Antiarrhythmic drugs for pharmacological cardioversion of atrial fibrillation and sex differences: Insights from the CANT II Study.

BACKGROUND: Data on sex differences in terms of action of antiarrhythmic agents (AADs) are limited. This study aimed to evaluate the clinical profile of patients with atrial fibrillation (AF), and efficacy and safety of AADs used for pharmacological cardioversion (PCV) of AF. METHODS: This research was a sub-analysis of the retrospective multicenter Cardioversion with ANTazoline II (CANT) registry, which comprised 1365 patients with short-duration AF referred for urgent PCV with the use of AAD. Patients were categorized according to and compared in terms of clinical parameters and PCV outcomes. The primary endpoint was return of sinus rhythm within 12 hours after drug infusion, and the composite safety endpoint involved bradycardia <45 bpm, hypotension, syncope, or death. RESULTS: The sex distribution of patients qualified for PCV was even (men, n = 725; 53.1%). Females were older and more symptomatic and had higher CHA2DS2-VASc scores, higher prevalence of tachyarrhythmia, and higher use of chronic anticoagulation. The overall efficacy (71.4% vs. 70.1%; P = 0.59) and safety (5.2% vs. 4.6%; P = 0.60) of PCV was comparable in men and women. Amiodarone (68.3% vs. 65.9%; P = 0.66) and antazoline (77.1% vs. 80.0%; P = 0.19) had similar efficacy in men and women, but propafenone had a lower rate of rhythm conversion in men (64.7% vs. 79.3%; P = 0.046). None of the assessed AADs differed in terms of safety profile in both sexes. CONCLUSION: Female patients with AF have different clinical profiles but similar efficacy and safety of AADs as compared to male participants. Propafenone has significantly lower efficacy in men, which requires further investigation.

Medical cardioversion of atrial fibrillation and flutter with class IC antiarrhythmic drugs in young patients with and without congenital heart disease.

INTRODUCTION: The use of flecainide and propafenone for medical cardioversion of atrial fibrillation (AF) and atrial flutter/intra-atrial reentrant tachycardia (IART) is well-described in adults without congenital heart disease (CHD). Data are sparse regarding their use for the same purpose in adults with CHD and in adolescent patients with anatomically normal hearts and we sought to describe the use of class IC drugs in this population and identify factors associated with decreased likelihood of success. METHODS: Single center retrospective cohort study of patients who received oral flecainide or propafenone for medical cardioversion of AF or IART from 2000 to 2022. The unit of analysis was each episode of AF/IART. We performed a time-to-sinus rhythm analysis using a Cox proportional hazards model clustering on the patient to identify factors associated with increased likelihood of success. RESULTS: We identified 45 episodes involving 41 patients. As only episodes of AF were successfully cardioverted with medical therapy, episodes of IART were excluded from our analyses. Use of flecainide was the only factor associated with increased likelihood of success. There was a statistically insignificant trend toward decreased likelihood of success in patients with CHD. CONCLUSIONS: Flecainide was more effective than propafenone. We did not detect a difference in rate of conversion to sinus rhythm between patients with and without CHD and were likely underpowered to do so, however, there was a trend toward decreased likelihood of success in patients with CHD. That said, medical therapy was effective in >50% of patients with CHD with AF.

Idiopathic premature ventricular complexes treatment: Comparison of flecainide, propafenone, and sotalol.

BACKGROUND: Beta-blockers (BB) or dihydropyridine calcium channel blockers (CCBs) are still the first choices in the treatment of idiopathic premature ventricular complexes (PVCs), with low-modest efficacy. Antiarrhythmic drugs (AADs) of Ic class are moderate to highly efficient but the evidence on their benefits is still limited. AIM: To compare effectiveness and safety of flecainide, propafenone, and sotalol in the treatment of symptomatic idiopathic PVCs. METHODS: Our single-center retrospective study analyzed 104 consecutive patients with 130 medication episodes of frequent idiopathic PVCs treated with AADs flecainide, propafenone (Ic class) or sotalol (III class). The primary outcome was complete/near complete reduction of PVCs after medication episode (PVCs burden reduction >99%), and the secondary outcome was significant PVC burden reduction (≥80%). RESULTS: The complete/near complete PVCs burden reduction occurred in 31% and was significant in 43% of treated patients. A reduction of PVC burden for >99% was achieved in 56% of patients on flecainide, in 11% of patients on propafenone (p = .002), and in 21% of patients receiving sotalol (p = .031). There was no difference between propafenone and sotalol (p = .174). A reduction of PVC burden for ≥80% was achieved in 64% of patients on flecainide, in 30% of patients on propafenone (p = .009), and 33% of patients on sotalol (p = .020). There was no difference between propafenone and sotalol (p = .661). CONCLUSIONS: The efficacy of AADs class Ic and III in the treatment of idiopathic PVCs was modest. Flecainide was the most effective AAD in the achievement of complete/near complete or significant PVC burden reduction, compared to propafenone and sotalol.

