Atrial fibrillation ablation improves outcomes in patients with end-stage heart failure: is it all gold the glitter in the CASTLE?

Comment on ‘Catheter ablation in end-stage heart failure with atrial fibrillation’ presented at the European Society of Cardiology Congress and simultaneously published in New England Journal of Medicine, https://doi.org/10.1056/NEJMoa2306037. The CASTLE-HTx (Catheter Ablation for Atrial Fibrillation in Patients with End-Stage Heart Failure and Eligibility for Heart Transplantation) is an investigator-initiated, open-label, superiority, randomized clinical trial aimed at assessing the safety and efficacy of catheter ablation in patients with advanced (including end-stage) heart failure (HF) and symptomatic atrial fibrillation (AF) referred to a single high-volume centre in Germany for evaluation for heart transplantation or implantation of a left ventricular assist device (LVAD).1,2 Patients had to be clinically stable, in New York Heart Association (NYHA) functional Class III or IV or in Class II, equipped with a device allowing for continuous heart rhythm monitoring, with a left ventricular ejection fraction (LVEF) of 35% or lower. Patients were randomly assigned in a 1:1 ratio to receive either first-time catheter ablation or medical therapy for AF (rate or rhythm control). The primary endpoint was a composite of all-cause mortality, worsening HF requiring implantation of a LVAD, or urgent heart transplantation. Secondary endpoints included the components of the primary endpoint, cardiovascular mortality, LVEF, and AF burden at 6 and 12 months. The study included 194 patients (97 assigned to ablation and 97 to medical therapy). The mean age in the ablation group was 62 years [standard deviation (SD), 12], and 88% were male. At baseline, 66% had NYHA Class III and IV symptoms, with a mean LVEF of 29% (SD, 6%). The medical therapy group had a mean age of 65 years (SD, 10), and 74% were male. At baseline, 71% had NYHA Class III and IV symptoms, and the mean LVEF was 25% (SD, 6%). Seventy percentage of patients had persistent or long-standing persistent AF, and both groups received guideline-directed HF medical therapy, with 46% of patients on treatment with amiodarone, 63% with sacubitril–valsartan, and 24% with sodium–glucose cotransporter 2 (SGLT2) inhibitors. The duration of follow-up was intended to be 3 years; however, early termination 1 year after the conclusion of enrolment was recommended by the data and safety monitoring board due to the large benefit observed in the ablation group. Ablation of AF was performed in 81 of 97 patients (84%) in the ablation group (at a median of 20 days after randomization) and in 16 of 97 patients (16%) in the medical therapy group. The median duration of follow-up was 18 months (interquartile range, 15–23). The primary endpoint occurred in 8 (8%) patients in the ablation group and 29 (30%) patients in the medical therapy group, for a hazard ratio (HR) of 0.24 [95% confidence interval (CI), 0.11–0.52; P < .001]. Among patients receiving catheter ablation, there were fewer deaths from any cause (6% vs. 20%; HR 0.29; 95% CI, 0.12–0.72), LVAD implantations (1% vs. 10%; HR 0.09; 95% CI, 0.01–0.70), and urgent heart transplant (1% vs. 6%, HR 0.15; 95% CI, 0.02–1.25). Ablation improved LVEF (improvement of 8% vs. 1% at 12 months) and reduced arrhythmia burden (reduction of 31% vs. 9% at 12 months). At 12-month follow-up, the rate of sinus rhythm persistence among event-free patients was low, 5% in the ablation group vs. 1% in the medical group. The use of amiodarone decreased in the ablation group (from 45% to 20%) and increased in the medical therapy group (from 47% to 57%). There were few, minor adverse events related to catheter ablation. Atrial fibrillation (AF) heavily impacts on prognosis of heart failure (HF), increasing morbidity and mortality burden. Management of symptomatic AF can be extremely challenging in HF patients, with limited effective pharmacological options and a pending risk of clinical deterioration. Data from CASTLE-AF, CABANA, CAMERA-MRI, and other randomized trials have demonstrated that catheter ablation of AF improves outcomes among patients with HF and symptomatic AF, reducing mortality and hospitalizations.3–6 However, subjects with end-stage HF eligible for heart transplantation were systematically excluded from these major trials, resulting in the elusiveness of guideline recommendations for this group of patients.7,8 The new evidence provided by the CASTLE-HTx, supporting the safety and efficacy of catheter ablation for advanced HF and symptomatic AF, represents a step forward in the treatment options for these patients, whose management is often conservative and based on medical therapy only.1 The size of the benefit and the very early separation of the Kaplan–Meier curves justify the anticipated termination of the trial and support a wider indication for catheter ablation in HF patients.7 The data appear even more impressive when considering that the 16% cross-over rate in the medical therapy arm might have diluted the effect size. In the CASTLE-AF trial, the mortality benefit from ablation occurred after 3 years of follow-up. Of note, only 5% of patients in the ablation group had sinus rhythm at follow-up. Thus, the early benefits recorded in Catheter Ablation for Atrial Fibrillation in Patients with End-Stage Heart Failure and Eligibility for Heart Transplantation (CASTLE-HTx) seem mostly driven by the increase in left ventricular ejection fraction and the decrease of AF burden rather than the restoration of sinus rhythm and can be at least in part explained by the selection of patients with advanced or end-stage HF. Some critical aspects of the study need to be considered when interpreting the extremely positive results of this trial. Up to one-third of patients in each group were in New York Heart Association functional Class II, with moderate limitation during ordinary activity. Alongside, paroxysmal AF, which is not typical in advanced HF, was reported in up to 32% of cases. Thus, at least in part, the enrolled patients appear to reflect a high-risk but clinically stable population referred to a specialized HF centre, rather than patients with advanced or end-stage HF. Moreover, INTERMACS classification,9 which would have helped to better characterize the remaining portion of patients, was not applied. If, on a side, the requirement of ‘stable conditions’ within the inclusion criteria suggests that the sickest patients, the so-called crush and burn and sliding on inotropes patients according to INTERMACS classification, were not included in the trial, the lack of a more specific characterization of the clinical presentation of these patients represents a further limitation of the study. Indeed, most patients with advanced HF, especially if aggravated by symptomatic AF, usually do not tolerate the ablation procedure well, which requires the patient to remain lying on the table for hours. This heterogeneity in the clinical profile of the HF population enrolled should be considered for the generalizability of the reported findings. Other limitations are as follows: (i) the open-label nature of the study may have an impact on allocation, treatment strategies, and patient retention, with possible associated bias; (ii) the small size of the recruited population, and the early termination of the trial, may have amplified the effect size and the related statistical uncertainty; and (iii) the success of the ablation procedures, performed by a limited number of experienced operators in a single high-volume centre, needs to be confirmed in a real-world setting. Although sizeable, adequately powered, and double-blinded studies are needed to confirm these data, the impressive results of the CASTLE-HTx support a new important alternative to the current strategies for the treatment of HF patients, showing that catheter ablation outperformed medical therapy in the treatment of AF in patients with advanced HF. The relevance of these findings in terms of clinical benefits and potential economic impact should encourage a reappraisal of the potential clinical advantages of AF ablation in the broad spectrum of HF. D.P. received speaker’s fees from Daiichi-Sankyo, outside the submitted work. M.V. reports personal fees for speaker bureau and/or consulting in Advisory Boards from, Astra Zeneca, Menarini Int, Novartis Pharma, Novo Nordisk, and Sanofi Pasteur, outside the submitted work.