Atrial Fibrillation Ablation in Heart Failure With Reduced vs Preserved Ejection Fraction: A Systematic Review and Meta-Analysis

Alireza Oraii; William F McIntyre; Ratika Parkash; Krzysztof Kowalik; Ghazal Razeghi; Alexander P Benz; Emilie P Belley-Côté; David Conen; Stuart J Connolly; Anthony S L Tang; Jeff S Healey; Jorge A Wong

doi:10.1001/jamacardio.2024.0675

. 2024 Apr 24;9(6):545–555. doi: 10.1001/jamacardio.2024.0675

Atrial Fibrillation Ablation in Heart Failure With Reduced vs Preserved Ejection Fraction

A Systematic Review and Meta-Analysis

Alireza Oraii ¹, William F McIntyre ^1,², Ratika Parkash ³, Krzysztof Kowalik ⁴, Ghazal Razeghi ⁴, Alexander P Benz ¹, Emilie P Belley-Côté ^1,², David Conen ^1,², Stuart J Connolly ^1,², Anthony S L Tang ⁵, Jeff S Healey ^1,², Jorge A Wong ^1,^2,^✉

¹Population Health Research Institute, Hamilton, Ontario, Canada

²Division of Cardiology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada

³Queen Elizabeth II Health Sciences Center, Halifax, Nova Scotia, Canada

⁴Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada

⁵Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada

Accepted for Publication: January 19, 2024.

Published Online: April 24, 2024. doi:10.1001/jamacardio.2024.0675

^✉

Corresponding Author: Jorge A. Wong, MD, MPH, Population Health Research Institute, 237 Barton St East, Hamilton, ON L8L 2X2, Canada (jorge.wong@phri.ca).

Author Contributions: Drs Oraii and Wong had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Oraii, McIntyre, Parkash, Connolly, Tang, Healey, Wong.

Acquisition, analysis, or interpretation of data: Oraii, McIntyre, Parkash, Kowalik, Razeghi, Benz, Belley-Côté, Conen, Tang, Healey, Wong.

Drafting of the manuscript: Oraii, McIntyre, Parkash, Wong.

Critical review of the manuscript for important intellectual content: Parkash, Kowalik, Razeghi, Benz, Belley-Côté, Conen, Connolly, Tang, Healey, Wong.

Statistical analysis: Oraii, Wong.

Obtained funding: Connolly.

Administrative, technical, or material support: Kowalik, Conen, Tang, Wong.

Supervision: McIntyre, Parkash, Belley-Côté, Healey, Wong.

Conflict of Interest Disclosures: Dr McIntyre reported receiving personal fees from Trimedic Therapeutics outside the submitted work. Dr Benz reported receiving personal fees from Bristol Myers Squibb (BMS) and AstraZeneca outside the submitted work and participating in an educational program supported by Boston Scientific (“Fellowship Herzrhythmus”). Dr Belley-Côté reported receiving grants from Abbott, Bayer, BMS-Pfizer, Roche Diagnostics, and Trimedic Therapeutics outside the submitted work. Dr Conen reported receiving personal fees from Roche Diagnostics, Trimedic Therapeutics, and Servier outside the submitted work. Dr Healey reported receiving grants from Boston Scientific and Medtronic outside the submitted work. No other disclosures were reported.

Data Sharing Statement: See Supplement 2.

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Corresponding author.

PMCID: PMC11044015 PMID: 38656292

This systematic review and meta-analysis investigates the efficacy of catheter ablation compared with rate or rhythm control among patients with atrial fibrillation and heart failure.

Key Points

Question

Among patients with atrial fibrillation (AF) and heart failure (HF), does the efficacy of catheter ablation compared with that of rate or rhythm control therapies interact with HF phenotype?

Findings

In this systematic review and meta-analysis of 12 randomized clinical trials including 2465 participants with HF, catheter ablation of AF compared with conventional medical therapies was associated with reduced risk of HF events in patients with reduced ejection fraction, while no benefit was observed in patients with preserved ejection fraction.

Meaning

This study found that patients with HF with preserved ejection fraction did not derive the same benefit from catheter ablation as patients with HF with reduced ejection fraction.

Abstract

Importance

Catheter ablation is associated with reduced heart failure (HF) hospitalization and death in select patients with atrial fibrillation (AF) and heart failure with reduced ejection fraction (HFrEF). However, the benefit in patients with HF with preserved ejection fraction (HFpEF) is uncertain.

Objective

To investigate whether catheter ablation for AF is associated with reduced HF-related outcomes according to HF phenotype.

Data Source

A systematic search of MEDLINE, Embase, and Cochrane Central was conducted among studies published from inception to September 2023.

Study Selection

Parallel-group randomized clinical trials (RCTs) comparing catheter ablation with conventional rate or rhythm control therapies in patients with HF, New York Heart Association functional class II or greater, and a history of paroxysmal or persistent AF were included. Pairs of independent reviewers screened 7531 titles and abstracts, of which 12 RCTs and 4 substudies met selection criteria.

Data Extraction and Synthesis

Data were abstracted in duplicate according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Pooled effect estimates were calculated using random-effects Mantel-Haenszel models. Interaction P values were used to test for subgroup differences.

Main Outcomes and Measures

The primary outcome was HF events, defined as HF hospitalization, clinically significant worsening of HF, or unscheduled visits to a clinician for treatment intensification. Secondary outcomes included cardiovascular and all-cause mortality.

