Next Article in Journal
Efficacy and Safety of Intravenous Ferric Carboxymaltose in Patients with Postoperative Anemia Following Same-Day Bilateral Total Knee Arthroplasty: A Randomized Controlled Trial
Previous Article in Journal
Thyroid Cancer Stem-Like Cells: From Microenvironmental Niches to Therapeutic Strategies
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JCM
Volume 10
Issue 7
10.3390/jcm10071456
jcm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Flecainide How and When: A Practical Guide in Supraventricular Arrhythmias

by
Carlo Lavalle
1,*,
Michele Magnocavallo
1,
Martina Straito
1,
Luca Santini
2,
Giovanni Battista Forleo
3,
Massimo Grimaldi
4,
Roberto Badagliacca
1,
Luigi Lanata
5 and
Renato Pietro Ricci
6
1
Department of Cardiovascular, Respiratory, Nephrological, Anesthesiological and Geriatric Sciences, “Sapienza” University of Rome, Policlinico Umberto I, 00161 Rome, Italy
2
Department of Cardiology, Ospedale GB Grassi, 00121 Ostia, Italy
3
Department of Cardiology, Azienda Ospedaliera-Universitaria “Luigi Sacco”, 20057 Milan, Italy
4
Department of Cardiology, Ospedale Generale Regionale F. Miulli, Acquaviva delle Fonti, 70021 Bari, Italy
5
Medical Affairs Department, Dompé Farmaceutici SpA, 20057 Milan, Italy
6
CardioArrhythmology Center, 00161 Rome, Italy
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2021, 10(7), 1456; https://doi.org/10.3390/jcm10071456
Submission received: 17 February 2021 / Revised: 19 March 2021 / Accepted: 29 March 2021 / Published: 2 April 2021
(This article belongs to the Section Cardiology)
Browse Figures
Versions Notes

Abstract

:
Transcatheter ablation was increasingly and successfully used to treat symptomatic drug refractory patients affected by supraventricular arrhythmias. Antiarrhythmic drug treatment still plays a major role in patient management, alone or combined with non-pharmacological therapies. Flecainide is an IC antiarrhythmic drug approved in 1984 from the Food and Drug Administration for the suppression of sustained ventricular tachycardia and later for acute cardioversion of atrial fibrillation and for sinus rhythm maintenance. Currently, flecainide is mostly used for sinus rhythm maintenance in atrial fibrillation (AF) patients without structural cardiomyopathy although recent studies enrolling different patient populations have demonstrated a good effectiveness and safety profile. How should we interpret the results of the CAST after the latest evidence? Is it possible to expand the indications of flecainide, and therefore, its use? This review aims to highlight the main characteristics of flecainide, as well as its optimal clinical use, delineating drug indications and contraindications and appropriate monitoring, based on the most recent evidence.

1. Introduction

In the recent years several non-pharmacological therapies, in particular transcatheter ablation, have been increasingly and successfully used to treat symptomatic drug refractory patients affected by supraventricular arrhythmias (SVT), especially atrial fibrillation (AF) [1,2]. Nevertheless, antiarrhythmic drug treatment still plays a major role in patient management, alone or combined with non-pharmacological therapies.
Flecainide is an IC antiarrhythmic drug approved in 1984 from the Food and Drug Administration for the suppression of sustained ventricular tachycardia (VT) and later for AF acute cardioversion and for sinus rhythm maintenance.
Currently, flecainide is mostly administered for sinus rhythm maintenance and, having regard to its effectiveness and safety profile, it may be considered underused [3,4,5]. The CAST study published in 1991 has strongly conditioned and limited the actual use of flecainide in clinical practice. The study was prematurely dismissed due to excess of mortality among patients treated with IC agents with a significant greater number of death and cardiac arrest due to arrhythmia than patients treated with placebo [6]. It is necessary to underline that many patients who died during the study had depressed left ventricular ejection fraction and intraventricular (IV) impulse disturbance, two conditions currently contraindicating the use of flecainide.
Differently from the CAST results, recent studies, enrolling different patient populations, have demonstrated a good safety profile of the drug combined with good clinical efficacy. This review aims to highlight the main characteristics of flecainide, as well as its optimal clinical use, delineating drug indications and contraindications and appropriate monitoring, based on the most recent evidence.

