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Use of Flecainide for the Treatment of Atrial Fibrillation

Open AccessPublished:January 09, 2020DOI:https://doi.org/10.1016/j.amjcard.2019.12.041
      Atrial fibrillation (AF) is the most common sustained arrhythmia and is associated with substantial morbidity and impairment of quality of life. Restoration and maintenance of normal sinus rhythm is a desirable goal for many patients with AF; however, this strategy is limited by the relatively small number of antiarrhythmic drugs (AADs) available for AF rhythm control. Although it is recommended in current medical guidelines as first-line therapy for patients without structural heart disease, the use of flecainide has been curtailed since the completion of the Cardiac Arrhythmia Suppression Trial. In clinical trials and real-world use, flecainide has proven to be more effective than other AADs for the acute termination of recent onset AF. Flecainide is also moderately effective and, with the exception of amiodarone, equivalent to other AADs for the chronic suppression of paroxysmal and persistent AF. In patients without structural heart disease, flecainide has been demonstrated to be safe and well tolerated relative to other AADs. Despite this favorable profile, flecainide is underutilized, likely due to a perceived risk of ventricular proarrhythmia, a concern that has not been borne out in patients without underlying structural heart disease. Guidelines for administration and use of flecainide are summarized in this review.
      Atrial fibrillation (AF) is the most common sustained arrhythmia and one which is associated with substantial morbidity and symptoms which negatively impact quality of life. Rhythm control is, therefore, a desirable goal for many patients with recurrent AF. Moreover, the recent availability of wearable, handheld, and implantable ECG monitoring devices with the capability to automatically detect AF
      • Bumgarner JM
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      Smartwatch algorithm for automated detection of atrial fibrillation.
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      Assessing the accuracy of an automated atrial fibrillation detection algorithm using smartphone technology: the iREAD study.
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      will generate continued growth in the numbers of patients requiring treatment for AF. However, there are relatively few antiarrhythmic drugs (AADs) currently available for AF rhythm control. Current medical guidelines include flecainide as a first-line agent for the conversion and suppression of intermittent episodes of AF in patients without structural heart disease.
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      • Agewall S
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      • Budts W
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      • Dobrev D
      • Ferro JM
      • Filippatos G
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      • Kolh P
      • Lip GY
      • Manolis A
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      • Ponikowski P
      • Rosenhek R
      • Ruschitzka F
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      • Sharma S
      • Suwalski P
      • Tamargo JL
      • Taylor CJ
      • Van Gelder IC
      • Voors AA
      • Windecker S
      • Zamorano JL
      • Zeppenfeld K
      2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with eacts.
      Although the safety of flecainide in patients without structural heart disease is well established and has been comprehensively reviewed,
      • Aliot E
      • Capucci A
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      Twenty-five years in the making: flecainide is safe and effective for the management of atrial fibrillation.
      its use continues to be limited,
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      Comparisons of hospitalization rates among younger atrial fibrillation patients receiving different antiarrhythmic drugs.
      primarily owing to concerns about the risk of ventricular proarrhythmia following the results of the Cardiac Arrhythmia Suppression Trial (CAST).
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      • Liebson PR
      • Mitchell LB
      • Peters RW
      • Obias-Manno D
      • Barker AH
      • Arensberg D
      • Baker A
      • Friedman L
      • Greene HL
      Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The cardiac arrhythmia suppression trial.
      The purpose of this report is to review the efficacy and safety of flecainide for the treatment of patients with AF, compare it with other approved AADs, and propose recommendations for its use, nearly 3 decades after the results of CAST were published.

      Background

      Cardiac Electrophysiology

      Flecainide is an antiarrhythmic agent with membrane stabilizing activity. It is categorized as a Vaughn-Williams Class IC agent based upon its properties of markedly slowing cardiac conduction with a minimal effect on ventricular repolarization.
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      • Miles Vaughan Williams E
      Characterization of a new oral antiarrhythmic drug, flecainide (r818).
      ,
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      • Boisten M
      Effect of flecainide on action potentials and alternating current-induced arrhythmias in mammalian myocardium.
      Flecainide's primary electrophysiological actions are due to its voltage and use-dependent block of cardiac voltage-gated sodium channels, causing inhibition of the transient peak inward sodium current (INa).
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      • Atkins J
      • Kass RS
      Common molecular determinants of flecainide and lidocaine block of heart Na+ channels: evidence from experiments with neutral and quaternary flecainide analogues.
      The combination of its use-dependent (rate-dependent) sodium channel block and its slow kinetics result in a greater reduction in myocardial tissue excitability during tachyarrhythmias. In addition to inhibiting the transient peak INa, flecainide also inhibits the slow inactivating component of INa, referred to as late INa,
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      • Rajamani S
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      A novel, potent, and selective inhibitor of cardiac late sodium current suppresses experimental arrhythmias.
      the rapid component of the delayed rectifier potassium (K+) current (IKr), and the time-dependent transient outward current Ito.
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      • Zhang Y
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      • Dempsey CE
      • Hancox JC
      Molecular basis of hERG potassium channel blockade by the class IC antiarrhythmic flecainide.
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      • Thomas GP
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      • Haase KK
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      Intravenous drug challenge using flecainide and ajmaline in patients with Brugada syndrome.
      In addition, flecainide inhibits the ryanodine receptor, RyR2.
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      • Laver D
      • Hwang HS
      • Davies SS
      • Roach DE
      • Duff HJ
      • Roden DM
      • Wilde AA
      • Knollmann BC
      Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans.
      The precise electrophysiological mechanism(s) responsible for flecainide's conversion and suppression of AF is unknown. Based upon results in human studies
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      • Engelen M
      • Franz MR
      • Ribbing M
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      • Haverkamp W
      • Eckardt L
      Electrophysiological effects of flecainide and sotalol in the human atrium during persistent atrial fibrillation.
      ,
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      • Heijman J
      • Wang Q
      • Chiang DY
      • Li N
      • Karck M
      • Wehrens XHT
      • Nattel S
      • Dobrev D
      Cellular and molecular mechanisms of atrial arrhythmogenesis in patients with paroxysmal atrial fibrillation.
      and experimental animal studies,
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      • Rabloczky G
      Frequency-dependent effects of class I, III and IV antiarrhythmic drugs on the conduction and excitability in rabbit ventricular muscle.
      • Wang Z
      • Page P
      • Nattel S
      Mechanism of flecainide's antiarrhythmic action in experimental atrial fibrillation.
      • Wang Z
      • Fermini B
      • Nattel S
      Mechanism of flecainide's rate-dependent actions on action potential duration in canine atrial tissue.
      • Wijffels MC
      • Dorland R
      • Mast F
      • Allessie MA
      Widening of the excitable gap during pharmacological cardioversion of atrial fibrillation in the goat: effects of cibenzoline, hydroquinidine, flecainide, and d-sotalol.
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      • Takeshita A
      • Sato T
      • Kanki H
      • Takatsuki S
      • Ogawa S
      Determination of refractory periods and conduction velocity during atrial fibrillation using atrial capture in dogs: direct assessment of the wavelength and its modulation by a sodium channel blocker, pilsicainide.
      the electrophysiological properties likely to contribute to flecainide's antiatrial fibrillatory effects include: (1) rate-dependent prolongation of atrial refractoriness, (2) greater prolongation of atrial refractory period than action potential duration (postrepolarization refractoriness), (3) decrease in excitability, and (4) suppression of spontaneous diastolic SR Ca2+ release.
      The precise mechanism(s) responsible for flecainide's ventricular proarrhythmic potential is also unknown. However, the ionic basis can be explained by exaggerated effects of inhibition of peak INa in partially depolarized (eg, ischemic) myocardium, rapid rates (use-dependence), and the slow kinetics of dissociation for the sodium channel. Based upon experiments in animal models, ventricular proarrhythmia attributed to sodium channel blocking drugs are caused by marked rate-dependent slowing of conduction in ischemic and infarcted myocardium, promoting heterogeneity of conduction and facilitating initiation of reentrant wavefront activity.
      • Nattel S
      Experimental evidence for proarrhythmic mechanisms of antiarrhythmic drugs.
      In rabbit and canine models of myocardial infarction (MI), programmed electrical stimulation in combination with flecainide administration enabled easily inducible
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      • Allessie M
      Proarrhythmic effects of flecainide. Experimental evidence for increased susceptibility to reentrant arrhythmias.
      ,
      • Ranger S
      • Nattel S
      Determinants and mechanisms of flecainide-induced promotion of ventricular tachycardia in anesthetized dogs.
      and spontaneous
      • Ranger S
      • Nattel S
      Determinants and mechanisms of flecainide-induced promotion of ventricular tachycardia in anesthetized dogs.
      reentrant ventricular tachycardia. These experimental findings of markedly increased susceptibility to ventricular proarrhythmia with flecainide administration in the setting of MI are consistent with the findings of the CAST (see section on FDA labeling and the CAST).
      Ventricular proarrhythmia with flecainide is rarely manifested as torsade de pointes, as is seen with QT-prolonging drugs, because the drug's inhibition of IKR is relatively weak and countered by its inhibition of peak and late sodium current.
      • Nogales Asensio JM
      • Moreno Sanchez N
      • Doncel Vecino LJ
      • Villar Mariscal C
      • Lopez-Minguez JR
      • Merchan Herrera A
      Torsade-de-pointes in a patient under flecainide treatment, an unusual case of proarrhythmicity.
      Unlike QT-prolonging drugs and torsade de pointes, sodium channel blocking drugs do not have a unique ECG signature that enables a specific diagnosis of drug-related ventricular arrhythmias. Ventricular tachyarrhythmias with ECG morphologies characterized by markedly widened or sinusoidal QRS complexes may occur in the presence of flecainide-induced sodium channel toxicity, and also in the absence of flecainide but the presence of hyperkalemia, ischemia, or severe left ventricular dysfunction. Flecainide toxicity due to high plasma concentrations can also masquerade as ventricular proarrhythmia, because of markedly widened QRS complex durations during supraventricular rhythms such as AF or flutter, as illustrated in a recent case report.
      • Bucklew EA
      • Reis SE
      • Kancharla K
      Wide QRS tachycardia in a man with a medical history of atrial fibrillation.
      The differential diagnosis of sodium channel toxicity can be clinically useful because, in addition to withdrawal of flecainide, treatment may include hypertonic sodium bicarbonate, lidocaine, cardiac pacing, and mechanical hemodynamic support if needed.
      • Di Grande A
      • Giuffrida C
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      Management of sodium-channel blocker poisoning: the role of hypertonic sodium salts.
      Flecainide prolongs the sinus node recovery time in some patients with underlying sinus node dysfunction
      • Vik-Mo H
      • Ohm OJ
      • Lund-Johansen P
      Electrophysiologic effects of flecainide acetate in patients with sinus nodal dysfunction.
      ,
      • Hellestrand KJ
      • Nathan AW
      • Bexton RS
      • Camm AJ
      Electrophysiologic effects of flecainide acetate on sinus node function, anomalous atrioventricular connections, and pacemaker thresholds.
      which may be the mechanism responsible for postconversion sinus pauses occasionally observed in patients following the conversion of AF to sinus rhythm (SR). Flecainide also increases pacing thresholds,
      • Hellestrand KJ
      • Nathan AW
      • Bexton RS
      • Camm AJ
      Electrophysiologic effects of flecainide acetate on sinus node function, anomalous atrioventricular connections, and pacemaker thresholds.
      but this effect has not proven to be of clinical significance with implanted cardiac pacemakers because programmed output settings routinely incorporate a safety margin.
      The effects of flecainide on the 12-lead electrocardiogram are primarily attributed to its marked effects on intra-atrial, AV node, His-Purkinje, and intraventricular conduction.
      • Hellestrand KJ
      • Bexton RS
      • Nathan AW
      • Spurrell RA
      • Camm AJ
      Acute electrophysiological effects of flecainide acetate on cardiac conduction and refractoriness in man.
      ,
      • Estes 3rd, NA
      • Garan H
      • Ruskin JN
      Electrophysiologic properties of flecainide acetate.
      Prolongation of the PR and QRS interval durations are concentration-dependent and readily apparent, ranging from 17% to 29% for PR and 11% to 27% for QRS in reported studies.
      • Estes 3rd, NA
      • Garan H
      • Ruskin JN
      Electrophysiologic properties of flecainide acetate.
      The vast majority of the prolongation of the QTc interval (ranging from 1% to 5%) is a consequence of the increase in QRS interval duration.
      • Estes 3rd, NA
      • Garan H
      • Ruskin JN
      Electrophysiologic properties of flecainide acetate.
      • Roden DM
      • Woosley RL
      Drug therapy. Flecainide.
      • Anderson JL
      • Stewart JR
      • Perry BA
      • Van Hamersveld DD
      • Johnson TA
      • Conard GJ
      • Chang SF
      • Kvam DC
      • Pitt B
      Oral flecainide acetate for the treatment of ventricular arrhythmias.

