Catheter Ablation vs Anti-arrhythmic Drug Therapy for Atrial Fibrillation Trial

Study Overview
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Brief Summary
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The (Catheter Ablation Versus Anti-arrhythmic Drug Therapy for Atrial Fibrillation Trial) CABANA Trial has the overall goal of establishing the appropriate roles for medical and ablative intervention for atrial fibrillation (AF). The CABANA Trial is designed to test the hypothesis that the treatment strategy of left atrial catheter ablation for the purpose of eliminating atrial fibrillation (AF) will be superior to current state-of-the-art therapy with either rate control or rhythm control drugs for decreasing the incidence of the composite endpoint of total mortality, disabling stroke, serious bleeding, or cardiac arrest in patients with untreated or incompletely treated AF.

Detailed Description
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The need for this trial arises out of 1) the rapidly increasing number of pts > 60 years of age with AF accompanied by symptoms and morbidity, 2) the failure of anti-arrhythmic drug therapy to maintain sinus rhythm and reduce mortality, 3) the rapidly increasing application of radio-frequency catheter ablation without appropriate evidence-based validation, and 4) the expanding impact of AF on health care costs. This study will randomize up to 2200 patients to a strategy of catheter ablation versus pharmacologic therapy with rate or rhythm control drugs. Each pt will have 1) characteristics similar to AFFIRM pts (≥65 yo or <65 with >1 risk factor for stroke, 2) Documented AF warranting treatment, and 3) Eligibility for both catheter ablation and ≥2 anti-arrhythmic or ≥2 rate control drugs. Pts will be followed every 6 months for an average of approximately 5 years and will undergo repeat trans-telephonic monitor, Holter monitor, and CT/MR studies to assess the impact of treatment. The CABANA trial will disclose the role of medical and non-pharmacologic therapies for AF, establish the cost and impact of therapy on quality of life and will help determine if AF is a modifiable risk factor for increased mortality.

Official Title
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Catheter Ablation vs Anti-arrhythmic Drug Therapy for Atrial Fibrillation Trial

Conditions
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Atrial Fibrillation, Arrhythmia

