Calvert, Peter

Gupta, Dhiraj

Lip, Gregory Y. H.

English

VBN (Videnbasen)  Aalborg Universitets forskningsportal

    Aalborg UniversitetAntazolinethe Lazarus of antiarrhythmic drugs?Calvert, Peter; Gupta, Dhiraj; Lip, Gregory Y. H.Published in:Polish Archives of Internal MedicineDOI (link to publication from Publisher):10.20452/pamw.16264Creative Commons LicenseCC BY-NC-SA 4.0Publication date:2022Document VersionPublisher's PDF, also known as Version of recordLink to publication from Aalborg UniversityCitation for published version (APA):Calvert, P., Gupta, D., & Lip, G. Y. H. (2022). Antazoline: the Lazarus of antiarrhythmic drugs? Polish Archivesof Internal Medicine, 132(6), [16264]. https://doi.org/10.20452/pamw.16264General rightsCopyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright ownersand it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.            - Users may download and print one copy of any publication from the public portal for the purpose of private study or research.            - You may not further distribute the material or use it for any profit-making activity or commercial gain            - You may freely distribute the URL identifying the publication in the public portal -Take down policyIf you believe that this document breaches copyright please contact us at vbn@aub.aau.dk providing details, and we will remove access tothe work immediately and investigate your claim.Downloaded from vbn.aau.dk on: November 19, 2022EDITORIAL Antazoline: the Lazarus of antiarrhythmic drugs? 1of AF. The authors retrospectively analyzed 1365 ED attendees with recent ‑onset AF in a multi‑center registry, all of whom underwent attempt‑ed pharmacological cardioversion. The choice of drug was at the discretion of the physician and consisted of amiodarone, propafenone, an‑tazoline, or a combination thereof. Success was defined as restoration of sinus rhythm within 12 hours. Of note, the patients who underwent electrical cardioversion following drug therapy, but before 12 hours, were excluded.The analysis was performed for the overall cohort and for PSM antazoline vs non‑antazo‑line groups. Successful cardioversion with any drug was achieved in 70.7% of patients, with the safety end point being met in 4.8%, most‑ly due to bradycardia (4.1%). In the non ‑PSM cohorts, antazoline was successful in 78.3% of cases and outperformed amiodarone (66.9%; P <0.001) and a composite group of combina‑tion therapies (59.2%; P <0.001) but was not statistically superior to propafenone (72.7%; P = 0.14). The safety end point was more fre‑quently met in the antazoline group (5.2%) than in the amiodarone group (2.1%; P = 0.03), and occurred at a similar rate as in the propafenone cohort (7.3%; P = 0.3). Again, bradycardia was the most frequent adverse effect. Similar find‑ings were seen following PSM.The authors should be congratulated for dem‑onstrating the safety and efficacy of a medication which is relatively unknown in most countries. However, a few points are worth considering.Firstly, registry data are invaluable for demon‑strating real ‑world practice, but are subject to un‑controllable bias, even despite PSM. For example, physician discretion to choose antiarrhythmics may mean that those given antazoline were more suited to this drug in some unmeasured way. PSM can correct for multiple measured variables but only randomization can control for unmeasured confounding. Hence, whilst this study provides When patients report to the emergency depart‑ment (ED) with acute ‑onset, uncomplicated atri‑al fibrillation (AF), cardioversion presents an op‑tion for rapid restoration of sinus rhythm and re‑lief of symptoms. There is an ongoing debate over cardioversion versus watchful waiting, as sponta‑neous reversion to sinus rhythm occurs in up to 70% of patients.1 Individualized care should al‑low for either possibility after an informed dis‑cussion between the physician and the patient re‑garding the benefits, risks, and preferences, tai‑lored to their specific circumstances.When pharmacological—over electrical—car‑dioversion is selected, a variety of options are available, such as flecainide, propafenone, sotalol, amiodarone, dofetilide, ibutilide, and vernakalant. Many readers may be unaware that antazoline can also be utilized for this purpose. New evidence is presented in the current issue of Polish Archives of Internal