Cryoballoon/Radiofrequency Ablation of Atrial Fibrillation Versus Medical Treatment for Heart

Not Applicable

Not yet recruiting

• Conditions: Atrial Fibrillation (AF)
• Interventions: Procedure: Catheter Ablation

• Registration Number: NCT06505798
• Lead Sponsor: University College, London

Brief Summary

Atrial fibrillation (AF) is a common heart rhythm disorder that causes an irregular heart beat and is a cause of heart failure (HF). Treatments include drugs to slow the heart rate, anti-arrhythmic drugs or ablation of the heart to help preserve normal rhythm. A number of trials have suggested that ablation may be superior to drug treatment to reduce hospitalisations or prevent early death. However, these studies have been small and the results not applicable to the general population with AF and heart failure in the UK. This international study will compare catheter ablation and optimal medical therapy versus optimal medical therapy alone to see if catheter ablation reduces unplanned heart failure hospitalisations and death rates and improves quality of life.

Detailed Description

Atrial fibrillation (AF) increases the severity of, and death from, heart failure (HF). Several small studies have demonstrated that restoration of sinus rhythm by catheter ablation in patients with HF improves left ventricular (LV) function and exercise tolerance. What is unknown is whether or not AF ablation reduces all-cause death and urgent CV hospitalisations in populations with HF. The current trial will answer this outstanding question, which is faced by HF clinicians and electrophysiologists on a daily basis. AF ablation can be performed very effectively and efficiently using a cryo-balloon or radio-frequency ablation PVI technique. These techniques have evolved slowly and are unlikely to change substantially over the course of this trial. One small trial (n=363) in implantable cardioverter-defibrillator and CRT defibrillator recipients (CASTLE-AF) reported a death benefit of AF ablation but the patients were highly selected and the death reduction was far higher than real world expected differences. Recent studies have noted that the population randomised in CASTLE-AF was not representative of the general HF population with only 7% of patients in the "real world" setting meeting the trial entry criteria. CASTLE-AF is therefore provocative but inconclusive; it has made little change to clinical practice. As no studies have investigated the death benefit in a general HF population, the proposed trial is necessary and warranted. This study is designed as a randomised, open label multicentre clinical trial in which catheter ablation and medical therapy is compared to medical therapy alone in patients with HF with reduced ejection fraction (\<50%) and paroxysmal or persistent AF to determine if this reduces all-cause death and urgent CV hospitalisations as well as improving QoL. By utilising the clinical and research networks of the British Heart Failure Society and British Heart Rhythm Society (BHRS) we will recruit 1200 patients. The current trial will be almost three times the size of the only previous inconclusive trial which was reported in the New England Journal of Medicine.

Study Timeline

• Status Verified: 2024-07
• Study First Submitted: 2024-07-01
• Study First Submitted QC: 2024-07-10
• Study First Posted: 2024-07-17
• Last Update Submitted: 2024-07-17
• Last Update Posted: 2024-07-19
• Study Start: 2024-09-15
• Primary Completion: 2031-12-15
• Study Completion: 2031-12-15

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 1200

Inclusion Criteria

1. Patients aged ≥18 years.

2. Patient is willing and able to give informed consent for participation.

3. Able and willing to comply with all study requirements, including ability to participate in study for 12 months.

4. Willing to allow their General Practitioner (GP) to be notified of participation in the study.

5. Patient with one of the following AF categories and at least one electrocardiogram (ECG) documentation of AF:

   • Paroxysmal AF defined as spontaneous self-terminating AF lasted > 6 hours and <7 days.
   • Persistent AF as defined by at least one episode of AF >7 days but not >3 years (since 1st documentation)

6. Optimal tolerated medical therapy for HF (including ACE-I (or ARB or ARNi), beta-blocker, SGLT2 inhibitor and mineralocorticoid receptor antagonist (MRA) and cardiac resynchronisation therapy (CRT) where indicated for at least 6 weeks (according to the most contemporary European Society of Cardiology (ESC) HF guidelines). Maximal doses of these drugs are not mandated.

