The Chicken or the Egg - Atrial Fibrillation and Heart Failure with Reduced Ejection Fraction: Importance of Early AF Treatment

The coexistence of atrial fibrillation (AF) and heart failure (HF) is well established. Both AF and HF are major health problems in the United States and may be responsible for recurrent hospitalization, having a substantial impact on utilization of healthcare resources and increased costs.^1,2 This coexistence can be at least partially explained by shared risk factors that include age, hypertension, diabetes, and obesity, as well as ischemic and nonischemic structural heart disease. HF promotes AF and AF promotes HF, while each may increase the morbidity and mortality of the other.³ The prevalence of AF has increased due to a variety of factors, including the impact of an aging population and increased risk associated with multiple comorbidities.

AF has reached epidemic proportions with a prevalence estimated at 5.2 million in 2010 and expected to rise to approximately 12.1 million in 2030.⁴ AF is more common in patients with more severe HF, present in approximately 5% of patients with NYHA class I symptoms, 10-15% with class II-III symptoms, and up to 50% with class IV symptoms.⁵ As AF can also impact on quality of life, there are many reasons to treat or prevent this disease. A more recent understanding of the importance of lifestyle and risk factor modification, such as weight loss, treatment of sleep apnea, and exercise, has increased awareness about ways to reduce AF burden or perhaps even prevent AF.^6,7

While prevention is key, it is clear that many individuals have already developed AF and the importance of early treatment is now better understood. In the AHA Scientific Statement, Gopinathannair et al presents a superb summary and critical review of managing AF in patients with heart failure and reduce ejection fraction (HFrEF), highlighting the importance of maintaining sinus rhythm.⁸ While guidelines are clear with respect to thromboembolic prophylaxis in the setting of AF with risk factors for stroke, we have only recently developed a better understanding of the importance of early treatment with respect to maintenance of sinus rhythm. The most recent 2020 ESC guidelines state that AF catheter ablation as first line therapy “Is recommended to reverse LV dysfunction in AF patients when tachycardia-induced cardiomyopathy is highly probable, independent of their symptom status,” (Class I recommendation, Level of Evidence B).⁹ In addition, these guidelines state that AF catheter ablation as first line therapy “should be considered in selected AF patients with HF with reduced LVEF to improve survival and reduce HF hospitalization” (Class IIa recommendation, Level of Evidence B). The 2019 ACC/AHA/HRS updated guidelines state that “AF catheter ablation may be reasonable in selected patients with symptomatic AF and HFrEF to potentially lower mortality rate and reduce hospitalization for HF” (Class IIB recommendation, Level of Evidence B-R).¹⁰

Since the time of publication of the most recent U.S. guideline update, we are fortunate to have additional data regarding the importance of early treatment of AF, specifically regarding the impact of early maintenance of sinus rhythm. The Early Treatment of Atrial Fibrillation for Stroke Prevention Trial (EAST-AFNET 4) randomly assigned 2789 patients who had early AF and cardiovascular conditions to receive either early rhythm control with antiarrhythmic drugs or AF ablation versus usual care.¹¹ Early rhythm control was associated with a lower risk of adverse cardiovascular outcomes compared with usual therapy. The definition of “early” in this study was within 1 year from diagnosis to be eligible for enrollment, with a median time of only 36 days following diagnosis. The trial was stopped for efficacy at after a median of 5.1 years. The first primary outcome, a composite of death from cardiovascular causes, stroke, or hospitalization with worsening of heart failure or acute coronary syndrome, occurred in 249 patients assigned to early rhythm control and in 316 patients assigned to usual care (hazard ratio, 0.79; 96% CI, 0.66 to 0.94; p = 0.005). Treatment in the early rhythm control group included initial antiarrhythmic with drugs in 87% and ablation in 8%, while 19.4% underwent ablation by 2-year follow-up. Stable HF was present at baseline in approximately 28% of patients in each group. These results are in contrast to prior studies, including one trial in HF patients, that failed to demonstrate superiority of rhythm control with antiarrhythmic drugs compared with rate control in patients with established AF, although prior trials did not focus on early rhythm control.^12,13,14