Results

A total of 12 RCTs with 2465 participants (mean [SD] age, 65.3 [9.7] years; 658 females [26.7%]) were included; there were 1552 participants with HFrEF and 913 participants with HFpEF. Compared with conventional rate or rhythm control, catheter ablation was associated with reduced risk of HF events in HFrEF (risk ratio [RR], 0.59; 95% CI, 0.48-0.72), while there was no benefit in patients with HFpEF (RR, 0.93; 95% CI, 0.65-1.32) (P for interaction = .03). Catheter ablation was associated with reduced risk of cardiovascular death compared with conventional therapies in HFrEF (RR, 0.49; 95% CI, 0.34-0.70) but a differential association was not detected in HFpEF (RR, 0.91; 95% CI, 0.46-1.79) (P for interaction = .12). Similarly, no difference in the association of catheter ablation with all-cause mortality was found between HFrEF (RR vs conventional therapies, 0.63; 95% CI, 0.47-0.86) and HFpEF (RR vs conventional therapies, 0.95; 95% CI, 0.39-2.30) groups (P for interaction = .39).

Conclusions and Relevance

This study found that catheter ablation for AF was associated with reduced risk of HF events in patients with HFrEF but had limited or no benefit in HFpEF. Results from ongoing trials may further elucidate the role of catheter ablation for AF in HFpEF.

Introduction

Atrial fibrillation (AF) and heart failure (HF) are rapidly growing cardiovascular epidemics, and the conditions often occur concomitantly; their coexistence carries a substantial incremental effect on morbidity and mortality.^1,2 However, HF phenotypes based on degree of left ventricular dysfunction have varying etiologies, clinical presentations, and long-term outcomes.³ HF with preserved ejection fraction (HFpEF) constitutes approximately half of HF cases and is expected to become the dominant form.⁴ Furthermore, AF is more prevalent in patients with HFpEF than in individuals with HF with reduced EF (HFrEF).^5,6

Evidence from randomized clinical trials (RCTs) suggests that catheter ablation may be superior to conventional rate or rhythm control therapies for improving clinical outcomes in patients with coexisting AF and HF.^7,8,9,10 However, these studies primarily included patients with HFrEF. It is unclear whether patients with HFpEF derive the same benefit from catheter ablation as patients with HFrEF. This gap of knowledge is of great importance given that most foundational HF therapies, including β-blockers, angiotensin receptor or neprilysin inhibitors, and mineralocorticoid receptor antagonists, that have been effective in patients with HFrEF have little or no efficacy in patients with HFpEF.^11,12,13,14

To our knowledge, there is no study to date that has comprehensively summarized and compared the randomized evidence on the differential efficacy of catheter ablation on HF-related outcomes in patients with HFrEF compared with those with HFpEF. This systematic review and meta-analysis aimed to assess the association of catheter ablation with HF-related outcomes in patients with HFrEF and HFpEF compared with conventional rate or rhythm control therapies.

Methods

Protocol and Registration

The protocol for this systematic review and meta-analysis was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42022359792). This study was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.

Search Strategy and Study Selection

We performed a literature search in MEDLINE, Embase, and Cochrane Central Register of Controlled Trials for studies published from inception to September 3, 2023, to identify RCTs evaluating the efficacy of catheter ablation compared with conventional therapies in patients with AF. We used a highly sensitive search strategy with appropriate subject headings and free-text keywords to capture relevant records (eTable 1 in Supplement 1). There were no language or publication date restrictions. Validated sensitivity-maximizing RCT filters were added to search terms, and the search strategy was approved by an academic librarian.^15,16 A manual search of the bibliography of identified studies and prior systematic reviews was performed to identify eligible studies. Pairs of independent reviewers (A.O., K.K., and G.R.) screened titles and abstracts of identified studies after deduplication. Full texts of potentially eligible studies were reviewed in duplicate, and disagreements were resolved through discussion with a third reviewer (J.A.W.).

Eligibility Criteria

We included parallel-group RCTs that compared the efficacy of catheter ablation vs conventional rate or rhythm control therapies in patients with HF, a New York Heart Association (NYHA) functional class score of II or greater, and a history of paroxysmal or persistent AF. The catheter ablation group had to include pulmonary vein isolation as the main ablation strategy with or without posterior left atrial wall isolation, additional linear lesions, or trigger modulation. Conventional therapies included rate control (ie, rate-lowering medications or atrioventricular junction ablation followed by pacemaker or cardiac resynchronization therapy device implantation) or rhythm control (ie, antiarrhythmic medications, electrical cardioversion, or both) strategies. We excluded studies that compared different ablation modalities or assigned patients to surgical ablation techniques. The primary outcome was HF events, defined as HF hospitalization, clinically significant worsening of HF leading to an intervention, or an unscheduled visit to a clinician for treatment intensification. Secondary outcomes included cardiovascular death and all-cause mortality. Additional outcomes of interest were change in left ventricular ejection fraction (LVEF), functional status as measured by a 6-minute walk test (6MWT), and quality of life as measured by the Minnesota Living With Heart Failure Questionnaire (MLHFQ), which produces a total score ranging from 0 to 105, with lower scores indicating better quality of life.

Data Extraction and Management

Pairs of reviewers (A.O., K.K., and G.R.) independently abstracted study data in duplicate using standardized data-extraction sheets. Data extracted from each study included the year of publication, sample size, eligibility criteria, ablation strategies, comparators, baseline characteristics, and follow-up duration. Reviewers searched manuscript text, tables, figures, and supplementary material for relevant information. In case detailed information was not presented in the article, we made measurements on graphic plots using the web-based semiautomated WebPlotDigitizer tool version 4.6 (Ankit Rohatgi).¹⁷ Disagreements were resolved through discussion with a third reviewer (J.A.W.).

