Fresh Advice From the 2025 European Heart Rhythm Association Practical Compendium of Antiarrhythmic Drugs

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EP LAB DIGEST. 2025;25(10):6.

Bradley P Knight, MD, FACC, FHRS 

Dear Readers,

Over the past 2 decades, advances in catheter ablation procedures and technologies have far outpaced progress in antiarrhythmic drug (AAD) development. However, there remains a significant role for pharmacological management of patients with heart rhythm disorders, highlighting the ongoing need to develop better drugs. In fact, one could argue that the growing atrial fibrillation (AF) epidemic has increased the need for both ablation and pharmacological therapies. Although some progress has been made with novel agents and alternative routes of administration—such as intravenous (IV) sotalol and intranasal calcium channel blockers—the overall pace of drug development has remained slow. Notably, although AADs are routinely prescribed in practice—for example, flecainide for paroxysmal AF or amiodarone for ventricular arrhythmias in patients with heart failure—not a single AAD carries a Class I recommendation in the most recent American College of Cardiology/American Heart Association/Heart Rhythm Society guidelines.¹

Earlier this year, the European Heart Rhythm Association (EHRA) released an updated clinical consensus statement on the use of AADs. The writing committee, chaired by Professor John Camm, described the document as a practical compendium, stating: “This document aims to provide practical instructions to clinicians in arrhythmia management through pharmacological strategies. The compendium highlights persistent challenges in arrhythmia treatment, including clinical constraints, procedural risks, and the complexity of certain arrhythmias.”² The document introduces a new ABC framework, organizing the use of AADs into Appropriate, Backup, and Complementary therapies. Appropriate therapies include the use of AADs as sole therapy for managing arrhythmias; backup therapy refers to using AADs when ablation and implantable device therapy are not options or have been ineffective; and complementary therapy refers to the adjunctive use of drugs in the peri-procedural setting or in combination with nonpharmacological approaches. The document also provides practical advice related to initiation of AADs and real-world scenarios that are often not addressed in classical guidelines.

Importantly, the compendium offers a modern update to the Vaughan Williams (VW) classification of AADs,³ ensuring both established and newer AADs are now incorporated and assigned to categories within the revised framework. Four new VW classes have been added. For example, ivabradine—an inhibitor of the hyperpolarization and cyclic nucleotide-gated channel-mediated pacemaker funny current (If)—is now classified as a VW Class 0 AAD. Mechanosensitive channel blockers are now designated as VW Class 5, gap junction channel blockers are Class 6, and upstream target modulators such as SGLT2 inhibitors are Class 7. 

In addition, the VW classes have been expanded with additional subclasses. The Class II category has been greatly broadened into 5 subclasses: IIa for β-blockers, IIb for β-agonists such as isoproterenol, IIc for muscarinic M2 receptor antagonists such as atropine, IId for acetylcholine release activators such as digoxin, and IIe for adenosine A1 receptor activators such as adenosine. In addition, ranolazine, a blocker of the late Na+ current, is now designated as a Class Id drug.

Several of the recommendations conflict with established guidelines and practice in the United States. A key example is the initiation of inpatient versus outpatient sotalol. The consensus document acknowledges the US Food and Drug Administration (FDA) requirement that all patients being initiated or re-initiated on sotalol should be hospitalized for at least 3 days—or until steady-state drug levels are reached—in a facility equipped for cardiac resuscitation and continuous ECG monitoring. However, it also suggests that outpatient initiation is acceptable except in patients with a QTc ≥450 ms (≥500 ms with intraventricular conduction delay), bradycardia (≤60 bpm), or other risk factors such as structural heart disease or renal dysfunction. The authors describe outpatient initiation as “safe” in low-risk patients, including males in sinus rhythm with normal renal function and electrolytes and no left ventricular hypertrophy. By contrast, they emphasize that dofetilide must always be initiated and dose-adjusted in the hospital. 

This approach raises several concerns. Most notably, citing a baseline QTc >450 ms as an indication for inpatient initiation is problematic, given that a prolonged QT interval is an absolute contraindication to sotalol use. Equally surprising is the absence of discussion regarding FDA-approved IV sotalol, which can be administered as a 1-hour infusion followed by 2 oral doses to achieve steady state more rapidly and reduce hospital length of stay compared with the traditional 3-day inpatient oral initiation.⁴ The only IV regimens mentioned are a bolus over 10 minutes or an infusion over 12 hours.

Another omission in this document is the rare mention or discussion of cost. The authors refer to costs only when summarizing the advantages of outpatient versus inpatient initiation, the high costs of drug development, and the cost savings associated with drugs that work quickly in the emergency department. Unfortunately, the difference in costs amongst AADs, at least in most countries, is often a big determinant as to which drugs are prescribed. 

The new AAD compendium regarding the use of pharmacological therapy for heart rhythm disorders by the EHRA group is a timely, practical, and comprehensive document that is worth reading and will serve as a very useful resource, guide, and reference moving forward. 

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. Dr Knight reports payment or honoraria from Convatec for a lecture. 

References

1.    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

2.    Merino JL, Tamargo J, Blomström-Lundqvist C, et al. Practical compendium of antiarrhythmic drugs: a clinical consensus statement of the European Heart Rhythm Association of the European Society of Cardiology. Europace. 2025;27(8):euaf076. doi:10.1093/europace/euaf076 

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

4.    Liu AY, Charron J, Fugaro D, et al. Implementation of an intravenous sotalol initiation protocol: implications for feasibility, safety, and length of stay. J Cardiovasc Electrophysiol. 2023;34(3):502-506. doi:10.1111/jce.15819