The following are key points to remember about the increasing role of rhythm control in patients with atrial fibrillation (AF):

1. AF management comprises three main domains summarized in the “ABC” scheme of the 2020 European Society of Cardiology AF guidelines; these are “A” for anticoagulation/avoid stroke, “B” for better symptom control using rate and rhythm management, and “C” for therapy of concomitant cardiovascular conditions.
2. PIAF, AFFIRM, RACE, AF-CHF, STAF, and J-RHYTHM are the key trials that have shown few significant differences in important endpoints between rhythm- and rate-control strategies. In AFFIRM and RACE, there was a trend towards a higher mortality for rhythm control compared with rate control. As a result of these trials, treatment currently defaults to initial rate control, with rhythm control being reserved to improve symptoms that persist despite adequate rate control.
3. Antiarrhythmic drugs (AADs) approximately double the likelihood of maintaining sinus rhythm compared with no rhythm-control therapy. AF ablation (pulmonary vein isolation) has been shown to be more effective than AADs in maintaining sinus rhythm, including when used as first-line treatment for rhythm control, and with a good safety record (RAAFT, RAAFT-2, STOP AF, EARLY-AF, and CRYO-First trials). However, ablation should not be seen as a one-off curative treatment for AF.
4. The use of “upstream” therapies (such as mineralocorticoid receptor antagonists, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and sodium-glucose co-transporter-2 inhibitors) has also been shown to be associated with improved maintenance of sinus rhythm.
5. Lifestyle adjustments such as weight loss, increased exercise, and the management of sleep apnea may also lead to reduction in AF burden.
6. Dronedarone is associated with a better safety profile and is thus supported as a first-line treatment option for rhythm management in some patient populations. The ATHENA trial showed that treatment with dronedarone reduced the risk of a primary outcome of hospitalization due to unexpected cardiovascular events or death from any cause compared with placebo.
7. In the CASTLE-AF trial, catheter ablation was associated with a reduced AF burden and an improved left ventricular ejection fraction compared with pharmacological treatment in patients with coexisting AF and heart failure.
8. The EAST-AFNET 4 study in patients with AF diagnosed within 12 months before randomization, who were at risk of stroke, supports early comprehensive AF treatment, altering the view on early rhythm control as a general treatment concept. The first primary outcome was a composite of death from cardiovascular causes, stroke (ischemic or hemorrhagic), or hospitalization with worsening heart failure or acute coronary syndrome, which was reduced by 21% in patients assigned to early rhythm control compared with usual care. The primary safety outcome was not different between randomized groups. Compared with those assigned to usual care, the occurrence of stroke was reduced by approximately one-third and total mortality was 16% lower in patients randomized to early rhythm control. These data showed a consistent beneficial effect of early rhythm control versus usual care, independent of whether the patient was symptomatic or asymptomatic. The use of amiodarone and dronedarone as AAD options in EAST-AFNET 4 and the availability of AF ablation in patients who failed AAD therapy may have contributed to this outcome given that they can be safely used in patients with structural heart disease.
9. Results from the ATTEST trial showed that early ablation as part of standard care was superior to AAD therapy alone in delaying progression from recurrent paroxysmal AF to persistent AF, with the effect apparent at 1 year of follow-up and maintained over 3 years.
10. There is an active search for more effective and safer AADs such as small conductance calcium-activated potassium (SK) channel inhibitors, TWIK-related acid-sensitive potassium channel (TASK-1) inhibitors, slow sodium channel inhibition and multichannel inhibitors, and alternative ablation approaches such as pulsed field ablation or electroporation.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Cardiovascular Care Team, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Anticoagulation Management and Atrial Fibrillation, Implantable Devices, EP Basic Science, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism, Acute Heart Failure, Sleep Apnea

Keywords: Angiotensin-Converting Enzyme Inhibitors, Anti-Arrhythmia Agents, Anticoagulants, Arrhythmias, Cardiac, Atrial Fibrillation, Catheter Ablation, Dronedarone, Electroporation, Heart Failure, Life Style, Mineralocorticoid Receptor Antagonists, Potassium Channels, Secondary Prevention, Sleep Apnea Syndromes, Stroke, Ventricular Function, Left, Weight Loss

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