Flecainide in clinical practice.

Flecainide, similar to encainide and propafenone, is IC class antiarrhythmic, inhibiting Nav1.5 sodium channels in heart muscle cells and modulates cardiac conduction. Despite its over 40-year presence in clinical practice, strong evidence and well-known safety profile, flecainide distribution in Europe has not always been equal. In Poland, the drug has been available in pharmacies only since October this year, and previously it had to be imported on request. Flecainide can be used successfully in both the acute and chronic treatment of cardiac arrhythmias. The main indication for flecainide is the treatment of paroxysmal supraventricular tachycardias, including atrial fibrillation, atrioventricular nodal re-entrant tachycardia, atrioventricular re-entrant tachycardia and ventricular arrhythmias in patients without structural heart disease. Beyond that, it may be used in some supraventricular tachycardia in children and for sustained fetal tachycardia. Many studies indicate its efficacy comparable to or better than previously used drugs such as propafenone and amiodarone, depending on the indication. This review aims to highlight the most important clinical uses of flecainide in the light of the latest scientific evidence and to provide an overview of the practical aspects of treatment, including indications, off-label use, contraindications, areas of use, monitoring of treatment and most common complications, taking into account special populations: children and pregnant women.

Medical therapy with flecainide and propafenone in atrial fibrillation: Long-term clinical experience in the tertiary care setting.

BACKGROUND: Flecainide and propafenone are Class Ic antiarrhythmic drugs that block the cardiac fast inwards Na+ current and are used for rhythm control in patients with atrial fibrillation (AF). However, data on long-term clinical efficacy and safety of these drugs in a real-world setting are scarce. METHODS: Patients with AF who received chronic flecainide or propafenone therapy were retrospectively studied from the database of a tertiary care center. The primary outcome of the study was clinical efficacy of Class Ic antiarrhythmics, which was assessed based on the improvement of arrhythmia-related symptoms at the time of last follow-up. RESULTS: Among the 361 patients (261 males, 72.3%) with a mean age of 56 ± 12 years, 287 (79.5%) were using long-term flecainide, and 74 (20.5%) patients propafenone. The majority of the patients had paroxysmal AF (n = 331, 91.7%) and had an atrioventricular-nodal blocking co-medication (n = 287, 79.5%). A total of 117 (32%) patients discontinued therapy after a median of 210 days (interquartile range 62-855 days). Clinical efficacy was observed in 188 (52%) patients. The most common reason for therapy discontinuation was adverse drug effects, particularly proarrhythmic effects (48% for flecainide and 33% for propafenone). Patients who did not clinically benefit from Class Ic antiarrhythmics more often underwent pulmonary vein isolation (p = 0.02). CONCLUSIONS: Long-term therapy with Class Ic antiarrhythmics showed clinical efficacy in approximately half of the patients with paroxysmal or persistent AF. However, these drugs were also associated with a relatively high rate of adverse events, and in particular proarrhythmic effects, which often resulted in therapy discontinuation rendering appropriate patient selection and therapy surveillance essential.

Safety of Pill-in-the-Pocket Class 1C Antiarrhythmic Drugs for Atrial Fibrillation.

