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Five-Year Outcomes of Catheter Ablation in Patients with Atrial Fibrillation and Left Ventricular Systolic Dysfunction T. JARED BUNCH, M.D., HEIDI T. MAY, Ph.D., M.S.P.H., TAMI L. BAIR, R.N., VICTORIA JACOBS, N.P., BRIAN G. CRANDALL, M.D., MICHAEL CUTLER, D.O., Ph.D., J. PETER WEISS, M.D., CHARLES MALLENDER, M.D., JEFFREY S. OSBORN, M.D., JEFFREY L. ANDERSON, M.D., and JOHN D. DAY, M.D. From the Intermountain Heart Institute, Intermountain Medical Center, Murray, Utah, USA

Catheter Ablation and Long-Term Outcomes. Background: Catheter ablation of atrial fibrillation (AF) is an established therapy for symptomatic patients. The long-term efficacy and impact of catheter ablation among patients with severe systolic heart failure (SHF) requires additional study to understand if outcomes achieved at 1 year are maintained and mechanisms of AF recurrence. Methods: Three groups with SHF and 5 years of follow-up were matched 1:4:4 by age (±5 years) and sex: AF ablation patients receiving their first ablation (n = 267), AF patients that did not receive an ablation (n = 1,068), and SHF patient without AF (n = 1,068). SHF was based upon clinical diagnosis and an ejection fraction (EF) ࣘ35%. Patients were followed for 5-year primary outcomes of AF recurrence, heart failure, stroke, death, and cardiac function. Results: At 5 years, 60.7% of patients had clinical recurrence of AF. Diabetes and a prior heart attack were significant predictors of long-term risk of AF recurrence. Long-term mortality rates were 27%, 55%, 50%, in the AF ablation, AF, and no AF groups, respectively (P < 0.0001), with the lower rates attributed to lower cardiovascular mortality. At 5 years, there was no difference in EF, yet HF hospitalizations were lower following AF ablation compared to patients with AF and no ablation. Stroke rates at 5 years trended to be lower in the AF ablation group, but the difference was not statistically significant. Conclusion: Recurrence rates of AF in patients with SHF after ablation are common at 5 years with an anticipated ongoing increase. Long-term AF-related comorbidities tended to be less in the AF ablation group. (J Cardiovasc Electrophysiol, Vol. pp. 1-8) atrial fibrillation, catheter ablation, heart failure, mortality, outcomes, stroke Background Atrial fibrillation (AF) remains the most common encountered sustained arrhythmia in clinical practice. The prevalence of AF has been increasing worldwide resulting in a tremendous burden on health care resources.1 In addition to a quantitative impact on quality of life and function, AF also adversely impacts mortality, stroke, heart failure (HF), and dementia.2,3 Heart failure is also a common clinical condition and shares many of the risk factors as AF such as aging, hypertension, ischemic heart disease, and diabetes.4,5 As such, these disease states are often coincident.6 The presence of both AF and HF has incremental adverse effect on therapeutic options, drug metabolism, renal function, and overall outcomes. T. Jared Bunch reports serving on an advisory board for Boston Scientific; Jeffrey S. Osborn reports speaker’s honorarium/consulting: Medtronic, Cook, Boston Scientific, St. Jude Medical. J. Peter Weiss reports speaker honorarium/consulting: Stereotaxis, Biosense Webster, St. Jude Medical. Other authors: No disclosures. Address for correspondence: T. Jared Bunch, M.D., Intermountain Medical Center, Eccles Outpatient Care Center, 5169 Cottonwood St, Suite 510, Murray, UT 84107, USA. Fax: 801-507-3584; E-mail: [email protected] Manuscript received 15 September 2014; Revised manuscript received 15 November 2014; Accepted for publication 4 December 2014. doi: 10.1111/jce.12602