      Hemodynamic Effects

      Flecainide has negative inotropic properties. Intravenous (IV) administration of flecainide, even in patients without structural heart disease hearts, can cause hypotension,
      • Markey GC
      • Salter N
      • Ryan J
      Intravenous flecainide for emergency department management of acute atrial fibrillation.
      and/or reduced stroke volume and cardiac output.
      • Muhiddin KA
      • Turner P
      • Blackett A
      Effect of flecainide on cardiac output.
      In patients with coronary artery disease, IV flecainide has been reported to reduce stroke volume, cardiac output, and ejection fraction; and increase pulmonary capillary wedge pressure, especially in those with concomitant left ventricular (LV) dysfunction.
      • Legrand V
      • Materne P
      • Vandormael M
      • Collignon P
      • Kulbertus HE
      Comparative haemodynamic effects of intravenous flecainide in patients with and without heart failure and with and without beta-blocker therapy.
      ,
      • Josephson MA
      • Kaul S
      • Hopkins J
      • Kvam D
      • Singh BN
      Hemodynamic effects of intravenous flecainide relative to the level of ventricular function in patients with coronary artery disease.
      The hemodynamic effects of flecainide with chronic oral administration are dependent on underlying LV function. In patients without structural heart disease or with minimal LV functional abnormalities, no effect on blood pressure or ejection fraction has been found.
      • Anderson JL
      • Stewart JR
      • Perry BA
      • Van Hamersveld DD
      • Johnson TA
      • Conard GJ
      • Chang SF
      • Kvam DC
      • Pitt B
      Oral flecainide acetate for the treatment of ventricular arrhythmias.
      ,
      • Duff HJ
      • Roden DM
      • Maffucci RJ
      • Vesper BS
      • Conard GJ
      • Higgins SB
      • Oates JA
      • Smith RF
      • Woosley RL
      Suppression of resistant ventricular arrhythmias by twice daily dosing with flecainide.
      ,
      • Hodges M
      • Haugland JM
      • Granrud G
      • Conard GJ
      • Asinger RW
      • Mikell FL
      • Krejci J
      Suppression of ventricular ectopic depolarizations by flecainide acetate, a new antiarrhythmic agent.
      However, in a study of patients with LV dysfunction, new or worsened heart failure was observed in 21% of patients, but only in those with a baseline ejection fraction of <30%.
      • de Paola AA
      • Horowitz LN
      • Morganroth J
      • Senior S
      • Spielman SR
      • Greenspan AM
      • Kay HR
      Influence of left ventricular dysfunction on flecainide therapy.

      Pharmacology

      The absorption of orally administered flecainide acetate is slow with peak plasma drug levels (Cmax) reached at an average of 3 hours (Tmax from 1 to 6 hours), but nearly complete (90% to 95% bioavailability).
      • Conard GJ
      • Ober RE
      Metabolism of flecainide.
      Flecainide does not undergo first past hepatic metabolism. Therapeutic flecainide plasma levels with a total daily dose of 200 to 500 mg range from 200 to 1,000 ng/ml,
      • Roden DM
      • Woosley RL
      Drug therapy. Flecainide.
      and within this range there is a linear relation between plasma level and dose.
      • Conard GJ
      • Ober RE
      Metabolism of flecainide.
      Flecainide undergoes hepatic oxidative metabolism via cytochrome CYP2D6 and CYP1A2. The mean elimination half-life of oral flecainide is about 13 hours (range 7 to 22 hours), and is unaffected by dose.
      • Conard GJ
      • Ober RE
      Metabolism of flecainide.
      Both flecainide and its major inactive metabolites are primarily excreted in the urine.
      • Conard GJ
      • Ober RE
      Metabolism of flecainide.
      The pharmacokinetics of IV flecainide is notable for a rapid initial distribution phase of about 5 minutes, and elimination half-life of 7 to 15 hours (mean 11 hours).
      • Conard GJ
      • Carlson GL
      • Frost JW
      • Ober RE
      • Leon AS
      • Hunninghake DB
      Plasma concentrations of flecainide acetate, a new antiarrhythmic agent, in humans.

      Flecainide Administration and AF Indications for Use

      Flecainide acetate is available globally in oral formulation; its IV formulation is available in many countries but not the United States. Oral and IV flecainide have a Class 1A designation for the acute pharmacologic conversion of recent AF. IV flecainide, where available, is commonly used in emergency departments for the acute termination of AF. Intermittent self-administration of oral flecainide for the acute termination of recent-onset AF, termed “pill-in-a-pocket,” has a Class IIA designation. Chronic administration of oral flecainide has a Class IA recommendation in current guidelines from the United States
      • January CT
      • Wann LS
      • Alpert JS
      • Calkins H
      • Cigarroa JE
      • Cleveland Jr., JC
      • Conti JB
      • Ellinor PT
      • Ezekowitz MD
      • Field ME
      • Murray KT
      • Sacco RL
      • Stevenson WG
      • Tchou PJ
      • Tracy CM
      • Yancy CW
      2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the heart rhythm society.
      and EU
      • Kirchhof P
      • Benussi S
      • Kotecha D
      • Ahlsson A
      • Atar D
      • Casadei B
      • Castella M
      • Diener HC
      • Heidbuchel H
      • Hendriks J
      • Hindricks G
      • Manolis AS
      • Oldgren J
      • Popescu BA
      • Schotten U
      • Van Putte B
      • Vardas P
      • Agewall S
      • Camm J
      • Baron Esquivias G
      • Budts W
      • Carerj S
      • Casselman F
      • Coca A
      • De Caterina R
      • Deftereos S
      • Dobrev D
      • Ferro JM
      • Filippatos G
      • Fitzsimons D
      • Gorenek B
      • Guenoun M
      • Hohnloser SH
      • Kolh P
      • Lip GY
      • Manolis A
      • McMurray J
      • Ponikowski P
      • Rosenhek R
      • Ruschitzka F
      • Savelieva I
      • Sharma S
      • Suwalski P
      • Tamargo JL
      • Taylor CJ
      • Van Gelder IC
      • Voors AA
      • Windecker S
      • Zamorano JL
      • Zeppenfeld K
      2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with eacts.
      for the suppression of AF in patients without structural heart disease with recurrent paroxysmal or persistent AF.

      FDA Labeling and the CAST

      Flecainide acetate (Tambocor) was initially approved in 1985 for the treatment of supraventricular and ventricular tachyarrhythmias. In 1987, it was included in a randomized clinical study of 4 AADs and placebo, the CAST.
      The Cardiac Arrhythmia Suppression Trial (CAST) Investigators
      Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction.
      The CAST sought to test the hypothesis that the suppression of premature ventricular contractions (PVCs) would prevent sudden cardiac death in patients with frequent ventricular ectopy and reduced ejection fraction following a recent MI. However, 2 of the AADs tested, encainide and flecainide, were found to increase mortality compared with placebo in an interim analysis in 1989, and their use in the trial was halted.
      • Echt DS
      • Liebson PR
      • Mitchell LB
      • Peters RW
      • Obias-Manno D
      • Barker AH
      • Arensberg D
      • Baker A
      • Friedman L
      • Greene HL
      Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The cardiac arrhythmia suppression trial.
      It is notable that the actual mortality rate with flecainide was 4.3%, lower than the assumed placebo mortality rate of 5% used to design the study. The majority of excess deaths were due to ventricular tachyarrhythmias or asystole, and the second most common cause was MI with shock. The mortality rate was relatively linear over the mean of 10 months of follow-up. Death attributed to proarrhythmia occurred despite suppression of PVCs on ambulatory monitoring. The total number of arrhythmias and myocardial ischemic events in the active drug and control groups were similar, but in the active drug groups these events were 5 times more lethal. The relative mortality risk was also 5 times higher in patients experiencing non-Q wave MI compared with Q wave MI during follow-up.
      • Akiyama T
      • Pawitan Y
      • Greenberg H
      • Kuo CS
      • Reynolds-Haertle RA
      Increased risk of death and cardiac arrest from encainide and flecainide in patients after non-q-wave acute myocardial infarction in the cardiac arrhythmia suppression trial. CAST investigators.
      Therefore, it is postulated that in the CAST population, lethal acute ischemia was the proarrhythmic mechanism responsible for both the deaths due to MIs and the triggering of ventricular tachyarrhythmias.
      • Anderson JL
      • Platia EV
      • Hallstrom A
      • Henthorn RW
      • Buckingham TA
      • Carlson MD
      • Carson PE
      Interaction of baseline characteristics with the hazard of encainide, flecainide, and moricizine therapy in patients with myocardial infarction. A possible explanation for increased mortality in the cardiac arrhythmia suppression trial (CAST).
      ,
      • Greenberg HM
      • Dwyer Jr., EM
      • Hochman JS
      • Steinberg JS
      • Echt DS
      • Peters RW
      Interaction of ischaemia and encainide/flecainide treatment: a proposed mechanism for the increased mortality in CAST I.
      There is also speculation that the negative inotropic properties of encainide and flecainide contributed to the lethality of the MIs and ventricular tachyarrhythmias. However, although there was a slightly higher heart failure event rate in patients assigned to encainide and flecainide, this did not translate to a higher mortality due to heart failure. In fact, no death associated with flecainide was attributed directly to progressive heart failure. Because of the CAST findings of proarrhythmia, the FDA label was amended to include a black box warning. Although the CAST patient population was comprised only of post-MI patients with reduced ejection fraction, the FDA determined that its use be contraindicated in patients with structural heart disease of any etiology.