BACKGROUND: Guidelines recommend that initial trial of a "pill-in-the-pocket" (PIP) Class 1C antiarrhythmic drug (AAD) for cardioversion of atrial fibrillation (AF) be performed in a monitored setting because of the potential for adverse reactions. OBJECTIVES: This study sought to characterize real-world, contemporary use of the PIP approach, including the setting of initiation and incidence of adverse events. METHODS: This retrospective cohort study included all patients at the Hospital of the University of Pennsylvania treated with a PIP approach for AF between 2007 and 2020. RESULTS: A total of 273 patients (age 56 ± 13 years; 182 [67%] male; CHA2DS2VASc score 1.1 ± 1.2) took a first dose of PIP AAD. Flecainide was used in 151 (55%) and propafenone in 122 (45%). The first dose of PIP AAD was taken in a monitored setting in 167 (62%). Significant adverse events occurred in 7 patients (3%), 2 of whom had taken the dose in a monitored setting. Significant adverse events included unexplained syncope (1 of 7), symptomatic bradycardia/hypotension (4 of 7), and 1:1 atrial flutter (2 of 7). All occurred in patients taking 300 mg of flecainide (n = 4) or 600 mg of propafenone (n = 3). Electrical cardioversion was performed in 29 (11%) patients because of failure of the AAD to terminate AF. One patient required intravenous fluids and vasopressors for 2 hours because of persistent hypotension and bradycardia. Two patients required permanent pacemakers for bradycardia. The remaining patients required no intervention. CONCLUSIONS: Our data support the current recommendation to initiate PIP AAD in a monitored setting because of rare significant adverse reactions that can require urgent intervention.

A Mechanistic Clinical Trial Using (R)- Versus (S)-Propafenone to Test RyR2 (Ryanodine Receptor) Inhibition for the Prevention of Atrial Fibrillation Induction.

BACKGROUND: Experimental data suggest ryanodine receptor-mediated intracellular calcium leak is a mechanism for atrial fibrillation (AF), but evidence in humans is still needed. Propafenone is composed of two enantiomers that are equally potent sodium-channel blockers; however, (R)-propafenone is an ryanodine receptor inhibitor whereas (S)-propafenone is not. This study tested the hypothesis that ryanodine receptor inhibition with (R)-propafenone prevents induction of AF compared to (S)-propafenone or placebo in patients referred for AF ablation. METHODS: Participants were randomized 4:4:1 to a one-time intravenous dose of (R)-propafenone, (S)-propafenone, or placebo. The study drug was given at the start of the procedure and an AF induction protocol using rapid atrial pacing was performed before ablation. The primary endpoint was 30 s of AF or atrial flutter. RESULTS: A total of 193 participants were enrolled and 165 (85%) completed the study protocol (median age: 63 years, 58% male, 95% paroxysmal AF). Sustained AF and/or atrial flutter was induced in 60 participants (84.5%) receiving (R)-propafenone, 60 (80.0%) receiving (S)-propafenone group, and 12 (63.2%) receiving placebo. Atrial flutter occurred significantly more often in the (R)-propafenone (N=23, 32.4%) and (S)-propafenone (N=26, 34.7%) groups compared to placebo (N=1, 5.3%, P=0.029). There was no significant difference between (R)-propafenone and (S)-propafenone for the primary outcome of AF and/or atrial flutter induction in univariable (P=0.522) or multivariable analysis (P=0.199, adjusted for age and serum drug level). CONCLUSIONS: There is no difference in AF inducibility between (R)-propafenone and (S)-propafenone at clinically relevant concentrations. These results are confounded by a high rate of inducible atrial flutter due to sodium-channel blockade. REGISTRATION: https://clinicaltrials.gov; Unique Identifier: NCT02710669.

Influence of CYP2D6 genetic variation on adverse events with propafenone in the pediatric and young adult population.

Propafenone is an antiarrhythmic drug metabolized primarily by cytochrome P450 2D6 (CYP2D6). In adults, propafenone adverse events (AEs) are associated with CYP2D6 poor metabolizer status; however, pediatric data are lacking. Subjects were tested for 10 CYP2D6 allelic variants and copy number status, and activity scores assigned to each genotype. Seventy-six individuals (median 0.3 [range 0-26] years old) were included. Propafenone AEs occurred in 29 (38%); 14 (18%) required drug discontinuation due to AE. The most common AEs were QRS (n = 10) and QTc (n = 6) prolongation. Those with AEs were older at the time of propafenone initiation (1.58 [0.13-9.92] vs. 0.20 [0.08-2.01] years old; p = 0.042). CYP2D6 activity scores were not associated with presence of an AE (odds ratio [OR] 0.48 [0.22-1.03]; p = 0.055) but with the total number of AE (ß1  = -0.31 [-0.60, -0.03]; p = 0.029), systemic AEs (OR 0.33 [0.13-0.88]; p = 0.022), and drug discontinuation for systemic AEs (OR 0.28 [0.09-0.83]; p = 0.017). Awareness of CYP2D6 activity score and patient age may aid in determining an individual's risk for an AE with propafenone administration.