Pharmacologic therapies to maintain sinus rhythm in SHF patients with AF are limited in efficacy and have inherent and disease-evolving toxicities. Their routine use demonstrated lack of improvement in mortality, stroke, or worsening HF in the AF-CHF trial.7 As such, nonpharmacologic approaches have evolved as long-term alternatives for AF disease management in patients with systolic heart failure (SHF). The results of the PABA-CHF trial, a trial of the most aggressive rate control strategy (AV node ablation with biventricular pacing) and the most aggressive rhythm control strategy (catheter ablation), revealed that patients treated aggressively with a nonpharmacologic rhythm control approach had better heart failure related outcomes.8 Given the limitations of pharmacologic therapies and the potential benefits of safer rhythm control therapies in AF patients with SHF, catheter ablation remains an important therapeutic option in the long-term management of AF in these patients. Observational studies of catheter ablation in patients with moderate–severe SHF have demonstrated safety and efficacy rates similar to patients with less severe structural heart disease although repeat procedures are more common, and more extensive ablation is often necessary.9,10 The randomized controlled trial of catheter ablation versus medical treatment of atrial fibrillation in heart failure (CAMTAF trial) reported that catheter ablation over 6 months in persistent AF patients was associated with improved functional status and cardiac function compared to rate control.11

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Journal of Cardiovascular Electrophysiology

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Heart failure is often a progressive disease and as such over time it will likely influence the overall success of rhythm control strategies like catheter ablation. It follows that favorable outcomes at 1 year following catheter ablation for AF may not be maintained at 5 years if the cardiomyopathy progresses. In this regard, long-term follow-up data are required to fully understand the long-term outcomes of catheter ablation in patients with moderate–severe left ventricular dysfunction both in regards to safety and efficacy. Therefore, in this study we report 5-year clinical outcomes of catheter ablation for symptomatic AF in patients with moderate-severe left ventricular dysfunction. Methods Patient Populations Three cohorts of SHF, ejection fraction ࣘ0.35) patients with 5-year follow-up and matched 1:4:4 by age (±5 years) and sex were studied: (1) symptomatic AF undergoing their first catheter ablation (n = 267); (2) symptomatic AF that did not receive catheter ablation (n = 1,068); and (3) patients with no AF (n = 1,068). The “no AF” patients with SHF, serving roughly as a 4:1 control population, were from the catheterization registry of the Intermountain Heart Collaborative Study. SHF was defined as having both a clinical diagnosis (International Classification of Diseases, Ninth Revision [ICD-9] code 428.2*) and an ejection fraction (EF) ࣘ0.35. These patients had no history of AF by examination of clinical notes, ICD-9 codes, and the system-wide electrocardiogram database. The Intermountain Healthcare Urban Central Institutional Review Board approved this study. Demographics and Clinical Assessments In addition to age and gender, clinical characteristics were collected, including diabetes status (diabetes mellitus: fasting blood glucose >125 mg/dL, clinical diagnosis of diabetes mellitus, or antidiabetic medication use; insulin resistance: fasting glucose between 110 and 125 mg/dL; and normal: fasting glucose 10 pack-year history. Prior cerebrovascular accident (CVA), transient ischemic attack (TIA), and myocardial infarction (MI) were physician-reported or determined by previous ICD-9 discharge diagnosis codes. AF subtype (paroxysmal, persistent, or permanent) was physician-reported at ablation hospitalization. Discharge medications (i.e., statin, other lipid lowering medications, ACE-inhibitors [ACEI], angiotensin receptor blocker [ARB], β-blocker, diuretic, digoxin, plavix) were also available. All patients were placed on warfarin for a minimum of 3 months after the ablation unless contraindicated. Warfarin use at last follow-up was determined to attempt to examine long-term use. We did not report AF subtype in this study. Subtype characterization was determined at the time of the ablation in AF ablation group. However, in the AF, nonablation group, subtype classification was limited by the retrospective design and subject to multiple potential confounding factors such as