2. Flecainide Pharmacology

2.1. Pharmacokinetics

Flecainide is nearly completely absorbed from the gastrointestinal tract (bioavailability: 85–90%) [7] reaching serum concentration peak in 1–3 h. Concentration from 0.2 to 1 mcg/mL provide the greatest therapeutic benefit whereas value higher than 0.7 to 1 mcg/mL have been associated with increased adverse effects [8]. The apparent volume of distribution is wide, about 40% of drug was binded to plasma proteins [9]. Flecainide is metabolized in the liver via cytochrome (CYP2D6 and CYP1A2), and then excreted in the urine. About 30% of an orally administered dose escapes liver metabolism and is excreted in the urine unchanged [7]. The half-life is about 20 h (range: 12–27 h) and it may be prolonged until 70 h in patients with heart failure, renal disease (creatinine clearance < 50 mL/min) and liver disease [10].

2.2. Pharmacodynamics

Flecainide works blocking the open-state fast inward Na+ channel Nav 1.5 in a rate- and voltage-dependent manner, reducing the rise of phase 0 of the action potential especially in His-Purkinje tissue and ventricular muscle [10,11,12]. Furthermore, flecainide at low dose inhibits rapid component of the delayed rectifier K+ current (IKr) and at higher concentrations inhibits Kito channels [13,14,15]. Overall, flecainide prolongs the duration of action potential and effective refractory period in ventricular fibers while they are both shortened in the Purkinje system, an effect probably consistent with Na+ channel blockade [14,15,16]. The drug also inhibits ryanodine receptor 2 reducing calcium sparks and thus arrhythmogenic calcium currents [17]. Moreover, flecainide reduces Na+ and Ca2+ inflow in myocardial cells and exerts a negative inotropic effect reducing cardiac output and stroke volume, especially for patients with coronary artery disease or left ventricular (LV) disfunction [18,19,20,21,22,23].

2.3. Controlled Release Flecainide

Controlled release flecainide allows a once-a-day administration. The pharmacokinetic profile is characterized by a reduced and delayed reaching maximum concentration and lower fluctuations of plasma concentrations during a dosing interval compared with immediate-release form. Serum concentration peak is reached in 26 h, the steady state plasma level is reached after 4–5 days ranging from 0.27 to 0.33 mcg/mL far from plasma level at risk of side effects [24,25]. Controlled release form improves treatment compliance and reduces the risk of side effects and interactions with other drugs preserving clinical benefit.

3. What Does “Structural Heart Disease” Mean? A Critical View

Based on the findings of the CAST trial, it reasonable consider how flecainide exerts a proarrhythmic effect in patients with recent acute myocardial infarction (AMI) and/or LV disfunction [6]. CAST patients were eligible for enrollment six days to two years after AMI if they had an average of six or more premature ventricular contraction per hour and a LV function < 55%. Unfortunately, the study was prematurely dismissed due to an increased proarrhythmic risk among patients treated with IC agents than patients treated with placebo [6]. For this reason, the European Society of Cardiology in 2020 Guidelines for the management of AF contraindicated the use of flecainide in patients affected by structural heart disease [1]. Despite this, a critical appraisal of the CAST trial is necessary; firstly, only in 17% of the enrolled patients a complete revascularization was performed, a clinical scenario now less and less frequent [6]. Moreover, a CAST sub analyses showed that during the late post-myocardial infarction period, therapy with flecainide was associated with a steeper increase in death/cardiac arrest rate in the non-Q-AMI group than in the Q-AMI group [26]. Lastly, 48% of CAST patients had severe left ventricular dysfunction. All these patients could have an augmented pro-arrhythmic risk, and therefore, it may be reasonable to perform a more detailed stratification of ischemic heart disease (Is the arrhythmia scar-related? Is there a critical coronary stenosis?).
Practice guidelines extended the findings of CAST to all IC agents and structural heart disease such as congenital heart disease, valvular or significant myocardial heart disease, although evidence are scarce. In recent years, some observational studies have shown promising results on the use of flecainide in patients with non-ischemic structural heart disease.
Flecainide can be useful in long QT syndrome type 3, an arrhythmogenic cardiomyopathy caused by gain-of-function mutations in the SCN5A-encoded Nav1.5 sodium channel involving a pathological increase in late sodium current and, consequently, prolonging QTc [27,28,29]. Long-term flecainide therapy shortened QTc interval and is relatively safe and effective in patients affected by Long QT syndrome type 3; in particular, no cardiac events occurred among patients who were fully compliant with flecainide administration while in patients who discontinued therapy a cardiac event has been observed in 30% of them [30].
Hyman et al., evaluated the safety and efficacy of premature ventricular contraction suppression with Class IC antiarrhythmic drugs in 20 patients with extrasystole-induced cardiomyopathy [31,32]. A satisfactory premature ventricular contraction suppression rate was obtained, and no sustained ventricular arrhythmias or sudden cardiac deaths were reported [31]. Moreover, the addition of flecainide in combination with sotalol or metoprolol demonstrated to be safe and effective in controlling recurrent arrhythmias in patients with arrhythmogenic right ventricular cardiomyopathy [33]. Furthermore, in patients with AF and left ventricular hypertrophic (ventricular wall thickness ≥ 1.4 cm) treatment with class IC agents did not have higher mortality compared with patients treated with amiodarone [34].
Data available are still incomplete and further studies are recommended. In the meanwhile, the criteria listed in the Figure 1 may drive the clinical choice in individual patients.

