Investigation of Cardioversion Versus Therapeutic Ablation for Persistent AF (ORBICA-AF)

Study Overview
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Brief Summary
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The main aim of the research is to investigate whether patients undergoing pulmonary vein isolation with catheter ablation for persistent atrial fibrillation (AF) will have lower rates of AF recurrence than those treated by DC cardioversion without an ablation procedure.

Detailed Description
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After adequate stroke prevention (e.g. anticoagulation) and rate control, the optimum strategy for patients who continue to be symptomatic with persistent AF has not been established. Cardioversion with antiarrhythmic medication is commonly used as a first-line rhythm control strategy despite very high recurrence rates of index arrhythmia and high serious complications associated with this strategy. Further treatment options, such as catheter ablation or implantation of a pacemaker and ablation of the atrioventricular (AV) node, are considered once AF recurs. The benefits of first-line ablation in patients presenting with persistent AF have not been tested. Investigators seek to perform a blinded, randomised trial comparing an electrical cardioversion-led strategy with a pulmonary-vein isolation strategy for the treatment of persistent atrial fibrillation. No blinded randomised controlled trial comparing early-ablation strategies to cardioversion-led strategies has been performed. The rationale for blinding where possible in clinical trials is well established. The recently published ORBITA trial performed a blinded, multicentre randomised trial of percutaneous coronary intervention (PCI) in stable angina compared to a placebo procedure. This trial demonstrated that the efficacy of invasive procedures can be assessed with a placebo procedure and that this type of trial remains necessary. Knowledge of treatment assignment influences physician behaviour, drug recommendations and encourages bias in outcome reporting. The treatment effect size and the effects of confounding factors will be exaggerated and thus limit the interpretation of the true patient-experienced outcomes of either strategy. In a comparison of surgical procedures, a sham control arm represents the gold standard of blinding. A systematic review of placebo-controlled surgical trials found no evidence of harm to participants assigned to the placebo group. For a procedure whose primary purpose is to give sustained symptomatic relief, definitive quantification of the true placebo-controlled effect size of AF ablation is necessary. There is a need to clarify the relationship between patient-reported symptoms and the arrhythmia itself. Patient-reported symptoms may not always be related to the severity of the arrhythmia or quality of life. No bias-resistant blinded, randomised, trial has yet been performed seeking to measure the benefits of AF ablation in persistent AF. The investigators of this trial have achieved successful recruitment and concluded the pilot phase (ORBITA AF trial; ClinicalTrials.gov Identifier: NCT03907982) with the goal of assessing feasibility and optimizing the study protocol prior to conducting a larger trial. The positive outcomes of the pilot phase have paved the way for this larger follow-on trial.

Official Title
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Objective Randomised Blinded Investigation of Cardioversion Versus Ablation for Persistent Atrial Fibrillation (ORBICA-AF)

Conditions
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Persistent Atrial Fibrillation, Cardiac Arrhythmia, Catheter Ablation

