Investigation of Therapeutic Ablation Versus Cardioversion for AF (ORBITA-AF)

Objective Randomised Blinded Investigation of Therapeutic Ablation Versus Cardioversion for Persistent Atrial Fibrillation

The main aim of the research is to investigate whether patients undergoing pulmonary vein isolation with cryoablation for atrial fibrillation (AF) will have lower rates of AF recurrence than those treated by DC cardioversion without an ablation procedure. The objectives of the Pilot Study are to validate the key study logistics with a view to optimising methods to be used in the main study.

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 the 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 has not been tested. We 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 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.

Patient and physician - blinded randomisation to intervention (DCCV, or Pulmonary Vein Isolation plus DCCV) Once subject participation in the trial is complete, the patient and physician will be unblinded.

DC cardioversion (DCCV) plus Pulmonary Vein Isolation (Cryoablation) At end of pulmonary vein isolation, DCCV performed (if patient still in AF). An implantable loop recorder will be inserted in the prepectoral area with local anaesthetic at the end of the procedure.

Acute treatment of heart rhythm by cardioversion. An implantable loop recorder will be inserted in the prepectoral area with local anaesthetic at the end of the procedure.

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.

The cryoballoon (CE marked) 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 freeze around the pulmonary veins to electrically isolate the vein, thus preventing pulmonary vein ectopy from triggering AF.

The Reveal device is inserted in the pre-pectoral position under the skin. This is performed with local anaesthetic and sedation at the end of the procedure clinic by the electrophysiologist performing the procedure. The device will provide a continuous recording of the heart rhythm and rate, and will be able to down load duration of AF episodes via a home monitoring system to establish the primary endpoint of the study.

Data on epsiodes of Atrial Fibrillation (rate, duration) will be provided by the loop recorder, and downloaded via a home monitoring system

Assessment of rates of events that are considered procedural complications during the DCCV +/- Pulmonary Vein isolation (PVI) procedure

Requirement for repeat procedures following the initial DCCV +/- pulmonary vein isolation (PVI) procedure for the study

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.

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 (Ware, Kosinski, and Keller, 1996). 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. Higher scores indicate a better outcome.

Assessment of patient reported outcome measures (PROMS) specific for atrial fibrillation (AF) in a series of 28 questions to assess the impact of AF on the subject's quality of life. Higher scores indicate a better outcome.

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

Inclusion Criteria: Patients who meet the following inclusion criteria will be eligible for the study; Ability to give informed consent Age 18-80 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: Patients who meet the following exclusion criteria will be ineligible for study participation; Creatinine clearance (eGFR) < 30mls/min Contraindication or unable to take anticoagulation Known contraindication to or unable to tolerate amiodarone Uncontrolled hypertension Contraindication to catheter ablation BMI > 35

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