Medicine (Pol Arch Intern Med), and in this editorial we will explore the existing evidence base in the context of these new findings.Antazoline is a first ‑generation antihista‑mine, exerting action via antagonism of the H1 receptor, and is commonly used in eye drops to treat allergic seasonal symptoms. As far back as 1946, it was recognized that antihistamines could exert a quinidine ‑like antiarrhythmic ef‑fect.2 In the 1960s, a small trial showed that antazoline could suppress ectopy and ventric‑ular arrhythmias but, interestingly, found no benefit in cardioversion or prevention of AF or atrial flutter.3Antazoline as an antiarrhythmic was seem‑ingly forgotten in the literature after the 1960s, though it may have continued to be used in some regions of Europe. Its revival began in 2012 (Sup‑plementary material, Figure S1).In the current edition of Pol Arch Intern Med, Wybraniec et al4 present the results of a propen‑sity score matched (PSM) registry analysis utiliz‑ing antazoline for pharmacological cardioversion EDITORIALAntazoline: the Lazarus of antiarrhythmic drugs?Peter Calvert1, Dhiraj Gupta1, Gregory Y. H. Lip1,21  Liverpool Center for Cardiovascular Science, University of Liverpool and Liverpool Heart and Chest Hospital, Liverpool, United Kingdom2  Department of Clinical Medicine, Aalborg University, Aalborg, DenmarkCorrespondence to:Gregory Y. H. Lip, MD, Liverpool Center for Cardiovascular Science, University of Liverpool and Liverpool Heart and Chest Hospital, Thomas Drive, Liverpool L14 3PE, United Kingdom, phone: +44 151 600 1616, email: gregory.lip@liverpool.ac.ukReceived: May 16, 2022.Accepted: May 17, 2022.Published online: June 29, 2022.Pol Arch Intern Med. 2022; 132 (6): 16264doi:10.20452/pamw.16264Copyright by the Author(s), 2022RELATED ARTICLEby Wybraniec et alPOLISH ARCHIVES OF INTERNAL MEDICINE 2022; 132 (6)2of strategy, either to electrical cardioversion or rate control.There are few studies of antazoline, and all orig‑inate from Poland, which limits the generalizabil‑ity to a wider global population.The only RCT of antazoline for AF was the An‑PAF study,5 published in 2017. This was a single‑‑center study of 74 patients, which assessed the efficacy and safety of antazoline vs placebo for cardioversion of recent ‑onset AF. The primary efficacy end point (cardioversion to sinus rhythm within approximately 2 hours) was met in 72.2% of the antazoline arm vs 10.5% of the placebo arm (P <0.0001), with a median time ‑to ‑cardioversion of 16 minutes. Most adverse events were mild and transient, although 1 patient required admission due to dyspnea and congestion.The remainder of the evidence base consists of observational studies (TAbLE 1).The quinidine ‑like action of antazoline sug‑gests a Vaughan–Williams class I effect. A study on healthy volunteers demonstrated hemody‑namic effects similar to those of other class I agents, with negative inotropy and prolongation valuable information, it cannot supplant random‑ized controlled trial (RCT) data.Secondly, the decision to exclude the patients who underwent electrical cardioversion within 12 hours of the drug exposure is questionable. The authors gave a sound reason, namely, to avoid underestimation of efficacy of the drugs with a longer onset of action, such as amioda‑rone. The effect of doing so, however, leads to exclusion of patients who may have undergone electrical cardioversion emergently; for exam‑ple, due to hemodynamic instability or conver‑sion to 1:1 atrial flutter. For this reason, conclu‑sions about the safety of antazoline must be in‑terpreted with caution.Thirdly, 24% of the patients received more than 1 antiarrhythmic drug, and 14 patients (1%) received 3 drugs. The wisdom of additive antiarrhythmics must be questioned: if a sin‑gle drug has failed, adding 1, or especially 2, further antiarrhythmics increases the risk of side effects and proarrhythmia substantially. In the setting of failed cardioversion with a sin‑gle agent, the wisest course would be a change TAbLE 1 Summary of the current clinical evidence base for antazoline in cardioversion of atrial fibrillationStudy Type N Setting Findings Side effectsPiotrowski et al,10 2014Prospective observational12 Accessory pathway ablationAntazoline successfully terminated AF, which developed during AP ablation, in 100% of cases.NoneBalsam et al,11 2015Prospective observational141 