Tirzepatide on Atrial Fibrillation Recurrence After Catheter Ablation in Patients With Obesity and HFpEF

Background and Rationale: Obesity and HFpEF are key drivers of AF onset and recurrence. In patients with both conditions, 12-month AF recurrence after catheter ablation reaches 40-55%. The LEGACY and ARREST-AF cohorts demonstrated that ≥10% weight loss approximately halves AF recurrence. Tirzepatide, a dual GIP/GLP-1 receptor agonist, achieved over 20% weight reduction in SURMOUNT-1 and improved heart failure outcomes in the SUMMIT trial of HFpEF with obesity. Whether tirzepatide reduces post-ablation AF recurrence has not been prospectively tested. TEAR-AF-HFpEF enrolls a population most likely to benefit mechanistically - obesity plus HFpEF - and tests the hypothesis with a hemodynamically defined HFpEF cohort.

Study Design: Multicenter randomized open-label parallel-group blinded-endpoint superiority trial. Eligible patients are randomized 1:1 within 48 hours of ablation, stratified by site, AF type (paroxysmal vs persistent), and BMI.

Intervention:

Tirzepatide arm: weekly subcutaneous tirzepatide starting at 2.5 mg/week with monthly 2.5 mg dose escalation to a target of 10 mg/week, advanced to 15 mg/week if tolerated, for 12 months.

Control arm: standard care without GLP-1 class drugs. Both arms receive identical structured lifestyle intervention (≥150 min/week moderate aerobic activity, sleep apnea screening), and standard-of-care guideline-directed therapies for AF, anticoagulation, and HFpEF.

Sample Size and Statistical Approach: A total of 602 participants (301 per arm) provides 80% power at two-sided α = 0.05, assuming 15% loss to follow-up. The primary analysis is an intention-to-treat Kaplan-Meier comparison with log-rank test and Cox proportional hazards modeling stratified by randomization factors.

Inclusion criteria

• Age 18 to 80 years
• Symptomatic atrial fibrillation (paroxysmal or persistent of ≤ 5 years duration), undergoing first-time catheter ablation
• Body weight criteria (aligned with NMPA-approved tirzepatide indication)，meeting at least one of the following:

• BMI ≥28.0 kg/m² (obesity threshold per Chinese criteria), OR
• BMI ≥24.0 kg/m² and <28.0 kg/m² (overweight per Chinese criteria) with at least one weight-related comorbidity: hypertension, dyslipidemia, type 2 diabetes mellitus (T2DM), obstructive sleep apnea syndrome (OSAS), or atherosclerotic cardiovascular disease (ASCVD)
• HFpEF defined by intraprocedural mean left atrial pressure ≥ 15 mmHg at rest
• Left ventricular ejection fraction ≥ 50% on echocardiography within 30 days prior to enrollment
• Provision of written informed consent

Exclusion criteria

• Prior use of any GLP-1 receptor agonist or GIP/GLP-1 dual receptor agonist
• Type 1 diabetes mellitus; or type 2 diabetes with HbA1c > 10%
• Personal history of pancreatitis; personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 (MEN2)
• Severe gastrointestinal disease, including gastroparesis or active inflammatory bowel disease
• Prior bariatric surgery
• Moderate or severe valvular heart disease, hypertrophic cardiomyopathy, cardiac amyloidosis, constrictive pericarditis, or restrictive cardiomyopathy
• Severe renal impairment (eGFR < 30 mL/min/1.73m²)
• Active malignancy, excluding basal cell carcinoma
• Acute coronary syndrome, stroke, percutaneous coronary intervention, or cardiac surgery within 30 days prior to enrollment
• Pregnancy, lactation, or planned pregnancy within 6 months
• Life expectancy < 12 months
• Concurrent participation in another interventional clinical trial
• Any condition that, in the investigator's judgment, would interfere with participation