Question: Which Antiarrhythmic Drugs Carry a Class I Recommendation for Rhythm Control in the 2023 AHA/ACC/ACCP/HRS Atrial Fibrillation Guideline? Answer: None.

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EP LAB DIGEST. 2024;24(6):6.

Dear Readers,

Despite the recent advances in nonpharmacologic interventional therapies for atrial fibrillation (AF), including catheter ablation as first-line therapy for patients considered appropriate candidates for rhythm control, antiarrhythmic drugs (AADs) continue to have an important role in disease management. Drugs can be used for chemical cardioversion to restore sinus rhythm, for maintenance of sinus rhythm, and for control of the ventricular response during AF. Many patients are treated with one or more AADs before considering catheter ablation, and many patients have recurrent atrial arrhythmias after ablation and continue to require an AAD for rhythm control. There are also many patients who are ineligible for an ablation procedure.

The Vaughan-Williams Classification categorizes AADs based on their effect on the cardiac action potential.¹ Drugs that block cardiac sodium channels slow conduction velocity, can prolong the duration of the QRS complex, and are referred to as Class I drugs. Class I AADs used to treat AF include flecainide and propafenone. While these drugs have different mechanisms of action, they are often used interchangeably and can be started safely as an outpatient in the absence of structural heart disease. These drugs are avoided in patients with heart disease because of the risk of causing proarrhythmia and increasing mortality in these patients.

In contrast, drugs that block cardiac potassium channels prolong the refractory period, can excessively prolong the QT interval, and are referred to as Class III drugs. Orally available Class III AADs that are used specifically to treat AF include dofetilide and sotalol. Dofetilide is considered a pure potassium channel blocker and sotalol is considered a potassium channel blocker plus a beta blocker. Until the recent availability of sotalol in intravenous form, both sotalol and dofetilide were exclusively prescribed as oral medications given twice daily. Both drugs are considered safe to use in patients with structural heart disease such as coronary artery disease, cardiomyopathy, and valvular heart disease, but both drugs are contraindicated in patients with QT prolongation at baseline. Sotalol is also avoided in patients who are not expected to tolerate the beta-blocking component of the drug, including patients with decompensated heart failure. Because dofetilide and sotalol can cause life-threatening ventricular proarrhythmia, these drugs are usually initiated in the hospital. Ibutilide is a potassium channel blocker that is available intravenously for the acute termination of atrial arrhythmias.

Two other drugs used to treat AF are also in the category of Class III AADs: amiodarone and dronedarone. Because amiodarone blocks most cardiac channels and receptors and has multiple actions, it shares properties with all the AAD categories. Amiodarone has been available for decades and perhaps because of its multiple actions on the heart, it is the most effective AAD of all. However, since amiodarone is also associated with organ toxicity when used long term, side effects, and multiple drug interactions, it is only used as a first-line agent for AF in patients with highly symptomatic AF who have no other options. The 2023 American Heart Association/American College of Cardiology/American College of Chest Physicians/Heart Rhythm Society Guideline for the Diagnosis and Management of Atrial Fibrillation states that “[A]miodarone is best reserved for patients who do not respond to other recommended antiarrhythmic agents or for whom other antiarrhythmic drugs are contraindicated.”² Dronedarone is the most recently developed AAD available in the United States and was derived from amiodarone with the hope that it would be as effective as amiodarone but not share its potential for organ toxicity. However, dronedarone has been shown to be significantly less effective than amiodarone, received a black box warning by the US Food and Drug Administration, is unsafe in patients with heart failure, and can be costly. 

Other than amiodarone, other currently available AADs are considered to have comparable efficacy for the prevention of recurrent AF. Therefore, the choice of AADs for rhythm control in patients with AF is based more on their (1) safety profile, (2) cost to hospitals and patients, (3) prescriber familiarity, and (4) convenience to an individual patient, rather than their potential efficacy. The updated guideline uses a standard Classification system corresponding with the strength of the recommendation, from class 1 (I) to class 3 (III).2 Notably, under “Recommendations for Specific Drug Therapy for Long-Term Maintenance of Sinus Rhythm,” no AAD—including amiodarone—was assigned a class I recommendation (“Is recommended,” the highest strength of recommendation). Sotalol now has a class IIb recommendation (“May/might be reasonable”) compared to dofetilide, which now has a class IIa recommendation (“Is reasonable”).

Catheter ablation is not always a treatment option for patients with AF, either because patients have contraindications, need acute rhythm control, or have limited access to the procedure as is true in many countries. In addition, catheter ablation does not always provide effective rhythm control in all patients. That is why, despite their limitations, the 6 commercially available AADs used to treat patients with AF (5 in Europe, where dofetilide is not available) are currently being prescribed to thousands of patients to reduce their AF burden. Physicians have been following this practice based on initial pivotal trials showing safety and efficacy as well as decades of experience. Therefore, it is surprising that in the latest AF guideline, not a single AAD is considered to have a class I indication. 

Disclosures: Dr Knight has served as a paid consultant to Medtronic and was an investigator in the PULSED AF trial. In addition, he has served as a consultant, speaker, investigator, and/or has received EP fellowship grant support from Abbott, AltaThera, AtriCure, Baylis Medical, Biosense Webster, Biotronik, Boston Scientific, CVRx, Philips, and Sanofi; he has no equity or ownership in any of these companies.

References

1. Vaughan Williams E. Classification of anti-arrhythmic drugs. In: Sandoe E, Flensted-Jensen E, Olsen K, eds. Symposium on Cardiac Arrhythmias. Astra; 1970:449-472.

2. Joglar JA, Chung MK, Armbruster AL, et al. 2023 ACC/AHA/ACCP/HRS guideline for the diagnosis and management of atrial fibrillation: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2024;149(1):e1-e156. doi:10.1161/CIR.0000000000001193