      Other Indications for Use

      Flecainide is indicated for patients with atrial flutter, paroxysmal supraventricular tachycardia, and the prevention of documented life-threatening ventricular arrhythmias. Flecainide may be particularly effective for patients with catecholaminergic polymorphic ventricular tachycardia, presumably due to its inhibitory action on RyR2 channels, and is a subject of an ongoing clinical trial.
      • Watanabe H
      • Chopra N
      • Laver D
      • Hwang HS
      • Davies SS
      • Roach DE
      • Duff HJ
      • Roden DM
      • Wilde AA
      • Knollmann BC
      Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans.
      ,
      • van der Werf C
      • Kannankeril PJ
      • Sacher F
      • Krahn AD
      • Viskin S
      • Leenhardt A
      • Shimizu W
      • Sumitomo N
      • Fish FA
      • Bhuiyan ZA
      • Willems AR
      • van der Veen MJ
      • Watanabe H
      • Laborderie J
      • Haissaguerre M
      • Knollmann BC
      • Wilde AA
      Flecainide therapy reduces exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia.
      It has also been used off-label in a small cohort of patients with PVC-induced cardiomyopathy, but without ischemic heart disease, resulting in a reduction in PVCs and improvement in ejection fraction with no evidence of proarrhythmia after a mean of 3.8 years of treatment.
      • Hyman MC
      • Mustin D
      • Supple G
      • Schaller RD
      • Santangeli P
      • Arkles J
      • Lin D
      • Muser D
      • Dixit S
      • Nazarian S
      • Epstein AE
      • Callans DJ
      • Marchlinski FE
      • Frankel DS
      Class IC antiarrhythmic drugs for suspected premature ventricular contraction-induced cardiomyopathy.

      Efficacy of Flecainide for the Treatment of AF

      Acute Conversion of AF

      Flecainide administration is highly effective for the conversion of AF to SR.
      • Goy JJ
      • Kaufmann U
      • Kappenberger L
      • Sigwart U
      Restoration of sinus rhythm with flecainide in patients with atrial fibrillation.
      ,
      • Crijns HJ
      • van Wijk LM
      • van Gilst WH
      • Kingma JH
      • van Gelder IC
      • Lie KI
      Acute conversion of atrial fibrillation to sinus rhythm: clinical efficacy of flecainide acetate. Comparison of two regimens.
      The most objective method by which to evaluate pharmacologic conversion rates is to randomize patients to drug or placebo and use a prespecified end point time to control for spontaneous conversion rates.
      • Van Gelder IC
      • Tuinenburg AE
      • Schoonderwoerd BS
      • Tieleman RG
      • Crijns HJ
      Pharmacologic versus direct-current electrical cardioversion of atrial flutter and fibrillation.
      Results from 4 such trials with flecainide are depicted in the histograms of Figure 1.
      • Donovan KD
      • Dobb GJ
      • Coombs LJ
      • Lee KY
      • Weekes JN
      • Murdock CJ
      • Clarke GM
      Efficacy of flecainide for the reversion of acute onset atrial fibrillation.
      • Donovan KD
      • Power BM
      • Hockings BE
      • Dobb GJ
      • Lee KY
      Intravenous flecainide versus amiodarone for recent-onset atrial fibrillation.
      • Romano S
      • Fattore L
      • Toscano G
      • Corsini F
      • Coppo A
      • Catanzaro M
      • Romano A
      • Martone A
      • Caccavale F
      • Iodice E
      • Di Maggio O
      • Corsini G
      Effectiveness and side effects of the treatment with propafenone and flecainide for recent-onset atrial fibrillation.
      • Boriani G
      • Biffi M
      • Capucci A
      • Botto G
      • Broffoni T
      • Ongari M
      • Trisolino G
      • Rubino I
      • Sanguinetti M
      • Branzi A
      • Magnani B
      Conversion of recent-onset atrial fibrillation to sinus rhythm: effects of different drug protocols.
      Overall, the conversion rate with flecainide ranged from 57% to 80%, higher than the conversion rate with placebo which ranged from 14% to 37%. The study with the 8-hour end point
      • Boriani G
      • Biffi M
      • Capucci A
      • Botto G
      • Broffoni T
      • Ongari M
      • Trisolino G
      • Rubino I
      • Sanguinetti M
      • Branzi A
      • Magnani B
      Conversion of recent-onset atrial fibrillation to sinus rhythm: effects of different drug protocols.
      utilized oral flecainide, whereas the other 3 studies
      • Donovan KD
      • Dobb GJ
      • Coombs LJ
      • Lee KY
      • Weekes JN
      • Murdock CJ
      • Clarke GM
      Efficacy of flecainide for the reversion of acute onset atrial fibrillation.
      • Donovan KD
      • Power BM
      • Hockings BE
      • Dobb GJ
      • Lee KY
      Intravenous flecainide versus amiodarone for recent-onset atrial fibrillation.
      • Romano S
      • Fattore L
      • Toscano G
      • Corsini F
      • Coppo A
      • Catanzaro M
      • Romano A
      • Martone A
      • Caccavale F
      • Iodice E
      • Di Maggio O
      • Corsini G
      Effectiveness and side effects of the treatment with propafenone and flecainide for recent-onset atrial fibrillation.
      utilized IV flecainide. The lower conversion rates observed in 2 studies
      • Donovan KD
      • Dobb GJ
      • Coombs LJ
      • Lee KY
      • Weekes JN
      • Murdock CJ
      • Clarke GM
      Efficacy of flecainide for the reversion of acute onset atrial fibrillation.
      ,
      • Donovan KD
      • Power BM
      • Hockings BE
      • Dobb GJ
      • Lee KY
      Intravenous flecainide versus amiodarone for recent-onset atrial fibrillation.
      are likely due to the shorter end point times at which conversion efficacy was assessed. In a meta-analysis of 6 studies,
      • Markey GC
      • Salter N
      • Ryan J
      Intravenous flecainide for emergency department management of acute atrial fibrillation.
      with a conversion end point time of 2 hours, IV flecainide administration was associated with a 69% conversion rate compared with 16% with placebo or verapamil.
      Figure 1
      Figure 1Acute AF conversion rates at 1 hour,
      • Donovan KD
      • Dobb GJ
      • Coombs LJ
      • Lee KY
      • Weekes JN
      • Murdock CJ
      • Clarke GM
      Efficacy of flecainide for the reversion of acute onset atrial fibrillation.
      2 hours,
      • Donovan KD
      • Power BM
      • Hockings BE
      • Dobb GJ
      • Lee KY
      Intravenous flecainide versus amiodarone for recent-onset atrial fibrillation.
      3 hours,
      • Romano S
      • Fattore L
      • Toscano G
      • Corsini F
      • Coppo A
      • Catanzaro M
      • Romano A
      • Martone A
      • Caccavale F
      • Iodice E
      • Di Maggio O
      • Corsini G
      Effectiveness and side effects of the treatment with propafenone and flecainide for recent-onset atrial fibrillation.
      and 8 hours
      • Boriani G
      • Biffi M
      • Capucci A
      • Botto G
      • Broffoni T
      • Ongari M
      • Trisolino G
      • Rubino I
      • Sanguinetti M
      • Branzi A
      • Magnani B
      Conversion of recent-onset atrial fibrillation to sinus rhythm: effects of different drug protocols.
      after administration of flecainide or placebo.