Risk of Bias and Certainty of Evidence

Pairs of reviewers (A.O. and K.K.) independently evaluated the risk of bias using the Cochrane Collaboration Risk of Bias tool version 2.¹⁸ An outcome-specific assessment was performed for each trial in the following domains: randomization process, deviations from intended interventions, missing outcome data, outcome measurements, and selection of reported results. The Grading of Recommendations Assessment, Development, and Evaluation framework was used to assess the certainty of the evidence.^19,20

Statistical Analysis

Data Synthesis

The pooled association of catheter ablation vs medical therapy with the risk of HF events, cardiovascular death, and all-cause mortality was calculated using the random-effects Mantel-Haenszel method. Event rates at the end of the last known follow-up were used for main analyses. Risk ratios (RRs) with 95% CIs were used for reporting summary estimates. The random-effects inverse variance method was used to calculate the pooled association of catheter ablation with change in LVEF, 6MWT, and MLHFQ from baseline, and mean difference (MD) with SD was used for reporting summary estimates. For the meta-analysis of continuous outcomes, data on change from baseline to the last measurement done within 2 years after randomization were pooled. Heterogeneity was tested using the χ² test of homogeneity and I² statistic.¹⁵ Sensitivity analyses were performed using fixed-effects models to assess the consistency of our findings. Because mortality data derived from an extended follow-up may be subject to a risk of cointervention bias, we performed an additional sensitivity analysis using mortality data derived from original trial publications instead of information from their substudies with extended follow-up. Statistical analyses were performed with the Review Manager software version 5.3 (Cochrane Collaboration). A P value < .05 was considered significant.

Subgroup Analyses Based on HFrEF vs HFpEF

Prespecified subgroup analyses of study outcomes was performed stratified by HFrEF and HFpEF subgroups. Authors of studies with potentially relevant subgroup data were contacted to request additional information.²¹ For data synthesis, study-specific definitions for categorizing patients as having HFrEF or HFpEF were used. In Packer et al,²² because most patients (711 of 778 patients [91.4%]) were classified as HFpEF and no subgroup estimates were provided for patients with HFrEF vs those with HFpEF, all patients were deemed to have HFpEF for the purposes of this analysis. Interaction P values were calculated to test the statistical significance of differences between subgroups. Interaction P values < .10 were considered significant.¹⁵

Results

The PRISMA diagram of the study selection process is shown in Figure 1. The electronic database search identified 7531 deduplicate records. We retrieved 205 full-text articles after title and abstract screening. A total of 16 studies met eligibility criteria and were included in the meta-analysis.^{7,8,9,10,21,22,23,24,25,26,27,28,29,30,31,32}

Included Studies

A total of 16 studies^{7,8,9,10,21,22,23,24,25,26,27,28,29,30,31,32} evaluated outcomes of patients with HF undergoing catheter ablation compared with patients undergoing conventional rate or rhythm control therapies for management of AF (Table). Among these studies, 12 studies^{7,8,9,10,21,22,23,24,25,26,30,32} were original RCTs with 2465 participants (mean [SD] age, 65.3 [9.7] years; 658 females [26.7%]), including 1552 participants with HFrEF and 913 participants with HFpEF, and 4 studies^27,28,29,31 evaluated longer-term outcomes on repeat RCT populations. All study participants had HF symptoms with an NYHA functional class score of II or greater, and among 2029 participants in 8 studies^{8,9,21,22,23,24,26,32} with available information, the NYHA class score was II for 1251 patients (61.7%), III for 741 patients (36.5%), and IV for 37 patients (1.8%). There were 9 RCTs^{7,8,9,10,23,24,25,26,32} that included patients with HFrEF alone (1245 patients), 1 study³⁰ that included patients with only HFpEF (31 patients), and 2 studies^21,22 that included a combination of patients with HFrEF or HFpEF (307 participants and 882 participants, respectively). HFpEF was defined as the presence of HF symptoms and an LVEF greater than 40% in Packer et al²²; a combination of HF symptoms, increased natriuretic peptide levels, and an LVEF greater than 45% in Parkash et al²¹; or a combination of HF symptoms, increased natriuretic peptide levels, an LVEF greater than 50%, structural or functional echocardiographic evidence of diastolic dysfunction (or both), and increased pulmonary capillary wedge pressure during right heart catheterization with cardiopulmonary exercise testing in Chieng et al.³⁰ All study participants had a history of AF, among whom 501 patients (20.3%) had paroxysmal and 1964 patients (79.7%) had persistent or long-standing persistent AF. Pulmonary vein isolation was the cornerstone of catheter ablation in all studies, with additional lesions (eg, left atrial posterior wall isolation, cavotricuspid isthmus ablation, or mitral annular lines) made at the discretion of operators. The comparator group was rate control in 6 trials,^{9,10,21,23,24,26} rhythm control in 1 trial,⁷ and a combination of rate or rhythm control in 5 trials.^{8,22,25,30,32}

Table. Baseline Characteristics of Included Studies.