Intervention / Treatment
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* Procedure: Pulmonary vein isolation
* Procedure: DC Cardioversion
* Device: Implantable loop recorder
* Procedure: Femoral sheath insertion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to give informed consent Age 18-85 years Persistent AF (atrial fibrillation lasting > 7days) of total continuous duration <2 years as documented in medical notes. Patients being considered for cardioversion. Exclusion Criteria: Creatinine clearance (eGFR) < 30mls/min Contraindication or unable to take anticoagulation Uncontrolled hypertension Contraindication for catheter ablation BMI > 40 Patients in Persistent AF who have had more than one previous cardioversion. Established diagnosis of Hypertrophic cardiomyopathy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomised, blinded, controlled trial with 2 arms
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Experimental: DCCV + PVI<br>An implantable loop recorder will be inserted in the pre pectoral area with local anaesthetic at least one week before the randomisation. Two femoral sheaths will be inserted at the groin area in all patients on the day of the procedure prior randomisation. This will be utilised as the access route for cardiac catheter insertion for ablation and for phrenic nerve pacing during the procedure. DC cardioversion (DCCV) plus Pulmonary Vein Isolation - At the end of pulmonary vein isolation, DCCV is performed (if the patient is still in AF). | Procedure: Pulmonary vein isolation<br>* The catheter ablation (with a CE [Conformité Européenne] marked device) is the key specified technique for performing pulmonary vein isolation in the ablation arm in this trial. This allows the physician electrophysiologist to perform a circumferential ablation around the pulmonary veins to electrically isolate the vein, thus preventing pulmonary vein ectopy from triggering AF.<br>* Other names: Catheter ablation;Procedure: DC Cardioversion<br>* DC cardioversion (DCCV) is used to treat irregular heart rhythms (commonly atrial fibrillation). The procedure involves sedation or anaesthetic and placement of electrodes on the chest. An electrical impulse is passed across the electrodes to return the heart rhythm to normal.<br>Device: Implantable loop recorder<br>* The Reveal device is inserted in the pre-pectoral position under the skin. This is performed with local anaesthetic and sedation at least a week before the randomisation. The device will provide a continuous recording of the heart rhythm and rate, and will be able to download duration of AF episodes via a home monitoring system to establish the primary endpoint of the study .<br>* Other names: Reveal LINQ;Procedure: Femoral sheath insertion<br>* Two femoral sheaths (7Fr) will be inserted using ultrasound guidance under local anaesthetic.<br>|
| Sham Comparator: DC cardioversion (DCCV) + Sham procedure<br>An implantable loop recorder will be inserted in the pre-pectoral area with local anaesthetic at least one week before the randomisation. Two femoral sheaths will be inserted at the groin area in all patients on the day of the procedure prior randomisation. This will be utilised as the access route for cardiac catheter insertion for intermittent phrenic nerve pacing during the procedure. DC Cardioversion and Sham procedure will be performed after randomisation. Intermittent phrenic nerve pacing will be employed for the sham group through the femoral venous sheath using a quadripolar catheter. | Procedure: DC Cardioversion<br>* DC cardioversion (DCCV) is used to treat irregular heart rhythms (commonly atrial fibrillation). The procedure involves sedation or anaesthetic and placement of electrodes on the chest. An electrical impulse is passed across the electrodes to return the heart rhythm to normal.<br>Device: Implantable loop recorder<br>* The Reveal device is inserted in the pre-pectoral position under the skin. This is performed with local anaesthetic and sedation at least a week before the randomisation. The device will provide a continuous recording of the heart rhythm and rate, and will be able to download duration of AF episodes via a home monitoring system to establish the primary endpoint of the study .<br>* Other names: Reveal LINQ;Procedure: Femoral sheath insertion<br>* Two femoral sheaths (7Fr) will be inserted using ultrasound guidance under local anaesthetic.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence of Persistent AF (AF episode lasting > 7 days) and other persistent atrial arrhythmias after 6 weeks of blanking period | Data on episodes of Atrial Fibrillation (rate, duration) will be provided by the loop recorder, and downloaded via a home monitoring system [ rhythm on ILR ECG] | Within 12 months following the procedure | 
| Recurrence of other persistent atrial arrhythmias after 6 weeks of blanking period. | Data on episodes of atrial arrhythmia other than AF will be provided by the loop recorder, and downloaded via a home monitoring system [ rhythm on ILR ECG] | Within 12 months following the procedure | 
| A change in the burden of AF, as measured by continuous monitoring through ILR (Implantable loop recorder) at 3 months | Percentage time the patient is in AF as measured by the ILR device (in percentage) compared to pre-randomisation | 3 months post randomisation | 
| Repeat procedure for treatment of Paroxysmal AF | Number of participants requiring repeat procedure for paroxysmal AF following the initial DCCV +/- pulmonary vein isolation (PVI) procedure for the study | within 12 months following the procedure | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death | Death of the patient | Within 12 months of study index procedure. | 
| Rates of Subject Hospital re-admission | Rates of admission of the subject back to hospital following the initial treatment for AF | Within 12 months of study index procedure. | 
| Procedural complications | Assessment of rates of events that are considered procedural complications during the DCCV +/- Pulmonary Vein isolation (PVI) procedure | Up to 7 days post procedure | 
| Bleeding events | Rates of bleeding in subjects following the study DCCV +/- pulmonary vein isolation (PVI) procedures | Within 7 days of the index procedure | 
| Rates of Repeat procedures | Requirement for repeat procedures following the initial DCCV +/- pulmonary vein isolation (PVI) procedure for the study | within 12 months following the procedure | 
| Cardiac function | Measurement of change in ejection fraction by echocardiogram | between baseline and 12 months following the procedure | 
| Percentage of clinical success of procedure | Clinical procedural success as defined by 75% or greater reduction in the number of AF episodes as measured by the insertable cardiac monitoring system (LINQ) device. | Within 12 months following the index procedure | 
| Change in quality of life score using in 12 item Short Form health survey (SF12) | Assessment of quality of life measures using Short Form Health Survey (SF12) questionnaire, which is a multipurpose short form survey with 12 questions, all selected from the SF-36 Health Survey. The questions are combined, scored, and weighted to create two scales that provide glimpses into mental and physical functioning and overall health-related-quality of life. Scores range from 0 to 100, with higher scores indicating better physical and mental health functioning. | Between baseline and 3, 6 and 12 months after procedure | 
| Change in quality of life measures using Atrial Fibrillation Effect on QualiTy-of-life(AFEQT) questionnaire | Assessment of AF specific symptoms to assess the impact of AF on the subject's quality of life. The responses on the 20-item AFEQT are scored on a 1 to 7 Likert scale. Overall and subscale scores range from 0 to 100. A score of 0 corresponds to complete disability, while a score of 100 describes the highest level of QoL | Between baseline and 3, 6 and 12 months after procedure | 
| Measuring Blinding index | Assessing the maintenance of blinding measured by Blinding index in both study participant and blinded medical staff. | Day 0 (within 24 hours post randomisation) and 3 months | 
| Measuring AF Burden | Percentage time the patient is in AF as measured by the ILR (Implantable loop recorder) device compared to pre-randomisation | At 3, 6 and 12 months follow up | 
| The occurrence of atrial tachyarrhythmias | Assessment of the occurence of other atrial tachyarrhythmia (Atrial flutter or Atrial tachycardia) in the continuous monitoring | Within 12 months following the index procedure | 
| Symptomatic Atrial fibrillation/Atrial tachycardia episodes | Number of symptomatic AF/AT triggered/reported by patients correlating to true episodes in the continuous monitoring. | At 3, 6, 12 months follow up | 
| Antiarrhythmic drug use | Assessment of the use of antiarrhythmic drugs (combined data collected on duration , dose and frequency of drug use) prior to and after the DCCV +/- PVI procedure | Between baseline and 12months after procedure |