Pulmonary vein isolationAntazoline terminated AF during PVI procedures with an efficacy of 83.6% (paroxysmal AF) / 31.1% (persistent AF).Nausea (2.1%), RBBB (1.4%), nonsustained VT (0.7%), hypotension (0.7%). All adverse effects resolved within 15 minutes of infusion cessation.Farkowski et al,12 2016Retrospective case ‑control432 Emergency departmentAntazoline outperformed propafenone for acute cardioversion of AF (71.6% vs 55.1%; P = 0.002).Hypotension (1.8%), bradycardia (9.6%); no statistical difference as compared with propafenone. Other mild side effects not described in detail.Maciąg et al5 (AnPAF), 2017Single ‑center randomized controlled trial74 Emergency departmentAntazoline outperformed placebo for acute cardioversion of AF (72.2% vs 10.5%; P <0.0001).Hypotension (2.8%), tachycardia (5.6%), hot flush (19.4%), drowsiness (8.3%), headache (5.6%), nausea (5.6%), heart failure (2.8%), bradycardia (5.6%).Wybraniec et al13 (CANT), 2018Retrospective observational450 Emergency departmentAntazoline was successful in 85.3% of cases, outperforming amiodarone (66.7%; P <0.001) and performing similarly to propafenone (78.6%; P = 0.317).No adverse events reported in the antazoline group.Farkowski et al,14 2018Retrospective observational334 Emergency departmentAntazoline was more effective in patients with CAD than those without (82.6% vs 63.8%; P = 0.0002).Chest discomfort (1 patient), bradycardia with sinus node dysfunction (1 patient). No interaction with prior MI was noted.Farkowski et al,15 2022Retrospective observational334 Emergency departmentAntazoline was similarly effective in patients over or under 75 years (78.2% vs 68.3%; P = 0.06).Hypotension (6 patients), bradycardia (32 patients); effects were similar between arms. Hospitalization for adverse events was numerically higher in the <75 years arm (9 vs 1; P = 0.17).Wybraniec et al,4 2022Retrospective observational1365 Emergency departmentAntazoline was successful in 78.3% of cases, outperforming amiodarone (66.9%; P <0.001) and performing similarly to propafenone (72.7%, P = 0.14).Bradycardia (4.8%), hypotension (0.8%). Composite safety end point was higher for antazoline vs amiodarone but similar to propafenone.Abbreviations: AF, atrial fibrillation; AP, accessory pathway; CAD, coronary artery disease; MI, myocardial infarction; N, number of patients; PVI, pulmonary vein isolation; RBBB, right bundle branch block; VT, ventricular tachycardiaEDITORIAL Antazoline: the Lazarus of antiarrhythmic drugs? 3REfEREnCEs1 Pluymaekers NAHA, Dudink EAMP, Luermans JGLM, et al. Early or de‑layed cardioversion in recent ‑onset atrial fibrillation. N Engl J Med. 2019; 380: 1499‑1508. 2 Dews PB, Graham JD. The antihistamine substance 2786 R.P. Br J Phar‑macol Chemother. 1946; 1: 278‑286. 3 Reynolds EW, Baird WM, Clifford ME. A clinical trial of antazoline in the treatment of arrhythmias. Am J Cardiol. 1964; 14: 513‑521. 4 Wybraniec MT, Maciąg A, Miśkowiec D, et al. Efficacy and safety of antazoline for cardioversion of atrial fibrillation: propensity score match‑ing analysis of a multicenter registry (CANT II Study). Pol Arch Intern Med. 2022; 132: 16234. 5 Maciag A, Farkowski MM, Chwyczko T, et al. Efficacy and safety of an‑tazoline in the rapid cardioversion of paroxysmal atrial fibrillation (the AnPAF Study). Europace. 2017; 19: 1637‑1642. 6 Piotrowski R, Giebułtowicz J, Baran J, et al. Antazoline ‑insights into drug ‑induced electrocardiographic and hemodynamic effects: results of the ELEPHANT II substudy. Ann Noninvasive Electrocardiol. 2017; 22: e12441. 7 Bińkowski BJ, Makowski M, Kubiński P, Lubiński A. Effect of antazoline on electrophysiological properties of atrial muscle and conduction system of the heart. Cardiovasc Drugs Ther. 2018; 32: 169‑173. 8 Ellermann C, Sterneberg M, Kochhäuser S, et al. Antiarrhythmic ef‑fect of antazoline in experimental models of acquired short‑ and long ‑QT‑‑syndromes. Europace. 2018; 20: 1699‑1706. 9 Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the di‑agnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio ‑Thoracic Surgery (EACTS): the Task Force for the diagnosis and management of atrial fibrillation of the Europe. Eur Heart J. 2021; 42: 373‑498.10 Piotrowski R, Kryński T, Baran J, et al. Antazoline for rapid termina‑tion of atrial fibrillation during ablation of accessory pathways. Cardiol J. 2014; 21: 299‑303. 