The Impact of First-Line Rhythm Therapy on AF Progression

Study Overview
=================
Brief Summary
-----------------
The PROGRESSIVE-AF Trial is a national, multi-center randomized controlled trial comparing early (first-line) catheter-based pulmonary vein isolation (PVI) using cryothermal energy to first-line anti-arrhythmic drug therapy. The aim of the trial is to evaluate if the initial treatment choice (ablation vs. pharmacotherapy) influences AF disease progression, as measured by continuous cardiac monitoring. The outcomes of interest are disease progression, quality of life, and healthcare utilisation. The targeted population consists of healthy patients with symptomatic paroxysmal AF without clinically significant heart diseases aged between 18 and 75 years. This study represents a new research project leveraging the existing EARLY-AF randomised clinical trial infrastructure to examine the novel endpoints of: 1) disease progression (time to first episode of persistent AF), 2) progressive AF burden (% time in AF), 3) Quality of Life, and 4) healthcare utilisation at 36 months of follow-up.

Detailed Description
-----------------
Project Aim: Atrial fibrillation is a major burden to healthcare systems. Contemporary costs of managing AF have been estimated to be up to 2.7% of total annual healthcare expenditures. A significant proportion of these expenses result from the direct costs associated with hospitalization and acute care. The CANet funded EARLY-AF Study aimed to determine whether EARLY invasive intervention resulted in a significant (i.e. >20%) reduction in arrhythmia recurrence and health care utilisation at one year of follow-up. The PROGRESSIVE AF study aims to evaluate the long-term effect of EARLY invasive intervention on disease progression and health care utilisation. Project Background: Atrial fibrillation (AF) is a chronic progressive disease characterized by exacerbations and remissions. Early on, AF is triggered by one or more ectopic foci in the atria and is perpetuated via micro re-entrant circuits in the atrial body or at the pulmonary venous-left atrial junction. With recurrent episodes the atria undergoes electrical, contractile, and structural remodelling resulting in a greater predisposition toward sustained arrhythmia. This results in the progression of incidental and paroxysmal (self-terminating) AF to persistent (AF requiring intervention for termination) and eventually permanent AF (recurrent AF of >1 year in duration for which cardioversion was unsuccessful). While anti-arrhythmic drugs (AADs) remain the first-line therapy, these medications have only modest efficacy at maintaining sinus rhythm over the long term. Moreover, these agents are associated with significant non-cardiac side-effects (e.g. heart failure or organ toxicity), as well as the potential for pro-arrhythmia (i.e. increased propensity towards malignant arrhythmias). Conversely, multiple randomized controlled trials have demonstrated that catheter ablation is superior to drug therapy in maintaining sinus rhythm when AADs have been ineffective, are contra-indicated or cannot be tolerated. While the evidence to date has demonstrated the universal superiority of ablation over AAD therapy, these studies have focused on medically refractory patients with more advanced forms of AF. While it has been postulated that early invasive intervention with catheter ablation may be beneficial, this assertion remains only hypothesis generating. As such we undertook the CANet funded EARLY-AF program. This multicenter collaboration sought to determine if an early invasive approach centered on cryoballoon based PVI was associated with a significant (i.e. >20%) reduction in arrhythmia episodes, AF symptoms, and healthcare utilization at one year of follow-up (i.e. the standard definition of success, as advocated by the Heart Rhythm Society). In recent years attention has turned to longer-term effectiveness and safety outcomes, focusing more on the durability of catheter ablation procedures. Given that catheter ablation is being offered to relatively young and otherwise healthy patients as a first-line treatment approach, a comprehensive assessment of long-term clinical effectiveness is of particular importance with respect to informed decision-making. Moreover, a comprehensive understanding of the downstream effects of ablation greatly informs the evaluation of the cost-effectiveness of invasive AF ablation procedures. The PROGRESSIVE AF project aims to leverage the infrastructure established with the EARLY-AF study to determine whether an a first-line invasive approach can alter the progressive pathoanatomical changes associated with AF, and by extension alter the disease trajectory (i.e. reduction in progression to persistent AF). The purpose of the current application is to undertake a 3 year follow-up study in order to better understand: 1) the natural history of AF (e.g. disease progression), 2) the relative ability of the two first-line treatment approaches to alter disease progression (e.g. AAD vs. pulmonary vein isolation), 3) the longer-term healthcare utilization associated with these two first-line treatment approaches, 4) the longer-term impact of these first-line approaches on patient reported outcomes. Project Hypothesis, Research Question(s) and Objectives: The majority of studies demonstrating the superiority of catheter ablation over anti-arrhythmic drug therapy have focused on medically refractory patients. This design pre-selects a group in whom medical therapy has been proven to be an ineffective therapy, and weights the benefit significantly towards the ablation arm. To date it is unknown whether the benefit of catheter ablation will be as substantial when delivered prior to medication failure (i.e. as a first-line ablation strategy). Moreover, it is unknown whether first-line ablation can alter the natural history of atrial fibrillation. Project Hypothesis: We hypothesize that early intervention with the cryoballoon as a first-line therapy will favourably alter the natural history of AF when compared to an approach of first-line antiarrhythmic drug therapy. Specifically, we hypothesize that first-line ablation will result in increased freedom from recurrent arrhythmia, reduced need for pharmacologic or invasive intervention, reduced hospital utilisation due to symptoms caused by documented atrial arrhythmias, as well as a reduced progression from paroxysmal to persistent or permanent AF. Objectives: The study is designed to evaluate of the impact of the early invasive management of AF with the Arctic Front cryoballoon. The primary objective of the study is to evaluate whether a first-line ablation strategy can reduce the progression from paroxysmal to persistent AF over  36 months of follow-up, as detected by continuous cardiac monitoring. The secondary objective of the study is to evaluate the burden of AF on follow-up, as well as the health related quality of life (HRQOL) impact associated with early invasive intervention, in comparison to primary AAD therapy. This analysis will be centered on an evaluation of generic and disease-specific HRQOL instruments in order to determine the impact of an early invasive approach. The tertiary objective of the study is to evaluate the economic impact of early invasive intervention, with a focus on healthcare utilization. These will be used to derive a summary measure of health outcome and to inform subsequent healthcare resource allocation decisions.

