Effectiveness of catheter ablation of atrial fibrillation according to heart failure etiology

Abstract Background Catheter ablation is an important rhythm control therapy in patients with atrial fibrillation (AF) with concomitant heart failure (HF). The objective of this study was to assess the comparative efficacy of AF ablation patients with ischemic vs nonischemic heart failure. Methods We conducted a retrospective, observational cohort study of patients with HF who underwent AF ablation. Outcomes were compared based on HF etiology and included in‐hospital events, symptoms (Mayo AF Symptom Inventory [MAFSI]), and functional status (New York Heart Association class) and freedom from atrial arrhythmias at 12 months. Results Among 242 patients (n = 70 [29%] ischemic, n = 172 [71%] nonischemic), patients with nonischemic cardiomyopathy were younger (mean age 64 ± 11.5 vs 69 ± 9.1, P = .002), more often female (36% vs 17%, P = .004), and had higher mean left‐ventricular ejection fraction (47% vs 42%, P = .0007). There were no significant differences in periprocedural characteristics, including mean procedure time (243 ± 74.2 vs 259 ± 81.8 minutes, P = .1) and nonleft atrial ablation (17% vs 20%, P = .6). All‐cause adverse events were similar in each group (15% vs 17%, P = .7). NYHA and MAFSI scores improved significantly at follow‐up and did not differ according to HF etiology (P = .5; P = .10‐1.00 after Bonferroni correction). There were no significant differences in freedom from recurrent atrial arrhythmia at 12‐months between ischemic (74%) and nonischemic patients (78%): adjusted RR 0.63, 95% confidence interval 0.33‐1.19. Conclusions Catheter ablation in patients with AF and concomitant heart failure leads to significant improvements in functional and symptom status without significant differences between patients with ischemic vs nonischemic HF etiology.


| INTRODUC TI ON
Atrial Fibrillation (AF) and heart failure (HF) are two of the most common cardiovascular diseases. They both reduce quality of life and longevity, particularly when they accompany one another. 1,2 AF is independently associated with worse left ventricular systolic function and worse quality of life in patients with HF. [3][4][5] Furthermore, the presence of HF complicates treatment for AF, as several antiarrhythmic drugs are contraindicated because of the potential for harm in HF. Yet, the remaining guideline-advocated medical therapies, including dofetilide and amiodarone, suffer from suboptimal effectiveness and still have potential for harm. Drug toxicity is likely partly attributable for the failure of a "rhythm control" strategy to prove superior to rate-only control in AF patients with or without HF. 6,7 Therefore, catheter ablation represents an appealing approach to the management of AF in these patients. [8][9][10][11][12][13] .
Catheter ablation of AF is currently recommended for patients with symptomatic AF refractory to antiarrhythmic therapy. 14 It has proven to be an effective therapy in patients with HF, 15 resulting in improved freedom from AF, functional status and left ventricular function. [11][12][13] In the recently published randomized controlled trial Catheter Ablation for Atrial Fibrillation with Heart Failure (CASTLE-AF), AF ablation in patients with systolic HF led to statistically significant reductions in hospitalization and mortality. 16 It is well appreciated that the etiology of cardiomyopathy and differences in underlying substrate influence outcomes in both catheter ablation of ventricular tachycardia and cardiac resynchronization therapy. 17,18 However, few studies have assessed the impact of HF etiology on outcomes of catheter ablation for concomitant AF. Accordingly, we sought to compare outcomes of AF ablation in patients with cardiomyopathy that was ischemic in origin, vs those with nonischemic cardiomyopathy. We hypothesized that patients with nonischemic cardiomyopathy may experience worse outcomes following AF ablation compared with patients with ischemic cardiomyopathy, because of a propensity for more extensive atrial myopathy.

