Safety of out-of-hospital initiation of flecainide in patients with atrial and ventricular arrhythmias and structurally normal heart

Aim. This study aimed at investigating the safety of out-of-hospital initiation of flecainide in patients presenting with atrial or ventricular arrhythmias and structurally normal heart.

Methods. Patients were followed 1 week, 1 month and 2 months after drug initiation either in person or through phone interviews and were asked to report symptoms suggestive of sustained arrhythmia, syncope, aborted sudden death and/or emergency room (ER) visits. QRS duration and QTc intervals were measured in a 12-lead ECG at each follow up. Patients were asked to fill out a treatment satisfaction questionnaire for medication (TSQM), four weeks after drug initiation.

Results. The mean patient age was 48.5 ± 15.7 years, 36 patients (52%) were females. The most frequent presenting arrhythmia was premature ventricular contractions in 34 (45.3%) patients followed by paroxysmal atrial fibrillation in 22 (29.3%) patients. There was a significant increase in the mean QRS duration (89.9 ± 6.8 msec vs 91.1±7 msec, P <0.001) and the mean QTc interval (417.4 ±10.6 msec vs 418 ± 10.4 msec, P = 0.025) at 1 week compared to baseline. Only one patient (1.3%) had a clinically significant (more than 25%) increase in the QRS duration requiring drug discontinuation. There was no reported life-threatening ventricular arrhythmia, syncope, ER visits or aborted sudden cardiac death. There was 6.7% incidence of cardiac adverse events including conduction system abnormalities and atrial flutter, 4% of patients experienced non-resolving extracardiac manifestations. The overall drug discontinuation rate was 10.7%. The mean TSQM score for effectiveness domain was 70.4 ± 23.8 while the mean of the side effects domain was 94.3 ± 14.6, that of convenience domain was 65.2 ± 10.5 and that of global satisfaction was 72.8 ± 21.8.

Conclusion. Out-of-hospital initiation of flecainide is safe and thus feasible, there was no reported documented or suspected life-threatening ventricular arrhythmias. Cardiac and extracardiac adverse events requiring drug discontinuation was effectively detected through clinical and ECG outpatient follow up.

1. Ramos E, O’Leary ME. State‐dependent Trapping of Flecainide in the Cardiac Sodium Channel. The Journal of Physiology. 2004;560(1): 37-49. https://doi.org/10.1113/jphysiol.2004.065003.

2. Yang P, Moreno JD, Miyake CY et al. ‘’In Silico’’ Prediction of Drug Therapy in Catecholaminergic Polymorphic Ventricular Tachycardia. The Journal of Physiology. 2015;594(3): 567-93. https://doi.org/10.1113/JP271282.

3. Bannister ML, MacLeod KT, George CH. Moving in the Right Direction: Elucidating the Mechanisms of Interaction Between Flecainide and the Cardiac Ryanodine Receptor. British Journal of Pharmacology. 2021;179(11): 2558-63. https://doi.org/10.1111/bph.15718.

4. Thireau J, Pasquié J-L, Martel E et al. New Drugs vs. Old Concepts: A Fresh Look at Antiarrhythmics. Pharmacology & Therapeutics. 2011;132(2): 125-45. https://doi.org/10.1016/j.pharmthera.2011.03.003.

5. Ruskin JN, Camm J, Dufton D et al. Orally inhaled flecainide for conversion of atrial fibrillation to sinus rhythm: INSTANT phase 2 trial. JACC: Clinical Electrophysiology. 2024;10(6): 1021-1033. https://doi.org/10.1016/j.jacep.2024.02.021.

6. Hauguel-Moreau M, Guedeney P, Dauphin C et al. Flecainide to Prevent Atrial Arrhythmia after Patent Foramen Ovale Closure, the AFLOAT Study: A Randomized Clinical Trial.” Circulation. 2024;150(21). https://doi.org/10.1161/CIRCULATIONAHA.124.071186.

7. Bertels A., Kammeraad AE, van Geloven N et al. ECTOPIC trial: The efficacy of flecainide Compared To metOprolol in reducing Premature ventrIcular Contractions: A randomized open-label crossover study in pediatric patients. Heart Rhythm. 2025;22(2):536-543.https://doi.org/10.1016/j.hrthm.2024.07.111.

8. Soroosh K, Sayegh M, Ibrahim R et al. The feasibility and safety of flecainide use among patients with varying degrees of coronary disease.Clinical Electrophysiology. 2023;9: 1172-1180. https://doi.org/10.1016/j.jacep.2022.12.021.

9. Echt DS, Liebson PR, Mitchell LB et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. The New England journal of medicine. 1991;324(12): 781-8. https://doi.org/10.1056/NEJM199103213241201.

