial fibrillation burden and ejection fraction in heart failure

      The Ablation Versus Amiodarone for Treatment of Persistent Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted Device (AATAC) trial established the superiority of ablation over amiodarone in achieving freedom from AF.
      • Di Biase L.
      • Mohanty P.
      • Mohanty S.
      • et al.
      Ablation versus amiodarone for treatment of persistent atrial fibrillation in patients with congestive heart failure and an implanted device: results from the AATAC Multicenter Randomized Trial.
      Although AF recurrence was evaluated based on remote monitoring of the implanted cardiac devices, formal information on AF burden was not reported. The CAMERA-MRI
      • Prabhu S.
      • Taylor A.J.
      • Costello B.T.
      • et al.
      Catheter ablation versus medical rate control in atrial fibrillation and systolic dysfunction.
      study randomized 68 patients with persistent AF and idiopathic HF with a left ventricular ejection fraction (LVEF) ≤ 45% to catheter ablation or medical rate control therapy. At 6 months, LVEF as assessed by cardiac magnetic resonance imaging improved by 18% ± 13% in the ablation arm compared with 4.4% ± 13% in the medical arm (P < .0001). The average AF burden measured by loop monitors post catheter ablation was 1.6% ± 5%. The adequacy of rate control therapy in the medical arm was confirmed by serial Holter monitoring. The restoration of sinus rhythm with a low AF burden was hence associated with a significant improvement in LVEF at 6 months of follow-up. However, the study had a small sample size, had short-term follow-up, and was underpowered to detect clinical outcomes of morbidity and mortality.

      Atrial fibrillation ablation and clinical outcomes in heart failure

      The Catheter Ablation versus Standard Conventional Treatment in Patients with Left Ventricular Dysfunction and Atrial Fibrillation (CASTLE-AF) trial was designed to test whether ablation of AF by PVI would improve the clinical endpoints of morbidity and mortality.
      • Marrouche N.F.
      • Brachmann J.
      • Andresen D.
      • et al.
      Catheter ablation for atrial fibrillation with heart failure.
      CASTLE-AF was an open-label, prospective, randomized, controlled, international, multicenter clinical trial. Patients 18 years or older with symptomatic paroxysmal or persistent AF, who had failed or were unwilling to take amiodarone therapy and with an LVEF ≤ 35%, were included in the study. Patients were also required to have a dual-chamber ICD or a cardiac resynchronization therapy defibrillator device with home monitoring capabilities. Patients with a left atrial diameter > 6 cm, contraindications to chronic anticoagulation therapy, previous ablation procedures, recent acute coronary syndromes or cerebrovascular accidents, or cardiac assist devices or patients awaiting cardiac transplantation were the major exclusions. After a run-in period of 5 weeks during which HF management was optimized, patients were randomized to catheter ablation or medical therapy for AF.
      After a median follow-up of 38.7 months, the composite endpoint of death or hospitalization for worsening HF occurred in 28.5% of patients in the ablation group compared to 44.6% of patients in the medical therapy group (P = .006). Patients who underwent catheter ablation had an increase in LVEF (8% vs 0.2%; P = .005), lower AF burden (27% vs 64%) and longer 6-minute walk distance at 12 months (41 meters vs 1 meter; P = .001). The mortality benefit in the ablation arm emerged after about 3 years, primarily driven by a lower rate of cardiovascular death. The study thus demonstrated that ablation was effective in lowering AF burden with an improvement in LVEF and clinical outcomes. Whether further reductions in AF burden would lead to additional improvement in clinical outcomes remains unanswered. The study had important limitations, including nonblinded randomization, which could have introduced bias; ablation performed by experienced high-volume operators, which could account for the low complication rates; baseline ICD and cardiac resynchronization therapy defibrillator therapy, which could have affected overall mortality; and a predominant rate control strategy in the medical therapy arm.

      Summary and knowledge gaps

      Trials of ablation in AF have focused on several broad patient groups: symptomatic patients who have failed medical therapy; clinical outcomes with ablation, potentially as first-line therapy, even in asymptomatic or minimally symptomatic patients; and patients with HF. While clinical trials have helped to clarify many factors associated with indications for and outcomes with ablation of AF, there remain many unanswered questions for further clinical studies. Table 6 summarizes our current understanding of ablation for AF and knowledge gaps that require further study. Key questions are the impact of ablation on clinical outcomes in asymptomatic and minimally symptomatic patients, how much reduction in AF is necessary to favorably impact clinical outcomes, and how a better understanding of mechanisms should dictate the timing and approach to ablation.
      Table 6Current conceptualization of ablation for atrial fibrillation and knowledge gaps requiring further study
      What Is Known
      Ablation reduces recurrences of AF and improves quality of life
      The foundational approach is PVI
      Radiofrequency ablation and cryoablation have similar safety and efficacy with respect to PVI
      Ablation of paroxysmal AF has a higher success rate than persistent or longstanding persistent AF
      Ablation as first-line therapy results in greater freedom from AF than AAD therapy; AF burden tends to be low early in the course of AF and not greatly affected by ablation
      Structural remodeling (LA enlargement and LV dysfunction) lowers success rates
      Ablation improves clinical outcomes in select patient populations
      Ablation in patients with HF lowers AF burden, improves LVEF, and reduces a composite of mortality or HF hospitalization
      Knowledge Gaps
      What are the mechanisms of AF beyond pulmonary vein triggers?
      What ancillary approaches will eliminate AF if PVI is not sufficient?
      In what circumstances is ablation futile and should not be pursued?
      What is the effect of ablation on clinical outcomes in asymptomatic patients?
      How are clinical outcomes different when ablation is offered to patients with and without HF?
      Should we aim for a reduction in burden or elimination of all recurrences with ablation? If reduction of AF burden is sufficient, how much reduction is necessary to be clinically meaningful?
      What kind of monitoring is ideal to assess outcomes in an ablation trial?
      How do cardiac structure and function influence procedural and clinical outcomes with ablation?
      How many patients with AF are truly cured with ablation vs just palliated? How does the underlying substrate affect long-term arrhythmia control?
      AAD = antiarrhythmic drug; AF = atrial fibrillation; HF = heart failure; LA = left atrium; LV = left ventricle; LVEF = left ventricular ejection fraction; PVI = pulmonary vein isolation.

      Funding Sources

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Disclosures

      Dr Amuthan: no relevant conflicts of interest; Dr Curtis: advisory board for Janssen Pharmaceuticals, Abbott, Sanofi Aventis, Milestone Pharmaceuticals; consulting for Medtronic, Inc; honoraria for speaking: Abbott, Medtronic, Inc, Zoll.

      Authorship

      All authors attest they meet the current ICMJE criteria for authorship.

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