Official Title
-----------------
The Impact of First-Line Rhythm Therapy on AF Progression

Conditions
-----------------
Atrial Fibrillation

Intervention / Treatment
-----------------
* Procedure: Cryoballoon-based PVI
* Drug: Anti-Arrhythmic Drug Therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Non-permanent AF documented on a 12 lead ECG, Trans Telephonic Monitoring (TTM) or Holter monitor within the last 24 months Age of 18 years or older on the date of consent Candidate for ablation based on AF that is symptomatic Informed Consent Exclusion Criteria: Regular (daily) use of a class 1 or 3 antiarrhythmic drug (pill-in-the-pocket AAD use is permitted) at sufficient therapeutic doses according to guidelines (flecainide >50 mg BID, sotalol >80 mg BID, propafenone >150 mg BID Previous left atrial (LA) ablation or LA surgery AF due to reversible cause (e.g. hyperthyroidism, cardiothoracic surgery) Active Intracardiac Thrombus Pre-existing pulmonary vein stenosis or PV stent Pre-existing hemidiaphragmatic paralysis Contraindication to anticoagulation or radiocontrast materials Left atrial anteroposterior diameter greater than 5.5 cm by transthoracic echocardiography Cardiac valve prosthesis Clinically significant (moderately-severe, or severe) mitral valve regurgitation or stenosis Myocardial infarction, PCI / PTCA, or coronary artery stenting during the 3-month period preceding the consent date Cardiac surgery during the three-month interval preceding the consent date Significant congenital heart defect (including atrial septal defects or PV abnormalities but not including PFO) NYHA class III or IV congestive heart failure Left ventricular ejection fraction (LVEF) less than 35% Hypertrophic cardiomyopathy (septal or posterior wall thickness >1.5 cm) Significant Chronic Kidney Disease (CKD - eGFR <30 µMol/L) Uncontrolled hyperthyroidism Cerebral ischemic event (strokes or TIAs) during the six-month interval preceding the consent date Pregnancy Life expectancy less than one (1) year Currently participating or anticipated to participate in any other clinical trial of a drug, device or biologic that has the potential to interfere with the results of this study Unwilling or unable to comply fully with study procedures and follow-up

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cryoballoon-based PVI<br>Sinus rhythm control via a pulmonary vein isolation (PVI) (first-line) procedure utilizing the the Arctic Front Cryoballoon Procedure. | Procedure: Cryoballoon-based PVI<br>* Patients randomized to first-line cryoballoon (CB) ablation will have the pulmonary vein isolation procedure performed according to standard clinical practice using the Arctic Front Cryoballoon ablation catheter. No anti-arrhythmic drugs will be prescribed in this arm.<br>|
| Active Comparator: Anti-Arrhythmic Drug Therapy<br>Sinus rhythm control via the use of anti-arrhythmic drug (AAD) therapy (first-line) based on local clinical practice, and according to guideline-suggested drug management for symptomatic patients with paroxysmal AF. | Drug: Anti-Arrhythmic Drug Therapy<br>* Antiarrhythmic drug therapy (Class I - flecainide, propafenone; Class III - sotalol, dronedarone) will prescribed and monitored based on local clinical practice, and according to guideline-suggested drug management for symptomatic patients with paroxysmal AF.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First Occurrence of Persistent Atrial Tachyarrhythmia | time to first occurrence of symptomatic or asymptomatic persistent atrial tachyarrhythmia (atrial fibrillation [AF], atrial flutter [AFL], or atrial tachycardia [AT]), as defined as the first occurrence of a continuous atrial tachyarrhythmia episode lasting ≥ 7 days in duration, or lasting 48 hours to 7 days in duration but requiring cardioversion for termination, as documented by implantable loop recorder. | Between 91 days following treatment initiation to final follow-up ( 36 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Atrial Fibrillation Burden | Percentage time in atrial fibrillation | Treatment initiation to final follow-up ( 36 months) | 
| Health Related Quality of Life | Change in disease-specific AFEQT score, and Generic EQ-5D score from baseline | Baseline, 12, 24, and 36 months following treatment initiation | 
| Symptom Status | Number of participants free from symptoms attributable to atrial fibrillation | Baseline, 12, 24, and 36 months following treatment initiation | 
| Healthcare utilisation | Number of participants experiencing an emergency department visit, cardioversion, and hospitalization >24 hours in a healthcare facility | Treatment initiation to final follow-up ( 36 months) | 
| Non-Protocol Ablation Procedure | Number of patients experiencing a repeat ablation procedures in those randomized to first line catheter ablation, or any ablation procedure performed in patients randomized to AAD therapy | Treatment initiation to final follow-up ( 36 months) | 
| Safety Outcomes related to Ablation or AAD therapy | Number of patients experiencing a major complication of ablation, or significant adverse drug events (death, ventricular pro-arrhythmia, syncope, hypotension, pacemaker insertion). | Treatment initiation to final follow-up ( 36 months) |