(1/2) Catheter Ablation Versus Antiarrhythmic and Heart Failure Drug Therapy in Preserved Ejection Fraction Heart Failure (CABANA-HF)

Project Summary Based on emerging data regarding the increase in morbidity and mortality among patients with heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF), there is a consensus for the need of a large, multi- center clinical trial to determine whether AF ablation in addition to guideline-directed medical therapy (GDMT) for HF provides additive benefit compared to GDMT alone. An ideal trial would enroll a sufficiently broad spectrum of patients to allow far-reaching applicability to the dramatically increasing numbers of patients with HFpEF and AF and yet would collect data to determine whether treatment efficacy varies across patient subtypes and underlying pathophysiology (e.g., extent of left atrial [LA] myopathy). Here we propose CABANA-HF, a 1552- patient, 2-arm randomized clinical trial conducted over 5 years (3 years of recruitment and 2 years of follow-up). The primary aim of CABANA-HF is to definitively determine whether standard percutaneous LA catheter ablation plus GDMT is superior to GDMT alone in HFpEF with AF. The primary endpoint will be the composite of cardiovascular (CV) mortality or worsening HF, defined as an unplanned hospitalization for HF or an urgent visit for HF. A blinded (to treatment assignment) independent Clinical Events Committee will review and classify all primary and major clinical secondary events. Major secondary endpoints of the trial will include all-cause mortality, all-cause mortality or worsening HF events, primary outcome components, time to recurrent AF, AF burden, quality of life, and incremental cost effectiveness. We will enroll patients with paroxysmal, persistent, or long-standing persistent AF plus HFpEF (ejection fraction ≥50%); NYHA functional class II or III symptoms; and ≥1 additional risk factor for worsening HF or death. Patients who are judged likely to require early AF ablation for adequate symptom control by the site investigative team will be excluded due to high likelihood of early crossover. Other exclusion criteria will focus on major comorbid conditions likely to create competing risks (e.g., restrictive cardiomyopathies, sustained ventricular tachycardia, severe valve disease, inability to take oral anticoagulants, as well as evidence of clinically refractory HF or unstable AF despite optimal GDMT). The concern of increasing morbidity and mortality in HFpEF patients with AF, along with limitations in results of past studies and preliminary data, provides a sufficient incentive to undertake this trial with an anticipated high likelihood of predicting a positive and informative outcome of the CABANA-HF trial.