7. New York Heart Association Classification (NYHA) class II to III

8. LVEF <50% (Cardiac imaging report of LVEF<50% within 1 year (by echocardiography, cardiac magnetic resonance imaging or nuclear cardiology assessment)) AND after optimisation of medical therapy (see previous definition).

   1. For those with LVEF 41-49% and without ongoing atrial fibrillation/flutter, N-terminal-pro B-type natriuretic peptide (NTproBNP) of ≥300pg/mL is required.
   2. For those with LVEF 41-49% and with ongoing atrial fibrillation/flutter, NTproBNP of ≥600pg/mL is required.
   3. For those with LVEF ≤40%, NTproBNP is not required.

Exclusion Criteria

1. Long standing (>3 year) persistent or permanent AF.
2. Previous atrioventricular (AV) nodal ablation
3. Previous pulmonary vein isolation (PVI) or surgical ablation.
4. Recent (<90 days) (type 1 spontaneous) myocardial infarction (type 2 myocardial infarctions are not an exclusion criterion), percutaneous coronary intervention, coronary artery bypass grafting, cardiac resynchronisation therapy or stroke.
5. Severe aortic or pulmonary valve disease.
6. Severe primary or secondary mitral valve regurgitation.
7. Active illness (other than HF) likely to result in death within 2 years.
8. Women who are pregnant or planning to become pregnant during the trial (Females of childbearing potential must have a negative pregnancy test seven days or fewer prior to enrolment).
9. Females who are breastfeeding.
10. Known allergy to contrast.
11. Contraindication for PVI.
12. Other conditions that may prevent subjects from adhering to the trial protocol, in the opinion of the investigator.
13. Currently participating in another randomised controlled trial of another drug or medical device.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
The catheter ablation	Catheter Ablation	Catheter ablation is an established therapeutic strategy in patients without HF that aims to convert AF to sinus rhythm in symptomatic, drug-refractory AF in patients.

Primary Outcome Measures

Name	Time	Method
Time to first all-cause death and urgent CV hospitalisation	2 years minimum (range: 2-5.5 years)	The primary outcome (time to first all-cause death and urgent CV hospitalisation) will be summarised by randomised group and analysed using a Cox proportional hazards regression model for time to first event, adjusting for factors used to balance the randomisation.

Secondary Outcome Measures

Name	Time	Method
Total (first and recurrent) all-cause death and urgent cardiovascular hospitalisations.	2 years minimum (range: 2-5.5 years)	Total (first and recurrent) number of all-cause deaths and urgent cardiovascular-related hospitalisations. Joint frailty models will be used to analyse time to death and recurrent urgent CV hospitalisations simultaneously. Additionally, negative binomial regression will be used to analyse the number of recurrent urgent CV hospitalisations.
Cardiovascular death	2 years minimum (range: 2-5.5 years)	Total number of cardiovascular-related deaths. Cox proportional hazards regression model for time to event, matching the primary outcome.
QoL at 6 and 12 months assessed using the KCCQ-CSS.	12 months	Quality of Life (QoL) at 6 and 12 months assessed using the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS). Linear mixed effects regression models will be used to analyse repeated measurements of QoL. Scored from 0- 100, with a higher score indicating better health.
Time to all-cause death	2 years minimum (range: 2-5.5 years)	Time to all-cause death will be analysed using Cox proportional hazards regression model for time to event, matching the primary outcome.
Total (first and recurrent) all-cause death and urgent HF hospitalisations	2 years minimum (range: 2-5.5 years)	Total (first and recurrent) number of all-cause deaths and urgent heart failure-related hospitalisations. Joint frailty models will be used to analyse time to death and recurrent urgent HF hospitalisations simultaneously. Additionally, negative binomial regression will be used to analyse the number of recurrent urgent HF hospitalisations.