Pharmacological Cardioversion in Patients with Recent-Onset Atrial Fibrillation and Chronic Kidney Disease Subanalysis of the CANT II Study.

Pharmacological cardioversion (PCV) is commonly a primary option for termination of recent-onset atrial fibrillation (AF) in emergency departments (ED). This is a subanalysis of the CANT II study, evaluating the effectiveness and safety of antazoline in patients (n = 777) at three stages of chronic kidney disease (CKD): Group I > 60 mL/min (n = 531), Group II 45−59 mL/min (n = 149), and Group III < 45 mL/min (n = 97). Patients in Group III were older and with a higher prevalence of co-morbidities; however, we did not find statistically significant differences in the overall effectiveness of PCV in comparison with the other groups. In patients receiving amiodarone, the PCV success rate was similar in all the studied groups, but along with a renal function decline, it decreased in patients receiving antazoline (79.1 vs. 35%; p < 0.001), and it increased almost significantly in patients receiving propafenone (69.9 vs. 100%; p = 0.067). In patients in Group I, antazoline restored a sinus rhythm as effectively as propafenone and amiodarone; however, in patients in Group III, both antazoline and amiodarone became less effective in restoring a sinus rhythm than propafenone (p = 0.002 and p = 0.034, respectively). The rate of safety endpoint was the highest in patients in Group III (eGFR < 45 mL/min), and it was significantly higher than in patients in Groups I and II (p = 0.008 and p = 0.036, respectively). We did not observe antazoline-related adverse events in any of the studied groups of patients. This real-world registry analysis revealed a different influence of CKD on the effectiveness of individual drugs, and while propafenone and amiodarone maintained their AF termination efficacy, antazoline became significantly less effective in restoring sinus rhythm.

Electrophysiological effects and clinical utility of propafenone in children.

AIM: This retrospective case series study sought to describe the safety and clinical effectiveness of propafenone for the control of arrhythmias in children with and without CHD or cardiomyopathy. METHODS: We reviewed baseline characteristics and subsequent outcomes in a group of 63 children treated with propafenone at 2 sites over a 15-year period Therapy was considered effective if no clinically apparent breakthrough episodes of arrhythmias were noted on the medication. RESULTS: Sixty-three patients (29 males) were initiated on propafenone at a median age of 2.3 years. CHD or cardiomyopathy was noted in 21/63 (33%). There were no significant differences between demographics, clinical backgrounds, antiarrhythmic details, side effect profiles, and outcomes between children with normal hearts and children with CHD or cardiomyopathy. Cardiac depression at the initiation of propafenone was more common amongst children with CHD or cardiomyopathy compared to children with normal hearts. Systemic ventricular function was diminished in 15/63 patients (24%) prior to starting propafenone and improved in 8/15 (53%) of patients once better rhythm control was achieved. Other than one child in whom medication was stopped due to gastroesophageal reflux, no other child experienced significant systemic or cardiac side effects during treatment with propafenone. Propafenone achieved nearly equal success in controlling arrhythmias in both children with normal hearts and children with congenital heart disease or cardiomyopathy (90% versus 86%, p = 0.88). CONCLUSION: Propafenone is a safe and effective antiarrhythmic medication in children.

Single-dose oral anti-arrhythmic drugs for cardioversion of recent-onset atrial fibrillation: a systematic review and network meta-analysis of randomized controlled trials.