4. Safety Data

Considering the pharmacodynamic effects of flecainide, is not surprising that it prolongs the PR (17–29%), the QT (4–11%) interval and the QRS complex (11–27%) [10]. It must be considered that most of the QT prolongation is due to the widening of the QRS complex, so that the JT interval and the rate-corrected QT interval remain unchanged or slightly increase (3–8%) [35,36]. An important proarrhythmic effect (3–5% of cases) is conversion of AF in atrial flutter with slow atrial rate (flutter IC) that may result in 1:1 atrioventricular (AV) conduction with high ventricular response and large QRS [37,38]. Concomitant therapy with AV blockade (β-blockers, verapamil, diltiazem, digoxin) could avoid this pro-arrhythmic effect [38]. Moreover, QRS duration (>120 ms), advanced kidney failure (creatinine clearance < 30 mL/min/1.73 m2), electrolyte abnormalities increase pro-arrhythmic effect of flecainide and should be carefully monitored [38].
Overall, a metanalysis of 122 prospective studies demonstrated that in patients with SVT and no significant LV impairment, proarrhythmic events were significantly lower with flecainide than placebo (2.7% vs. 4.8%; p < 0.001) without significant differences in terms of total mortality [39].
Lastly, due to flecainide effect on the Na channels, the major non-cardiac side effects are related to its anesthetic properties; the most frequent are dizziness and visual disturbances while headache, gastrointestinal disturbances and metallic taste are rare [40].

4.1. Patients with Pacemaker and Implantable Cardioverter Defibrillator

In the last few years, use of implantable cardiac electronic devices has become increasingly common and at least 50% of these patients may develop AF requiring antiarrhythmic therapy [41]. Early raised issue of negative effects of flecainide on pacing and defibrillation threshold are not a concern anymore due to progress in lead technology, automatic setting of pacemaker output and use of biphasic high energy shocks [42]. On the other hand, antiarrhythmic drugs may enhance rhythm control in patients with pacemaker and AF in a hybrid approach [43]. Boriani demonstrated that use of flecainide was associated with lengthened atrial tachycardia cycles and consequently higher atrial anti-tachycardia pacing efficacies [43]. This effect was probably correlated either to prolongation of atrial wavelength or widening of the temporal excitable gap during AF. Atrial anti-tachycardia pacing cannot terminate AF, but it can terminate atrial tachycardia episodes that are the first step in AF disease history [44,45]. For these reasons, flecainide administration could increase atrial anti-tachycardia pacing efficacy that represented an independent predictor of permanent or persistent AF risk.
Otherwise, in patients with VT and implantable cardioverter defibrillator, flecainide may induce lengthening of cycle length of VT due to IV conduction delay resulting in out-of-window VT which will not be treated by defibrillator. On the contrary, in case of SVT, enlargement of QRS morphology induced by flecainide may result in inappropriate shocks [46].

4.2. Patients with Sinus Bradycardia and/or AV-IV Conduction Disturbances

The effect of flecainide on the healthy sinoatrial node is irrelevant: sinus rate, sinoatrial conduction and sinus node recovery times are usually not affected by long-term drug administration [47]. On the other hand, administration of flecainide in patients affected by sinus node dysfunction or atrial conduction disorders depresses sinus activity and increases significantly the corrected sinus node recovery time [48]. Due to dose-dependent prolongation of AV and IV conduction, unless a cardiac stimulator is available for emergency cardiac stimulation, flecainide should not be administered in patients with second degree or superior AV block, right or left bundle branch block [8,10,49].
Interaction between antiarrhythmic drugs and autonomic nervous system is very different; while flecainide exerts a mild vagolytic effect, other anti-arrhythmic drugs such as propafenone or amiodarone have anti-adrenergic effect [42,50]. For this reason, flecainide could be the first drug therapy in the maintenance treatment of SVT in patients with physiological bradycardia.