| ME THODS
We conducted a retrospective observational cohort study within the Duke Center for Atrial Fibrillation. Consecutive AF catheter ablation procedures in adult patients (≥18 years) at the Duke University Medical Center from January 1, 2007 and June 30, 2013 were reviewed for inclusion in the analysis cohort. Only patients with a baseline clinical diagnosis of HF were included, and heart failure was defined clinically by the patient's primary cardiologist based upon signs and symptoms at the time of their HF diagnosis. 19,20 This included both HF with reduced and preserved ejection fraction. For the purpose of this analysis, the cohort was stratified by ischemic and nonischemic etiology. This was also defined by the patient's primary cardiologist, as to whether coronary artery disease, if present, was the predominant contributor to the patient's HF. Coronary artery disease was defined as an epicardial stenosis of 70% or greater (>50% in the left main coronary artery). Moreover, HF etiology was also confirmed with cardiovascular imaging (focal wall motion abnormalities on echocardiography and/or scar pattern on cardiac MRI). Hybrid catheter-based and/or surgical procedures (open or thoracoscopic) and those using cryoballoon or laser ablation were excluded. Thus, for the purpose of this analysis, only radiofrequency ablation procedures were included. All procedures were performed under general anesthesia. Heparin was administered at the time of trans-septal puncture and activated clotting times were maintained between 300 and 400 seconds. Ablation was performed with open-irrigated catheters and the use of an electroanatomic mapping system (CARTO (Biosense-Webster Inc, Diamond Bar, CA) or NavX (St. Jude Medical, Minneapolis, MN)). Intracardiac ultrasound was used in all cases. In all cases, pulmonary vein isolation was performed using a circumferential approach with documentation of entrance and exit block with the use of a circular decapolar catheter. Additional ablation lesions were performed at the discretion of the primary operator, and were most commonly driven by clinical circumstances. Anticoagulation was continued for a minimum of 3 months postprocedure and thereafter according to guideline recommendations based upon the CHA 2 DS 2-VASc score.
For each ablation, baseline demographics, medical history, imaging, laboratory data, and medical therapies were reviewed and abstracted. The diagnosis of obstructive sleep apnea was determined by polysomnography demonstrating apnea hypopnea index > 15 or apnea hypopnea index 5-14 with suggestive symptoms. 21 The index operative report was reviewed and abstracted as well. In-hospital, periprocedural outcomes, as well as arrhythmia outcomes up to 12 months were recorded. Adverse events included any access site adverse events, pericardial tamponade, stroke or transient ischemic attack (TIA), acute HF, or in-hospital death. Symptom status was assessed using the New York Heart Association HF classification scale, and using an abbreviated form of the disease-specific Mayo AF Symptom Inventory. 22 Clinical outcomes at last follow-up included use of antiarrhythmic therapy, symptomatic recurrence, and documented arrhythmia recurrence. These assessments were based on clinical follow-up of reported symptoms and arrhythmia recurrence was defined as: atrial tachycardia, atrial flutter, or atrial fibrillation (AT/AF/AFL) on a 12-lead electrocardiogram; AT/AF/ AFL ≥ 30 seconds on a continuous monitor or implantable device; or AT/AF/AFL that required cardioversion. We employed a 3-month blanking period for the arrhythmia endpoint. In addition to chart review of primary data, assessment of symptoms and adverse events K E Y W O R D S atrial fibrillation, cardiomyopathy, catheter ablation, heart failure, outcomes was performed by direct patient phone call starting 1-week postprocedure, with an additional call at 3, 6 and 12 months, in addition to scheduled clinic visits. Symptoms were assessed using the modified Mayo AF-Specific Symptom Inventory (MAFSI) questionnaire, which was administered in clinic preprocedurally and by phone call postprocedurally. Electrocardiograms were performed at regularly scheduled clinic visits at 3, 6, and 12 months. Additional ECG monitoring was performed at the discretion of individual providers and in the presence of symptoms concerning for arrhythmia recurrence.
Patients with an implanted device received routine quarterly device interrogation including assessment for arrhythmia recurrence. 22