      Acute Conversion of AF With Flecainide Compared With Other Antiarrhythmic Agents

      The other Class IC antiarrhythmic agent approved for acute conversion of AF is propafenone, whose use is also restricted to patients without structural heart disease. Figure 2 depicts the conversion rates for flecainide and propafenone in 5 randomized controlled studies comparing the agents directly.
      • Romano S
      • Fattore L
      • Toscano G
      • Corsini F
      • Coppo A
      • Catanzaro M
      • Romano A
      • Martone A
      • Caccavale F
      • Iodice E
      • Di Maggio O
      • Corsini G
      Effectiveness and side effects of the treatment with propafenone and flecainide for recent-onset atrial fibrillation.
      ,
      • Kondili A
      • Kastrati A
      • Popa Y
      Comparative evaluation of verapamil, flecainide and propafenone for the acute conversion of atrial fibrillation to sinus rhythm.
      • Suttorp MJ
      • Kingma JH
      • Jessurun ER
      • Lie AHL
      • van Hemel NM
      • Lie KI
      The value of class IC antiarrhythmic drugs for acute conversion of paroxysmal atrial fibrillation or flutter to sinus rhythm.
      • Capucci A
      • Boriani G
      • Botto GL
      • Lenzi T
      • Rubino I
      • Falcone C
      • Trisolino G
      • Della Casa S
      • Binetti N
      • Cavazza M
      Conversion of recent-onset atrial fibrillation by a single oral loading dose of propafenone or flecainide.
      • Martinez-Marcos FJ
      • Garcia-Garmendia JL
      • Ortega-Carpio A
      • Fernandez-Gomez JM
      • Santos JM
      • Camacho C
      Comparison of intravenous flecainide, propafenone, and amiodarone for conversion of acute atrial fibrillation to sinus rhythm.
      In each study, the conversion rate with flecainide (range 50% to 90%) was higher than with propafenone (range 25% to 72%).
      Figure 2
      Figure 2Acute AF conversion rates at 1 hour,
      • Kondili A
      • Kastrati A
      • Popa Y
      Comparative evaluation of verapamil, flecainide and propafenone for the acute conversion of atrial fibrillation to sinus rhythm.
      ,
      • Suttorp MJ
      • Kingma JH
      • Jessurun ER
      • Lie AHL
      • van Hemel NM
      • Lie KI
      The value of class IC antiarrhythmic drugs for acute conversion of paroxysmal atrial fibrillation or flutter to sinus rhythm.
      3 hours,
      • Romano S
      • Fattore L
      • Toscano G
      • Corsini F
      • Coppo A
      • Catanzaro M
      • Romano A
      • Martone A
      • Caccavale F
      • Iodice E
      • Di Maggio O
      • Corsini G
      Effectiveness and side effects of the treatment with propafenone and flecainide for recent-onset atrial fibrillation.
      ,
      • Capucci A
      • Boriani G
      • Botto GL
      • Lenzi T
      • Rubino I
      • Falcone C
      • Trisolino G
      • Della Casa S
      • Binetti N
      • Cavazza M
      Conversion of recent-onset atrial fibrillation by a single oral loading dose of propafenone or flecainide.
      and 8 hours
      • Martinez-Marcos FJ
      • Garcia-Garmendia JL
      • Ortega-Carpio A
      • Fernandez-Gomez JM
      • Santos JM
      • Camacho C
      Comparison of intravenous flecainide, propafenone, and amiodarone for conversion of acute atrial fibrillation to sinus rhythm.
      after administration of flecainide or propafenone. Note that oral agents were administered in the study by Capucci et al.
      • Capucci A
      • Boriani G
      • Botto GL
      • Lenzi T
      • Rubino I
      • Falcone C
      • Trisolino G
      • Della Casa S
      • Binetti N
      • Cavazza M
      Conversion of recent-onset atrial fibrillation by a single oral loading dose of propafenone or flecainide.
      Other antiarrhythmic agents recommended in medical guidelines for AF conversion are all categorized as having predominantly Class III effects. These include 3 IV agents: amiodarone, ibutilide, and vernakalant (not available in the United States); and oral dofetilide (not available in Europe). Beta-blockers, calcium channel blockers, and digoxin, while often given concomitantly for rate control, are not recommended alone for rhythm control therapy as they have not been shown to result in AF conversion compared with placebo.
      • Kirchhof P
      • Benussi S
      • Kotecha D
      • Ahlsson A
      • Atar D
      • Casadei B
      • Castella M
      • Diener HC
      • Heidbuchel H
      • Hendriks J
      • Hindricks G
      • Manolis AS
      • Oldgren J
      • Popescu BA
      • Schotten U
      • Van Putte B
      • Vardas P
      • Agewall S
      • Camm J
      • Baron Esquivias G
      • Budts W
      • Carerj S
      • Casselman F
      • Coca A
      • De Caterina R
      • Deftereos S
      • Dobrev D
      • Ferro JM
      • Filippatos G
      • Fitzsimons D
      • Gorenek B
      • Guenoun M
      • Hohnloser SH
      • Kolh P
      • Lip GY
      • Manolis A
      • McMurray J
      • Ponikowski P
      • Rosenhek R
      • Ruschitzka F
      • Savelieva I
      • Sharma S
      • Suwalski P
      • Tamargo JL
      • Taylor CJ
      • Van Gelder IC
      • Voors AA
      • Windecker S
      • Zamorano JL
      • Zeppenfeld K
      2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with eacts.
      Of the AADs recommended for acute conversion of AF to SR, amiodarone is the most commonly used in the United States despite the fact that it is not approved for the treatment of supraventricular arrhythmias,
      • Chevalier P
      • Durand-Dubief A
      • Burri H
      • Cucherat M
      • Kirkorian G
      • Touboul P
      Amiodarone versus placebo and class 1C drugs for cardioversion of recent-onset atrial fibrillation: a meta-analysis.
      and conversion of AF and SR with the drug is delayed due to its pharmacokinetics. Based upon a meta-analysis of studies comparing IV amiodarone with placebo and/or Class IC agents,
      • Chevalier P
      • Durand-Dubief A
      • Burri H
      • Cucherat M
      • Kirkorian G
      • Touboul P
      Amiodarone versus placebo and class 1C drugs for cardioversion of recent-onset atrial fibrillation: a meta-analysis.
      unlike flecainide, the AF conversion rate with IV amiodarone administration was similar to placebo at 1 to 2 hours after administration, higher than placebo but lower than flecainide at 6 to 8 hours after administration, and only at 24 hours was the conversion rate with amiodarone comparable with the rates attained at 6 to 8 hours with flecainide.
      • Chevalier P
      • Durand-Dubief A
      • Burri H
      • Cucherat M
      • Kirkorian G
      • Touboul P
      Amiodarone versus placebo and class 1C drugs for cardioversion of recent-onset atrial fibrillation: a meta-analysis.
      Shown in Figure 3 are conversion rates over time from 2 studies evaluating IV amiodarone and oral
      • Donovan KD
      • Power BM
      • Hockings BE
      • Dobb GJ
      • Lee KY
      Intravenous flecainide versus amiodarone for recent-onset atrial fibrillation.
      or IV flecainide.
      • Martinez-Marcos FJ
      • Garcia-Garmendia JL
      • Ortega-Carpio A
      • Fernandez-Gomez JM
      • Santos JM
      • Camacho C
      Comparison of intravenous flecainide, propafenone, and amiodarone for conversion of acute atrial fibrillation to sinus rhythm.
      In an emergency room propensity score case-matched study comparing Class IC agents with amiodarone, higher AF conversion rates (73% vs 53%, p <0.05) combined with equivalent adverse event rates resulted in a lower hospital admission rate with Class IC drugs (27% vs 52%, p <0.05).
      • Bonora A
      • Turcato G
      • Franchi E
      • Taioli G
      • Dilda A
      • Zerman G
      • Maccagnani A
      • Pistorelli C
      • Olivieri O
      Efficacy and safety in pharmacological cardioversion of recent-onset atrial fibrillation: a propensity score matching to compare amiodarone vs class 1C antiarrhythmic drugs.
      Figure 3
      Figure 3Acute AF conversion rates at various time points after administration of po flecainide or IV amiodarone
      • Donovan KD
      • Power BM
      • Hockings BE
      • Dobb GJ
      • Lee KY
      Intravenous flecainide versus amiodarone for recent-onset atrial fibrillation.
      (left bars) and IV flecainide or IV amiodarone
      • Martinez-Marcos FJ
      • Garcia-Garmendia JL
      • Ortega-Carpio A
      • Fernandez-Gomez JM
      • Santos JM
      • Camacho C
      Comparison of intravenous flecainide, propafenone, and amiodarone for conversion of acute atrial fibrillation to sinus rhythm.
      (right bars). nr = not reported.
      A meta-analysis of randomized studies found the overall AF conversion rate within 2 hours to be higher with flecainide (66%) compared with the AADs amiodarone, propafenone, sotalol, procainamide, and ibutilide (46%).
      • Markey GC
      • Salter N
      • Ryan J
      Intravenous flecainide for emergency department management of acute atrial fibrillation.
      Randomized studies directly comparing flecainide AF conversion rates with dofetilide and vernakalant are not available; however, in studies with a placebo comparator, the conversion rates were lower than reported for flecainide.
      • Hassan OF
      • Al Suwaidi J
      • Salam AM
      Anti-arrhythmic agents in the treatment of atrial fibrillation.
      Thus, acute conversion of recent onset AF is higher with flecainide than any other antiarrhythmic agent.

      Pill-in-the-Pocket Approach

      Because flecainide and propafenone have been shown to be effective for acute conversion of AF when administered as an oral loading dose,
      • Crijns HJ
      • van Wijk LM
      • van Gilst WH
      • Kingma JH
      • van Gelder IC
      • Lie KI
      Acute conversion of atrial fibrillation to sinus rhythm: clinical efficacy of flecainide acetate. Comparison of two regimens.
      ,
      • Capucci A
      • Boriani G
      • Botto GL
      • Lenzi T
      • Rubino I
      • Falcone C
      • Trisolino G
      • Della Casa S
      • Binetti N
      • Cavazza M
      Conversion of recent-onset atrial fibrillation by a single oral loading dose of propafenone or flecainide.
      ,
      • Alp NJ
      • Bell JA
      • Shahi M
      Randomised double blind trial of oral versus intravenous flecainide for the cardioversion of acute atrial fibrillation.
      their use has been extended to intermittent self-administration by the patient, referred to as “pill-in-the-pocket” (PiP). This treatment strategy has been employed for selected patients who are able to reliably self-identify symptomatic episodes of AF or are able to obtain confirmation from a wearable, implantable, or portable ECG monitoring device. Patients generally have an initial AF episode treated under medical supervision and, if conversion is successful and without major adverse events, the treatment is prescribed for home use. Because patients are prescreened for efficacy and safety and are able to self-treat soon after AF onset, the conversion rate can be high and the overall duration of AF relatively short. In 1 study,
      • Alboni P
      • Botto GL
      • Baldi N
      • Luzi M
      • Russo V
      • Gianfranchi L
      • Marchi P
      • Calzolari M
      • Solano A
      • Baroffio R
      • Gaggioli G
      Outpatient treatment of recent-onset atrial fibrillation with the "pill-in-the-pocket" approach.
      initial acute conversion in the emergency room was successful and without adverse events in 78% of patients treated. Of 165 patients subsequently self-treating 618 episodes of AF with flecainide or propafenone, the conversion rate was 94% and the mean AF duration was 113 ± 84 minutes. In 84% of the 165 patients, self-treatment was successful for all AF recurrences. In a similar study,
      • Andrade JG
      • MacGillivray J
      • Macle L
      • Yao RJR
      • Bennett M
      • Fordyce CB
      • Hawkins N
      • Krahn A
      • Jue J
      • Ramanathan K
      • Tsang T
      • Gin K
      • Deyell MW
      Clinical effectiveness of a systematic "pill-in-the-pocket" approach for the management of paroxysmal atrial fibrillation.
      70% of patients were initially treated successfully and safely, and those 30 patients subsequently had 159 episodes of AF, 97% of which were successfully self-treated. This treatment strategy significantly reduced the number of emergency room visits,
      • Alboni P
      • Botto GL
      • Baldi N
      • Luzi M
      • Russo V
      • Gianfranchi L
      • Marchi P
      • Calzolari M
      • Solano A
      • Baroffio R
      • Gaggioli G
      Outpatient treatment of recent-onset atrial fibrillation with the "pill-in-the-pocket" approach.
      ,
      • Andrade JG
      • MacGillivray J
      • Macle L
      • Yao RJR
      • Bennett M
      • Fordyce CB
      • Hawkins N
      • Krahn A
      • Jue J
      • Ramanathan K
      • Tsang T
      • Gin K
      • Deyell MW
      Clinical effectiveness of a systematic "pill-in-the-pocket" approach for the management of paroxysmal atrial fibrillation.
      the need for electrical cardioversion,
      • Andrade JG
      • MacGillivray J
      • Macle L
      • Yao RJR
      • Bennett M
      • Fordyce CB
      • Hawkins N
      • Krahn A
      • Jue J
      • Ramanathan K
      • Tsang T
      • Gin K
      • Deyell MW
      Clinical effectiveness of a systematic "pill-in-the-pocket" approach for the management of paroxysmal atrial fibrillation.
      and the need for hospitalization
      • Alboni P
      • Botto GL
      • Baldi N
      • Luzi M
      • Russo V
      • Gianfranchi L
      • Marchi P
      • Calzolari M
      • Solano A
      • Baroffio R
      • Gaggioli G
      Outpatient treatment of recent-onset atrial fibrillation with the "pill-in-the-pocket" approach.
      compared with a similar time period before initiating the PiP approach.

      Chronic Suppression of AF With Flecainide

      The primary role of chronic therapy with flecainide and other AADs is to delay the time to AF recurrence and reduce AF burden. It is difficult to determine actual AF recurrence rates from reported studies of chronic suppression because they are based upon routine intermittent ECG monitoring and documented symptomatic events. Asymptomatic episodes occurring outside of ECG monitoring periods and symptomatic episodes without ECG documentation are not usually reflected in the reported results. Chronic oral flecainide administration has been shown to reduce the incidence of AF recurrence and prolong the interval between episodes in patients with paroxysmal and persistent AF in small placebo-controlled studies,
      • Van Gelder IC
      • Crijns HJ
      • Van Gilst WH
      • Van Wijk LM
      • Hamer HP
      • Lie KI
      Efficacy and safety of flecainide acetate in the maintenance of sinus rhythm after electrical cardioversion of chronic atrial fibrillation or atrial flutter.
      • Pietersen AH
      • Hellemann H
      Usefulness of flecainide for prevention of paroxysmal atrial fibrillation and flutter. Danish-Norwegian flecainide multicenter study group.
      • Anderson JL
      • Gilbert EM
      • Alpert BL
      • Henthorn RW
      • Waldo AL
      • Bhandari AK
      • Hawkinson RW
      • Pritchett EL
      Prevention of symptomatic recurrences of paroxysmal atrial fibrillation in patients initially tolerating antiarrhythmic therapy. A multicenter, double-blind, crossover study of flecainide and placebo with transtelephonic monitoring. Flecainide supraventricular tachycardia study group.
      • Kirchhof P
      • Andresen D
      • Bosch R
      • Borggrefe M
      • Meinertz T
      • Parade U
      • Ravens U
      • Samol A
      • Steinbeck G
      • Treszl A
      • Wegscheider K
      • Breithardt G
      Short-term versus long-term antiarrhythmic drug treatment after cardioversion of atrial fibrillation (FLec-SL): a prospective, randomised, open-label, blinded endpoint assessment trial.
      and 65% of patients were AF-free at 9 months in a larger uncontrolled study.
      • Clementy J
      • Dulhoste MN
      • Laiter C
      • Denjoy I
      • Dos Santos P
      Flecainide acetate in the prevention of paroxysmal atrial fibrillation: a nine-month follow-up of more than 500 patients.

