(N-NITROSO) PROPAFENONE INDUCED ADVANCED NODULAR MELANOMA-FIRST REPORTED CASE IN THE WORLD LITERATURE: THE INEXTRICABLE LINKS BETWEEN THE PHOTOCARCINOGENESIS, DRUG RELATED NITROSOGENESIS AND PHARMACO-ONCOGENESIS.

Onco-pharmacogenesis or pharmaco-oncogenesis of skin cancer is a concept , which could also be considered as an "end product" of drug-mediated Nitrosogenesis or of the permissive regime for carcinogens to be (un)controlled released in drugs. Their controlled distribution remains until 2025 as a forced and non-alternative and there is no indication of any possibility to introduce a full elimination regime against the already mentioned carcinogenic availability. There are three main worrying facts that determine the need for these elimination regimes: 1) the clinicopathological correlations concerning the intake of a heterogeneous class of drugs and the subsequent development of relatively homogeneous tumours/ such as melanoma, 2) the recently proven mutagenic/ carcinogenic action of certain nitrosamines, but this time directly on human DNA, and 3) the fact that some of the nitrosamines are potent photocarcinogens that exert their genotoxic effects only after irradiation with UVA/ also recently proven/. In addition to the rhetoric mentioned above, there is also an overlap in mutational patterns between the genes previously generally accepted to affect melanomas - p53 / RAS oncogenes , with those identified as target genes, but being affected "mutationally", by certain nitrosamines. The processes of photocarcinogenesis, nitrosogenesis and oncopharmacogenesis of skin cancer are inextricably linked and should not be considered and analysed unilaterally or in a semi-invasive manner. Cataloguing the type of nitrosamines and their precise concentration on drug leaflets and prescription/official websites with permanent access to clinicians and end-users remains the only safe and effective weapon in the fight against (un)controlled contamination. The pharmaceutical industry and regulators remain the creators, the 'parents' of onco-pharmacogenesis, nitrosogenesis, and therefore the processes involved in the generation and progression of skin cancer. The impossibility of establishing elimination regimes for certain mutagens and/or carcinogens already proven to be present in medicines remains a mystery. In practice, end consumers find themselves in a state of enforced tolerance of certain genotoxic substances that are not even declared as available. Clinicians in the face of dermatologists/ dermatological surgeons remain the analysers and identifiers of these globalization processes. Once again, we present a patient who took the antiarrhythmic (nitroso-) drug propafenone and developed a relatively short-term nodular melanoma with a subsequent fatal outcome. We comment on the role of drug-mediated nitrosogenesis and its relationship to photocarcinogenesis and onco-pharmacogenesis.

A case of lethal suicidal intoxication with propafenone and diazepam.

Diazepam poisoning is a common emergency situation, but propafenone poisoning is relatively rare. We reported a case of propafenone poisoning combined with diazepam. An 18-year-old female patient was admitted to our hospital with an overdose of oral propafenone and diazepam. The patient was treated with medication that proved to be useful, but the sinus rhythm could not be recovered, and cardiac arrest occurred. A bipolar temporary pacemaker and extracorporeal membrane oxygenation (ECMO) were installed. However, even with multiple electrode positions, effective capture could not be achieved. The patient eventually died. We should be alert to the possibility of co-poisoning.

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.

NITROSAMINE CONTAMINATION WITHIN CARDIAC MULTIMEDICATION - SARTANS (VALSARTAN), CALCIUM CHANNEL BLOCKERS (AMLODIPINE AND NIFEDIPINE), AND ANTIARRHYTHMICS (PROPAFENONE) AS A SIGNIFICANT FACTOR IN THE DEVELOPMENT AND PROGRESSION OF MULTIPLE KERATINOCYTIC CANCERS: ADVANCEMENT ROTATION FLAP FOR KERATOACANTHOMA OF THE UPPER LIP AND UNDERMINING SURGERY FOR BCC OF THE SHOULDER AS AN OPTIMAL DERMATOSURGICAL APPROACH.