| Statistical methods
Baseline and ablation characteristics were described using counts and percentages (categorical) or mean and standard deviation (continuous). Univariate comparisons of baseline and ablation characteristics were made using Chi-squared or Fisher's exact test for categorical variables and ANOVA for continuous variables as appropriate. Changes in NYHA classification between baseline and the latest follow-up were analyzed using Wilcoxon signed rank test within each HF etiology group; changes were compared between the groups using Wilcoxon rank-sum test.
Comparisons of in-hospital and 12-month outcomes between HF etiology groups were performed using Chi-square tests. This study was approved by the Duke University Institutional Review Board, which granted a common rule exemption to the requirement of individual patient informed consent. All statistical analyses of the aggregate, deidentified data were performed by the Duke Clinical Research Institute using SAS software (version 9.4, SAS Institute). P < .05 was considered statistically significant. ). There were important differences in baseline characteristics between the two groups, including age (mean 69 for ischemic vs 64 for nonischemic, P = .002), gender (female 17% for ischemic vs 36% for nonischemic, P = .004), and mean leftventricular ejection fraction (LVEF, 42% for ischemic vs 47% for nonischemic, P = .0007, Table 1). At baseline, there were no major differences in medical therapy between the two groups-patients not on antiarrhythmic therapy comprised 40% of the ischemic group and 35% of the nonischemic group (P = .28). Ablation procedure characteristics are shown in Table S1 and were roughly balanced between ischemic and nonischemic patients, including mean procedure times (259 minutes for ischemic vs 243 for nonischemic, P = .13), mean ablation time (58 minutes for ischemic, 56 for nonischemic, P = .6), and mean fluoroscopy time (51 minutes for ischemic vs 54 for nonischemic, P = .44). The most common adjunctive ablation, beyond PVI, was a left atrial roof line in both groups (40% for ischemic vs 41% of nonischemic, P = .92).

| Maintenance of sinus rhythm
Unadjusted clinical outcomes are shown in Table 2. Overall, freedom from recurrent atrial arrhythmia was 76.8% at 12-months

| D ISCUSS I ON
Results from randomized clinical trials demonstrate a robust benefit of AF catheter ablation in patients with systolic HF, including improvement in quality of life and reductions in HF hospitalization and mortality. 16 However, the 329 patient DECAAF study included a relatively few patients with congestive heart failure (n = 15) and coronary artery disease (n = 26) and found no statistical association between either factor and atrial fibrosis. 30 Importantly, we did not observe differences in outcomes between patients with ischemic cardiomyopathy vs those with nonischemic cardiomyopathy. A systematic review has shown greater improvement in ventricular function in cohorts with less ischemic disease undergoing catheter ablation for AF. 24 This finding was consistent in a recent, smaller cohort (n = 100) in which improved AF control was observed in patients with idiopathic cardiomyopathy undergoing ablation, compared to patients with known causes of structural heart disease. 31 Similar to our study findings, there F I G U R E 1 Change in NYHA class distribution from baseline to last followup after ablation, stratified by heart failure etiology. NYHA = New York Heart Association functional classification with class I = no limitation in normal activity, class II = mild symptoms only in normal activity, class III = marked symptoms during daily activities but asymptomatic at rest, and class IV = severe limitations with symptoms at rest   34 Patients with less severe left ventricular dysfunction (LVEF 25%-35%) received more benefit from AF ablation than those with severe LV dysfunction (LVEF < 25%) in CASTLE-AF. 16 Detailed analysis of the HF population in the CABANA trial have not yet been published, but will hopefully provide additional insights.

| Limitations
This is a single-center, retrospective, observational study, which may limit generalizability. Furthermore, the diagnosis of heart failure with preserved ejection fraction was made clinically, and formal diagnostic criteria for this entity vary even in the context of carefully con-

| CON CLUS IONS
Consistent with prior experience, catheter ablation for AF in patients with concomitant HF is associated with substantial improvement in symptoms, functional status, and freedom from recurrent atrial arrhythmia. While the underlying myopathic processes may be different in patients with ischemic and nonischemic HF, we found no significant differences in outcomes according to HF etiology following catheter ablation of AF. Unlike other electrophysiologic interventions, patients with ischemic and nonischemic cardiomyopathy appear to derive a similar magnitude of benefit following AF ablation. Further investigations are needed to determine which subgroups of patients with concomitant AF and HF are most likely to benefit from catheter ablation.