      Chronic Suppression of AF With Flecainide Compared With Other AADs

      Large retrospective studies and meta-analyses of AAD therapy that report 1-year AF recurrence rates range from 44% to 67%.
      • Qin D
      • Leef G
      • Alam MB
      • Rattan R
      • Munir MB
      • Patel D
      • Khattak F
      • Adelstein E
      • Jain SK
      • Saba S
      Comparative effectiveness of antiarrhythmic drugs for rhythm control of atrial fibrillation.
      • Alegret JM
      • Vinolas X
      • Grande A
      • Castellanos E
      • Asso A
      • Tercedor L
      • Carmona JR
      • Medina O
      • Alberola AG
      • Fidalgo ML
      • Perez-Alvarez L
      • Sabate X
      Clinical effectiveness of antiarrhythmic treatment after electrical cardioversion in patients without structural heart disease.
      • Gwag HB
      • Chun KJ
      • Hwang JK
      • Park SJ
      • Kim JS
      • Park KM
      • On YK
      Which antiarrhythmic drug to choose after electrical cardioversion: a study on non-valvular atrial fibrillation patients.
      • Lafuente-Lafuente C
      • Valembois L
      • Bergmann JF
      • Belmin J
      Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation.
      The efficacy of flecainide was found to be similar to other AADs,
      • Qin D
      • Leef G
      • Alam MB
      • Rattan R
      • Munir MB
      • Patel D
      • Khattak F
      • Adelstein E
      • Jain SK
      • Saba S
      Comparative effectiveness of antiarrhythmic drugs for rhythm control of atrial fibrillation.
      ,
      • Gwag HB
      • Chun KJ
      • Hwang JK
      • Park SJ
      • Kim JS
      • Park KM
      • On YK
      Which antiarrhythmic drug to choose after electrical cardioversion: a study on non-valvular atrial fibrillation patients.
      or similar with the exception of somewhat greater efficacy with amiodarone.
      • Alegret JM
      • Vinolas X
      • Grande A
      • Castellanos E
      • Asso A
      • Tercedor L
      • Carmona JR
      • Medina O
      • Alberola AG
      • Fidalgo ML
      • Perez-Alvarez L
      • Sabate X
      Clinical effectiveness of antiarrhythmic treatment after electrical cardioversion in patients without structural heart disease.
      ,
      • Lafuente-Lafuente C
      • Valembois L
      • Bergmann JF
      • Belmin J
      Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation.
      Hospitalization rates for AF following AAD prescriptions for a new diagnosis of AF or atrial flutter have been analyzed using health utilization data. In the TREAT-AF study, which employed propensity score matching, not only were hospitalization rates for AF or atrial flutter found to be lower with Class IC drugs, but also for cardiovascular disease, heart failure, and ischemic stroke.
      • Kipp R
      • Askari M
      • Fan J
      • Field ME
      • Turakhia MP
      Real-world comparison of classes IC and III antiarrhythmic drugs as an initial rhythm control strategy in newly diagnosed atrial fibrillation: from the treat-af study.
      Another analysis using claims data
      • Allen LaPointe NM
      • Dai D
      • Thomas L
      • Piccini JP
      • Peterson ED
      • Al-Khatib SM
      Antiarrhythmic drug use in patients <65 years with atrial fibrillation and without structural heart disease.
      found higher AF hospitalization rates with dronedarone and lower AF hospitalization rates with amiodarone, but no difference between sotalol and Class IC AADs. Thus, with the exception of amiodarone, the long-term efficacy of flecainide is comparable with other approved AADs.

      Prophylactic Flecainide Post Cardiac Ablation

      AF recurrence is common in the 3-month atrial healing period immediately following catheter ablation, referred to as the blanking period.
      • Willems S
      • Khairy P
      • Andrade JG
      • Hoffmann BA
      • Levesque S
      • Verma A
      • Weerasooriya R
      • Novak P
      • Arentz T
      • Deisenhofer I
      • Rostock T
      • Steven D
      • Rivard L
      • Guerra PG
      • Dyrda K
      • Mondesert B
      • Dubuc M
      • Thibault B
      • Talajic M
      • Roy D
      • Nattel S
      • Macle L
      Redefining the blanking period after catheter ablation for paroxysmal atrial fibrillation: Insights from the advice (adenosine following pulmonary vein isolation to target dormant conduction elimination) trial.
      Prophylactic AAD therapy during the blanking period has been found to be an effective strategy even in previously drug refractory patients. Several randomized trials which have included flecainide have shown that the incidence of recurrent AF is modestly reduced on AADs (3% to 52%) compared with placebo (22% to 59%).
      • Kaitani K
      • Inoue K
      • Kobori A
      • Nakazawa Y
      • Ozawa T
      • Kurotobi T
      • Morishima I
      • Miura F
      • Watanabe T
      • Masuda M
      • Naito M
      • Fujimoto H
      • Nishida T
      • Furukawa Y
      • Shirayama T
      • Tanaka M
      • Okajima K
      • Yao T
      • Egami Y
      • Satomi K
      • Noda T
      • Miyamoto K
      • Haruna T
      • Kawaji T
      • Yoshizawa T
      • Toyota T
      • Yahata M
      • Nakai K
      • Sugiyama H
      • Higashi Y
      • Ito M
      • Horie M
      • Kusano KF
      • Shimizu W
      • Kamakura S
      • Morimoto T
      • Kimura T
      • Shizuta S
      Efficacy of antiarrhythmic drugs short-term use after catheter ablation for atrial fibrillation (EAST-AF) trial.
      • Roux JF
      • Zado E
      • Callans DJ
      • Garcia F
      • Lin D
      • Marchlinski FE
      • Bala R
      • Dixit S
      • Riley M
      • Russo AM
      • Hutchinson MD
      • Cooper J
      • Verdino R
      • Patel V
      • Joy PS
      • Gerstenfeld EP
      Antiarrhythmics after ablation of atrial fibrillation (5A study).
      • Duytschaever M
      • Demolder A
      • Phlips T
      • Sarkozy A
      • El Haddad M
      • Taghji P
      • Knecht S
      • Tavernier R
      • Vandekerckhove Y
      • De Potter T
      Pulmonary vein isolation with vs. without continued antiarrhythmic drug treatment in subjects with recurrent atrial fibrillation (POWDER-AF): results from a multicentre randomized trial.

      Safety of Flecainide in Patients With AF

      Major Safety Issues With Flecainide

      The 2.5-fold excess mortality due to proarrhythmic effects associated with the use of encainide and flecainide in the CAST occurred in a highly selected population of patients with previous MI, frequent ventricular ectopy, and depressed LV ejection fraction.
      • Echt DS
      • Liebson PR
      • Mitchell LB
      • Peters RW
      • Obias-Manno D
      • Barker AH
      • Arensberg D
      • Baker A
      • Friedman L
      • Greene HL
      Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The cardiac arrhythmia suppression trial.
      Despite the fact that the CAST was carried out in a high-risk cohort of patients with advanced structural heart disease, potential safety concerns about the risk for ventricular proarrhythmia in other populations has persisted. Flecainide-induced proarrhythmia manifesting as ventricular tachycardia can be either monomorphic or polymorphic, but very rarely has the morphologic characteristics of torsade de pointes, as discussed in the section on flecainide electrophysiology. Despite these concerns, the safety of flecainide in patients without structural heart disease is now well established.
      Three additional arrhythmia-related safety issues have been reported to be associated with the use of flecainide in patients with AF. First, there is the potential for AF to be converted to atrial flutter as a result of the conduction slowing effects of flecainide.
      • Chimienti M
      • Cullen Jr., MT
      • Casadei G
      Safety of flecainide versus propafenone for the long-term management of symptomatic paroxysmal supraventricular tachyarrhythmias. Report from the Flecainide and Propafenone Italian Study (FAPIS) group.
      When this occurs, the atrial (flutter) rate may be slowed enough to permit one-to-one AV conduction, resulting in a rapid ventricular rate. In patients with healthy AV node function, the concomitant administration of a β blocker or nondihydropyridine calcium channel blocker markedly reduces the likelihood of this adverse event. Second, is the possibility of a prolonged sinus pause immediately following successful conversion of AF to SR.
      • Naccarelli GV
      • Dorian P
      • Hohnloser SH
      • Coumel P
      Prospective comparison of flecainide versus quinidine for the treatment of paroxysmal atrial fibrillation/flutter. The flecainide multicenter atrial fibrillation study group.
      These offset pauses occur primarily in patients with underlying sinus node dysfunction. Third, flecainide, like many other sodium channel blocking drugs, may unmask the ECG pattern of underlying Brugada syndrome, leading to ventricular tachycardia and, thereby, a risk for sudden cardiac death.
      Another major safety issue associated with administration of flecainide is related to its potential for adverse hemodynamic effects resulting from the negative inotropic effect of the drug. Hypotension can be observed following IV administration regardless of underlying LV function. Worsening heart failure has been observed in patients with underlying LV dysfunction receiving chronic oral therapy, which is why the use of flecainide is contraindicated in patients with LV dysfunction or heart failure. Minor adverse effects associated with flecainide administration include dizziness, visual disturbances, paresthesias, headache, dyspnea, and nausea.