4.3. Flecainide in Association with Other Antiarrhythmic Drugs

In some AF patients, a combined anti-arrhythmic strategy may be necessary to maintain sinus rhythm and reduce symptomatic AF recurrences. Flecainide in combination with amiodarone is interesting, not only because it may be effective when the efficacy of each is inadequate as a single-drug therapy, but also because it may allow a reduction in their respective dosages and side effects [51,52,53].
Overall, beta blockers are the most used antiarrhythmic drug in association with flecainide. Capucci et al. have demonstrated that combination therapy with flecainide and metoprolol significantly reduced recurrences of AF at 1-year follow-up when compared with flecainide alone [54,55]. The association of flecainide with other AV blockers like digoxin is less frequent; close monitoring of serum digoxin concentrations is recommended because it could increase by 15–19% with co-administration of flecainide [56,57]. In the same way, the combination of flecainide with verapamil should be use with caution because of potential additive effects on myocardial contractility and on AV conduction [57].

4.4. Flecainide in Pregnancy and in Pediatric Population

ESC guidelines recommend avoiding any antiarrhythmic drug during the first trimester of pregnancy [58]. Overall, there is no clear evidence of the teratogenic effect of flecainide. Therefore, it could be used for the treatment of fetal arrhythmias [52].
The treatment of SVTs in the pediatric population is more complex: the immaturity of the cardiac structures can lead to the development of arrhythmias which may resolve spontaneously within the first year [59,60]; moreover, due to the different pharmacokinetics and pharmacodynamics characteristics, administration of drugs in children must be exercised in the extreme caution [61,62,63].

5. Vademecum for the Management of Flecainide

A 12-lead electrocardiogram is mandatory before starting the therapy; symptomatic bradycardia, second degree or superior AV block, QRS > 120 ms or Brugada syndrome contraindicate the flecainide prescription. It’s reasonable to perform an echocardiogram to evaluate LV function and exercise stress testing in high-risk patients to exclude the possibility of coronary artery disease. It is strongly suggested to test the first dose under medical observation. The minimum effective plasma concentration of flecainide is about 200 ng/mL while optimal range is between 200 ng/mL and 400 ng/mL [64]. This plasma concentration leads to a QRS prolongation of about 10 ms; a prolongation of 40 ms or more is associated to an increased probability of cardiovascular adverse effects [64].
A practical approach to flecainide dose ranging, in absence of kidney failure, is as follows (see also—Figure 2):
  • Exclude contraindications (structural heart disease, symptomatic bradycardia, second degree or superior AV block, QRS > 120 ms or Brugada syndrome).
  • Record an ECG with a paper speed of 50 mm/sec and calculate the QRS duration (1 mm = 20 ms).
  • Administer a loading oral dose of 250 mg (200 mg if the weight is lower than 70 kg).
  • At plasma concentration peak, after 90–120 min, evaluate blood pressure and record an ECG with a paper speed of 50 mm/s and calculate the QRS duration.
  • Rule out Brugada ECG pattern and AV block.
    • If the QRS duration is increased within 20 ms, prescribe 100 mg twice daily or 200 mg once daily. Check again the ECG after one week.
    • If the QRS duration is increased between 20 and 40 ms or is wider than 120 ms, prescribe 50 mg twice daily or 100 mg once daily. Check again the ECG after 5 days.
    • If the QRS duration is increased more than 40 ms or is wider than 130 ms, or a Brugada pattern is detected, consider flecainide contraindicated in that patient.
Jcm 10 01456 g002 550
Figure 2. Flowchart for administration of flecainide. * Loading oral dose of 200 mg is recommended if the weight is lower than 70 kg.
Figure 2. Flowchart for administration of flecainide. * Loading oral dose of 200 mg is recommended if the weight is lower than 70 kg.
Jcm 10 01456 g002
The proarrhythmic risk and other serious adverse effects can be minimized by keeping strict adherence to treatment, limiting the number of drugs prescribed, starting the treatment at low doses that will be increased on the basis of the patient’s response and comorbidities. The recommended dose of flecainide in SVTs are reported in Table 1.
ECG monitoring is suggested in case of drug adjustments or concomitant therapy with other antiarrhythmic drugs, particularly in the elderly and in patients with hepatic and/or renal dysfunction. For appropriately selected patients who have received an initial oral loading dose under monitored conditions, a “pill in the pocket” strategy could be suggested for patient self-administration at the onset of recurrent AF. A practical guide on the management of adverse events due to flecainide is provided in Table 2.

