The COMBINE-AF Trial

Atrial fibrillation (AF), often called AFib, is the most common type of irregular heartbeat. Normally, the heart beats in a steady rhythm. In AF, the upper chambers of the heart (the atria) beat very fast and irregularly, which prevents blood from being pumped out completely. People with AF may feel heart palpitations (a racing or fluttering feeling), dizziness, shortness of breath, fatigue, and chest discomfort. Over time, AF increases the risk of blood clots, stroke, heart failure, and other serious health problems.

What is long-standing persistent AF?

AF is classified by how long it lasts. This study focuses on long-standing persistent AF, which is defined as continuous AF that lasts for more than 12 months. In this form of AF, the heart's upper chambers have undergone significant changes-often called "atrial remodeling." These changes make the heart tissue more prone to sustaining irregular rhythms and make the condition harder to treat compared to shorter-lasting forms of AF. Many patients with long-standing persistent AF continue to have symptoms even after trying antiarrhythmic medications (drugs designed to control heart rhythm), and finding an effective treatment remains a challenge.

Why is this study needed?

Catheter ablation is a procedure that uses energy to create small scars in specific areas of the heart to block abnormal electrical signals. Pulmonary vein isolation (PVI) is the standard ablation procedure for AF, where the doctor isolates the areas where most abnormal signals start. However, in patients with long-standing persistent AF, PVI alone is often not enough. Studies show that only about half of patients remain in normal heart rhythm 12 months after PVI alone. Researchers believe that additional ablation lines-created along specific pathways outside the pulmonary veins-may help block more abnormal electrical circuits and improve outcomes. The main challenge is that doctors do not yet know which combination of ablation lines works best.

Newer energy technologies may also help. Pulsed field ablation (PFA) is a new, non-thermal ablation technology that uses short, high-voltage electrical pulses to kill heart cells that cause abnormal signals. Unlike traditional heat-based methods (such as radiofrequency ablation), PFA is more selective. It targets heart tissue while causing less damage to nearby structures like the esophagus (the tube connecting the throat to the stomach) and the phrenic nerves (which control breathing). This makes PFA potentially safer for treating areas near these sensitive structures. Radiofrequency (RF) ablation uses heat and remains a reliable method for creating precise, targeted lesions. This study combines both technologies: PFA for isolating the pulmonary veins and the back wall of the left atrium, and RF for creating additional linear lesions.

What does this study aim to find out?

The main goal of this study is to determine whether adding extra ablation lines-specifically the mitral isthmus line (supplemented by ethanol infusion into the vein of Marshall) and the cavotricuspid isthmus line-to the standard PVI plus posterior wall isolation can help more patients with long-standing persistent AF stay in normal heart rhythm at 12 months after the procedure. The study will also compare the two treatment groups in terms of safety, procedure time, AF burden, quality of life, and other health outcomes.

What type of study is this?

This is a prospective, multicenter, randomized, controlled trial. "Prospective" means participants are followed forward in time. "Multicenter" means the study is being conducted at multiple hospitals. "Randomized" means participants are assigned to one of two treatment groups by chance (like flipping a coin) to ensure that the groups are similar and the results are reliable. "Controlled" means the outcomes of the new treatment are compared against a standard treatment.

How many people will take part?

A total of 430 participants will be enrolled across multiple centers in China.

Who can join?

To be eligible, participants must:

Be between 18 and 75 years old

Have long-standing persistent AF that has lasted between 1 and 3 years

Have symptoms of AF (such as palpitations, fatigue, or shortness of breath) that did not improve after trying at least one antiarrhythmic medication

Have a documented AF episode within the 3 years before joining the study

Be willing and able to follow the study procedures and sign an informed consent form

Participants cannot join if they have certain other heart conditions (such as previous heart surgery or a left atrial thrombus), have had a previous AF ablation procedure, have a left atrial diameter larger than 55 mm, have severely reduced heart pumping function, or have other serious medical conditions that would make study participation unsafe.

What happens during the study?

After joining the study, participants will be randomly assigned to one of two groups.

Group 1 (Control group) - Standard ablation: Participants in this group will receive PFA to isolate the pulmonary veins (the large veins that carry blood from the lungs to the heart) and to create a "box lesion" that isolates the posterior wall of the left atrium. This combination (PVI plus posterior wall isolation) is currently a common approach for treating long-standing persistent AF.

Group 2 (Study group) - Modified linear ablation: Participants in this group will receive the same PFA to isolate the pulmonary veins and the posterior wall of the left atrium. In addition, they will receive ethanol infusion in the vein of Marshall, and receive RF ablation to create two extra linear lesions:

Mitral isthmus (MI) line - an ablation line along the area between the mitral valve (which controls blood flow between the left atrium and left ventricle) and the left inferior pulmonary vein. This ablation is supplemented by infusing a small amount of alcohol (ethanol) into the vein of Marshall (a small vein in the heart wall) to help create a more complete and lasting block.

Cavotricuspid isthmus (CTI) line - an ablation line at the bottom of the right atrium that targets abnormal electrical signals that can cause a different type of fast heartbeat called atrial flutter.

Both procedures are performed under sedation or general anesthesia (medication to make the participant sleep and not feel pain). The doctor guides a thin, flexible tube called a catheter through a vein in the leg up to the heart to deliver the ablation energy.

What is the follow-up schedule?

Participants will be followed for 12 months after the procedure. Follow-up visits will occur at 1 month, 3 months, 6 months, 9 months, and 12 months. At these visits, participants will undergo:

Physical exams

Electrocardiograms (ECGs, which record the heart's electrical activity)

24-hour Holter monitoring (at 1 and 3 months) or 3-day Holter monitoring (at 6, 9, and 12 months) - these are portable heart rhythm recorders that the participant wears at home

Echocardiograms (at 3, 6, and 12 months) - an ultrasound of the heart to check its structure and function

Quality of life questionnaires (the AFEQT and EQ-5D-5L surveys) to assess how AF and the treatment affect daily life

Neurocognitive assessments to evaluate memory and thinking skills

Recording of any symptoms, medications, or health events between visits

In addition, participants will be asked to use a portable heart monitor whenever they feel heart symptoms between scheduled visits.

What is the main outcome being measured?

The primary outcome is the percentage of participants who remain in normal sinus rhythm (regular heart rhythm) at 12 months after the procedure, excluding a 3-month blanking period right after the procedure when the heart is healing and temporary rhythm changes do not count as failure. This means that between 3 months and 12 months after the procedure, participants must not have any episode of AF, atrial flutter, or atrial tachycardia lasting more than 30 seconds, recorded by ECG or Holter monitor.

What other outcomes will be measured?

• Atrial Fibrillation Burden at 12 Months [Срок оценки: From month 3 to month 12 after the ablation procedure]
• Incidence of Serious Procedure-Related Complications [Срок оценки: From the start of the ablation procedure to 30 days post-procedure]
• Cardiovascular Hospitalization During Follow-up [Срок оценки: From the date of ablation to 12 months post-ablation]
• Total Procedure Time [Срок оценки: On the day of the ablation procedure]
• Acute Success Rates of Linear Ablation Lesions [Срок оценки: During the ablation procedure (intraoperative)]
• Change in AFEQT Overall Score at 12 Months [Срок оценки: Baseline and at 3 and 12 months after the ablation procedure]
• Change in Montreal Cognitive Assessment (MoCA) Score at 12 Months [Срок оценки: Baseline and at 3 and 12 months after the ablation procedure]