      Analyses of Mortality

      Following the results of the CAST, numerous flecainide safety analyses were performed for patients with supraventricular tachyarrhythmias. A meta-analysis of 91 randomized controlled trials of AAD therapy for short-term AF rhythm control, with a mean follow-up of 46 days, found 99% survival in both drug and control groups.
      • Nichol G
      • McAlister F
      • Pham B
      • Laupacis A
      • Shea B
      • Green M
      • Tang A
      • Wells G
      Meta-analysis of randomised controlled trials of the effectiveness of antiarrhythmic agents at promoting sinus rhythm in patients with atrial fibrillation.
      There was no evidence of an adverse mortality effect with any AAD including flecainide. In contrast, analyses of chronic suppression of AF have found differing all-cause mortality rates among AADs. In the Swedish Patient registry of patients receiving AADs with propensity scored-matched controls, followed for a mean of 3.5 years, a significantly higher total mortality rate was observed in patients treated with amiodarone compared with sotalol, and a significantly lower total mortality rate with chronic flecainide therapy compared with sotalol.
      • Friberg L
      Ventricular arrhythmia and death among atrial fibrillation patients using anti-arrhythmic drugs.
      This analysis also found a higher composite arrhythmic end point rate with amiodarone compared with sotalol, and an equivalent arrhythmic end point rate with flecainide compared with sotalol. A meta-analysis that compared 1-year mortality rates in 59 randomized controlled trials comprised of AADs for chronic AF suppression found that none resulted in a mortality benefit and that only Class IA agents and sotalol were associated with an increase in mortality compared with controls.
      • Lafuente-Lafuente C
      • Valembois L
      • Bergmann JF
      • Belmin J
      Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation.
      The AFFIRM trial randomized 4,060 patients to rate or rhythm control drug treatment strategies for AF using mortality as the primary end point.
      • Wyse DG
      • Waldo AL
      • DiMarco JP
      • Domanski MJ
      • Rosenberg Y
      • Schron EB
      • Kellen JC
      • Greene HL
      • Mickel MC
      • Dalquist JE
      • Corley SD
      A comparison of rate control and rhythm control in patients with atrial fibrillation.
      Although no difference in mortality was observed between the rate versus rhythm control arms, a propensity score-matched subset analysis of mortality with individual AADs provided further insights.
      • Saksena S
      • Slee A
      • Waldo AL
      • Freemantle N
      • Reynolds M
      • Rosenberg Y
      • Rathod S
      • Grant S
      • Thomas E
      • Wyse DG
      Cardiovascular outcomes in the affirm trial (atrial fibrillation follow-up investigation of rhythm management). An assessment of individual antiarrhythmic drug therapies compared with rate control with propensity score-matched analyses.
      There was no difference in mortality in the minority of patients randomized to rhythm control and receiving flecainide (8%) compared with the rate control arm. However, a majority of patients randomized to rhythm control received amiodarone (63%), resulting in a trend toward higher total mortality, and a significantly higher incidence of noncardiovascular mortality compared with the rate control arm. Furthermore, a separate AFFIRM analysis found that the (nonsignificant) excess mortality in the rhythm control arm was entirely noncardiovascular in etiology, and primarily pulmonary and cancer-related, which are disease states most closely associated with chronic amiodarone use.
      • Steinberg JS
      • Sadaniantz A
      • Kron J
      • Krahn A
      • Denny DM
      • Daubert J
      • Campbell WB
      • Havranek E
      • Murray K
      • Olshansky B
      • O'Neill G
      • Sami M
      • Schmidt S
      • Storm R
      • Zabalgoitia M
      • Miller J
      • Chandler M
      • Nasco EM
      • Greene HL
      Analysis of cause-specific mortality in the atrial fibrillation follow-up investigation of rhythm management (affirm) study.
      Since the majority of patients in the rhythm control arm received amiodarone, it is plausible that the excess noncardiovascular mortality associated with amiodarone use was primarily responsible for the overall lack of difference in mortality between rate and rhythm strategies in the AFFIRM. Mortality was also compared in a propensity-matched cohort analysis of patients with LV hypertrophy treated for persistent AF with amiodarone and nonamiodarone AADs.
      • Chung R
      • Houghtaling PL
      • Tchou M
      • Niebauer MJ
      • Lindsay BD
      • Tchou PJ
      • Chung MK
      Left ventricular hypertrophy and antiarrhythmic drugs in atrial fibrillation: impact on mortality.
      A trend toward higher mortality was found with amiodarone compared with nonamiodarone drugs, and a significantly higher mortality was found with amiodarone compared with the subset of patients receiving Class 1C agents. Overall, these analyses suggest that acute and chronic therapy with flecainide does not confer a mortality benefit or risk compared with controls in patients with AF, but that flecainide may confer a lower mortality risk compared with sotalol and amiodarone. Furthermore, there appears to be a higher risk of death with chronic amiodarone therapy compared with controls.

      Analyses of Ventricular Proarrhythmic Effects During Acute Administration

      Most of safety analyses addressing proarrhythmia combine acute and chronic studies of flecainide administration and also combine all types of arrhythmia-related adverse events. To consider the specific concern of proarrhythmia due to ventricular tachyarrhythmias in the setting of acute administration for AF conversion, individual studies were reviewed. Combining the results from the 4 randomized controlled studies of acute AF conversion with flecainide, shown in Figure 1,
      • Donovan KD
      • Dobb GJ
      • Coombs LJ
      • Lee KY
      • Weekes JN
      • Murdock CJ
      • Clarke GM
      Efficacy of flecainide for the reversion of acute onset atrial fibrillation.
      • Donovan KD
      • Power BM
      • Hockings BE
      • Dobb GJ
      • Lee KY
      Intravenous flecainide versus amiodarone for recent-onset atrial fibrillation.
      • Romano S
      • Fattore L
      • Toscano G
      • Corsini F
      • Coppo A
      • Catanzaro M
      • Romano A
      • Martone A
      • Caccavale F
      • Iodice E
      • Di Maggio O
      • Corsini G
      Effectiveness and side effects of the treatment with propafenone and flecainide for recent-onset atrial fibrillation.
      • Boriani G
      • Biffi M
      • Capucci A
      • Botto G
      • Broffoni T
      • Ongari M
      • Trisolino G
      • Rubino I
      • Sanguinetti M
      • Branzi A
      • Magnani B
      Conversion of recent-onset atrial fibrillation to sinus rhythm: effects of different drug protocols.
      1 event in 292 patients treated with flecainide and 1 event in 254 patients treated with placebo was considered to be ventricular proarrhythmia. Combining the results from 3 studies using the PiP approach with either flecainide or propafenone, there was no evidence of ventricular proarrhythmia in the 433 patients treated in-hospital for their initial episode or any of the 990 episodes in 274 patients treated out-of-hospital.
      • Alboni P
      • Botto GL
      • Baldi N
      • Luzi M
      • Russo V
      • Gianfranchi L
      • Marchi P
      • Calzolari M
      • Solano A
      • Baroffio R
      • Gaggioli G
      Outpatient treatment of recent-onset atrial fibrillation with the "pill-in-the-pocket" approach.
      ,
      • Andrade JG
      • MacGillivray J
      • Macle L
      • Yao RJR
      • Bennett M
      • Fordyce CB
      • Hawkins N
      • Krahn A
      • Jue J
      • Ramanathan K
      • Tsang T
      • Gin K
      • Deyell MW
      Clinical effectiveness of a systematic "pill-in-the-pocket" approach for the management of paroxysmal atrial fibrillation.
      ,
      • Alboni P
      • Botto GL
      • Boriani G
      • Russo G
      • Pacchioni F
      • Iori M
      • Pasanisi G
      • Mancini M
      • Mariconti B
      • Capucci A
      Intravenous administration of flecainide or propafenone in patients with recent-onset atrial fibrillation does not predict adverse effects during 'pill-in-the-pocket' treatment.

      Analyses of Total Arrhythmia-Related Adverse Events

      A large meta-analysis of 122 studies
      • Wehling M
      Meta-analysis of flecainide safety in patients with supraventricular arrhythmias.
      that included both acute and chronic treatment with flecainide for supraventricular tachyarrhythmias found that the incidence of all arrhythmia-related adverse events with flecainide was significantly lower than that of active comparators and placebo controls (2.5% vs 3.2%, p <0.001). A more recent meta-analysis of studies on acute AF conversion
      • Markey GC
      • Salter N
      • Ryan J
      Intravenous flecainide for emergency department management of acute atrial fibrillation.
      found that the incidence of arrhythmia-related adverse events was similar for IV flecainide, placebo, amiodarone, propafenone, sotalol, dofetilide, and ibutilide. The same study reported that the risk of hypotension with IV flecainide was statistically significantly higher than with placebo but not higher than with other AADs.

      Analyses of Total Adverse Events

      In a propensity score case-matched study of acute AF conversion, the total adverse event rate with IV Class IC drugs and amiodarone was found to be similar (3.4% and 3.9%, respectively), and the most common event was minor hypotension.
      • Bonora A
      • Turcato G
      • Franchi E
      • Taioli G
      • Dilda A
      • Zerman G
      • Maccagnani A
      • Pistorelli C
      • Olivieri O
      Efficacy and safety in pharmacological cardioversion of recent-onset atrial fibrillation: a propensity score matching to compare amiodarone vs class 1C antiarrhythmic drugs.
      In a meta-analysis of 122 studies of acute and chronic AAD administration, the total rate of adverse cardiac events was 5.6% for flecainide compared with 5.8% for placebo and active control groups combined.
      • Wehling M
      Meta-analysis of flecainide safety in patients with supraventricular arrhythmias.
      The incidence of major adverse events with acute and chronic administration of flecainide in the currently indicated treatment population (ie, no structural heart disease), is summarized in Table 1. These studies support the conclusion that the risk of major adverse events with flecainide, including mortality, ventricular proarrhythmia, and other arrhythmia-related events, is similar to other AADs used to treat AF.
      Table 1Flecainide safety issues
      IndicationMajor adverse eventsRelative incidence
      Rare <1%, Unusual 1% to <3%, Occasional 3% to <10%, Frequent ≥10%.
      Acute conversion
      • Markey GC
      • Salter N
      • Ryan J
      Intravenous flecainide for emergency department management of acute atrial fibrillation.
      ,
      • Donovan KD
      • Dobb GJ
      • Coombs LJ
      • Lee KY
      • Weekes JN
      • Murdock CJ
      • Clarke GM
      Efficacy of flecainide for the reversion of acute onset atrial fibrillation.
      • Donovan KD
      • Power BM
      • Hockings BE
      • Dobb GJ
      • Lee KY
      Intravenous flecainide versus amiodarone for recent-onset atrial fibrillation.
      • Romano S
      • Fattore L
      • Toscano G
      • Corsini F
      • Coppo A
      • Catanzaro M
      • Romano A
      • Martone A
      • Caccavale F
      • Iodice E
      • Di Maggio O
      • Corsini G
      Effectiveness and side effects of the treatment with propafenone and flecainide for recent-onset atrial fibrillation.
      • Boriani G
      • Biffi M
      • Capucci A
      • Botto G
      • Broffoni T
      • Ongari M
      • Trisolino G
      • Rubino I
      • Sanguinetti M
      • Branzi A
      • Magnani B
      Conversion of recent-onset atrial fibrillation to sinus rhythm: effects of different drug protocols.
      ,
      • Alboni P
      • Botto GL
      • Baldi N
      • Luzi M
      • Russo V
      • Gianfranchi L
      • Marchi P
      • Calzolari M
      • Solano A
      • Baroffio R
      • Gaggioli G
      Outpatient treatment of recent-onset atrial fibrillation with the "pill-in-the-pocket" approach.
      ,
      • Andrade JG
      • MacGillivray J
      • Macle L
      • Yao RJR
      • Bennett M
      • Fordyce CB
      • Hawkins N
      • Krahn A
      • Jue J
      • Ramanathan K
      • Tsang T
      • Gin K
      • Deyell MW
      Clinical effectiveness of a systematic "pill-in-the-pocket" approach for the management of paroxysmal atrial fibrillation.
      ,
      • Steinberg JS
      • Sadaniantz A
      • Kron J
      • Krahn A
      • Denny DM
      • Daubert J
      • Campbell WB
      • Havranek E
      • Murray K
      • Olshansky B
      • O'Neill G
      • Sami M
      • Schmidt S
      • Storm R
      • Zabalgoitia M
      • Miller J
      • Chandler M
      • Nasco EM
      • Greene HL
      Analysis of cause-specific mortality in the atrial fibrillation follow-up investigation of rhythm management (affirm) study.
      Sudden cardiac death, ventricular tachyarrhythmiaRare
      1:1 atrial flutterUnusual
      Bradyarrhythmia, sinus pause, heart blockUnusual
      HypotensionOccasional (mostly with IV)
      Chronic prevention
      • Crijns HJ
      • van Wijk LM
      • van Gilst WH
      • Kingma JH
      • van Gelder IC
      • Lie KI
      Acute conversion of atrial fibrillation to sinus rhythm: clinical efficacy of flecainide acetate. Comparison of two regimens.
      ,
      • Pietersen AH
      • Hellemann H
      Usefulness of flecainide for prevention of paroxysmal atrial fibrillation and flutter. Danish-Norwegian flecainide multicenter study group.
      ,
      • Anderson JL
      • Gilbert EM
      • Alpert BL
      • Henthorn RW
      • Waldo AL
      • Bhandari AK
      • Hawkinson RW
      • Pritchett EL
      Prevention of symptomatic recurrences of paroxysmal atrial fibrillation in patients initially tolerating antiarrhythmic therapy. A multicenter, double-blind, crossover study of flecainide and placebo with transtelephonic monitoring. Flecainide supraventricular tachycardia study group.
      ,
      • Clementy J
      • Dulhoste MN
      • Laiter C
      • Denjoy I
      • Dos Santos P
      Flecainide acetate in the prevention of paroxysmal atrial fibrillation: a nine-month follow-up of more than 500 patients.
      ,
      • Chimienti M
      • Cullen Jr., MT
      • Casadei G
      Safety of flecainide versus propafenone for the long-term management of symptomatic paroxysmal supraventricular tachyarrhythmias. Report from the Flecainide and Propafenone Italian Study (FAPIS) group.
      ,
      • Naccarelli GV
      • Dorian P
      • Hohnloser SH
      • Coumel P
      Prospective comparison of flecainide versus quinidine for the treatment of paroxysmal atrial fibrillation/flutter. The flecainide multicenter atrial fibrillation study group.
      Sudden cardiac death, ventricular tachyarrhythmiaRare
      1:1 atrial flutterUnusual
      Bradyarrhythmia, sinus pause, heart blockUnusual
      Worsened heart failureRare
      low asterisk Rare <1%, Unusual 1% to <3%, Occasional 3% to <10%, Frequent ≥10%.