6. Flecainide in Atrial Fibrillation

6.1. Flecainide in Converting Recent Onset of Atrial Fibrillation

In the acute setting, flecainide is very effective in restoring sinus rhythm with high percentages of success, greater than both propafenone and amiodarone as well as with shorter cardioversion times [65,66,67,68,69,70,71,72,73] (Table 3).
Flecainide is also effective when administered orally; an Italian multicenter study evaluated the efficacy and safety of “pill in the pocket” therapy with flecainide or propafenone in 210 of 268 hospitalized patients for AF onset by less than 48 h who were effectively treated in hospital setting [74]. The pill in the pocket strategy was effective in 94% of patients with an average resolution time of 113 min; adverse events were 7% and in only one case was a high ventricular response atrial flutter. The “pill in the pocket” strategy is currently indicated as a therapeutic strategy in selected patients, with recent onset of AF without significant structural or ischemic heart disease or pro-arrhythmic conditions as Brugada syndrome [1,75,76] and able to self-diagnose AF in which could be avoided the emergency room admission [77,78,79].

6.2. Pre-Treatment with Flecainide in Patients Undergoing Electrical Cardioversion

There are strong evidence supporting the use of flecainide prior cardioversion: in a prospective, randomized, double-blinded study were enrolled 54 patients with persistent AF scheduled to electrical cardioversion. Patients that received flecainide before cardioversion had a more successful first shock in comparison to placebo (65% vs. 30% respectively, p = 0.04) [80]. Moreover, Boriani et al. demonstrated that flecainide reduces atrial defibrillation threshold increasing procedure success rate in patients with persistent AF [81]. Overall, a pre-treatment with flecainide should be considered in patients at high risk of failure for electrical cardioversion (left atrium dilatation, previous cardioversion failure).

6.3. Flecainide in Long Term Rhythm Control

The maintenance of the sinus rhythm is more advantageous than rate-control both in terms of survival and quality of life [82,83,84,85,86,87,88]. According the 2020 ESC Guidelines, catheter ablation is indicated after one failed/intolerant treatment with class I or III drug or to improve symptoms of AF recurrences in patients with paroxysmal and persistent AF [1,89,90]. A rhythm control strategy based on drug administration could be preferable when catheter ablation was hazardous. In this scenario, amiodarone could be considered the most effective in the maintenance of sinus rhythm, but for the high adverse effect rate, a lot of patients withdraw prematurely the treatment [91,92,93]. Otherwise, several studies showed as flecainide was effective in reducing the recurrences of paroxysmal AF and safer when compared to other antiarrhythmic drugs, including amiodarone (Table 4). To reduce adverse event rate a flecainide short-term treatment should be considered for patients with AF who are at increased risk for complications and amiodarone is contraindicated [94]. Indeed, the randomized Flec-SL blinded trial compare flecainide (200–300 mg per day) for four weeks (short-term treatment) with flecainide for six months (long-term treatment) in patients with persistent AF after an effective cardioversion; short-term treatment after cardioversion is less effective than long-term treatment, but in any case, it can prevent most recurrences of AF [92].

7. Flecainide in Other Supraventricular Arrhythmias

Although procainamide is the drug of choice in patients with atrio-ventricular reentrant tachycardia, flecainide is effective and safe by directly slowing or blocking conduction over the Na+ dependent fast accessory pathway [58]. Flecainide is efficient in approximately 85% to 90% of patients, with 30% reporting an absence of tachycardia [98,99]. Flecainide is also successful in terminating pre-excited AF in hemodynamically stable patients with high-ventricular response and should be considered in the prevention of SVT in pregnant patients with the Wolff–Parkinson–White syndrome [100,101]. However, the gold standard for patients with symptomatic recurrences remains catheter ablation and pharmacological therapy would be reserved for cases where ablation is not desired or feasible [58].
Atrial premature beats and atrial tachycardia are a common finding in older individuals and frequent atrial premature beats are considered a marker of atrial electrical vulnerability and predictors of incident AF [102,103]. The use of flecainide is effective in addition to optimization of medical therapy when catheter ablation was not feasible [104]. Data to support the recommendation for flecainide for maintenance of sinus rhythm in patients with atrial flutter is derived from trials that pooled patients with AF and atrial flutter [105,106]. It is no longer recommended for acute cardioversion of macro-re-entrant atrial arrhythmias and no longer mentioned for chronic therapy of typical atrial flutter [58]. Recommended dose of flecainide in SVTs is reported in Table 1.

8. Conclusions

Flecainide is highly effective for the acute termination and for the chronic suppression of AF. An excellent safety profile is described in patients with minimal or no signs of structural heart disease while mounting promising evidence will be available in patients with cardiomyopathy. The “pill in the pocket” approach reduces the need for emergency care and should be more widely employed in patients to achieve rhythm control without long term antiarrhythmic drug exposure and to avoid the necessity for electrical conversion. A 12-lead ECG is required before starting therapy while ECG monitoring is suggested in case of drug adjustments or concomitant therapy with other antiarrhythmic drugs, particularly in the elderly and in patients with hepatic and/or renal dysfunction.

