Catheter Ablation in End-Stage Heart Failure with Atrial Fibrillation - Article Summary

Summary Author: Lukas Lauer

Brief Summary:

Heart failure (HF) affects an estimated 6.7 million people in the US and accounts for 1.2 million hospitalizations annually (1). Atrial fibrillation (Afib) is the most common dysrhythmia, affecting an estimated 3.8 million people in the US and was listed as the cause of death for 26.5K patients in 2019 (2). HF and Afib have a reciprocal relationship – HF begets Afib and Afib begets HF. Indeed, when compared with HF alone, patients with comorbid HF and Afib face increased hospitalizations and mortality (3).

The principal goals of treatment for Afib are to reduce symptoms, prevent tachycardia mediated cardiomyopathy, and reduce the risk of stroke (4). For Afib without comorbid HF, studies have found catheter ablation (CA) to be superior to antiarrhythmic drugs for symptomatic relief but have not assessed for reductions in cardiac or all-cause mortality (Fig. 1). Thus, most professional societies still recommend CA only after a patient has failed at least one anti-arrhythmic drug (5, 6).

In 2018, Marrouche et al. found that for patients with HF and symptomatic Afib, CA with Guideline Directed Medical Therapy (GDMT) is superior to GDMT alone on its composite primary endpoint of death from any cause or hospitalization due to heart failure exacerbation. However, this study excluded patients that were eligible for heart transplantation and required patients to have already failed at least one anti-arrhythmic drug (7, 8).Thus, Sohns et al. conducted the CASTLE-HTx trial to answer the question: Are patients in end stage HF with symptomatic Afib less likely to die of any cause or need a Left Ventricular Assist Device (LVAD) or urgent heart transplant if they receive CA and GDMT rather than GDMT alone?

Study Design:

The trial was a single center, unblinded, randomized controlled trial. It was powered to detect a hazard ratio of .5 with a sample size of 97 patients per arm. The authors considered a hazard ratio of .75 to be clinically significant.

Inclusion Criteria: Symptomatic Afib, HF ≥ New York Heart Association (NYHA) II, Left Ventricular Ejection Fraction ≤ 35%, impaired functional capacity as assessed by 6-minute walk test, referred to transplant center for evaluation of eligibility for transplant or LVAD implantation, dual-chamber implantable cardiac defibrillator with home monitoring capabilities already implanted
Time Period: November 2020 – May 2022
Study arms:

o CA + GDMT

o GDMT only

Primary Endpoint (PE): death from any cause or LVAD implantation or urgent heart transplant at 3 years
Secondary Endpoints (all components of PE):

o Death from any cause

o LVAD implantation

o Urgent heart transplant

Crossover: Patients in the GDMT arm were allowed to crossover to the CA arm. Their data was included with the GDMT arm per the intention to treat design.

Findings:

97 patients were randomized to each arm and the median duration of follow up was approximately 18 months in both arms. A primary end-point event occurred in 8 patients (8%) in the ablation arm and 29 patients (30%) in the GDMT arm (Hazard Ratio (HR), 0.24; 95% confidence interval (CI), 0.11 to 0.52; P<0.001). For secondary endpoints, death was less likely for patients in the ablation group (HR, 0.29; 95% CI, 0.12 to 0.72), as was LVAD implantation (HR, 0.09; 95% CI, 0.01 to 0.70) and urgent heart transplant (HR, 0.15; 95% CI, 0.02 to 1.25). Procedure complications were minimal.

The trial was initially designed to analyze the cumulative incidence of the primary endpoint at three years, but on May 16, 2023, 1 year after enrollment was completed, the study ended as recommended by the Data and Safety Monitoring Board due to an unexpectedly large treatment difference favoring the CA arm. Sohns et al. concluded that catheter ablation with GDMT was superior to GDMT alone for end stage HF patients with symptomatic Afib. Patients in the CA arm lived longer and were less likely to require a transplant or LVAD.

Limitations:

Blinding: Neither patients nor physicians were blinded to the intervention which allowed for the possibility of biasing the data as knowledge of group assignment affects behavior (9). For example, physicians may have been more hesitant to offer transplantation to a patient known to be on the CA arm because they believed CA works and wanted to see a positive study result.
Single Site: This trial was performed by two cardiac electrophysiologists at one hospital in Germany. Whether these results are reproducible across geographies and across operators remains a question.
Patient Selection: 31% of patients were NYHA functional class II, meaning they only experienced mild symptoms during everyday activity. Other reviewers have suggested that the authors should limit future studies to only those with class III or IV HF to best encompass truly end-stage patients likely to require transplant or LVAD implantation. Additionally, the study excluded patients with certain comorbidities including uncontrolled hypertension or end stage renal disease requiring dialysis. This limits external validity and highlights the need to consider individual patient characteristics in clinical decision making.
Early Termination: Although terminating the study early may have been necessary to maintain clinical equipoise, a shorter study period may have missed the longer-term benefits or harms of the intervention.
Crossover: In the CA arm, 81 of 97 (84%) patients underwent ablation, while in the GDMT arm, 16 of 97 (16%) patients crossed over and underwent ablation. They were still included in the GDMT only arm due to the study’s intention to treat design. This was a limitation in the execution of the trial. However, crossover makes it harder to detect a difference between study arms, so the significant result despite patient crossover actually bolsters the author’s conclusions.

Main Takeaway

Despite the study’s limitations, Sohns et al. provide reasonably strong evidence that CA with GDMT is superior to GDMT alone for end stage HF patients with symptomatic Afib. Their findings suggest that CA may be able to delay or eliminate the need for transplant or LVAD implantation. A subsequent study with additional sites, patients, and operators as well as limiting the study to NYHA class III or IV patients is warranted to conclude definitively that CA is superior.

References:

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