Source	Trial acronym	Inclusion criteria	Ablation strategy	Comparator	Patients undergoing ablation/comparator group, No.	Age, mean (SD) y	Sex, No. (%)		Baseline LVEF, mean (SD), %	Baseline 6MWT, mean (SD), m	Baseline MLHFQ, mean (SD)	Follow-up, mo
Source	Trial acronym	Inclusion criteria	Ablation strategy	Comparator	Patients undergoing ablation/comparator group, No.	Age, mean (SD) y	Males	Females	Baseline LVEF, mean (SD), %	Baseline 6MWT, mean (SD), m	Baseline MLHFQ, mean (SD)	Follow-up, mo
Di Biase et al,⁷ 2016	AATAC	Persistent AF; NYHA II-III; LVEF≤40%	PVI ±linear lesions ± CFAE	Rhythm control	102/101	61.0 (10.5)	151 (74.4)	52 (25.6)	29.5 (6.7	349 (121)	51.0 (25.5)	24
Hunter et al,²⁶ 2014; Zakeri et al,²⁸ 2023	CAMTAF and long-term outcomes	Persistent AF; NYHA II-IV; LVEF<50%	PVI + CFAE ± linear lesions	Rate control	26/24	57.0 (11.3)	48 (96.0)	2 (4.0)	32.7 (10.0)	Not available	44.2 (23.0)	6 and 93.6
Jones et al,²³ 2013; Wong et al,²⁹ 2018	ARC-HF and long-term outcomes	Persistent AF; NYHA II-IV; LVEF≤35%	PVI ± CFAE ± linear lesions	Rate control	26/26	63.0 (9.5)	45 (86.5)	7 (13.5)	23.2 (7.9)	414 (94)	45.5 (22.1)	12 and 86.4
Khan et al,²⁴ 2008	PABA-CHF	Paroxysmal/; persistent AF; NYHA II-III; LVEF≤40%	PVI ± CFAE ± linear lesions	AVJ ablation + CRT	41/40	60.5 (8.0)	74 (91.4)	7 (8.6)	28.0 (7.5)	275 (49)	89.0 (11.4)	6
MacDonald et al,⁹ 2011	NA	Persistent AF; NYHA II-IV; LVEF<35%	PVI ± CFAE ± linear lesions	Rate control	22/19	63.3 (7.5)	32 (78.0)	9 (22.0)	39.3 (11.3)	334 (121)	57.4 (20.9)	6
Marrouche et al,⁸ 2018; Sanders et al,³¹ 2019	CASTLE-AF and substudy abstract	Paroxysmal or persistent AF; NYHA II-IV; LVEF≤35%	PVI ± CFAE ± linear lesions	Rate or rhythm control	179/184	64.2 (11.6)	311 (85.7)	52 (14.3)	31.8 (8.6)	Not available	Not available	36
Prabhu et al,¹⁰ 2017; Sugumar et al,²⁷ 2020	CAMERA-MRI and long-term outcomes	Persistent AF; NYHA II-IV; LVEF≤45%	PVI + PWI	Rate control	33/33	60.5 (10.3)	60 (91.0)	6 (9.0)	33.0 (8.6)	490 (139)	Not available	6 and 48
Kuck et al,²⁵ 2019	AMICA	Persistent AF; NYHA II-III; LVEF≤35%	PVI ± CFAE ± linear lesions	Rate or rhythm control	100/95	65.0 (8.0)	176 (90.3)	19 (9.7)	26.3 (9.2)	321 (107)	37.0 (24.1)	12
Packer et al,²² 2021	CABANA HF substudy	Paroxysmal or persistent AF; NYHA II-IV	PVI ± CFAE ± linear lesions ± ganglion plexus	Rate or rhythm control	378/400	67.7 (8.2)	433 (55.7)	345 (44.3)	55.3 (8.2)	Not available	Not available	48
Parkash et al,²¹ 2022	RAFT-AF	Paroxysmal or persistent AF; NYHA II-III; increased NT-proBNP	PVI ± CFAE ± linear lesions	Rate control	214/197	66.7 (8.3)	305 (74.2)	106 (25.8)	40.6 (14.8)	354 (104)	Not available	36
Chieng et al,³⁰ 2023	RCT-STALL	Paroxysmal or persistent AF; NYHA II-IV; LVEF≥50%; increased BNP level; increased PCWP	PVI + PWI ± linear lesions	Rate or rhythm control	16/15	66.1 (7.5)	15 (48.4)	16 (51.6)	59.5 (4.9)	Not available	44.0 (22.8)	6
Sohns et al,³² 2023	CASTLE-HTx	Paroxysmal or persistent AF; NYHA II-IV; LVEF≤35%; referred for heart transplant or LVAD implant	PVI ± CFAE ± linear lesions	Rate or rhythm control	97/97	63.5 (11.1)	157 (80.9)	37 (19.1)	27.0 (6.3)	304 (67)	Not available	18

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Abbreviations: 6MWT, 6-minute walk test; AF, atrial fibrillation; AVJ, atrioventricular junction; BNP, brain natriuretic peptide; CFAE, complex fractionated atrial electrograms; CRT, cardiac resynchronization therapy; HF, heart failure; LVAD, left ventricular assist device; LVEF, left ventricular ejection fraction; MLHFQ, Minnesota Living with Heart Failure Questionnaire; NA, not applicable; NT-proBNP; N-terminal fragment of the prohormone brain natriuretic peptide; NYHA, New York Heart Association; PCWP, pulmonary capillary wedge pressure; PVI, pulmonary vein isolation; PWI, posterior wall isolation.

Risk of Bias Assessment

Detailed outcome-specific assessment of risk of bias for each study is summarized in eFigure 1 in Supplement 1. Owing to the open-label design in included studies, there was some concern for bias in all studies with respect to deviations from intended interventions. This risk was higher in the Catheter Ablation vs Standard Conventional Therapy in Patients With Left Ventrical Dysfunction and Atrial Fibrillation (CASTLE-AF)⁸ and Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA)²² trials, which had a large number of withdrawals and losses to follow-up. The open-label design in the setting of patients with AF and HF who receive several other cointerventions is also subject of concern for bias in measurement of outcomes. Although this was mitigated in these trials by blinded outcome assessment, knowledge of treatment assignment may have affected the behavior of patients and health care personnel throughout the study. While this risk is higher in the measurement of subjective outcomes, this may also affect hard clinical outcomes because the knowledge of treatment assignments may consciously or subconsciously lead to cointervention bias.