Author Contributions

Conceptualization, C.L.; L.S.; G.B.F.; M.G.; R.B.; R.P.R.; methodology, C.L.; L.S.; G.B.F.; M.G.; R.B.; R.P.R.; writing—original draft preparation, C.L.; M.M.; M.S.; M.G.; writing—review and editing, C.L.; L.S.; G.B.F.; M.G.; R.B.; R.P.R.; visualization, C.L.; M.M.; M.S.; M.G.; supervision, C.L.; L.S.; G.B.F.; M.G.; R.B.; L.L.; R.P.R.; project administration, L.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

Lavalle, Santini, Forleo, Grimaldi, Badagliacca and Ricci have received speaker honoraria from Dompè SPA, Italy. L. Lanata is employee of Dompé SPA, Italy. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Abbreviations

AFAtrial Fibrillation
AMIAcute Myocardial Infarction
AVAtrioVentricular
IVIntraVentricular
LVLeft Ventricular
SVTSupraVentricular Tachycardia
VTVentricular Tachycardia

References

  1. Hindricks, G.; Potpara, T.; Dagres, N.; Arbelo, E.; Bax, J.J.; Blomström-Lundqvist, C.; Boriani, G.; Castella, M.; Dan, G.-A.; Dilaveris, P.E.; et al. 2020 ESC Guidelines for the Diagnosis and Management of Atrial Fibrillation Developed in Collaboration with the European Association of Cardio-Thoracic Surgery (EACTS). Eur. Heart J. 2020, ehaa612. [Google Scholar] [CrossRef]
  2. Della Rocca, D.G.; Mohanty, S.; Trivedi, C.; Biase, L.D.; Natale, A. Percutaneous Treatment of Non-Paroxysmal Atrial Fibrillation: A Paradigm Shift from Pulmonary Vein to Non-Pulmonary Vein Trigger Ablation? Arrhythm. Electrophysiol. Rev. 2018, 7, 256. [Google Scholar] [CrossRef]
  3. Nieuwlaat, R.; Capucci, A.; Camm, A.J.; Olsson, S.B.; Andresen, D.; Davies, D.W.; Cobbe, S.; Breithardt, G.; Le Heuzey, J.-Y.; Prins, M.H.; et al. Atrial Fibrillation Management: A Prospective Survey in ESC Member Countries. Eur. Heart J. 2005, 26, 2422–2434. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Saksena, S.; Slee, A.; Waldo, A.L.; Freemantle, N.; Reynolds, M.; Rosenberg, Y.; Rathod, S.; Grant, S.; Thomas, E.; Wyse, D.G. Cardiovascular Outcomes in the AFFIRM Trial (Atrial Fibrillation Follow-Up Investigation of Rhythm Management). J. Am. Coll. Cardiol. 2011, 58, 1975–1985. [Google Scholar] [CrossRef] [Green Version]
  5. Allen LaPointe, N.M.; Dai, D.; Thomas, L.; Piccini, J.P.; Peterson, E.D.; Al-Khatib, S.M. Comparisons of Hospitalization Rates Among Younger Atrial Fibrillation Patients Receiving Different Antiarrhythmic Drugs. Circ. Cardiovasc. Qual. Outcomes 2015, 8, 292–300. [Google Scholar] [CrossRef] [Green Version]
  6. Echt, D.S.; Liebson, P.R.; Mitchell, L.B.; Peters, R.W.; Obias-Manno, D.; Barker, A.H.; Arensberg, D.; Baker, A.; Friedman, L.; Greene, H.L.; et al. Mortality and Morbidity in Patients Receiving Encainide, Flecainide, or Placebo: The Cardiac Arrhythmia Suppression Trial. N. Engl. J. Med. 1991, 324, 781–788. [Google Scholar] [CrossRef]
  7. Conard, G.J.; Ober, R.E. Metabolism of Flecainide. Am. J. Cardiol. 1984, 53, B41–B51. [Google Scholar] [CrossRef]
  8. Anderson, J.L.; Stewart, J.R.; Perry, B.A.; Van Hamersveld, D.D.; Johnson, T.A.; Conard, G.J.; Chang, S.F.; Kvam, D.C.; Pitt, B. Oral Flecainide Acetate for the Treatment of Ventricular Arrhythmias. N. Engl. J. Med. 1981, 305, 473–477. [Google Scholar] [CrossRef]
  9. Tjandra-Maga, T.; Verbesselt, R.; Hecken, A.; Mullie, A.; Schepper, P. Flecainide: Single and Multiple Oral Dose Kinetics, Absolute Bioavailability and Effect of Food and Antacid in Man. Br. J. Clin. Pharmacol. 1986, 22, 309–316. [Google Scholar] [CrossRef] [Green Version]