Intervention / Treatment
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* Device: Left atrial ablation
* Drug: Rate or Rhythm Control Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Over the preceding 6 months have: ≥2 paroxysmal (electrocardiographic documentation of at least 1) atrial fibrillation (AF) episodes lasting ≥1 hour in duration: (that terminate spontaneously within 7 days or cardioversion is performed within 48h of AF onset): or electrocardiographic documentation of 1 persistent AF episode: (sustained for ≥7 days or cardioversion is performed more than 48h after AF onset): or electrocardiographic documentation of 1 longstanding persistent AF episode: (continuous AF of duration >1 year). Warrant active therapy (within the past 3 months) beyond simple ongoing observation Be eligible for catheter ablation and ≥2 sequential rhythm control and/or ≥2 rate control drugs. Be ≥65 yrs of age, or <65 yrs with one or more of the following risk factors for stroke: Hypertension (treated and/or defined as a blood pressure >140/90 mmHg) [90], Diabetes (treated and/or defined as a fasting glucose ≥126 mg/dl) [91], Congestive heart failure (including systolic or diastolic heart failure), Prior stroke, transient ischemic attack or systemic emboli, Atherosclerotic vascular disease (previous myocardial infarction (MI), peripheral arterial disease or aortic plaque), left atrial (LA) size >5.0 cm (or volume index ≥40 cc/m2), or ejection fraction (EF) ≤35. Have the capacity to understand and sign an informed consent form. Be ≥18 years of age. NOTE- Subjects <65 yrs of age whose only risk factor is hypertension must have a second risk factor or left ventricular (LV) hypertrophy to qualify.Patients receiving new drug therapy initiated within the previous 3 months may continue that therapy if randomized to the drug therapy arm. Patients may have documented atrial flutter in addition to atrial fibrillation and remain eligible for enrollment. Exclusion Criteria: Lone AF in the absence of risk factors for stroke in patients <65 years of age Patients who in the opinion of the managing clinician should not yet receive any therapy for AF Patients who have failed >2 membrane active anti-arrhythmic drugs at a therapeutic dose due to inefficacy or side effects (Table 5.2.2) An efficacy failure of full dose amiodarone treatment >8 weeks duration at any time Reversible causes of AF including thyroid disorders, acute alcohol intoxication, recent major surgical procedures, or trauma Recent cardiac events including MI, percutaneous intervention (PCI), or valve or bypass surgery in the preceding 3 months Hypertrophic obstructive cardiomyopathy (outflow track) Class IV angina or Class IV congestive heart failure (CHF) (including past or planned heart transplantation) Other arrhythmias mandating anti-arrhythmic drug therapy (i.e. ventricular tachycardia (VT), ventricular fibrillation (VF)) Heritable arrhythmias or increased risk for torsade de pointes with class I or III drugs Prior LA catheter ablation with the intention of treating AF Prior surgical interventions for AF such as the MAZE procedure Prior AV nodal ablation Patients with other arrhythmias requiring ablative therapy Contraindication to appropriate anti-coagulation therapy Renal failure requiring dialysis Medical conditions limiting expected survival to <1 year Women of childbearing potential (unless post-menopausal or surgically sterile) Participation in any other clinical mortality trial (Participation in other non-mortality trials should be reviewed with the clinical trial management center) Unable to give informed consent NOTE- Prior ablation of the cavo-tricuspid isthmus alone is not an exclusion if the patient develops subsequent recurrent AF. Planned atrial flutter ablation in combination with the left atrial ablation is not an exclusion.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Left Atrial Ablation<br>Pulmonary vein isolation using a circumferential ablative approach in the left atrium. Ablation may be performed using circular mapping catheter-guided ablation, antral isolation using a circular guided approach, or wide area circumferential ablation. | Device: Left atrial ablation<br>* St. Jude: Livewire TC™ , Therapy™ Dual / Thermocouple, Safire,Therapy Cool Path Biosense Webster: NAVI-STAR, NAVI-STAR/NAVI-STAR DS, Celsius Braided/Long Tip, NAVI-STAR™ and Celsius™ ThermoCool, NAVI-STAR® RMT, Celsius® RMT, ThermoCool® SF Medtronic CryoCath LP: Freezor®/Freezor MAX®, Artic Front®, Cardiac Ablation System Bard: Stinger Boston Scientific: Blazer II RF/XP, Blazer RPM, Chilli II Cooled, SteeroCath<br>|
| Active Comparator: Rate or Rhythm Control Therapy<br>Current state-of-the-art drug therapy for atrial fibrillation (rate control or rhythm control). Treating physicians will be encouraged to follow the American College of Cardiology / American Heart Association / European Society of Cardiology Atrial Fibrillation Guidelines with regard to drug therapy for atrial fibrillation. The specific choice of rate control versus rhythm control drug therapy and the specific drugs to be used will ultimately be left to the discretion of the treating physician. | Drug: Rate or Rhythm Control Therapy<br>* Rate control: Metoprolol 50-100mg, Atenolol 50-100mg, Propranolol 40-80mg, Acebutolol 200-300mg, Carvedilol 6.25-25mg, Diltiazem 180-240mg, Verapamil 180-240mg, Digoxin 0.125-0.25mg Rhythm control: Propafenone 450-625mg, Flecainide 200-300mg, Sotalol 240-320mg, Dofetilide 500-1000mcg, Amiodarone 200-400mg, Quinidine 600-900mg, Dronedarone 800mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Composite of Total Mortality, Disabling Stroke, Serious Bleeding, or Cardiac Arrest in Patients Warranting Therapy for AF. | All events for each component of the primary endpoint were reviewed and adjudicated in a blinded fashion by an independent clinical events committee using prospectively determined event definitions. Death was defined as all-cause mortality, disabling stroke (including intracranial bleeding) as an irreversible physical limitation defined by a Rankin Stroke Scale ≥2, and serious bleeding as bleeding accompanied by hemodynamic compromise that required surgical intervention or a transfusion of ≥3 units of blood. | From date of enrollment until time-to-first event over a median follow-up of 48.5 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With All-cause Mortality | All deaths were reviewed and adjudicated by the Clinical Events Committee | From date of enrollment until date of death over a median follow-up of 48.5 months. | 