HF Events

In a meta-analysis of 7 RCTs^{7,8,9,10,21,22,25} with 2057 participants (mean [SD] age, 65.8 [9.5] years; 589 females [28.6%]; mean follow-up, 35.5 months), there was a significant reduction in risk of HF events after catheter ablation (RR, 0.66; 95% CI, 0.55-0.79) compared with conventional rate or rhythm control therapies in patients with AF and HF (Figure 2A). These studies included a combination of patients with HFrEF (1108 participants; mean [SD] age, 64.0 [10.2] years; 291 females [26.3%]) and HFpEF (949 participants; mean [SD] age, 67.8 [8.2] years; 409 females [43.1%]). Catheter ablation was associated with a decrease in risk of HF events compared with conventional therapies in patients with HFrEF (107 of 560 patients [19.1%] vs 178 of 548 patients [32.5%]; RR, 0.59; 95% CI, 0.48-0.72), while no benefit was observed in patients with HFpEF (51 of 468 patients [10.9%] vs 55 of 481 patients [11.4%]; RR, 0.93; 95% CI, 0.65-1.32) (Figure 2B). Interaction analysis showed an interaction of HFpEF vs HFrEF status in the association of catheter ablation with HF event risk (P for interaction = .03). While there was evidence of moderate certainty in patients with HFrEF, findings in patients with HFpEF were based on low-certainty evidence (eTable 2 in Supplement 1).

Figure 2. — Outcomes are shown in A, patients with HF overall and B, patients with heart failure with reduced ejection fraction (HFrEF) vs those with heart failure with preserved ejection fraction (HFpEF). M-H indicates Mantel-Haenszel; NA, not applicable.

Cardiovascular Mortality

In a meta-analysis of 6 RCTs^{8,21,22,25,26,32} with 1991 participants (mean [SD] age, 66.1 [9.5] years; 561 females [28.2%]; mean follow-up, 35.8 months), there was a significant reduction in risk of cardiovascular mortality after catheter ablation (RR, 0.56; 95% CI, 0.40-0.77) compared with conventional rate or rhythm control in patients with AF and HF (Figure 3A). These studies included a combination of patients with HFrEF (1042 participants; mean [SD] age, 64.4 [10.4] years; 263 females [25.2%]) and the same population of 949 patients with HFpEF. Catheter ablation compared with conventional therapies was associated with reduced risk of cardiovascular death in patients with HFrEF (37 of 526 patients [7.0%] vs 78 of 516 patients [15.1%]; RR, 0.49; 95% CI, 0.34-0.70) but not in patients with HFpEF (15 of 468 patients [3.2%] vs 17 of 481 patients [3.5%]; RR, 0.91; 95% CI, 0.46-1.79) (Figure 3B), although no interaction was found (P for interaction = .12). These findings were based on moderate-certainty evidence in patients with HFrEF and low-certainty evidence in patients with HFpEF (eTable 2 in Supplement 1).

Figure 3. — Outcomes are shown in A, patients with heart failure overall and B, patients with heart failure with reduced ejection fraction (HFrEF) vs those with heart failure with preserved ejection fraction (HFpEF). M-H indicates Mantel-Haenszel; NA, not applicable.

All-Cause Mortality

In a meta-analysis of 9 RCTs^{7,8,21,22,25,27,28,29,32} with 2312 participants (mean [SD] age, 65.4 [9.8] years; 626 females [27.1%]; mean follow-up, 38.2 months), there was a significant relative risk reduction in all-cause mortality with catheter ablation (RR, 0.67; 95% CI, 0.52-0.86) compared with conventional rate or rhythm control therapies (Figure 4A). These studies included a combination of patients with HFrEF (1363 participants; mean [SD] age, 63.7 [10.4] years; 328 females [24.1%]) and the same population of 949 patients with HFpEF. Catheter ablation compared with conventional therapies was associated with reduced risk of all-cause mortality in patients with HFrEF (84 of 687 patients [12.2%] vs 137 of 676 patients [20.3%]; RR, 0.63; 95% CI, 0.47-0.86) but not in patients with HFpEF (34 of 468 patients [7.3%] vs 43 of 481 patients [8.9%]; RR, 0.95; 95% CI, 0.39-2.30) (Figure 4B); however, no interaction was found (P for interaction = .39). These findings were based on moderate-certainty evidence in patients with HFrEF and low-certainty evidence in patients with HFpEF (eTable 2 in Supplement 1).

Figure 4. — Outcomes are shown in A, patients with heart failure overall and B, patients with heart failure with reduced ejection fraction (HFrEF) vs those with heart failure with preserved ejection fraction (HFpEF). M-H indicates Mantel-Haenszel; NA, not applicable.

Change in LVEF, 6MWT, and MLHFQ

In a meta-analysis of 11 RCTs^{7,8,9,10,21,23,24,25,26,30,32} (1329 patients with HFrEF and 202 patients with HFpEF), catheter ablation was associated with a greater improvement in LVEF (MD, 5.79%; 95% CI, 3.37% to 8.21%) compared with conventional therapies. In subgroup analysis, improvement in LVEF was 6.5% (95% CI, 3.80% to 9.19%) in patients with HFrEF and 2.5% (95% CI, −4.64% to 9.67%) in patients with HFpEF (P for interaction = .31) (eFigure 2 in Supplement 1). In pooled data from 8 RCTs^{7,8,9,10,21,23,24,25} (1082 patients with HFrEF and 171 patients with HFpEF), catheter ablation compared with conventional therapies was associated with improved 6MWT score (MD, 21.76 m; 95% CI, 1.39 m to 42.13 m). In subgroup analysis, the improvement in 6MWT was 20.2 m (95% CI, −1.94 m to 42.33 m) among patients with HFrEF and 35.2 m (95% CI, −6.70 m to 77.10 m) among those with HFpEF (P for interaction = .53) (eFigure 3 in Supplement 1). In a meta-analysis of 9 RCTs^{7,9,21,23,24,25,26,30,31} (1155 patients with HFrEF and 202 patients with HFpEF), catheter ablation compared with conventional therapies was associated with a significant improvement in MLHFQ score (MD, −10.28 points; 95% CI, −16.55 to −4.01 points). In subgroup analysis, improvement in MLHFQ was −8.77 points (95% CI, −15.3 to −2.23 points) in HFrEF and −18.55 points (95% CI, −47.94 to 10.84 points) in HFpEF (P for interaction = .52) (eFigure 4 in Supplement 1). These findings were based on evidence with low certainty (eTable 2 in Supplement 1).