11 Balsam P, Koźluk E, Peller M, et al. Antazoline for termination of atrial fibrillation during the procedure of pulmonary veins isolation. Adv Med Sci. 2015; 60: 231‑235. 12 Farkowski MM, Maciąg A, Żurawska M, et al. Comparative effective‑ness and safety of antazoline ‑based and propafenonebased strategies for pharmacological cardioversion of short ‑duration atrial fibrillation in the emer‑gency department. Pol Arch Med Wewn. 2016; 126: 381‑387. 13 Wybraniec MT, Wróbel W, Wilkosz K, et al. Pharmacological cardiover‑sion with antazoline in atrial fibrillation: the results of the CANT Study. J Am Heart Assoc. 2018; 7: e010153. 14 Farkowski MM, Maciag A, Zurawska M, et al. Clinical effectiveness and safety of antazoline ‑based therapy in patients with stable coronary ar‑tery disease undergoing pharmacological cardioversion of short ‑duration atrial fibrillation in the emergency department. Cardiovasc Ther. 2018; 36: e12469. 15 Farkowski MM, Maciąg A, Żurawska M, et al. Rapid pharmacological cardioversion of recent ‑onset atrial fibrillation using antazoline in elderly pa‑tients. Pol Arch Intern Med. 2022; 132: 16120. of the P ‑wave, QRS, and corrected QT interval.6 In invasive electrophysiological studies, antazo‑line caused significant interatrial conduction de‑lay and QT prolongation without significantly af‑fecting the AV ‑nodal conduction,7 again similar‑ly to other class I drugs.These findings may suggest a risk if antazo‑line is used in individuals with structural heart disease, heart failure, or genetic QT pathology—although, interestingly, animal models demon‑strated potential benefit of antazoline in long and short QT syndromes.8 There is also a poten‑tial risk of conversion to 1:1 atrial flutter, as is seen with other class I drugs, such as flecainide.Despite these potential risks, the studies de‑scribed above did not show significant safety concerns.Currently, the European Society of Cardiology guidelines recommend vernakalant, flecainide, or propafenone as first ‑line cardioversion agents.9 Antazoline does not feature in the guidelines.Proarrhythmia is a limiting factor for many antiarrhythmics and there is a need for effec‑tive and safe antiarrhythmics for acute cardio‑version of AF. Whether or not antazoline could fill this gap remains to be proven. The current evidence base, including the present study, is limited to mostly observational studies and a single RCT, all from Polish cohorts (TAbLE 1). These studies do show potential benefits, with encouraging success rates and cardioversion frequently achieved in less than half an hour. However, further research is warranted in more diverse populations before this drug can be en‑dorsed strongly.In conclusion, antazoline—a “lost ‑and ‑found” antiarrhythmic—shows promise for acute con‑version of new ‑onset, uncomplicated AF. Suc‑cessful cardioversion rates appear encouraging, and adverse events, mainly bradycardia, are rela‑tively infrequent. However, the current evidence base is limited to mostly observational studies from a single country and larger ‑scale RCTs are required.suppLEmEnTARy mATERIALSupplementary material is available at www.mp.pl/paim.ARTICLE InfORmATIOnDIsCLAImER The opinions expressed by the author(s) are not necessarily those of the journal editors, Polish Society of Internal Medicine, or publisher.COnfLICT Of InTEREsT DG: institutional research grants from Biosense Webster, Boston Scientific and Medtronic and speaker fees from Boston Scientific; GYHL: consultant and speaker for BMS / Pfizer, Boehringer Ingel‑heim, and Daiichi‑Sankyo. No fees are received personally. PC declares no conflict of interst.OpEn ACCEss This is an Open Access article distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 Inter‑national License (CC BY ‑NC ‑SA 4.0), allowing third parties to copy and re‑distribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited, distrib‑uted under the same license, and used for noncommercial purposes only. For commercial use, please contact the journal office at pamw@mp.pl.HOw TO CITE Calvert P, Gupta D, Lip GYH. Antazoline: the Lazarus of an‑tiarrhythmic drugs? Pol Arch Intern Med. 2022; 132: 16264. doi:10.20452/pamw.16264

Antazoline:the Lazarus of antiarrhythmic drugs?

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Antazoline:the Lazarus of antiarrhythmic drugs?

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