The data on the polycontamination of multimedication in polymorbid patients with a heterogeneous class of carcinogens/nitrosamines, NDSRIs (classified according to the FDA regulation to the companies of 2023 to those with a carcinogenic potency between 1 and 5), are one of the most important steps to clarify the concept of skin cancer nitrosogenesis/ pathogenesis. The FDA is the first regulatory institution in the world to courageously declare that a problem exists and should be addressed. The main and currently unexplained and somewhat controversial issue lies in 1) the sporadic nature of polycontamination in different geographical regions, and 2) the lack of official data from the established international, but also regional pharmaceutical market regulators on the results of the checks conducted for nitrosamine contamination of the respective batches. It is this that leads scientists to the idea of (albeit seemingly) speculative but entirely possible controlled contamination of the production in certain geographical regions. This (hypo)thesis is supported, albeit indirectly, by the fact that: a recent regional check for possible contamination of sartans in a particular geographical region was not indicative of the presence of any nitrosamines/NDSRIs. But this fact is indicative of several extremely important things: 1) contamination is not ubiquitous, its genesis is heterogeneous; 2) contamination could be completely avoided at production level in certain geographical regions; 3) ˝controlled contamination˝ or carelessness of a heterogeneous nature should be excluded by the relevant regulators. Regular inspection and certification of medicinal products in relevant geographical regions to exclude contamination with nitrosamines/NDSRIs would be the surest method to protect public health globally. The initial parameters of the restrictive processes for the availability of nitrosamines in medicines have been established by the most powerful regulator globally in the face of the FDA, with the hope being that manufacturers will find a short-term solution to the problem. We report another patient who simultaneously developed 2 cutaneous tumors under potentially/actually nitrosamine contaminated drugs such as: beta blockers- atenolol, calcium antagonists- nifedipine/amlodipine, sartans- valsartan and antiarrhythmics- propafenone. One of the tumors was localized in the upper lip area (keratoacanthoma) and the other in the right shoulder area (basal cell carcinoma). Successful surgical treatment of the tumors was performed in the form of upper lip advancement rotation flap and elliptical excision of the second lesion. The evolution/growth rate of the tumors in relation to the potential mutagens/carcinogens heterogeneous in their potency contained in the drugs is commented.

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.

Propafenone versus amiodarone for supraventricular arrhythmias in septic shock: a randomised controlled trial.

PURPOSE: Acute onset supraventricular arrhythmias can contribute to haemodynamic compromise in septic shock. Both amiodarone and propafenone are available interventions, but their clinical effects have not yet been directly compared. METHODS: In this two-centre, prospective controlled parallel group double blind trial we recruited 209 septic shock patients with new-onset arrhythmia and a left ventricular ejection fraction above 35%. The patients were randomised in a 1:1 ratio to receive either intravenous propafenone (70 mg bolus followed by 400-840 mg/24 h) or amiodarone (300 mg bolus followed by 600-1800 mg/24 h). The primary outcomes were the proportion of patients who had sinus rhythm 24 h after the start of the infusion, time to restoration of the first sinus rhythm and the proportion of patients with arrhythmia recurrence. RESULTS: Out of 209 randomized patients, 200 (96%) received the study drug. After 24 h, 77 (72.8%) and 71 (67.3%) were in sinus rhythm (p = 0.4), restored after a median of 3.7 h (95% CI 2.3-6.8) and 7.3 h (95% CI 5-11), p = 0.02, with propafenone and amiodarone, respectively. The arrhythmia recurred in 54 (52%) patients treated with propafenone and in 80 (76%) with amiodarone, p < 0.001. Patients with a dilated left atrium had better rhythm control with amiodarone (6.4 h (95% CI 3.5; 14.1) until cardioversion vs 18 h (95% CI 2.8; 24.7) in propafenone, p = 0.05). CONCLUSION: Propafenone does not provide better rhythm control at 24 h yet offers faster cardioversion with fewer arrhythmia recurrences than with amiodarone, especially in patients with a non-dilated left atrium. No differences between propafenone and amiodarone on the prespecified short- and long-term outcomes were observed.

Pharmacological cardioversion of atrial fibrillation: practical considerations.