Sensitivity Analyses

Sensitivity analyses using fixed-effects models were consistent with main analyses (eFigure 5 in Supplement 1). In addition, findings on all-cause mortality based on original trial publications were similar and consistent with our main analyses using substudies with extended follow-up.

Discussion

To our knowledge, this study is the first systematic review and meta-analysis of randomized evidence to assess whether the efficacy of catheter ablation in the association with reduced HF-related outcomes is different according to HF phenotype. We found that catheter ablation compared with conventional therapies was associated with reduced risk of HF events in patients with HFrEF while having no apparent benefit in patients with HFpEF; this finding was significant on interaction testing. A similar pattern was seen for cardiovascular and all-cause mortality, but this analysis was underpowered to detect a differential association in patients with HFpEF using interaction testing. RCTs are needed to reach definitive conclusions about the role of catheter ablation in patients with HFpEF.

The global prevalence of HF ranges between 1% and 3% in the general population.³³ While the prevalence of HFrEF has remained steady or has even declined over the years, the prevalence of HFpEF is increasing and HFpEF may become the most prevalent form of HF in the future.³⁴ Hence, a great deal of attention has been redirected toward the treatment of patients with HFpEF over the past decade. AF is a coexistent condition in more than half of patients with HFpEF and is associated with an approximately 30% to 40% increase in HF hospitalizations and mortality.^35,36 Consistent with our findings, patients with HFpEF are additionally more often females and are of older age.³⁷ These inherent differences and underlying multisystem abnormalities seen in patients with HFpEF likely significantly contribute to the limited or absent benefit associated with several therapeutic options with proven efficacy in patients with HFrEF.³⁸ While the 2020 European Society of Cardiology guideline for management of AF assigned class I recommendation to catheter ablation for treatment of AF in patients with HFrEF, the optimal strategy for management of AF in patients with HFpEF is still unclear.³⁹ Earlier observational data found no significant differences in procedural success or long-term cardiovascular outcomes between patients with HFrEF and those with HFpEF undergoing catheter ablation.^40,41 However, further observational studies comparing the efficacy of catheter ablation with that of conventional therapies in patients with HFpEF showed inconsistent results.^42,43

To our knowledge, this systematic review and meta-analysis has for the first time pooled the most up-to-date randomized evidence to compare the differential efficacy of catheter ablation in the reduction of HF-related outcomes according to HF phenotype. The currently available randomized evidence suggests that catheter ablation for AF was associated with reduced risk of HF events in patients with HFrEF but with no or limited efficacy in patients with HFpEF. The association with cardiovascular death and all-cause mortality may also be similar to that of HF events given that differences in point estimates were similar for the different outcomes. However, we found no statistical evidence of effect modification for mortality between patients with HFrEF and HFpEF. This nonsignificant interaction P value may reflect lack of power owing to the small number of deaths from a limited number of studies enrolling patients with HFpEF, which consequently resulted in wide CIs in this group. This argument was supported in the comparison of HF events, where testing for subgroup differences using similar but more precise pooled estimates showed statistical significance. These observations indicate lack of sufficient power for drawing definitive conclusions about differential mortality benefit with catheter ablation according to HF phenotype.

There are 3 RCTs, each with its own limitations, that have addressed the impact of catheter ablation on HF-related outcomes in patients with HFpEF to date.^21,22,30 The CABANA trial²² was not specifically designed to enroll patients with HF and relied on NYHA functional classification to define HF based on breathlessness and exertion intolerance. This has raised concerns on whether the functional impairment observed in these patients was attributable to AF itself or a true representation of HF.⁴⁴ This is because of the overlapping symptoms between AF and HF that make them difficult to distinguish, more specifically in the presence of preserved left ventricular function.⁴⁵ The Rhythm Control-Catheter Ablation With or Without Anti-arrhythmic Drug Control of Maintaining Sinus Rhythm Versus Rate Control With Medical Therapy and/or Atrio-ventricular Junction Ablation and Pacemaker Treatment for Atrial Fibrillation (RAFT-AF) trial,²¹ although using more definitive criteria to describe HFpEF based on elevated natriuretic peptide, was stopped early for futility and failed to show improvements in major cardiovascular outcomes. However, this was the first RCT to provide groupwise, within-study comparisons between patients with HFrEF and those with HFpEF. Lastly, Randomised Controlled Study of Atrial Fibrillation and Left Ventricular Remodelling in Heart Failure With Preserved Ejection Fraction (RCT-STALL)³⁰ used the strictest criteria to define HFpEF based on confirmatory invasive hemodynamic parameters. This led to a highly selective enrollment of a cohort of patients with HFpEF at earlier stages of the disease, which may not be generalizable to patients with more severe illness and multiple comorbidities seen in clinical practice. Although RCT-STALL findings were suggestive of major functional improvements after catheter ablation, this proof-of-concept study was not powered to evaluate major clinical end points. It is still unclear whether observed improvements in invasive hemodynamic parameters could be translated to prevention of long-term outcomes. Important knowledge gaps are being targeted in the ongoing Catheter-Based Ablation of Atrial Fibrillation Compared to Conventional Treatment in Patients With Heart Failure With Preserved Ejection Fraction (CABA-HFPEF; NCT05508256) and Catheter Ablation in Atrial Fibrillation Patients With HFpEF (STABLE-SR IV; NCT06125925) RCTs. These studies are currently recruiting patients with AF and concomitant HFpEF to assess the efficacy of catheter ablation compared with medical therapy in reducing major cardiovascular outcomes. These studies may provide more conclusive evidence on the benefit of catheter ablation in patients with HFpEF.