So why might early rhythm control be beneficial? It is well established that atrial remodeling and fibrosis can occur with AF. AF begets AF. Extensive scarring in the left atrium measured by late gadolinium enhancement MRI predicts poor response to catheter ablation of AF; arrhythmia recurrence was significantly higher when ≥30% fibrosis was present on preprocedural MRI scanning.¹⁵ In addition, AF can lead to a tachycardia-induced cardiomyopathy and the presence of ventricular fibrosis is associated with reduced likelihood of reverse ventricular remodeling. In the Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction (CAMERA-MRI) study, the absence of late gadolinium enhancement predicted greater improvements in absolute LVEF (10.7%; p = 0.0069) and normalization at 6 months (73% vs. 29%; p = 0.0093) in patients undergoing catheter ablation.¹⁶ However, while guidelines recommend catheter ablation “to reverse LV dysfunction in AF patients when a tachycardia-induced cardiomyopathy is highly probable,” it is not always clear which came first, the AF or the cardiomyopathy with reduced EF – “the chicken or the egg.” Co-diagnosis of AF and HF at the same time may suggest greater benefit from restoration of sinus rhythm, implying that AF may be more likely to have caused the cardiomyopathy, although this is not always the case.¹⁷ Patients most likely to benefit from restoration of sinus rhythm with catheter ablation may include those with no alternate explanation for cardiomyopathy, absence of myocardial fibrosis, patients co-diagnosed with AF and heart failure and those with a high AF burden.¹⁸

Regardless of which disease came first, we now have data demonstrating the benefit of catheter ablation of AF in maintaining sinus rhythm compared with medical therapy. The findings are particularly promising for patients with HF. The AF Ablation Versus Amiodarone for Treatment of Persistent Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted Device (AATAC) trial demonstrated improved AF-free survival in patients who underwent ablation compared with those treated with amiodarone who had persistent AF, a dual-chamber chamber or CRT implantable cardioverter defibrillator (ICD), New York Heart Association Class II to III symptoms and left ventricular ejection fraction (LVEF) <40%.¹⁹ A significantly lower mortality rate was also observed in the catheter ablation group (8% versus 18%, p=0.037). The Catheter Ablation for Atrial Fibrillation with Heart Failure (CASTLE-AF) trial demonstrated that catheter ablation improved all-cause mortality or HF hospitalization in patients with paroxysmal or persistent AF compared with medical therapy (28.5% vs. 44.6%; hazard ratio 0.62, 95% CI 0.43 to 0.87; p = 0.007) in the setting of HF, LVEF <35% and an ICD.²⁰ Patients undergoing ablation in CASTLE-AF ranged in age from 56-71 years (median 64 years) and 69% had NYHA class I-II symptoms; thus, results may not necessarily apply to sicker, older and more frail AF patients with HF. In the Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial, patients with AF who had clinically diagnosed stable HF at the time of enrollment, catheter ablation produced clinically important improvements in survival, freedom from AF recurrence, and quality of life compared with drug therapy.²¹ In this HF cohort of CABANA, most patients with HF had preserved LV function. In the intention-to-treat analysis, the ablation arm had a 36% relative reduction in the primary composite endpoint of death, disabling stroke, serious bleeding, or cardiac arrest (hazard ratio 0.64; 95% CI, 0.41 to 0.99) and a 43% relative reduction in all-cause mortality (HR 0.57; 95% CI, 0.33 to 0.96) compared with the drug therapy arm.

While there are many important points raised by Gopinathannair et al.⁸ about managing AF in HF patients with reduced ejection fraction in the AHA Scientific Statement, one of the key take-home messages is to consider sinus rhythm maintenance early in the disease process, prior to development of fibrosis and remodeling. One study demonstrated that there may be “a point of no return,” with a chance of maintaining sinus rhythm estimated at <10% following ablation when left atrial volume was ≥130 cc, associated with an odds ratio for recurrence of 22.0 (95% CI = 2.5–191.0, P = 0.005) after adjustment for persistent AF.²² For patients with HFrEF, there are very limited options with antiarrhythmic drug therapy as well as limited efficacy of these drugs in maintaining sinus rhythm, not to mention potential side effects, including possible proarrhythmia and negative inotropic effects, in addition to potential long-term drug toxicity related to amiodarone. Delayed intervention may lead to cumulative effects of AF which may not be reversible at a much later date when rhythm control is eventually elected. In experienced hands with contemporary technology, catheter ablation can be performed with low risk at experienced centers, even in patients with HF. This Scientific Statement also nicely outlines knowledge gaps and many important areas for future research. In addition to investigation of specific mechanisms underlying the development or progression of AF and its relationship to cardiomyopathy, as well as identifying optimal AF ablation strategies, better refinement of patient selection and timing of AF ablation in patients with HFrEF is needed.