AIMS: Single oral dose anti-arrhythmic drugs (AADs) are used to cardiovert recent-onset atrial fibrillation (AF); however, the optimal agent is uncertain. METHODS: We performed a systematic review and network meta-analysis of randomized trials testing single oral dose AADs vs. any comparator to cardiovert AF <7 days duration. We searched MEDLINE, Embase, and CENTRAL to April 2020. The primary outcome was successful cardioversion at timepoint nearest 8 h after administration. RESULTS: From 12 712 citations, 22 trials (2320 patients) were included. Thirteen trials included patients with some degree of heart failure; 19 included patients with some degree of ischaemic heart disease vs. placebo or rate-control (32% success) at 8 h, flecainide [73%, network odds ratio (OR) 7.6, 95% credible interval (CrI) 4.4-14.0], propafenone (70%, OR 4.6, CrI 2.9-7.3), and pilsicainide (59%, OR 10.0, CrI 1.8-69.0), but not amiodarone (28%, OR 1.0, CrI 0.4-2.8) were superior. Flecainide (OR 7.5, CrI 2.6-24.0) and propafenone (OR 4.5, CrI 1.6-13.0) were superior to amiodarone; propafenone vs. flecainide did not statistically differ (OR 0.6, CrI 0.3-1.1). At longest follow-up, amiodarone was superior to placebo (OR 11.0, CrI 3.2-41.0), flecainide vs. amiodarone (OR 0.79, CrI 0.19-3.1), and propafenone vs. amiodarone (OR 0.36, CrI 0.092-1.4) were not statistically different, and flecainide was superior to propafenone (OR 2.2, CrI 1.1-4.8). Atrial and ventricular tachyarrhythmias, bradyarrhythmias, and hypotension were rare with PO AADs. CONCLUSION: Single oral dose Class 1C AADs are effective and safe for cardioversion of recent-onset AF. Flecainide may be superior to propafenone. Amiodarone is a slower acting alternative.

Comparison of Amiodarone and Propafenone in Blanking Period after Radiofrequency Catheter Ablation in Patients with Atrial Fibrillation: A Propensity Score-Matched Study.

BACKGROUND: Amiodarone and propafenone are commonly used to maintain sinus rhythm in patients with atrial fibrillation (AF). However, it is not known which one is better in reducing early recurrence (ER) during the blanking period (the first three months after catheter ablation). OBJECTIVE: To compare the efficacy and safety of amiodarone and propafenone in reducing ER during the blanking period after radiofrequency catheter ablation (RFCA) in AF patients. MATERIALS AND METHODS: A total of 694 patients who underwent their first RFCA between May 2014 and May 2018 were enrolled in this retrospective study. Subsequently, 202 patients were excluded according to the exclusion criteria. The remaining 492 patients were divided into two groups based on the choice of antiarrhythmic drugs (AADs) (amiodarone or propafenone) in the blanking period. The primary outcomes were incidence of ER and AAD-associated adverse effects during the blanking period after RFCA. Propensity score matching (PSM) analyses were used to compare the outcomes of the two groups while controlling for confounders. RESULTS: Among the 492 patients who took AADs in the blanking period (187 amiodarone and 305 propafenone), PSM selected 135 unique pairs of patients with similar characteristics. Amiodarone was associated with a lower ER incidence rate (23.7% versus 48.9%, p < 0.001) and a similar rate of AAD-associated adverse effects (2.1% versus 1.5%, p = 0.652). Treatment with amiodarone in the blanking period was significantly associated with a lower ER incidence rate compared to treatment with propafenone (HR = 0.416, 95% CI 0.272-0.637, p < 0.001). CONCLUSIONS: Compared with propafenone, amiodarone was associated with a lower ER incidence rate, and they had similar rates of AAD-associated adverse effects. Treatment with amiodarone in the blanking period was shown to be more effective in reducing ER than propafenone.

Propafenone-associated Gross Hematuria: A Case Report and Review of the Literature.

PURPOSE: Propafenone hydrochloride has been widely used for the treatment of supraventricular and ventricular arrhythmias. We present a case report of an 81-year-old patient with propafenone-associated gross hematuria. METHODS: The Naranjo Adverse Drug Reaction Probability Scale was used to assess causality. We also performed a literature search to find publications that report propafenone-associated gross hematuria. FINDINGS: The Naranjo scale generated a score of 6, suggesting a probable association between gross hematuria and propafenone therapy. Thirteen publications that reported an association between gross hematuria and propafenone administration were found. IMPLICATIONS: A probable association exists between gross hematuria and propafenone.