Limitations

Our results should be interpreted in light of several limitations. Pooled effect estimates in patients with HFpEF were mostly heterogeneous, with wide CIs, mainly because of limited available randomized evidence in these patients. Included studies also used variable criteria for defining HFpEF, which likely further contributed to the heterogeneity. Additionally, owing to the lack of within-study subgroup estimates in patients with HFrEF vs those with HFpEF in the CABANA trial²² and because more than 90% of participants had an LVEF greater than 40%, we categorized all participants with HF in CABANA as having HFpEF. The assessment of heterogeneity between 2 subgroups is ideally performed if each individual trial provides within-study subgroup comparisons. However, owing to the limited available randomized evidence published to date among patients with HFpEF, this systematic review and meta-analysis tested for subgroup differences between patients with HFrEF and those with HFpEF mainly based on between-study comparison of available trials. Although we were able to acquire within-study subgroup data from the RAFT-AF trial and used this information in subgroup comparisons to mitigate previously mentioned potential biases, possible treatment interactions observed in our study should be cautiously interpreted. Future and ongoing RCTs in patients with HFpEF may provide clearer answers to fill this important knowledge gap.

Conclusions

This systematic review and meta-analysis found that catheter ablation for AF was superior to conventional rate or rhythm control therapies in the reduction of HF events in patients with HFrEF but such benefit did not extend to patients with HFpEF. A similar pattern was seen for cardiovascular and all-cause mortality, but this analysis was likely underpowered to demonstrate a treatment interaction. Future and ongoing well-designed, large RCTs are needed to delineate the role of catheter ablation in reducing HF-related outcomes in patients with HFpEF.

Supplement 1.

eTable 1. Search Strategy

eTable 2. Certainty of Evidence

eFigure 1. Risk of Bias Assessment

eFigure 2. Change in Left Ventricular Ejection Fraction

eFigure 3. Change in 6-Minute Walk Test

eFigure 4. Change in Minnesota Living With Heart Failure Questionnaire

eFigure 5. Sensitivity Analyses

jamacardiol-e240675-s001.pdf^{(1MB, pdf)}

Supplement 2.

Data Sharing Statement

jamacardiol-e240675-s002.pdf^{(136.6KB, pdf)}

References

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eTable 1. Search Strategy

eTable 2. Certainty of Evidence

eFigure 1. Risk of Bias Assessment

eFigure 2. Change in Left Ventricular Ejection Fraction

eFigure 3. Change in 6-Minute Walk Test

eFigure 4. Change in Minnesota Living With Heart Failure Questionnaire

eFigure 5. Sensitivity Analyses

jamacardiol-e240675-s001.pdf^{(1MB, pdf)}

Supplement 2.

Data Sharing Statement

jamacardiol-e240675-s002.pdf^{(136.6KB, pdf)}

[hoi240015r1] 1.Santhanakrishnan R, Wang N, Larson MG, et al. Atrial fibrillation begets heart failure and vice versa: temporal associations and differences in preserved versus reduced ejection fraction. Circulation. 2016;133(5):484-492. doi: 10.1161/CIRCULATIONAHA.115.018614 [DOI] [PMC free article] [PubMed] [Google Scholar]

[hoi240015r2] 2.Wang TJ, Larson MG, Levy D, et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. Circulation. 2003;107(23):2920-2925. doi: 10.1161/01.CIR.0000072767.89944.6E [DOI] [PubMed] [Google Scholar]

[hoi240015r3] 3.Chioncel O, Lainscak M, Seferovic PM, et al. Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry. Eur J Heart Fail. 2017;19(12):1574-1585. doi: 10.1002/ejhf.813 [DOI] [PubMed] [Google Scholar]

[hoi240015r4] 4.Dunlay SM, Roger VL, Redfield MM. Epidemiology of heart failure with preserved ejection fraction. Nat Rev Cardiol. 2017;14(10):591-602. doi: 10.1038/nrcardio.2017.65 [DOI] [PubMed] [Google Scholar]

[hoi240015r5] 5.Son MK, Park JJ, Lim NK, Kim WH, Choi DJ. Impact of atrial fibrillation in patients with heart failure and reduced, mid-range or preserved ejection fraction. Heart. 2020;106(15):1160-1168. doi: 10.1136/heartjnl-2019-316219 [DOI] [PMC free article] [PubMed] [Google Scholar]

[hoi240015r6] 6.Zafrir B, Lund LH, Laroche C, et al. ; ESC-HFA HF Long-Term Registry Investigators . Prognostic implications of atrial fibrillation in heart failure with reduced, mid-range, and preserved ejection fraction: a report from 14 964 patients in the European Society of Cardiology Heart Failure Long-Term Registry. Eur Heart J. 2018;39(48):4277-4284. doi: 10.1093/eurheartj/ehy626 [DOI] [PubMed] [Google Scholar]

[hoi240015r7] 7.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. Circulation. 2016;133(17):1637-1644. doi: 10.1161/CIRCULATIONAHA.115.019406 [DOI] [PubMed] [Google Scholar]

[hoi240015r8] 8.Marrouche NF, Brachmann J, Andresen D, et al. ; CASTLE-AF Investigators . Catheter ablation for atrial fibrillation with heart failure. N Engl J Med. 2018;378(5):417-427. doi: 10.1056/NEJMoa1707855 [DOI] [PubMed] [Google Scholar]

[hoi240015r9] 9.MacDonald MR, Connelly DT, Hawkins NM, et al. Radiofrequency ablation for persistent atrial fibrillation in patients with advanced heart failure and severe left ventricular systolic dysfunction: a randomised controlled trial. Heart. 2011;97(9):740-747. doi: 10.1136/hrt.2010.207340 [DOI] [PubMed] [Google Scholar]

