Articles
Science Matters: Research Summary of the PRAGUE-25 Randomized Trial
About the Author: Michael Katsnelson MD, PhD, FACC is currently a research fellow at Washington University in St. Louis School of Medicine. He specializes in advanced heart failure/transplant cardiology, and his main research interest lies in studying the role of the innate immune system in the progression of ischemic cardiomyopathy.
Background: Previous studies such as LEGACY (Long-Term Effect of Goal-Directed Weight Management in an Atrial Fibrillation Cohort: A Long Term Follow Up Study) have demonstrated that the presence of obesity is a strong predictor for the development of atrial fibrillation. Progressive weight loss has a dose dependent effect on reduction of AF burden and improvement of AF-related symptoms in the absence of rhythm control strategies. Sustained weight loss also results in reversal of cardiac remodeling as evidenced by a decrease in the left atrial volume and a reduction in the amount of left ventricular hypertrophy. The achievement of sustained weight loss was improved by participation in a physician-directed clinic that focused on increasing a patient’s physical activity and promoting healthy eating habits. Clinical trials such as CABANA and EARLY-AF have established catheter ablation (CA) as the most effective treatment for symptomatic AF. Patients undergoing CA demonstrated improved freedom from AF recurrence when compared to treatment with anti-arrhythmic medications (AADs). However, in the clinical trials comparing CA with AADs, directed lifestyle modification was not included in the medical therapy arm. The authors of the PRAGUE 25 clinical trial sought to answer the question of whether the combination of anti-arrhythmic medications plus lifestyle changes may serve as a noninferior alternative to catheter ablation in obese patients with symptomatic AF.
Materials and Methods: PRAGUE 25 is a randomized controlled trial designed to investigate the non-inferiority of AADs + lifestyle modifications compared to CA for management of symptomatic AF in obese patients. Criteria for inclusion in the trial were the presence of symptomatic AF and BMI 30-40 kg/m2. Important exclusion criteria were BMI>40 kg/m2, LVEF<40%, contraindication to use of AADs and limitations which could significantly affect the ability to exercise. Eligible patients were randomized in a 1:1 ratio to either CA or AADs + lifestyle modification. Follow up visits were performed at 3, 6, 9 and 12 months from the day of CA or the initiation of the AADs + lifestyle modification program. Following randomization all patients underwent baseline CPET, transthoracic echocardiogram, quality of life analysis using the Atrial Fibrillation Effect on Quality of Life Questionnaire, blood chemistry and 7-day Holter recording. During the 12-month follow-up visit echocardiogram, quality of life evaluation, biochemistry and CPET were repeated. The primary endpoint of the trial was absence of any atrial arrhythmia lasting >30 seconds during the 1-year follow-up period. Evaluation of arrhythmia recurrence was conducted by 7-day Holter monitoring performed following each outpatient visit, ECGs conducted during the outpatient visits, and documented AF noted at emergent patient visits. Secondary endpoints were changes in AF burden, changes in peak VO2 max during CPET, quality of life score, and metabolic parameters (body weight, lipid levels, HgA1c) compared between the baseline and 12-month follow-up visit.
Results: The authors demonstrated that after a follow-up period of 12 months, 73% of patients in the CA group and 34.6% of patients in the AADs + lifestyle modification group remained free of atrial arrhythmia episodes lasting >30 seconds. The criteria for noninferiority were not met and in fact, CA was superior to the combination of AAD therapy plus lifestyle changes at 12 months of follow-up. These results were similar in the post hoc subgroup analysis which included men vs women, presence or absence of diabetes, paroxysmal vs persistent atrial fibrillation, BMI <35 vs ≥35. The AF burden (percentage of time in AF) decreased to a similar degree in both groups as demonstrated by ambulatory Holter monitoring. Both groups also reported similar improvements in quality-of-life measures as evidenced by the increase in AFEQT score. The VO2 max increased significantly in the AADs + lifestyle modification group when compared to baseline values, although there was no significant difference when compared to the CA group following 12 months of therapy. Importantly, patients in the AAD + lifestyle modification group maintained weight loss over the course of the 12-month follow-up period and exhibited a significant decline in the HgA1c level when compared to the CA group.
Discussion: Notably, patients enrolled in the trial failed to achieve the target 10% decrease in body weight which was the goal at the onset of the trial. Notably, GLP-1 agonists were utilized in only a minority of patients (14.6%). It is conceivable that with wider use of GLP-1 agonists patients may have been able to achieve a more significant degree of weight loss and this may have translated into greater freedom from AF recurrence. Obstructive sleep apnea was also not specifically addressed in the trial and concurrent therapy with non-invasive positive pressure ventilation may have further decreased the risk of atrial arrhythmia recurrence. On the surface the trial demonstrated that catheter ablation is superior to therapy with anti-arrhythmic agents, which is similar to the results noted in earlier studies such as CABANA. However, the importance of weight loss for improving the burden of AF symptoms and overall cardiovascular health cannot be overstated. Patients enrolled in the trial who participated in the intensive lifestyle modification program experienced an improvement in cardiovascular fitness as evidenced by higher VO2 max and improvement in metabolic parameters such as a decrease in the HgA1c. A common practice among electrophysiologists currently is to delay catheter ablation for a time in order to give patients time to make lifestyle changes which may help to improve the symptom burden associated with AF. From the results of the study, one may argue that it may be prudent to proceed with catheter ablation upfront without attempting an initial period of lifestyle modification. After the catheter ablation procedure patients may be encouraged to make lifestyle changes such as smoking cessation, weight loss, increased physical activity, treatment of obstructive sleep apnea and abstinence from alcohol. These lifestyle changes will be expected to improve cardiovascular health and increase longevity.
Link of article - https://www.jacc.org/doi/epdf/10.1016/j.jacc.2025.04.042
