Atrial Fibrillation, Heart Failure With Preserved Ejection Fraction (HFpEF), Tirzepatide
Conditions
Keywords
Atrial Fibrillation, Tirzepatide, GIP/GLP-1 receptor agonist, Obesity, HFpEF
Brief summary
This multicenter, randomized, open-label, blinded-endpoint trial evaluates whether weekly subcutaneous tirzepatide for 12 months reduces atrial fibrillation (AF) recurrence after catheter ablation in adults with obesity and heart failure with preserved ejection fraction (HFpEF). HFpEF is diagnosed by direct intraprocedural measurement of mean left atrial pressure (mLAP ≥ 15 mmHg at rest) during the ablation procedure, providing a hemodynamically anchored, homogeneous study population free from the diagnostic ambiguities of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and E/e' in AF patients. Approximately 602 participants will be randomized 1:1 to tirzepatide (titrated to a target of 10 mg/week, maximum 15 mg/week) plus standard care, or standard care alone. Both groups receive an identical structured lifestyle intervention. The primary endpoint is the first documented AF/atrial flutter/atrial tachycardia episode lasting ≥ 30 seconds, occurring between day 91 and day 365 after ablation, adjudicated by an independent blinded clinical endpoint committee.
Detailed description
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.
Interventions
DRUGTirzepatide
Dual GIP and GLP-1 receptor agonist administered as a weekly subcutaneous injection. Titrated from 2.5 mg/week to a target of 10 mg/week (maximum 15 mg/week) over 12 weeks, then maintained at the maximum tolerated dose for the remainder of the 12-month treatment period.
BEHAVIORALStructured Lifestyle Intervention
Guideline-directed AF management (rate/rhythm control, anticoagulation by CHA2DS2-VASc). Guideline-directed HFpEF therapy (MRA, SGLT2 inhibitor as clinically indicated). Structured lifestyle intervention: monthly dietitian-led counseling targeting a 500 kcal/day caloric deficit; exercise prescription of ≥150 min/week moderate aerobic; smoking cessation and alcohol moderation counseling.
Sponsors
Yunlong Wang
Shanghai Zhongshan Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
SINGLE (Outcomes Assessor)
Masking description
Participants and treating physicians are unmasked. All rhythm events are adjudicated by an independent blinded Clinical Endpoint Committee (CEC). Imaging and biomarker core laboratories operate in blinded fashion. Statistician is blinded until the primary analysis is locked.
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Recurrence of atrial fibrillation, atrial flutter, or atrial tachycardia | Day 91 through Week 52 after catheter ablation | Any documented atrial arrhythmia - defined as AF, atrial flutter (AFL), or atrial tachycardia (AT) - lasting ≥30 seconds, in the absence of antiarrhythmic drug (AAD) use |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Monitoring Time Spent in AF (AF Burden) | At Week 12, Week 26, and Week 52 | Percentage of total monitoring time spent in AF, measured by 7-day ambulatory ECG patch. |
| Change in body weight | Baseline to Week 52 | Absolute and percentage change in body weight (kg) from baseline to 52 weeks. |
| Change in body mass index (BMI) | Baseline to Week 52 | Change from baseline to 52 weeks in BMI (kg/m²) |
| Change in waist circumference | Baseline to Week 52 | Change from baseline to 52 weeks in waist circumference (cm). |
| Change in left atrial volume index (LAVI) | Baseline to Week 52 | Change in echocardiographic LAVI (mL/m²) from baseline to 52 weeks, measured by core laboratory |
| Change in Echocardiographic E/e' Ratio | Baseline to Week 52 | Change in echocardiographic E/e' from baseline to 52 weeks, measured by core laboratory. |
| Time to First Hospitalization for Heart Failure | Day 1 through Week 52 | Time to first hospitalization for heart failure, adjudicated by the CEC. |
| Time to Cardiovascular Death | Day 1 through Week 52 | Time to cardiovascular death |
| Time to Death From Any Cause | Day 1 through Week 52 | Time to death from any cause. |
| Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score | Baseline to Week 52 | Change in KCCQ overall summary score and clinical summary score from baseline to 52 weeks. Both scores range from 0 to 100, with higher scores indicating better health status (fewer symptoms, less physical limitation, and better quality of life). |
| Change in Serum NT-proBNP Concentration | Baseline to Week 52 | Change in serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration from baseline to 52 weeks, measured by central laboratory. |
| Change in Serum High-Sensitivity C-Reactive Protein (hs-CRP) Concentration | Baseline to Week 52 | Change in serum hs-CRP concentration from baseline to 52 weeks, measured by central laboratory. |
Countries
China
Contacts
PRINCIPAL_INVESTIGATORYunlong Wang, PHD
Beijing Anzhen Hospital
Outcome results
None listed