      Recommendations for Flecainide Administration and Management

      There are a number of important benefits to early conversion and prevention of recurrent AF. The concept that “AF begets AF,” demonstrated in animal studies,
      • Wijffels MC
      • Kirchhof CJ
      • Dorland R
      • Allessie MA
      Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats.
      is attributed to atrial mechanical dysfunction and structural and electrical remodeling.
      • Nattel S
      Experimental evidence for proarrhythmic mechanisms of antiarrhythmic drugs.
      A greater AF burden is associated with a higher risk of cardiovascular complications, progression of paroxysmal AF to chronic AF, and a higher incidence of stroke.
      • Nattel S
      • Guasch E
      • Savelieva I
      • Cosio FG
      • Valverde I
      • Halperin JL
      • Conroy JM
      • Al-Khatib SM
      • Hess PL
      • Kirchhof P
      • De Bono J
      • Lip GY
      • Banerjee A
      • Ruskin J
      • Blendea D
      • Camm AJ
      Early management of atrial fibrillation to prevent cardiovascular complications.
      Additionally, it is generally accepted that anticoagulation is indicated when AF exceeds 48 hours in duration. Early conversion is an advantage not only to patients but to the healthcare system as well by reducing resource utilization and hospital admission rates.
      The choice among rhythm control strategies is a topic that has been discussed extensively elsewhere.
      • Van Gelder IC
      • Tuinenburg AE
      • Schoonderwoerd BS
      • Tieleman RG
      • Crijns HJ
      Pharmacologic versus direct-current electrical cardioversion of atrial flutter and fibrillation.
      ,
      • Hakalahti A
      • Biancari F
      • Nielsen JC
      • Raatikainen MJP
      Radiofrequency ablation vs. antiarrhythmic drug therapy as first line treatment of symptomatic atrial fibrillation: systematic review and meta-analysis.
      • Calkins H
      • Hindricks G
      • Cappato R
      • Kim Y-H
      • Saad EB
      • Aguinaga L
      • Akar JG
      • Badhwar V
      • Brugada J
      • Camm J
      • Chen P-S
      • Chen S-A
      • Chung MK
      • Cosedis Nielsen J
      • Curtis AB
      • Davies DW
      • Day JD
      • d'Avila A
      • de Groot NMS
      • Di Biase L
      • Duytschaever M
      • Edgerton Jr,
      • Ellenbogen KA
      • Ellinor PT
      • Ernst S
      • Fenelon G
      • Gerstenfeld EP
      • Haines DE
      • Haissaguerrre M
      • Helm RH
      • Hylek E
      • Jackman WJ
      • Jalife J
      • Kalman JM
      • Kautzner J
      • Kottkamp H
      • Kuck K-H
      • Kumagai K
      • Lee R
      • Lewalter T
      • Lindsay BD
      • Macle L
      • Mansour M
      • Marchlinski FE
      • Michaud GF
      • Nakagawa H
      • Natale A
      • Nattel S
      • Okumura K
      • Packer D
      • Pokushalov E
      • Reynolds RE
      • Sanders P
      • Scanavacca M
      • Schilling R
      • Tondo C
      • Tsao H-M
      • Verma A
      • Wilber DG
      • Yamane T
      2017 HRS/EHRA/ECAS/APHS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation.
      • January CT
      • Wann LS
      • Calkins H
      • Field ME
      • Chen LY
      • Furie KL
      • Cigarroa JE
      • Heidennreich PA
      • Cleveland Jr, JC
      • Murray KT
      • Ellinor PT
      • Shea JB
      • Ezekowitz MD
      • Tracy CM
      • Yancy CW
      2019 AHA/ACC/HRS Focused update of the 2014 AHA/ACC/HRS Guideline for the management of patietns with atrial fibrillation.
      • Packer DL
      • Mark DB
      • Robb RA
      • Monahan KH
      • Bahnson TD
      • Poole JE
      • Noseworthy PA
      • Rosenberg YD
      • Jeffries N
      • Mitchell B
      • Flaker GC
      • Plkushalov E
      • Romanov A
      • Bunch TJ
      • Noelker G
      • Ardashev A
      • Revishvili A
      • Wiber DJ
      • Cappato R
      • Kuck K-H
      • Hindricks G
      • Davies DW
      • Kowey PR
      • Naccarelli GV
      • Reiffel JA
      • Piccini JP
      • Silverstein AP
      • Al-Khalidi HR
      • Lee KL
      for the CABANA Investigators
      Effect of catheter ablation vs antiarrhythmic drug therapy on mortality, stroke, bleeding, and cardiac arrest among patients with atrial fibrillation. The CABANA randomized clinical trial.
      • Mark DM
      • Anstrom KJ
      • Sheng S
      • Piccini JP
      • Baloch KN
      • Monahan KH
      • Daniels MR
      • Bahnson TD
      • Poole JE
      • Rosenberg Y
      • Lee KL
      • Packer DL
      for the CABANA Investigators
      Effect of catheter ablation vs medical therapy on quality of life among patients with atria l fibrillation. The CABANA randomized clinical trial.
      • Albert CM
      • Bhatt DL
      Catheter ablation for atrial fibrillation. Lessons learned from CABANA.
      In general, treatment should be individualized, primarily based upon symptoms, quality of life, and patient preference. In patients with heart failure, there is clear evidence of combined mortality and rehospitalization benefit with cardiac ablation.
      • Packer DL
      • Mark DB
      • Robb RA
      • Monahan KH
      • Bahnson TD
      • Poole JE
      • Noseworthy PA
      • Rosenberg YD
      • Jeffries N
      • Mitchell B
      • Flaker GC
      • Plkushalov E
      • Romanov A
      • Bunch TJ
      • Noelker G
      • Ardashev A
      • Revishvili A
      • Wiber DJ
      • Cappato R
      • Kuck K-H
      • Hindricks G
      • Davies DW
      • Kowey PR
      • Naccarelli GV
      • Reiffel JA
      • Piccini JP
      • Silverstein AP
      • Al-Khalidi HR
      • Lee KL
      for the CABANA Investigators
      Effect of catheter ablation vs antiarrhythmic drug therapy on mortality, stroke, bleeding, and cardiac arrest among patients with atrial fibrillation. The CABANA randomized clinical trial.
      ,
      • Mourrouche NF
      • Brachmann J
      • Andresen D
      • Siebels J
      • Boersma L
      • Jordaens L
      • Merkely B
      • Polushalov E
      • Sanders P
      • Proff J
      • Schunkert H
      • Crhirst H
      • Vogt J
      • Bansch D
      for the CASTLE-AF investigators
      Catheter ablation for atrial fibrillation with heart failure.
      Importantly, the use of cardiac ablation and AADs are not mutually exclusive. For instance, in young patients who are good candidates for both flecainide and cardiac ablation, acute conversion and a trial of chronic suppression using flecainide has utility as initial therapy while evaluating AF frequency and symptoms, during the postablation blanking period,
      • Kaitani K
      • Inoue K
      • Kobori A
      • Nakazawa Y
      • Ozawa T
      • Kurotobi T
      • Morishima I
      • Miura F
      • Watanabe T
      • Masuda M
      • Naito M
      • Fujimoto H
      • Nishida T
      • Furukawa Y
      • Shirayama T
      • Tanaka M
      • Okajima K
      • Yao T
      • Egami Y
      • Satomi K
      • Noda T
      • Miyamoto K
      • Haruna T
      • Kawaji T
      • Yoshizawa T
      • Toyota T
      • Yahata M
      • Nakai K
      • Sugiyama H
      • Higashi Y
      • Ito M
      • Horie M
      • Kusano KF
      • Shimizu W
      • Kamakura S
      • Morimoto T
      • Kimura T
      • Shizuta S
      Efficacy of antiarrhythmic drugs short-term use after catheter ablation for atrial fibrillation (EAST-AF) trial.
      • Roux JF
      • Zado E
      • Callans DJ
      • Garcia F
      • Lin D
      • Marchlinski FE
      • Bala R
      • Dixit S
      • Riley M
      • Russo AM
      • Hutchinson MD
      • Cooper J
      • Verdino R
      • Patel V
      • Joy PS
      • Gerstenfeld EP
      Antiarrhythmics after ablation of atrial fibrillation (5A study).
      • Duytschaever M
      • Demolder A
      • Phlips T
      • Sarkozy A
      • El Haddad M
      • Taghji P
      • Knecht S
      • Tavernier R
      • Vandekerckhove Y
      • De Potter T
      Pulmonary vein isolation with vs. without continued antiarrhythmic drug treatment in subjects with recurrent atrial fibrillation (POWDER-AF): results from a multicentre randomized trial.
      ,
      • Stabile G
      • Bertaglia E
      • Senatore G
      • De Simone A
      • Zoppo F
      • Donnici G
      • Turco P
      • Pascotto P
      • Fazzari M
      • Vitale DF
      Catheter ablation treatment in patients with drug-refractory atrial fibrillation: a prospective multi-centre, randomized, controlled study (catheter ablation for the cure of atrial fibrillation study).
      and for postablation recurrences.
      For patients with AF and minimal or no structural heart disease, flecainide has clear clinical utility for the early termination of AF and for the prevention of AF recurrences. Both IV and oral flecainide have demonstrated the highest efficacy rates for acute pharmacologic conversion of recent-onset AF, with a safety profile comparable with or better than other agents. For selected patients, the PiP approach can, in addition to rapid conversion of AF, obviate the need for emergency room visits.
      • Alboni P
      • Botto GL
      • Baldi N
      • Luzi M
      • Russo V
      • Gianfranchi L
      • Marchi P
      • Calzolari M
      • Solano A
      • Baroffio R
      • Gaggioli G
      Outpatient treatment of recent-onset atrial fibrillation with the "pill-in-the-pocket" approach.
      ,
      • Andrade JG
      • MacGillivray J
      • Macle L
      • Yao RJR
      • Bennett M
      • Fordyce CB
      • Hawkins N
      • Krahn A
      • Jue J
      • Ramanathan K
      • Tsang T
      • Gin K
      • Deyell MW
      Clinical effectiveness of a systematic "pill-in-the-pocket" approach for the management of paroxysmal atrial fibrillation.
      ,
      • Alboni P
      • Botto GL
      • Boriani G
      • Russo G
      • Pacchioni F
      • Iori M
      • Pasanisi G
      • Mancini M
      • Mariconti B
      • Capucci A
      Intravenous administration of flecainide or propafenone in patients with recent-onset atrial fibrillation does not predict adverse effects during 'pill-in-the-pocket' treatment.
      Current medical guidelines recommend the use of flecainide as a first-line agent for pharmacologic conversion of AF in patients without structural heart disease. Amiodarone is a second-line choice because of lower efficacy rates and delayed time to conversion, primarily for patients with structural heart disease.
      For the prevention of AF recurrence in patients with paroxysmal or persistent AF and no or minimal structural heart disease, flecainide has demonstrated efficacy and safety equivalent to that of propafenone, sotalol, dronedarone, and dofetilide. Current guidelines
      • January CT
      • Wann LS
      • Alpert JS
      • Calkins H
      • Cigarroa JE
      • Cleveland Jr., JC
      • Conti JB
      • Ellinor PT
      • Ezekowitz MD
      • Field ME
      • Murray KT
      • Sacco RL
      • Stevenson WG
      • Tchou PJ
      • Tracy CM
      • Yancy CW
      2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the heart rhythm society.
      state that there is no clear preferred choice of AAD to use for this indication, but emphasize that amiodarone should be considered a second-line agent due to its greater long-term toxicity. Caution should be exercised in prescribing flecainide to patients with known sinus, AV node, or infranodal conduction delays, and flecainide should be avoided entirely in patients with myocardial ischemia or infarction, coronary artery disease, LV dysfunction, or congestive heart failure. The following of AF treatment guidelines by practitioners remain a significant issue. The ORBIT-AF study
      • Barnett AS
      • Kim S
      • Fonarow GC
      • Thomas LE
      • Reiffel JA
      • Allen LA
      • Freeman JV
      • Naccarelli G
      • Mahaffey KW
      • Go AS
      • Kowey PR
      • Ansell JE
      • Gersh BJ
      • Hylek EM
      • Peterson ED
      • Piccini JP
      Treatment of atrial fibrillation and concordance with the American Heart Association/American College of Cardiology/Heart Rhythm Society guidelines: findings from ORBIT-AF (outcomes registry for better informed treatment of atrial fibrillation).
      sought to evaluate concordance with current guidelines in a registry of 176 sites in the United States. The guideline found to have the lowest concordance of only 44% stipulates that flecainide or propafenone should not be used in patients with coronary artery disease. The guideline with the next lowest concordance of 65% stipulates that amiodarone should only be used as first-line therapy in patients with heart failure, LV hypertrophy, or LV dysfunction.