The choice between rhythm and rate control strategy represents one of the most intriguing dilemmas in the management of atrial fibrillation (AF). Although the advantage of rhythm over rate control in terms of outcome has not been unequivocally proven, the initial management of patients with symptomatic episodes of AF frequently involves early cardioversion. As electrical cardioversion (EC) is challenging in terms of fasting status and involvement of an anesthesiologic team, pharmacological cardioversion (PC) is usually selected as the first step toward rhythm conversion. Qualification criteria for PC or EC are similar and should comprise assessment of hemodynamic status, estimation of arrhythmic episode duration, evaluation of anticoagulation regimen, exclusion of other supraventricular arrhythmias, and assessment of the chance of rhythm conversion and persistence of sinus rhythm. Finally, the choice of adequate antiarrhythmic drug (AAD) depends on the presence of structural heart disease (SHD) and local experience. In patients without any SHD, complications occur rarely, hence traditional (propafenone, flecainide) or nonclassical Vaughan-Williams class I (antazoline) or class III (vernakalant, ibutilide, or dofetilide) drugs are preferred. The presence of SHD consistent with any left ventricular hypertrophy, heart failure, myocardial ischemia, or valvular heart disease limits the choice of AAD to amiodarone. Given the risk of ventricular proarrhythmia of AAD, safety should always prevail over the enticing possibility of rhythm conversion. The present review aims to provide a comprehensible summary of proper qualification for PC, selection of suitable AAD, and state­of­the­art periprocedural management of patients with recent­onset 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.

Early initiation of anti-relapse antiarrhythmic therapy in patients with atrial fibrillation and flutter after pharmacological cardioversion with refralon.

Aim      Evaluating the efficacy and safety of early administration of antirecurrence antiarrhythmic therapy (AAT) following restoration of sinus rhythm (SR) with refralon.Aim      Evaluating the efficacy and safety of early administration of antirecurrence antiarrhythmic therapy (AAT) following restoration of sinus rhythm (SR) with refralon.Material and methods  The study included 247 patients with atrial fibrillation/atrial flutter (AF/AFL) (142 men) who underwent pharmacological cardioversion (PCV) with refralon. A 4-step schedule of drug administration was used (successive intravenous infusions at doses of 5, 5, 10, and 10 µg/kg; maximum total dose was 30 µg/kg). Patients who recovered SR and had no contraindications were prescribed antirecurrence AAT in the early (≤24 h; n=101) or delayed (≥24 h; n=95) period. Lappaconitine hydrobromide, propafenone, and sotalol were administered orally as the antirecurrence therapy. The decision on the time of initiating ATT and the choice of the drug and its dose was taken by the attending physician individually. The safety criteria included a prolonged PQ interval >200 ms; second- or third-degree atrioventricular block; QRS complex duration >120 ms; QT prolongation >500 ms; and heartbeat pauses >3 s. The efficacy criteria included the absence of sustained recurrence of AF/AFL after initiation of AAT and the duration of hospitalization after PCV. Patients were followed up during the study until they were discharged from the hospital.Results SR was recovered in 229 (92.7 %) patients. In the group of early AAT initiation, a PQ duration >200 ms was observed in 8 (7.9 %) patients, whereas in the group of delayed AAT initiation, in 7 patients (7.4 %; p=1.000). A wide QRS complex >120 ms was recorded in 1 (1.1 %) patient of the delayed AAT initiation group and in none of the patients of the early AAT initiation group (p=0.485). Ventricular arrhythmogenic effects and QT prolongation >500 ms were not detected in any patient. Numbers of early AF recurrence did not differ in the groups of early and delayed AAT initiation: 6 (5.9 %) vs. 5 (5.3 %), respectively (p=1.000). Median duration of hospitalization after PCV was 4 days in the group of early AAT initiation and 5 days in the group of delayed AAT initiation (р=0.009).Conclusion      Early initiation of the refralon AAT does not increase the risk of drug adverse effects and reduces the duration of stay in the hospital.

Clinical and economic outcomes associated with use of anti-arrhythmic drugs versus ablation in atrial fibrillation.

