Over the past decades, only a limited number of novel antiarrhythmic drugs have reached clinical practice. Increasing regulatory requirements, relatively small target populations, and reduced industrial interest have contributed to the slowdown in antiarrhythmic drug development (1). Consequently, comprehensive knowledge and optimal utilization of existing agents have become increasingly important (2). This short review aims to support clinical decision-making by presenting the indications of propafenone and discussing selected clinical scenarios extending beyond guideline-based administration.

Propafenone is a class IC antiarrhythmic drug (3). Its principal mechanism of action involves the blockade of cardiac sodium channels, resulting in slowing of phase 0 depolarization. This leads to prolongation of refractoriness in atrial, atrioventricular nodal, and ventricular tissue, as well as accessory pathways in Wolff-Parkinson-White (WPW) syndrome. In addition, propafenone exhibits β-adrenergic receptor-blocking properties, potassium channel-blocking effects (4), and mild calcium channel–blocking activity. The substance’s half-life ranges between 2 and 10 hours, with hepatic metabolism playing a main role.

According to the 2024 ESC guidelines (5), propafenone has two principal indications in the management of atrial fibrillation (AF):

Propafenone is recommended for pharmacological cardioversion in patients without severe left ventricular hypertrophy, impaired left ventricular systolic function (heart failure with reduced ejection fraction, HFrEF), or coronary artery disease (5). The recommended oral dose for acute cardioversion is 450–600 mg, while intravenous administration is recommended at 1.5–2 mg/kg over 10 minutes (Figure 1, Tables 1 and 2). The “pill-in-the-pocket” approach represents a specific form of self-administered pharmacological cardioversion that may be considered in patients with infrequent paroxysmal AF following careful evaluation. This strategy can avoid emergency department presentation or hospitalization in selected cases.

Propafenone is also recommended for rhythm control therapy in patients with AF without structural heart disease. Although catheter ablation has evolved, and is increasingly considered as the first-line rhythm control strategy in many patients (6, 7), antiarrhythmic drugs continue to play an important role in several clinical scenarios, including patients awaiting ablation, those in whom the procedure is postponed due to comorbidities, patients declining invasive treatment, and those experiencing post-ablation recurrences (5, 8). In such situations, propafenone remains particularly relevant, as long-term amiodarone therapy might be limited by cumulative toxicity (9), while alternative agents recommended by guidelines (dronedarone and flecainide) may not be available in certain European healthcare systems.

The ESC guidelines also address AF during pregnancy, noting that propafenone may be considered for long-term rhythm control to reduce symptoms and improve maternal and fetal outcomes when rate-control drugs are ineffective or not tolerated.

The 2019 ESC supraventricular tachycardia guidelines provide detailed recommendations regarding propafenone use across multiple arrhythmia mechanisms (10). In acute settings, intravenous propafenone may be considered for:

For long-term rhythm control, propafenone may be considered in focal atrial tachycardia when ablation is not feasible or not preferred and no structural or ischemic heart disease is present. Similarly, the drug may reduce arrhythmic events in patients with WPW syndrome (without structural heart disease) when ablation is not desired. Comparable indications apply during pregnancy for prevention of supraventricular tachycardia episodes in women with WPW syndrome.

The use of antiarrhythmic drugs in ventricular arrhythmias - particularly in the presence of structural heart disease - requires appropriate consideration due to potential proarrhythmic effects and increased risk of sudden cardiac death (11). Although the 2022 ESC ventricular arrhythmia guidelines do not directly recommend propafenone, the closely related class IC agent flecainide is recommended for several indications, including frequent idiopathic premature ventricular complexes or ventricular tachycardia originating from either ventricle (Class IIa recommendation) (12). Several studies support the efficacy and safety of propafenone in similar clinical scenarios (13, 14), and no clinically meaningful differences between propafenone and flecainide have been observed regarding reduction of ectopic burden or improvement of ectopy-induced cardiomyopathy (15). The guidelines also discuss flecainide use in rare inherited arrhythmia syndromes, including catecholaminergic polymorphic ventricular tachycardia (CPVT) and Andersen–Tawil syndrome (ATS). While available evidence suggests that propafenone may have comparable efficacy to flecainide in CPVT (16, 17), case reports indicate limited effectiveness in ATS, where flecainide appears to be more efficient (18, 19).

A particularly challenging clinical scenario involves therapy-refractory malignant ventricular tachycardia in patients with structural heart disease and implantable cardioverter-defibrillator (ICD) therapy, amiodarone treatment, and catheter ablation attempts. In such cases, escalation of antiarrhythmic therapy - even off-label - may be considered. Although more evidence exists for mexiletine in this context (2, 20-22), propafenone may be considered in selected patients when alternative options are unavailable (23).

The most common adverse effects of propafenone include bradycardia, headache, dysgeusia, and dizziness. Palpitations, chest pain, fatigue, nausea, and vomiting may also occur. Less frequent adverse events include syncope, tremor, paraesthesia, abdominal pain, and constipation. Agranulocytosis, hepatic injury, lupus-like syndrome, and bronchospasm have also been reported. Overall, propafenone is generally well tolerated by patients. Clinically relevant drug interactions include concomitant use with apixaban (increased bleeding risk) and metoprolol (risk of hypotension and bradycardia). The most important contraindications include coronary artery disease, heart failure with reduced ejection fraction, severe left ventricular hypertrophy, Brugada syndrome, and significant conduction disturbances. Propafenone should not be used for pharmacological cardioversion of atrial flutter (5). Patients with a history of tachycardia-induced cardiomyopathy may be at an increased risk of proarrhythmic effects. After initiation of propafenone therapy - often combined with a β-blocker - follow-up ECG assessment is recommended within 1-2 weeks. Treatment should be discontinued if QRS duration increases by more than 25% or exceeds 130 ms, or if new bundle branch block or conduction abnormalities develop (see also Figure 12 in the original ESC guidelines (12)). Concomitant administration of a β-blocker (or alternatively diltiazem or verapamil) should also be considered because propafenone may occasionally convert AF to atrial flutter, which paradoxically may increase ventricular rate through improved atrioventricular conduction (5).

Propafenone is a widely applicable and readily available antiarrhythmic agent with multiple clinically relevant indications. When contraindications are carefully considered and patient selection is appropriate, propafenone may contribute substantially to personalized rhythm management strategies in patients with atrial fibrillation, focal atrial tachycardia, WPW syndrome, and selected ventricular arrhythmias.