      Recommendations for Dosing and Administration

      Recommendations are summarized in Table 2. Blood pressure should be monitored due to the negative inotropic properties of the drug. Continuous ECG monitoring is needed to evaluate changes in QRS duration, the conversion of AF to atrial flutter with 1:1 AV conduction, and postconversion sinus pauses. For appropriately selected patients who have received an initial oral loading dose under monitored conditions in whom conversion is successful and there are no adverse events, flecainide can be safely prescribed for patient self-administration at the onset of recurrent AF.
      • Alboni P
      • Botto GL
      • Baldi N
      • Luzi M
      • Russo V
      • Gianfranchi L
      • Marchi P
      • Calzolari M
      • Solano A
      • Baroffio R
      • Gaggioli G
      Outpatient treatment of recent-onset atrial fibrillation with the "pill-in-the-pocket" approach.
      ,
      • Andrade JG
      • MacGillivray J
      • Macle L
      • Yao RJR
      • Bennett M
      • Fordyce CB
      • Hawkins N
      • Krahn A
      • Jue J
      • Ramanathan K
      • Tsang T
      • Gin K
      • Deyell MW
      Clinical effectiveness of a systematic "pill-in-the-pocket" approach for the management of paroxysmal atrial fibrillation.
      For patients in whom the ability to self-diagnosis AF is questionable, it is recommended that the diagnosis be confirmed with a wearable, portable, or implanted ECG device.
      Table 2Flecainide dosing and administration
      IndicationDose rangeComments
      Acute conversion
       Oral200-300 mg, single administration
      • January CT
      • Wann LS
      • Alpert JS
      • Calkins H
      • Cigarroa JE
      • Cleveland Jr., JC
      • Conti JB
      • Ellinor PT
      • Ezekowitz MD
      • Field ME
      • Murray KT
      • Sacco RL
      • Stevenson WG
      • Tchou PJ
      • Tracy CM
      • Yancy CW
      2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the heart rhythm society.
      ,
      • Kirchhof P
      • Benussi S
      • Kotecha D
      • Ahlsson A
      • Atar D
      • Casadei B
      • Castella M
      • Diener HC
      • Heidbuchel H
      • Hendriks J
      • Hindricks G
      • Manolis AS
      • Oldgren J
      • Popescu BA
      • Schotten U
      • Van Putte B
      • Vardas P
      • Agewall S
      • Camm J
      • Baron Esquivias G
      • Budts W
      • Carerj S
      • Casselman F
      • Coca A
      • De Caterina R
      • Deftereos S
      • Dobrev D
      • Ferro JM
      • Filippatos G
      • Fitzsimons D
      • Gorenek B
      • Guenoun M
      • Hohnloser SH
      • Kolh P
      • Lip GY
      • Manolis A
      • McMurray J
      • Ponikowski P
      • Rosenhek R
      • Ruschitzka F
      • Savelieva I
      • Sharma S
      • Suwalski P
      • Tamargo JL
      • Taylor CJ
      • Van Gelder IC
      • Voors AA
      • Windecker S
      • Zamorano JL
      • Zeppenfeld K
      2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with eacts.
      First treatment under medical supervision

      Anticipate maximum effect and conversion after 2-4 hours monitor BP, ECG
       Intravenous1.5-2 mg/kg, maximum 150 mg, infused over 10 min
      • Kirchhof P
      • Benussi S
      • Kotecha D
      • Ahlsson A
      • Atar D
      • Casadei B
      • Castella M
      • Diener HC
      • Heidbuchel H
      • Hendriks J
      • Hindricks G
      • Manolis AS
      • Oldgren J
      • Popescu BA
      • Schotten U
      • Van Putte B
      • Vardas P
      • Agewall S
      • Camm J
      • Baron Esquivias G
      • Budts W
      • Carerj S
      • Casselman F
      • Coca A
      • De Caterina R
      • Deftereos S
      • Dobrev D
      • Ferro JM
      • Filippatos G
      • Fitzsimons D
      • Gorenek B
      • Guenoun M
      • Hohnloser SH
      • Kolh P
      • Lip GY
      • Manolis A
      • McMurray J
      • Ponikowski P
      • Rosenhek R
      • Ruschitzka F
      • Savelieva I
      • Sharma S
      • Suwalski P
      • Tamargo JL
      • Taylor CJ
      • Van Gelder IC
      • Voors AA
      • Windecker S
      • Zamorano JL
      • Zeppenfeld K
      2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with eacts.
      Anticipate maximum effect and conversion at end of infusion Monitor BP closely, ECG
      Chronic prevention50-200 mg bidStart at 100 mg bid, adjust after 4 days.

      Monitor ECG, check QRS duration before dose escalation
      For the chronic prevention of AF recurrence, it is not necessary to hospitalize the patient for initiation of therapy. However, it is important to obtain 12-lead ECGs at baseline, at steady state and before increasing the dosage. In addition, patients should have an echocardiogram to document the presence of normal LV function and exercise stress testing to rule out the presence of inducible myocardial ischemia before the initiation of chronic oral therapy. The most commonly used doses are 100 to 150 mg bid.
      • Kirchhof P
      • Benussi S
      • Kotecha D
      • Ahlsson A
      • Atar D
      • Casadei B
      • Castella M
      • Diener HC
      • Heidbuchel H
      • Hendriks J
      • Hindricks G
      • Manolis AS
      • Oldgren J
      • Popescu BA
      • Schotten U
      • Van Putte B
      • Vardas P
      • Agewall S
      • Camm J
      • Baron Esquivias G
      • Budts W
      • Carerj S
      • Casselman F
      • Coca A
      • De Caterina R
      • Deftereos S
      • Dobrev D
      • Ferro JM
      • Filippatos G
      • Fitzsimons D
      • Gorenek B
      • Guenoun M
      • Hohnloser SH
      • Kolh P
      • Lip GY
      • Manolis A
      • McMurray J
      • Ponikowski P
      • Rosenhek R
      • Ruschitzka F
      • Savelieva I
      • Sharma S
      • Suwalski P
      • Tamargo JL
      • Taylor CJ
      • Van Gelder IC
      • Voors AA
      • Windecker S
      • Zamorano JL
      • Zeppenfeld K
      2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with eacts.
      Flecainide is usually initiated at 100 mg bid, though a minority of patients will respond to doses as low as 50 mg BID. The dose may be escalated based on QRS duration prolongation of less than 50% over baseline after 4 days of administration.

      Concomitant Therapy With Beta-Blocking Agents

      The concomitant administration of beta-blocking therapy is recommended for both acute conversion and chronic AF suppression to reduce the potential for rapid AV node conduction should flecainide convert AF to atrial flutter.
      • January CT
      • Wann LS
      • Alpert JS
      • Calkins H
      • Cigarroa JE
      • Cleveland Jr., JC
      • Conti JB
      • Ellinor PT
      • Ezekowitz MD
      • Field ME
      • Murray KT
      • Sacco RL
      • Stevenson WG
      • Tchou PJ
      • Tracy CM
      • Yancy CW
      2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the heart rhythm society.
      However, β blockers should not be prescribed in patients with advanced sinus node dysfunction or abnormalities in AV node conduction. Beta blockers alone are rarely effective in the acute conversion of AF or the prevention of recurrence in patients without heart failure.
      • Capucci A
      • Pianger L
      • Ricciotti J
      • Gabrielli D
      • Guerra F
      Flecainide-metoprolol combination reduces atrial fibrillation clinical recurrences and improves tolerability at 1-year follow-up in persistent symptomatic atrial fibrillation.

      Conclusions

      Flecainide acetate is highly effective for the acute termination of recent onset AF and is moderately effective for the chronic suppression of AF. The drug has an excellent safety profile when administered to patients with minimal or no structural heart disease. Flecainide is more effective and safer than other AADs for the acute conversion of patients in AF. Despite its favorable safety and efficacy profile in patients with no or minimal structural heart disease, flecainide is underutilized due to misconceptions about the risk for ventricular proarrhythmia, a safety concern that has not been observed. Pharmacologic conversion of episodic AF with flecainide should be considered in eligible patients to accomplish rhythm control without chronic drug exposure and to avoid the necessity for electrical conversion. The ideal pharmacologic approach is one that appropriately selected patients can self-administer to terminate AF rapidly and safely. The PiP approach avoids the need for these patients to seek emergency care. With the recent availability of wearable, handheld, and implanted ECG monitors with accurate automated AF detection, the PiP approach with its inherent advantages has the potential to be more widely employed in clinical practice.

      Disclosures

      Debra Echt reports receiving consulting income and stock options from InCarda Therapeutics. Jeremy Ruskin reports receiving honoraria from InCarda Therapeutics, Acesion Pharma, Correvio, Huya Bioscience, and Pfizer.

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