Aim: To evaluate the clinical and economic impact of antiarrhythmic drugs (AADs) compared with ablation both as individual treatments and as combination therapy without/with considering the order of treatment among patients with atrial fibrillation (AFib). Materials & methods: A budget impact model over a one-year time horizon was developed to assess the economic impact of AADs (amiodarone, dofetilide, dronedarone, flecainide, propafenone, sotalol, and as a group) versus ablation across three scenarios: direct comparisons of individual treatments, non-temporal combinations, and temporal combinations. The economic analysis was conducted in accordance with CHEERS guidance as per current model objectives. Results are reported as costs per patient per year (PPPY). The impact of individual parameters was evaluated using one-way sensitivity analysis (OWSA). Results: In direct comparisons, ablation had the highest annual medication/procedure cost ($29,432), followed by dofetilide ($7661), dronedarone ($6451), sotalol ($4552), propafenone ($3044), flecainide ($2563), and amiodarone ($2538). Flecainide had the highest costs for long-term clinical outcomes ($22,964), followed by dofetilide ($17,462), sotalol ($15,030), amiodarone ($12,450), dronedarone ($10,424), propafenone ($7678) and ablation ($9948). In the non-temporal scenario, total costs incurred for AADs (group) + ablation ($17,278) were lower compared with ablation alone ($39,380). In the temporal scenario, AADs (group) before ablation resulted in PPPY cost savings of ($22,858) compared with AADs (group) after ablation ($19,958). Key factors in OWSA were ablation costs, the proportion of patients having reablation, and withdrawal due to adverse events. Conclusion: Utilization of AADs as individual treatment or in combination with ablation demonstrated comparable clinical benefits along with costs savings in patients with AFib.

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.

Cardiovascular outcomes in patients with atrial fibrillation concomitantly treated with antiarrhythmic drugs and non-vitamin k antagonist oral anticoagulants.

AIMS: Limited data compared antiarrhythmic drugs (AADs) with concomitant non-vitamin K antagonist oral anticoagulants in atrial fibrillation patients, hence the aim of the study. METHODS AND RESULTS: National health insurance database were retrieved during 2012-17 for study. We excluded patients not taking AADs, bradycardia, heart block, heart failure admission, mitral stenosis, prosthetic valve, incomplete demographic data, and follow-up <3 months. Outcomes were compared in Protocol 1, dronedarone vs. non-dronedarone; Protocol 2, dronedarone vs. amiodarone; and Protocol 3, dronedarone vs. propafenone. Outcomes were acute myocardial infarction (AMI), ischaemic stroke/systemic embolism, intracranial haemorrhage (ICH), major bleeding, cardiovascular death, all-cause mortality, and major adverse cardiovascular event (MACE) (including AMI, ischaemic stroke, and cardiovascular death). In Protocol 1, 2298 dronedarone users and 6984 non-dronedarone users (amiodarone = 4844; propafenone = 1914; flecainide = 75; sotalol = 61) were analysed. Dronedarone was associated with lower ICH (HR = 0.61, 95% CI = 0.38-0.99, P = 0.0436), cardiovascular death (HR = 0.24, 95% CI = 0.16-0.37, P < 0.0001), all-cause mortality (HR = 0.33, 95% CI = 0.27-0.42, P < 0.0001), and MACE (HR = 0.56, 95% CI = 0.45-0.70, P < 0.0001). In Protocol 2, 2231 dronedarone users and 6693 amiodarone users were analysed. Dronedarone was associated with significantly lower ICH (HR = 0.53, 95%=CI 0.33-0.84, P = 0.0078), cardiovascular death (HR = 0.20, 95% CI = 0.13-0.31, P < 0.0001), all-cause mortality (HR 0.27, 95% CI 0.22-0.34, P < 0.0001), and MACE (HR = 0.53, 95% CI = 0.43-0.66, P < 0.0001), compared with amiodarone. In Protocol 3, 812 dronedarone users and 2436 propafenone users were analysed. There were no differences between two drugs for primary and secondary outcomes. CONCLUSION: The use of dronedarone with NOACs was associated with cardiovascular benefits in an Asian population, compared with non-dronedarone AADs and amiodarone.

Drug repurposing of propafenone to discover novel anti-tumor agents by impairing homologous recombination to delay DNA damage recovery of rare disease conjunctival melanoma.