| Number of Participants With Mortality or Cardiovascular (CV) Hospitalization | Hospitalization was characterized by the site principal investigator (PI) and reported as part of the hospitalization case report form. | From date of enrollment until time-to-first event of death or CV hospitalization over a median follow-up of 48.5 months. | 
| Number of Participants With Mortality, Disabling Stroke, or CV Hospitalization (for Heart Failure or Acute Ischemic Events) | Disabling stroke (including intracranial bleeding) was defined as an irreversible physical limitation defined by a Rankin Stroke Scale ≥2 and the reason for hospitalization was characterized by the site PI and reported as part of the hospitalization case report form. | From date of enrollment until time-to-first event of death, stroke, or CV hospitalization (for heart failure or acute ischemic event) over a median follow-up of 48.5 months. | 
| Number of Participants With Cardiovascular Death | Cardiovascular death as determined by the Clinical Events Committee based on the available data provided by the Principal Investigator | From date of enrollment until date of a cardiovascular death over a median follow-up of 48.5 months. | 
| Number of Participants With Cardiovascular Death or Disabling Stroke | Disabling stroke (including intracranial bleeding) was defined as an irreversible physical limitation defined by a Rankin Stroke Scale ≥2. | From date of enrollment until time-to-first event of a cardiovascular death or disabling stroke over a median follow-up of 48.5 months. | 
| Number of Participants With an Arrhythmic Death or Cardiac Arrest | All deaths and cardiac arrest events were adjudicated by the Clinical Events Committee | From date of enrollment until time-to-first event for an arrhythmic death or cardiac arrest over a median follow-up of 48.5 months. | 
| Number of Participants With Heart Failure Death | All deaths were categorized and adjudicated by the Clinical Events Committee | From date of enrollment until date of heart failure death over a median follow-up of 48.5 months. | 
| Number of Participants Free From Recurrent Atrial Fibrillation (AF) Following the 90 Day Blanking Period | Data from patients using the study provided ECG event recording system were analyzed. A 30-second episode of AF in either group, confirmed through blinded review by an ECG Core Lab Committee was used for defining the endpoint of recurrent AF. | From date of therapy initiation until date of first AF recurrence following a 90 day wait (blanking) period over a median follow-up of 48.5 months. | 
| Number of Participants With Cardiovascular Hospitalization | The reason for hospitalization was characterized by the site PI and reported as part of the hospitalization case report form. | From date of enrollment until date of cardiovascular hospitalization over a median follow-up of 48.5 months. | 
| Changes in Quality of Life Measures - AFEQT | Atrial Fibrillation Effect on Quality of Life (AFEQT) Overall Score (Scale: 0 = complete disability, 100 = no disability). The AFEQT is a 21-item AF-specific, health-related QOL questionnaire designed to assess the effect of atrial fibrillation on patient quality of life. The AFEQT has an Overall Score (calculated from 18 of the questions) and subscale scores in three domains: symptoms, daily activities, and treatment concern. Overall and subscale scores range from 0 (corresponds to complete disability) to 100 (no AF-related disability). | Baseline ,12 month, 5 years | 
| Changes in Quality of Life Measures - MAFSI Frequency Score | The Mayo AF-Specific Symptom Inventory (MAFSI) is a questionnaire comprised of a 10-item AF symptom checklist that asked about both the frequency and severity of each symptom. MAFSI frequency of symptoms over the past month was recorded as 0 (never), 1 (rarely), 2 (sometimes), 3 (often), and 4 (always) for each of the 10 items listed in the questionnaire. The 10 item responses were summed for a total Frequency Score that ranged from 0 (no AF symptoms) to 40 (worst score). | Baseline, 12 Month, 5 Year | 
| Changes in Quality of Life Measures - MAFSI Severity Score | The Mayo AF-Specific Symptom Inventory (MAFSI) is a questionnaire comprised of a 10-item AF symptom checklist that asked about both the frequency and severity of each symptom. MAFSI severity scores over the past month were recorded as 1 (mild), 2 (moderate), and 3 (extreme) for each of the 10 items listed in the questionnaire. The 10 items items were then summed for the total Severity Score that ranged from 0 (no AF symptoms) to 30 (most severe AF symptoms). | Baseline, 12 Month, 5 Year | 
| Number of Participants With Adverse Events/Complications | Comparing individual non-endpoint adverse events between ablative and drug therapy is difficult due to the substantial difference in the types of adverse events expected. Ablation-related events were counted among all patients that were randomized to and received an ablation. Drug-related events were counted among all patients that were randomized to and received drug therapy. | From treatment start date to date of event over a median follow-up of 48.5 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Atrial Fibrillation, Left Atrial Ablation, Pulmonary Vein Isolation, Catheter Ablation, Antiarrhythmic Drug Therapy