frequency of clinic visits and/or ECG and ambulatory telemetry monitors. The ablation approach including extent of ablation, use of additional ablation beyond pulmonary vein isolation, anticoagulation strategy, and catheter-tip technology and mapping guidance were based upon individual operator choice and not from system-wide guidelines. Patient Follow-Up and Event Assessment Clinical outcomes were evaluated at 5 years and included death, HF hospitalization, dementia, CVA, TIA, and AF recurrence. All outcomes, except death and AF recurrence, were determined by ICD-9 codes and were defined as HF hospitalization: ICD-9 code 428*, 398.91, 402.01, 402.11, 402.91, 404.01, 404.03, 404.11, 404.13, 404.91, or 404.93; dementia: ICD 9 codes 290–294, 331, or equivalent; CVA: ICD-9 codes 436*, 433._1, and 434._1; TIA: ICD-9 code 435*. AF recurrences were documented through review of the AF ablation registry with ambulatory heart monitors performed at 3, 6, 9, and 12 months post ablation and then thereafter based upon recurrence of clinical symptoms. All electrocardiograms or any ordered ambulatory monitor performed after 12 months from both routine and cardiovascular assessment were also reviewed for arrhythmia recurrence and available through the system-wide healthcare network electrocardiogram database. Recurrences of atrial fibrillation were considered significant for this endpoint. Deaths were determined by telephone survey, hospital records, and Utah State Health Department records (death certificates) and were verified through Social Security death records. Patients not listed as deceased in any registry were considered to be alive. Statistical Analysis The Student’s t-test and the chi-square statistic were used to evaluate baseline and clinical characteristics among the patient groups. For the AF ablation group, demographics were collected at the time of the first ablation procedure. For the non-AF cohort, baseline demographics were collected at the time of diagnostic catheterization. The AF no ablation group demographics were collected at the first time of AF diagnosis. To confirm associations determined by univariable analysis, multivariable Logistic regression (SPSS, version 22.0; Chicago, IL, USA) was performed to determine odd ratios (ORs). Kaplan–Meier survival estimates and the log rank test were used to determine initial associations with the endpoints. Final models entered the significant (P < 0.05) and confounding (10% change in HR) baseline covariables. Twotailed P values of ࣘ0.05 were designated to be nominally significant. Results The baseline characteristics of the 3 groups are shown in Table 1. Although age was similar, those that had AF without an ablation tended to be slightly older. Rates of hypertension, TIA or stroke, and smoking history were similar. Patients with AF without an ablation had higher rates of coronary artery disease and prior myocardial infarction compared to AF ablation patients, but both groups were significantly lower than the no AF population. Aggregate CHADS2 scores were similar between groups. The lowest left atrial volumes

Bunch et al. Catheter Ablation and Long-Term Outcomes

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TABLE 1 Baseline Patient Demographics of Systolic Heart Failure Patients with AF That Underwent an Ablation Compared to SHF Patients with AF That Did Not Undergo Ablation and SHF with No History of Atrial Fibrillation Characteristics Age (years) Sex (male) Hypertension Hyperlipidemia Diabetes Smoking CVA history TIA history MI history Renal failure CAD † Ejection fraction (%) LA volume (mL) Normal Mild Moderate Severe Aspirin Warfarin (last F/U) Clopidogrel Ace inhibitor Angiotensin receptor blocker β-Blocker Calcium channel blocker Diuretic † An

Low EF AF Ablation (n = 267)

Low EF AF, No Ablation (n = 1,068)

Low EF No AF (n = 1,068)

P Value

66.4 ± 12.2 78.3% 74.9% 60.7% 33.0% 39.3% 4.1% 4.9% 14.2% 17.6% 59.2% 27.4 ± 5.9

68.5 ± 12.7 78.3% 69.0% 50.8% 35.6% 39.3% 5.8% 3.5% 33.2% 24.0% 69.4% 26.6 ± 6.6

66.0 ± 13.8 78.3% 70.1% 58.1% 37.5% 44.9% 5.5% 4.3% 45.2% 19.6% 78.7% 27.2 ± 7.0