Pharmacological Intervention to Prevent NOAF After TAVR

Transcatheter aortic valve replacement (TAVR) is an established treatment for patients with symptomatic severe aortic stenosis. Although TAVR is less invasive than surgical valve replacement, post-procedural atrial arrhythmias-particularly atrial fibrillation (AF)-remain common and are associated with increased risks of stroke, heart failure, and mortality. Recent evidence suggests that a high burden of premature atrial contractions (PACs) and short episodes of atrial tachycardia (AT) occurring within the first days after TAVR may serve as precursors to new-onset AF (NOAF). However, the clinical significance of these early arrhythmias and the optimal management strategy are not well defined, and current guidelines lack consensus on the use of antiarrhythmic drugs (AADs) in this setting.

This Phase 4, prospective, multicenter, randomized, open-label, parallel-group trial aims to determine whether early pharmacological intervention with either amiodarone (a class III AAD) or metoprolol (a beta-blocker) can reduce the incidence of NOAF within 90 days post-TAVR, compared with observation alone. A total of approximately 1383 patients undergoing TAVR across six centers in China will be screened. Patients who are in sinus rhythm pre-TAVR (confirmed by 24-hour Holter within 72 hours before the procedure) and who develop a high burden of atrial arrhythmias within the first 7 days after TAVR-defined as either ≥1,000 PACs per 24 hours or episodes of atrial tachycardia lasting 3-30 seconds-will be considered for randomization.

Eligible patients are randomly assigned in a 1:1:1 ratio to one of three arms: (1) control (observation, no AAD initiated), (2) metoprolol succinate (starting at 47.5 mg once daily, with dose titration every 48 hours to achieve a target resting heart rate of 60-80 bpm), or (3) amiodarone (loading dose of 200 mg three times daily until a cumulative dose of 3 g is reached, followed by a maintenance dose of 200 mg once daily). Randomization is performed centrally using a computer-generated sequence, stratified by participating center. The study is open-label for participants and investigators, but endpoint adjudication (including the primary outcome) is performed by an independent outcomes assessor blinded to treatment allocation.

All patients undergo continuous in-hospital telemetry after TAVR and wear an ambulatory ECG patch from intensive care unit admission onward, with data analyzed every 24 hours for up to 7 days. After randomization, patients are followed at 30, 60, and 90 days. At each follow-up visit, a 12-lead ECG, 72-hour Holter monitor, and laboratory tests (including complete blood count, liver and renal function, cardiac enzymes, BNP, electrolytes, thyroid function, and coagulation profile) are performed.

A protocol-guided drug tapering and discontinuation strategy is implemented for the metoprolol and amiodarone groups. At each follow-up, if a patient demonstrates <1,000 PACs per 24 hours and no atrial tachycardia on Holter, the drug dose is reduced by 50%. If the same criteria are met at the subsequent follow-up, the drug is discontinued. For safety, drug discontinuation is also mandated for symptomatic bradycardia (heart rate <50 bpm or 50-60 bpm with syncope, dizziness, or fatigue), asymptomatic bradycardia (heart rate <50 bpm), or ECG findings of PR interval >200 ms, QT interval >450 ms, or development of Mobitz type I second-degree AV block or higher. In the control and metoprolol groups, if a patient develops atrial flutter, atrial fibrillation, or an atrial tachycardia episode lasting >30 seconds during follow-up, rescue therapy with amiodarone (or propafenone if amiodarone is contraindicated) is initiated.

The primary outcome is the incidence of new-onset atrial fibrillation (NOAF) within 90 days post-randomization, defined as any documented AF episode lasting >30 seconds on 12-lead ECG, telemetry, or Holter monitoring. Secondary outcomes include freedom from any atrial arrhythmia at 90 days (i.e., PACs <1,000/24h, no atrial tachycardia, flutter, or fibrillation); a safety composite endpoint of high-degree atrioventricular block (HD-AVB: Mobitz type II second-degree AVB, third-degree AVB, or advanced AVB) or permanent pacemaker implantation; a clinical efficacy composite endpoint of all-cause mortality, stroke, or cardiovascular-related rehospitalization at 90 days; and the rate of permanent drug discontinuation due to adverse effects.

Statistical analyses will be performed on an intention-to-treat population. The primary outcome will be compared among the three groups using the Chi-square test, with logistic regression to adjust for potential confounders. Time-to-first NOAF will be analyzed using Kaplan-Meier methods with log-rank test. A two-sided p-value <0.05 is considered statistically significant. A Data Safety Monitoring Board will regularly review safety data, with particular attention to the rates of AV block and pacemaker implantation.

The study is approved by the Institutional Review Board of Shanghai East Hospital (lead site) and will be conducted in accordance with the Declaration of Helsinki and ICH Good Clinical Practice guidelines. Written informed consent is obtained from all participants prior to any study-specific procedures. Results will be disseminated through peer-reviewed publications and presentations at international cardiology conferences.

Inclusion criteria

• Undergoing TAVR for symptomatic severe aortic stenosis (defined as aortic valve area < 1.0 cm², mean gradient ≥ 40 mmHg, or peak jet velocity ≥ 4.0 m/s).
• Sinus rhythm confirmed by a 24-hour Holter monitor within 72 hours pre-TAVR.
• Post-TAVR (within 24 hours) Holter monitoring or continuous telemetry reveals either:

• ≥1,000 premature atrial contractions (PACs) per 24 hours; OR
• Episodes of atrial tachycardia lasting 3 to 30 seconds.
• Provided written informed consent.

Exclusion criteria

• Known history of paroxysmal or persistent atrial fibrillation/flutter prior to TAVR.
• Presence of other significant arrhythmias pre-TAVR (e.g., >1,000 premature ventricular contractions/24h, Mobitz Type I second-degree AV block or higher, sick sinus syndrome).
• Current use of antiarrhythmic drugs (including beta-blockers, amiodarone, propafenone) prior to randomization.
• Concurrent participation in another investigational device or drug study that could confound results.
• Contraindications to amiodarone or metoprolol (e.g., severe bradycardia, cardiogenic shock, thyroid dysfunction, severe liver disease, QT prolongation).
• Undergoing any other concurrent cardiac surgical procedure.