Traditionally, the rationale for rhythm control for atrial fibrillation (AF) has been focused on quality of life. More recently, the EAST-AFNET 4 clinical trial (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial) demonstrated a reduction in the composite of death resulting from cardiovascular cause, stroke, or hospitalization with worsening of heart failure or acute coronary syndrome with early rhythm control. Management of AF in patients with concomitant heart failure requires additional considerations relative to the general population. Meta-analysis data of >50 000 patients have demonstrated that in patients with heart failure, AF is associated with 40% higher odds of death among patients included in randomized trials and 14% higher odds of death in patients in observational studies. The antiarrhythmic medication options in patients with heart failure are limited. Historically, catheter ablation for AF has been shown to be more effective than antiarrhythmic drugs at maintaining sinus rhythm, including in patients with heart failure, but had not been shown to improve clinical outcomes.[4,5] A series of more recent clinical trials now provides a growing body of evidence to change that, in particular for patients with heart failure, although no single trial has been conclusive.[5–8] Thus, any additional randomized data comparing the clinical impact of ablation to control in patients with heart failure are welcome.
Catheter ablation received a Class IIb (Level of Evidence B, randomized) in the 2019 American Heart Association/American College of Cardiology/Heart Rhythm Society guidelines for AF in selected patients with symptomatic AF and heart failure with reduced left ventricular ejection fraction (HFrEF) "to potentially lower mortality rate and reduce hospitalization for heart failure." It received a Class IIa (Level of Evidence B) recommendation in the 2020 European Society of Cardiology guidelines for AF, which stated that "ablation should be considered in patients with HFrEF who have been selected for rhythm control treatment to improve quality of life and LV [left ventricular] function, and to reduce heart failure hospitalization and, potentially, mortality." The 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America guideline for the management of heart failure provides a Class IIa recommendation for catheter ablation for patients with heart failure and symptoms caused by AF "to improve symptoms and quality of life."
The recent evidence the guidelines cite suggesting a benefit of catheter ablation on clinical outcomes came from 2 randomized trials, AATAC (Ablation vs Amiodarone for Treatment of Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted ICD/CRTD; 203 patients) and CASTLE-AF (Catheter Ablation for Atrial Fibrillation With Heart Failure; 363 patients),[5,6] of selected patients with AF and HFrEF and implanted defibrillators. Although AATAC found lower rates of death and hospitalization as secondary outcomes, CASTLE-AF was designed to assess the effect on death or hospitalization for heart failure with 3 years of follow-up and found a 38% relative risk reduction. Limitations to CASTLE-AF include failure to reach the target sample size, low power with only 133 primary outcome events, and omission of a substantial portion of patients from the primary analysis attributable to exclusions and loss to follow-up. Therefore, in aggregate, these trials should be interpreted as providing modest evidence for benefit on clinical outcomes, as reflected in the guidelines.
Investigators of the largest randomized trial of ablation versus medical therapy, CABANA (Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation), reported a prespecified subgroup analysis of 778 (of the 2204 total) patients with symptomatic heart failure (New York Heart Association class II or greater) at baseline, showing a significant reduction in the primary composite of death, disabling stroke, serious bleeding, or cardiac arrest, as well as a reduction in mortality. Although supportive of a treatment benefit of catheter ablation with heart failure, this was a subgroup analysis of a trial not showing a significant reduction in its primary outcome, without a significant subgroup-by-treatment interaction. This included HFrEF and heart failure with preserved ejection fraction, with most patients in this analysis having an ejection fraction >40%.
In this issue of Circulation, Parkash et al report the results of the RAFT-AF trial (Randomized Ablation-Based Rhythm-Control Versus Rate-Control Trial in Patients With Heart Failure and Atrial Fibrillation). In this modest-sized randomized trial, 411 patients with high-burden paroxysmal or persistent AF, symptomatic heart failure (60% with ejection fraction ≤45%), and elevated NT-proBNP (N-terminal pro-B-type natriuretic peptide) were randomized to catheter ablation or rate control. The trial was stopped early on recommendation of the Data Monitoring Committee, which made the determination of futility. Enrollment was slower than expected, and the Data Monitoring Committee, at the interim analysis in September 2017, found a trend for worse outcome with catheter ablation (hazard ratio for confirmed primary outcome events, 1.32) and calculated a 19% probability of a statistically significant improvement if the trial were completed with the originally hypothesized treatment effect in the remaining patients. This met the prespecified criteria for futility. However, the final results found the opposite of what was seen in the interim analysis: There was a modest, nonsignificant benefit (50 versus 64 primary events of mortality or heart failure events) with ablation, representing a 29% relative risk reduction that did not reach statistical significance (P=0.066). The secondary outcomes (change in ejection fraction, 6-minute walk distance, and change in NT-proBNP) all favored ablation. It is unfortunate that the trial was not completed as planned to the original sample size of 1000 patients or to the subsequent planned sample size of 600 patients. This trial provides an important cautionary tale to Data Monitoring committees about the risk of early termination of trials for futility. Trials are generally designed to need the entire sample size and planned events to reliably estimate modest treatment effects, and interim data can be unreliable to estimate final results. An example is the ISIS-2 trial (Second International Study of Infarct Survival) in which deaths with aspirin versus placebo were roughly even after 350 (of the final 1800) deaths, a finding that might have led to a determination of futility and prevented completion of one of the most important trials ever conducted.
Nevertheless, even before the RAFT-AF trial results, evidence was building for a benefit of catheter ablation for patients with AF. A meta-analysis of 6 randomized trials assessing catheter ablation versus antiarrhythmic medication for first-line therapy of paroxysmal AF (without heart failure) found that among 1212 patients, ablation was associated with a 38% relative risk reduction in AF burden relative to antiarrhythmic medications (32.3% recurrence with ablation versus 53% recurrence with antiarrhythmic medications; P<0.001). Thus, 5 patients would need to be treated with ablation instead of antiarrhythmic medication to prevent 1 patient from having arrhythmia recurrence. Coupled with improved safety and emerging evidence of improved clinical outcomes and quality of life, this has caused a shift toward more patients with paroxysmal AF having ablation early in their clinical course of AF.
With modest evidence for clinical benefit in relatively small trials of patients with heart failure, considerable uncertainty remains as to which patients within the heart failure population will derive clear benefit from catheter ablation. For example, patients with a component of their cardiomyopathy that is tachycardia mediated appear to have greater benefit from catheter ablation, which is why these patients have a Class I recommendation for ablation in the European Society of Cardiology guidelines for AF. Subgroup analyses from CASTLE-AF found that patients with less severe heart failure symptoms—class I and II compared with class III and IV symptoms—appeared to have a greater reduction in the primary outcome with ablation (Pinteraction=0.028). Patients in the CAMERA-MRI study (Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Heart Failure—An MRI-Guided Multicenter Randomized Controlled Trial) with left ventricular scar on cardiac magnetic resonance imaging tended to have less improvement in their ejection fraction after ablation relative to patients without left ventricular scar. More studies are needed to better understand the optimal heart failure population for ablation.
In addition to the trials suggesting benefit on clinical outcomes, several clinical trials have demonstrated improvement in ejection fraction and lower recurrence of AF among patients with HFrEF. Although RAFT-AF would have been much more valuable if had been carried to completion, it adds to the growing evidence that for patients with heart failure, especially those with reduced ejection fraction, catheter ablation appears to have meaningful clinical benefit.
Sources of Funding
Circulation. 2022;145(23):1705-1707. © 2022 American Heart Association, Inc.