  10. Holmes, B.; Heel, R.C. Flecainide A Preliminary Review of Its Pharmacodynamic Properties and Therapeutic Efficacy. Drugs 1985, 29, 1–33. [Google Scholar] [CrossRef]
  11. Josephson, M.A.; Ikeda, N.; Singh, B.N. Effects of Flecainide on Ventricular Function: Clinical and Experimental Correlations. Am. J. Cardiol. 1984, 53, B95–B100. [Google Scholar] [CrossRef]
  12. Campbell, T.J.; Williams, E.M.V. Voltage- and Time-Dependent Depression of Maximum Rate of Depolarisation of Guinea-Pig Ventricular Action Potentials by Two New Antiarrhythmic Drugs, Flecainide and Lorcainide. Cardiovasc. Res. 1983, 17, 251–258. [Google Scholar] [CrossRef]
  13. Anno, T.; Hondeghem, L.M. Interactions of Flecainide with Guinea Pig Cardiac Sodium Channels. Importance of Activation Unblocking to the Voltage Dependence of Recovery. Circ. Res. 1990, 66, 789–803. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Follmer, C.H.; Colatsky, T.J. Block of Delayed Rectifier Potassium Current, IK, by Flecainide and E-4031 in Cat Ventricular Myocytes. Circulation 1990, 82, 289–293. [Google Scholar] [CrossRef] [Green Version]
  15. Tamargo, J. Pharmacology of Cardiac Potassium Channels. Cardiovasc. Res. 2004, 62, 9–33. [Google Scholar] [CrossRef] [Green Version]
  16. Singh, B.N.; Nademanee, K.; Josephson, M.A.; Ikeda, N.; Venkatesh, N.; Kannan, R. The Electrophysiology and Pharmacology of Verapamil, Flecainide, and Amiodarone: Correlations with Clinical Effects and Antiarrhythmic Actions. Ann. N. Y. Acad. Sci. 1984, 432, 210–235. [Google Scholar] [CrossRef]
  17. Mehra, D.; Imtiaz, M.S.; van Helden, D.F.; Knollmann, B.C.; Laver, D.R. Multiple Modes of Ryanodine Receptor 2 Inhibition by Flecainide. Mol. Pharm. 2014, 86, 696–706. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  18. Muhiddin, K.A.; Turner, P.; Blackett, A. Effect of Flecainide on Cardiac Output. Clin. Pharm. 1985, 37, 260–263. [Google Scholar] [CrossRef] [PubMed]
  19. Legrand, V.; Vandormael, M.; Collignon, P.; Kulbertus, H.E. Hemodynamic Effects of a New Antiarrhythmic Agent, Flecainide (R-818), in Coronary Heart Disease. Am. J. Cardiol. 1983, 51, 422–426. [Google Scholar] [CrossRef]
  20. Duff, H.J.; Roden, D.M.; Maffucci, R.J.; Vesper, B.S.; Conard, G.J.; Higgins, S.B.; Oates, J.A.; Smith, R.F.; Woosley, R.L. Suppression of Resistant Ventricular Arrhythmias by Twice Daily Dosing with Flecainide. Am. J. Cardiol. 1981, 48, 1133–1140. [Google Scholar] [CrossRef]
  21. Hodges, M.; Haugland, J.M.; Granrud, G.; Conard, G.J.; Asinger, R.W.; Mikell, F.L.; Krejci, J. Suppression of Ventricular Ectopic Depolarizations by Flecainide Acetate, a New Antiarrhythmic Agent. Circulation 1982, 65, 879–885. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Josephson, M.A.; Kaul, S.; Hopkins, J.; Kvam, D.; Singh, B.N. Hemodynamic Effects of Intravenous Flecainide Relative to the Level of Ventricular Function in Patients with Coronary Artery Disease. Am. Heart J. 1985, 109, 41–45. [Google Scholar] [CrossRef]
  23. De Paola, A.A.V.; Horowitz, L.N.; Morganroth, J.; Senior, S.; Spielman, S.R.; Greenspan, A.M.; Kay, H.R. Influence of Left Ventricular Dysfunction on Flecainide Therapy. J. Am. Coll. Cardiol. 1987, 9, 163–168. [Google Scholar] [CrossRef] [Green Version]
