The Impact of "First-Line" Rhythm Therapy on AF Progression

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.