Study Rationale

Why has rhythm control therapy of AF not been effective in the prevention of deaths and stroke? This may in part be due to the fact that the tested interventions, mainly ion channelblocking drugs, may have proarrhythmic effects, especially in patients with left ventricular hypertrophy or severe heart failure. Proarrhythmia, however, is a relatively rare event, even in high-risk patient groups. More importantly, the rhythm control interventions used in the published trials were only moderately effective (e.g. sinus rhythm rates at the end of followup in the AFFIRM trial were 30% in the “rate control” group and 60% in the rhythm control group). It has been suspected that the negative outcome of rhythm control therapy in the AFFIRM trial is a consequence of “positive patient selection”; i.e. that enrolled patients were selected by having survived a phase of AF-related complications. Furthermore, the AF-CHF trial probably suffered from a similar bias by preferably enrolling patients without marked AF-related symptoms. Much of the atrial damage induced by AF was probably irreversible in the AF-CHF patients (e.g. 3.5% stroke, or 1% per year). Interestingly, stroke rates in AF-CHF were numerically smaller in the rhythm control group (3% vs. 4% 17), as well as in the dronedarone arm of the ATHENA trial. Furthermore, anticoagulant therapy was often withdrawn from patients in rhythm control arms, e.g. in the AFFIRM trial, based on the assumption that sinus rhythm was present, resulting in a potentially avoidable excess risk of ischemic stroke, potentially induced by asymptomatic recurrences of AF.

The causes underlying AF are multifactorial. AF itself causes marked changes in atrial electrophysiology (“electrical remodelling”) and in the molecular function and structure of the atria ("structural remodelling"). Ion channel-blocking antiarrhythmic drugs, the main intervention in the published “rhythm control” trials, may counter the “electrical remodelling”, but leave other mechanisms untouched. These vicious circles initiate and maintain AF, and contribute to AF-related complications.

The marked molecular and structural changes in the atria (“atrial cardiomyopathy”) induced by AF include calcium overload, atrial fibrosis, myolysis, myocellular hypertrophy, activation of the rennin-angiotensin system, and atrial contractile dysfunction. These profound changes may still be reversible during early phases of the arrhythmia, but provoke relevant and permanent atrial damage during later stages of AF.

Furthermore, many patients with AF suffer from focal triggering sources that initiate AF. These focal initiators can be treated by isolation of the pulmonary veins (“catheter ablation of AF”).

Taken together, insufficient, non-structured and delayed therapy of the multiple factors that lead to AF, maintain it, and cause its complications have most likely contributed to the limited efficacy of rhythm control interventions in the past “rhythm control strategy” trials. There is, hence, a growing need for a trial that tests whether a structured and early antiarrhythmic intervention is beneficial for AF patients. The tools for such an early AF therapy are available to clinical cardiologists, but have so far not been systematically applied to the AF patient population.

This trial protocol, therefore, suggests a controlled trial that tests the hypothesis that an early, standardized rhythm control therapy strategy can prevent cardiovascular outcomes attributable to AF. This therapeutic strategy will be compared to usual care as defined by the ACC/AHA/ESC guidelines for the treatment of AF.