10. Moffett BS, Valdés SO, Lupo PJ et al. Flecainide Use in Children With Cardiomyopathy or Structural Heart Disease. Pediatric Cardiology. 2014;36(1): 146-50. https://doi.org/10.1007/s00246-014-0978-3.

11. Maura ZM, Wolfes J, Schleberger R et al. Use of class IC antiarrhythmic drugs in patients with structural heart disease and implantable cardioverter defibrillator. Clinical Research in Cardiology. 2024: 1-9. https://doi.org/10.1007/s00392-024-02394-6.

12. Alboni P, Botto GL, Boriani G et al. Intravenous Administration of Flecainide or Propafenone in Patients With Recent-Onset Atrial Fibrillation Does Not Predict Adverse Effects During ‘Pill-in-the-Pocket’ Treatment. Heart. 2010;96(7): 546-9. https://doi.org/10.1136/hrt.2009.187963.

13. Kartalis A, Afendoulis D, Voutas P et al. Acute Management of Paroxysmal Atrial Fibrillation With Intravenous Flecainide Plus Oral Beta-Blockers. International Journal of Translational Medicine. 2024;4(2): 334-41. https://doi.org/10.3390/ijtm4020021.

14. Basza M, Maciejewski C, Bojanowicz W et al. Flecainide in clinical practice. Cardiology journal. 2023;30(3): 473-82. https://doi.org/10.5603/CJ.a2023.0018.

15. Zimetbaum PJ, Schreckengost VE, Cohen DJ et al. Evaluation of outpatient initiation of antiarrhythmic drug therapy in patients reverting to sinus rhythm after an episode of atrial fibrillation. American Journal of Cardiology. 1999;83(3): 450-2. https://doi.org/10.1016/s0002-9149(98)00885-6.

16. Bazett’s formula - QT interval corrected. In: Gilbert-Kawai ET, Wittenberg MD, editors. Essential Equations for Anaesthesia: Key Clinical Concepts for the FRCA and EDA. Cambridge: Cambridge University Press; 2014.

17. Atkinson MJ, Sinha A, Hass SL et al. Validation of a general measure of treatment satisfaction, the Treatment Satisfaction Questionnaire for Medication (TSQM), using a national panel study of chronic disease. Health and quality of life outcomes. 2004;2:1-13. https://doi.org/10.1186/1477-7525-2-12.

18. Tamargo J, Capucci A, Mabo P. Safety of flecainide. Drug safety. 2012;35(4): 273-89. https://doi.org/10.2165/11599950-000000000-00000.

19. Tamargo J, Heuzey JYL, Mabo P. Narrow Therapeutic Index Drugs: A Clinical Pharmacological Consideration to Flecainide. European Journal of Clinical Pharmacology. 2015;71(5): 549-67. https://doi.org/10.1007/s00228-015- 1832-0.

20. Hill AC, Silka MJ, Bar‐Cohen Y. A Comparison of Oral Flecainide and Amiodarone for the Treatment of Recurrent Supraventricular Tachycardia in Children. Pacing and Clinical Electrophysiology. 2019;42(6): 670-7. https://doi.org/10.1111/pace.13662.

21. Alboni P, Botto GL, Boriani G et al. Intravenous administration of flecainide or propafenone in patients with recent-onset atrial fibrillation does not predict adverse effects during ‘pill-in-the-pocket’ treatment. Heart (British Cardiac Society). 2010;96(7): 546-9. https://doi.org/10.1136/hrt.2009.187963.

22. Frendl G, Sodickson A, Chung MK et al. 2014 AATS Guidelines for the Prevention and Management of Perioperative Atrial Fibrillation and Flutter for Thoracic Surgical Procedures. Journal of Thoracic and Cardiovascular Surgery. 2014;148(3): e153-e93. https://doi.org/10.1016/j.jtcvs.2014.06.036.

23. Ting S, Lee D, MacLean D, Sheerin N. Paranoid Psychosis and Myoclonus: Flecainide Toxicity in Renal Failure. Cardiology. 2008;111(2): 83-6. https://doi.org/10.1159/000119694.

24. Oudijk MA, Ruskamp JM, Ambachtsheer BE et al. Drug Treatment of Fetal Tachycardias. Pediatric Drugs. 2002;4(1):49-63. https://doi.org/10.2165/00128072-200204010-00006.

25. Thomas SAL, Ferguson RL, Wilson DG. Flecainide Administration in Children: Dosage, Drug Levels, and Clinical Effect. Cardiology in the Young. 2022;33(10) : 2072-7. https://doi.org/10.1017/S1047951122003729.