Conjunctival melanoma (CM), a rare and fatal malignant ocular tumor, lacks proper diagnostic biomarkers and therapy. Herein, we revealed the novel application of propafenone, an FDA-approved antiarrhythmic medication, which was identified effective in inhibiting CM cells viability and homologous recombination pathway. Detailed structure-activity relationships generated D34 as one of the most promising derivatives, which strongly suppressed the proliferation, viability, and migration of CM cells at submicromolar concentrations. Mechanically, D34 had the potential to increase γ-H2AX nuclear foci and aggravated DNA damage by suppressing homologous recombination pathway and its factors, particularly the complex of MRE11-RAD50-NBS1. D34 bound to human recombinant MRE11 protein and inhibited its endonuclease activity. Moreover, D34 dihydrochloride significantly suppressed tumor growth in the CRMM1 NCG xenograft model without obvious toxicity. Our finding shows that propafenone derivatives modulating the MRE11-RAD50-NBS1 complex will most likely provide an approach for CM targeted therapy, especially for improving chemo- and radio-sensitivity for CM patients.

An open-label randomized noninferior study of generic name and brand name of propafenone for rhythm control in patients with paroxysmal atrial fibrillation.

BACKGROUND: Propafenone is a class IC antiarrhythmic agent that is commonly used as the first-line therapy for patients with paroxysmal atrial fibrillation (AF) in Taiwan. This study compared the efficacy and safety of generic (Rhynorm) and brand name (Rytmonorm) propafenone for rhythm control of paroxysmal AF in Taiwan. METHODS: This was an open-label randomized multicenter noninferior study conducted in Taiwan. We enrolled 76 patients with AF. To investigate the efficacy of propafenone, we used a wearable electrocardiogram (ECG) event recorder to evaluate the daily burden of AF episodes in patients for 24 weeks. The primary efficacy endpoint was the frequency of AF with clinical significance, which was indicated by AF duration ≥30 seconds. The safety endpoints included proarrhythmic or hemodynamic adverse events. RESULT: To analyze the efficacy and safety of these agents, 71 patients (five patients with screen failure) were randomized to two groups, specifically a Rhynorm group (n = 37) and a Rytmonorm group (n = 34), for 24 weeks of the treatment period. The baseline patient characteristics were comparable between the groups. However, the Rhynorm group was older (65.4 ± 8.40 vs 59.8 ± 10.8 years; p = 0.02). The primary efficacy endpoint at week 24 decreased by 4.76% ± 18.5% (from 24.3% ± 33.9% to 19.0% ± 28.7%; p = 0.13) in the Rhynorm group and by 3.27% ± 15.2% (from 16.9% ± 26.4% to 13.6% ± 19.2%; p = 0.22) in the Rytmonorm group, with an intergroup difference of 1.5% ± 17.0%; p = 0.71. This finding indicates that Rhynorm is not inferior to Rytmonorm ( p = 0.023 for noninferiority). The safety profile of the agents was comparable between the two groups. CONCLUSION: Our results verified that Rhynorm was noninferior to Rytmonorm in terms of efficacy and safety for treating paroxysmal AF in Taiwan ( ClinicalTrials.gov Identifier: NCT03674658).

Negative Inotropic Effects of Class I Antiarrhythmics on Guinea Pig Ventricular Myocardium: Correlation with L-Type Ca2+ Channel Blockade.

The negative inotropic effects of nine Vaughan Williams class I antiarrhythmic drugs were examined in guinea pig ventricular tissue preparations. The drugs decreased the contractile force of papillary muscles with different potencies: the potency order was propafenone > aprindine > cibenzoline > flecainide > ranolazine > disopyramide > pilsicainide > mexiletine > GS-458967. The potency of drugs correlated with the reported IC50 values to block the L-type Ca2+ channel rather than the Na+ channel. The effects of drugs were roughly the same when examined under a high extracellular K+ solution, which inactivates the Na+ channel. Furthermore, the attenuation of the extracellular Ca2+-induced positive inotropy was strong with propafenone, moderate with cibenzoline, and weak with pilsicainide. These results indicate that the negative inotropic effects of class I antiarrhythmic drugs can be largely explained by their blockade of the L-type Ca2+ channel.

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.