Author + information
- aBaker Heart and Diabetes Institute, Melbourne, Australia
- bHeart Centre, The Alfred Hospital, Melbourne, Australia
- cDepartment of Medicine, University of Melbourne, Melbourne, Australia
- dDepartment of Cardiology, Royal Melbourne Hospital, Melbourne, Australia
- ↵∗Address for correspondence:
Dr. Peter M. Kistler, Heart Centre, Alfred Hospital, 55 Commercial Road, Melbourne, VIC 3004, Australia.
Atrial fibrillation (AF) is an emerging epidemic of cardiovascular disease, associated with significant morbidity, hospitalizations, stroke, heart failure (HF), and a doubling of all-cause mortality (1). Over the last 2 decades, we have witnessed a paradigm shift in the management of AF. Whereas the AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) study (2) cast doubt over a pharmacological rhythm control strategy in light of poor antiarrhythmic efficacy and associated toxicity, catheter ablation (CA) has emerged as an increasingly safe and effective tool at maintaining sinus rhythm. However, whether restoration of sinus rhythm with CA translates to an improvement in survival has yet to be determined.
In this issue of JACC: Clinical Electrophysiology, the meta-analysis by Khan et al. (3), largely powered by the positive outcomes from the CASTLE-AF (Catheter Ablation Versus Standard Conventional Treatment in Patients With Left Ventricular Dysfunction and Atrial Fibrillation) (4) and AATAC (Ablation vs. Amiodarone for Treatment of Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted ICD/CRTD) (5) studies in patients with HF, is a large meta-analysis of randomized controlled trials comparing AF ablation with pharmacological therapy. In 2,272 patients with AF and HF with a mean left ventricular (LV) ejection fraction of 28%, there was a 48% relative risk reduction in all-cause mortality. With a number needed to treat (NNT) to achieve a mortality benefit of ∼10 over an average follow-up of 19 months, this benefit compares favorably with all other prognosis-altering therapies in systolic HF. To achieve a significant reduction in mortality with angiotensin-converting enzyme inhibitor therapy an NNT of 22 was required at 41 months (6), and an NNT of 26 was required at 12 months follow-up for beta-blockers (7). This begs the question: should ablation be offered as a first-line therapy in patients with HF and AF?
The relationship between AF and HF is complex. The atrial “kick” contributes 15% to 20% to LV filling at rest (8), and this contribution rises to 40% with exertion. AF is both a precipitant of HF and a cause of cardiomyopathy, mediated by loss of atrial contraction, rhythm irregularity, and tachycardia. HF also predisposes patients to AF secondary to elevated left atrial pressures resulting in left atrial remodeling. The end result is pathological ventricular cellular and structural remodeling and neurohormonal activation (9). It thus seems intuitive that patients with HF have the most to gain from sinus rhythm, with CA punctuating this vicious cycle.
The sensitivity analysis demonstrates that CASTLE-AF was pivotal to achieving a statistically significant mortality benefit in this meta-analysis. Critics have drawn attention to that study’s unblinded design, relatively low event rate, and loss to follow-up and have called for a larger, sham-controlled randomized trial (by pointing to renal denervation as an example of medical “‘reversals” ). It is difficult to see how this would be achievable or ethical. Unlike renal denervation, AF ablation has a clear procedural endpoint of pulmonary vein isolation, and both LV function and AF burden are objectively assessed. Moreover, CASTLE-AF (enrolling 363 patients at 33 centers over 8 years) builds on the positive results from 6 randomized trials demonstrating significant improvements in ejection fraction, functional capacity, recurrent arrhythmia, hospitalization, and B-type natriuretic peptide.
Although atrial arrhythmia recurrence rates were markedly lower with CA than with pharmacological therapy (29% vs. 72%, respectively) patient selection for AF ablation in these patients remains critical. The CAMERA-MRI (Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction) study provided some assistance demonstrating the greatest improvements in LV ejection fraction in patients undergoing CA for persistent AF with dilated or unexplained cardiomyopathy particularly in the absence of delayed enhancement on cardiac magnetic resonance (11). Older patients and those with New York Heart Association functional class IV symptoms were underrepresented in these studies.
Conversely Khan et al. (3) did not identify a mortality benefit for CA in patients with AF and normal LV systolic function. This is perhaps not surprising given the striking differences in these “healthier” patients with predominantly paroxysmal AF (69%) and preserved systolic function. In addition, the average follow-up of 14 months may be too short to allow a mortality benefit to emerge. The soon to be released outcome of the CABANA (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation) trial, which randomized patients with AF who had a CHA2DS2VASc score ≥1 to either CA or medical therapy, is eagerly anticipated. Although a mortality benefit was not present, the meta-analysis demonstrated a substantial reduction in arrhythmia recurrence (27% vs. 64%) and cardiac hospitalization (10% vs. 32%). This has significant implications for quality of life and health care use costs. Khan et al. (3) provides the reader with a sobering reminder of the morbidity that may accompany intervention, including bleeding (3.7% vs. 0.2% with medical therapy) and pericardial complications (2.3% vs. 0.1%), and provides an important counterbalance to the perceived benefit of CA. Although high-volume centers report major complication rates of <1% (12), the incidence in real-world centers is significantly higher (13). There are several limitations in interpreting the results of the meta-analysis with considerable variation in ablation strategies, rhythm versus rate control pharmacotherapy, intensity of AF surveillance, and a duration of follow-up that is relatively short for a mortality outcome study.
Khan et al. (3) conclude that CA should be considered as first-line therapy for all AF types. Although the improvements in morbidity and mortality in patients with systolic HF may justify this approach, the perceived benefits must be more closely considered in patients with preserved ventricular function and considered against the potential for complications and health care expenditure.
↵∗ Editorials published in JACC: Clinical Electrophysiology reflect the views of the author and do not necessarily represent the views of JACC: Clinical Electrophysiology or the American College of Cardiology.
Dr. Voskoboinik is supported by co-funded National Health and Medical Research Council and National Heart Foundation post-graduate scholarships and Baker Bright Sparks scholarships. Dr. Kistler has reported that he has no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Clinical Electrophysiology author instructions page.
- 2018 American College of Cardiology Foundation
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