[hoi240015r10] 10.Prabhu S, Taylor AJ, Costello BT, et al. Catheter ablation versus medical rate control in atrial fibrillation and systolic dysfunction: the CAMERA-MRI study. J Am Coll Cardiol. 2017;70(16):1949-1961. doi: 10.1016/j.jacc.2017.08.041 [DOI] [PubMed] [Google Scholar]

[hoi240015r11] 11.van Veldhuisen DJ, Cohen-Solal A, Böhm M, et al. ; SENIORS Investigators . Beta-blockade with nebivolol in elderly heart failure patients with impaired and preserved left ventricular ejection fraction: data from SENIORS (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure). J Am Coll Cardiol. 2009;53(23):2150-2158. doi: 10.1016/j.jacc.2009.02.046 [DOI] [PubMed] [Google Scholar]

[hoi240015r12] 12.Yamamoto K, Origasa H, Hori M; J-DHF Investigators . Effects of carvedilol on heart failure with preserved ejection fraction: the Japanese Diastolic Heart Failure Study (J-DHF). Eur J Heart Fail. 2013;15(1):110-118. doi: 10.1093/eurjhf/hfs141 [DOI] [PubMed] [Google Scholar]

[hoi240015r13] 13.Pitt B, Pfeffer MA, Assmann SF, et al. ; TOPCAT Investigators . Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370(15):1383-1392. doi: 10.1056/NEJMoa1313731 [DOI] [PubMed] [Google Scholar]

[hoi240015r14] 14.Solomon SD, McMurray JJV, Anand IS, et al. ; PARAGON-HF Investigators and Committees . Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med. 2019;381(17):1609-1620. doi: 10.1056/NEJMoa1908655 [DOI] [PubMed] [Google Scholar]

[hoi240015r15] 15.Higgins J, Thomas J, Chandler J, et al. Cochrane Handbook for Systematic Reviews of Interventions: Version 6.3. Cochrane; 2022. Accessed March 18, 2024. https://training.cochrane.org/handbook/archive/v6.3 [Google Scholar]

[hoi240015r16] 16.Lefebvre C, Glanville J, Briscoe S, et al. Technical Supplement to Chapter 4: Searching for and selecting studies. In: Higgins JPT, Thomas J, Chandler J, et al. Cochrane Handbook for Systematic Reviews of Interventions: Version 6.3. Cochrane; 2022. Accessed March 18, 2024. https://training.cochrane.org/handbook/archive/v6.3/technical-supplement-chapter-4-searching-and-selecting-studies-v63. [Google Scholar]

[hoi240015r17] 17.Rohatgi A. WebPlotDigitizer 4.6. Accessed March 18, 2024. https://automeris.io/WebPlotDigitizer.

[hoi240015r18] 18.Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. doi: 10.1136/bmj.l4898 [DOI] [PubMed] [Google Scholar]

[hoi240015r19] 19.Schünemann H, Brożek J, Guyatt G, Oxman A, eds. GRADE Handbook. Updated October 2013. The GRADE Working Group; 2013, Accessed March 18, 2024. https://gdt.gradepro.org/app/handbook/handbook.html [Google Scholar]

[hoi240015r20] 20.McMaster University; Evidence Prime . GRADEpro GDT. Accessed March 18, 2024. https://www.gradepro.org/

[hoi240015r21] 21.Parkash R, Wells GA, Rouleau J, et al. Randomized ablation-based rhythm-control versus rate-control trial in patients with heart failure and atrial fibrillation: results from the RAFT-AF trial. Circulation. 2022;145(23):1693-1704. doi: 10.1161/CIRCULATIONAHA.121.057095 [DOI] [PubMed] [Google Scholar]

[hoi240015r22] 22.Packer DL, Piccini JP, Monahan KH, et al. ; CABANA Investigators . Ablation versus drug therapy for atrial fibrillation in heart failure: results from the CABANA trial. Circulation. 2021;143(14):1377-1390. doi: 10.1161/CIRCULATIONAHA.120.050991 [DOI] [PMC free article] [PubMed] [Google Scholar]

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PERMALINK

Atrial Fibrillation Ablation in Heart Failure With Reduced vs Preserved Ejection Fraction

Alireza Oraii, MD

William F McIntyre, MD, PhD

Ratika Parkash, MD, MSc

Krzysztof Kowalik, MSc

Ghazal Razeghi, BSc

Alexander P Benz, MD, MSc

Emilie P Belley-Côté, MD, PhD

David Conen, MD, MPH

Stuart J Connolly, MD

Anthony S L Tang, MD

Jeff S Healey, MD, MSc

Jorge A Wong, MD, MPH

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Data Source

Study Selection

Data Extraction and Synthesis

Main Outcomes and Measures

Results

Conclusions and Relevance

Introduction

Methods

Protocol and Registration

Search Strategy and Study Selection

Eligibility Criteria

Data Extraction and Management

Risk of Bias and Certainty of Evidence

Statistical Analysis

Data Synthesis

Subgroup Analyses Based on HFrEF vs HFpEF

Results

Figure 1. Study Flowchart.

Included Studies

Table. Baseline Characteristics of Included Studies.

Risk of Bias Assessment

HF Events

Figure 2. Efficacy of Catheter Ablation in Reduction of Heart Failure (HF) Events.

Cardiovascular Mortality

Figure 3. Efficacy of Catheter Ablation in Reduction of Cardiovascular Mortality.

All-Cause Mortality

Figure 4. Efficacy of Catheter Ablation in Reduction of All-Cause Mortality.

Change in LVEF, 6MWT, and MLHFQ

Sensitivity Analyses

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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Links to NCBI Databases