Authors

• Krisztián Kássa — Gottsegen National Cardiovascular Center, Budapest, Hungary — ORCID: 0000-0001-9175-4219
• Máté Vámos — University of Szeged, Department of Internal Medicine, Cardiology Center, Szeged, Hungary — ORCID: 0000-0003-1611-4443

Abstract

The development of novel antiarrhythmic agents has decelerated considerably in recent decades, necessitating broader and more specific use of currently available medications. This underscores the importance of a thorough understanding of antiarrhythmic drugs used in clinical practice. In this summary, we discuss the role of propafenone in the management of atrial fibrillation, supraventricular tachycardias, and selected ventricular arrhythmias, with particular emphasis on current European Society of Cardiology (ESC) guideline recommendations and further clinically relevant applications.

Keywords

antiarrhythmic drugs, propafenone, arrhythmias, safety

DOI

Full Text

## Introduction 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. ## Atrial fibrillation According to the 2024 ESC guidelines (5), propafenone has two principal indications in the management of atrial fibrillation (AF): - Pharmacological cardioversion - Long-term maintenance of sinus rhythm 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**Table 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. [[figure:f1]] ### TABLE 1: Indications of propafenone based on recent ESC guidelines. | **Indication** | **Class of** **indication** | **Level of** **evidence** | | --- | --- | --- | | **Rhythm control for atrial fibrillation (ESC 2024)** (5) | | | | Intravenous flecainide or propafenone is recommended when pharmacological cardioversion of recent-onset AF is desired, excluding patients with severe left ventricular hypertrophy, HFrEF, or coronary artery disease | I | A | | Flecainide or propafenone is recommended in patients with AF requiring long-term rhythm control to prevent recurrence and progression of AF, excluding those with impaired left ventricular systolic function, severe left ventricular hypertrophy, or coronary artery disease. | I | A | | A single self-administered oral dose of flecainide or propafenone (pill-in-the-pocket) should be considered for patient-led cardioversion in selected patients with infrequent paroxysmal AF, after efficacy and safety assessment and excluding those with severe left ventricular hypertrophy, HFrEF, or coronary artery disease | IIa | B | | Concomitant use of a beta-blocker, diltiazem, or verapamil should be considered in AF patients treated with flecainide or propafenone, to prevent 1:1 conduction if their rhythm is transformed to atrial flutter. | IIa | C | | Flecainide or propafenone may be considered for longer-term rhythm control in pregnancy, if rate controlling drugs are ineffective or not tolerated, to reduce symptoms and improve maternal and fetal outcomes | IIb | C | | **Focal atrial tachycardia (ESC 2019)** (10) | | | | For acute therapy in hemodynamically stable patients, if agents such as adenosine, beta-blockers, verapamil, or diltiazem are ineffective, intravenous ibutilide, flecainide, propafenone, or amiodarone may be considered. | IIb | C | | Beta-blockers or non-dihydropyridine calcium channel blockers (verapamil or diltiazem in the absence of HFrEF), or propafenone or flecainide in the absence of structural or ischemic heart disease, should be considered if ablation is not desirable or feasible. | IIa | C | | Accessory pathway-mediated reentry tachycardia (ESC 2019) (10) | | | | Propafenone or flecainide may be considered in patients with AVRT and without ischemic or structural heart disease, if ablation is not desirable or feasible | IIb | B | | Flecainide or propafenone should be considered for prevention of SVT in patients with WPW syndrome, and without ischemic or structural heart disease. | IIa | C | | Flecainide or propafenone (i.v.) may be considered in hemodynamically stable patients with pre-excited atrial fibrillation. | IIb | B | | In pregnant women, flecainide or propafenone should be considered for prevention of SVT in patients with WPW syndrome and without ischemic or structural heart disease. | IIa | C | [†] AVRT = atrioventricular re-entry tachycardia; ESC = European Society of Cardiology; HFrEF = heart failure with reduced ejection fraction; AF = atrial fibrillation; SVT = supraventricular tachycardia; WPW = Wolff–Parkinson–White ### TABLE 2: Intravenous and oral dosing of propafenone for specific indications. | **Administration** | **Starting dose** | **Maintenance dose** | **Indications** | **Contraindication** | | --- | --- | --- | --- | --- | | Oral | 450-600 mg | 450-900 mg (2-3 times daily) | cardioversion of AF, maintenance of SR | • Severe LV hypertrophy • Structural heart disease • Brugada-syndrome • Severe kidney or liver disease • Severe sinus bradycardia, conduction disease, wide QRS duration • Not for CV of atrial flutter • Recovered tachycardia-induced cardiomyopathy (proarrhythmic risk may be increased) | | PVC, VT | | | | | | Intravenous | 1.5-2 mg/kg – in 10 minutes | - | cardioversion of AF | | [†] AF = atrial fibrillation, SR = sinus rhythm; PVC = premature ventricular complex, VT = ventricular tachycardia 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. ## Supraventricular tachycardias 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: - Focal atrial tachycardia in hemodynamically stable patients when adenosine, β-blockers, or calcium channel blockers are ineffective; - Atrioventricular re-entry tachycardia (AVRT) in patients with WPW syndrome without structural or ischemic heart disease when catheter ablation is not feasible; - Pre-excited atrial fibrillation, where AV nodal blocking agents are contraindicated. 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. ## Ventricular arrhythmias 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). ## Contraindications and situations requiring particular caution 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). ## Conclusions 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.

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