  24. Coumel, P.; Maison-Blanche, P.; Tarral, E.; Périer, A.; Milliez, P.; Leenhardt, A. Pharmacodynamic Equivalence of Two Flecainide Acetate Formulations in Patients with Paroxysmal Atrial Fibrillation by QRS Analysis of Ambulatory Electrocardiogram. J. Cardiovasc. Pharmacol. 2003, 41, 771–779. [Google Scholar] [CrossRef]
  25. Tennezé, L.; Tarral, E.; Ducloux, N.; Funck-Brentano, C. Pharmacokinetics and Electrocardiographic Effects of a New Controlled-Release Form of Flecainide Acetate: Comparison with the Standard Form and Influence of the CYP2D6 Polymorphism. Clin. Pharm. 2002, 72, 112–122. [Google Scholar] [CrossRef]
  26. Anderson, J.L.; Platia, E.V.; Hallstrom, A.; Henthorn, R.W.; Buckingham, T.A.; Carlson, M.D.; Carson, P.E. 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). Circulation 1994, 90, 2843–2852. [Google Scholar] [CrossRef] [Green Version]
  27. Shimizu, W.; Antzelevitch, C. Cellular and Ionic Basis for T-Wave Alternans under Long-QT Conditions. Circulation 1999, 99, 1499–1507. [Google Scholar] [CrossRef] [Green Version]
  28. Priori, S.G.; Blomström-Lundqvist, C.; Mazzanti, A.; Blom, N.; Borggrefe, M.; Camm, J.; Elliott, P.M.; Fitzsimons, D.; Hatala, R.; Hindricks, G.; et al. 2015 ESC Guidelines for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC)Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur. Heart J. 2015, 36, 2793–2867. [Google Scholar] [CrossRef] [Green Version]
  29. Tarantino, N.; Della Rocca, D.G.; De Leon De La Cruz, N.S.; Manheimer, E.D.; Magnocavallo, M.; Lavalle, C.; Gianni, C.; Mohanty, S.; Trivedi, C.; Al-Ahmad, A.; et al. Catheter Ablation of Life-Threatening Ventricular Arrhythmias in Athletes. Medicina 2021, 57, 205. [Google Scholar] [CrossRef] [PubMed]
  30. Chorin, E.; Taub, R.; Medina, A.; Flint, N.; Viskin, S.; Benhorin, J. Long-Term Flecainide Therapy in Type 3 Long QT Syndrome. EP Eur. 2018, 20, 370–376. [Google Scholar] [CrossRef]
  31. Hyman, M.C.; Mustin, D.; Supple, G.; Schaller, R.D.; Santangeli, P.; Arkles, J.; Lin, D.; Muser, D.; Dixit, S.; Nazarian, S.; et al. Class IC Antiarrhythmic Drugs for Suspected Premature Ventricular Contraction–Induced Cardiomyopathy. Heart Rhythm. 2018, 15, 159–163. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Della Rocca, D.G.; Santini, L.; Forleo, G.B.; Sanniti, A.; Del Prete, A.; Lavalle, C.; Di Biase, L.; Natale, A.; Romeo, F. Novel Perspectives on Arrhythmia-Induced Cardiomyopathy: Pathophysiology, Clinical Manifestations and an Update on Invasive Management Strategies. Cardiol. Rev. 2015, 23, 135–141. [Google Scholar] [CrossRef]
  33. Ermakov, S.; Gerstenfeld, E.P.; Svetlichnaya, Y.; Scheinman, M.M. Use of Flecainide in Combination Antiarrhythmic Therapy in Patients with Arrhythmogenic Right Ventricular Cardiomyopathy. Heart Rhythm. 2017, 14, 564–569. [Google Scholar] [CrossRef]
  34. Chung, R.; Houghtaling, P.L.; Tchou, M.; Niebauer, M.J.; Lindsay, B.D.; Tchou, P.J.; Chung, M.K. Left Ventricular Hypertrophy and Antiarrhythmic Drugs in Atrial Fibrillation: Impact on Mortality: Lvh, Antiarrhythmic Drugs, and Mortality. Pacing Clin. Electrophysiol. 2014, 37, 1338–1348. [Google Scholar] [CrossRef] [Green Version]
  35. Roden, D.M.; Woosley, R.L. Flecainide. N. Engl. J. Med. 1986, 315, 36–41. [Google Scholar] [CrossRef] [PubMed]
  36. Platia, E.V.; Estes, N.A.M.; Heine, D.L.; Griffith, L.S.C.; Garan, H.; Ruskin, J.N.; Reid, P.R. Flecainide: Electrophysiologic and Antiarrhythmic Properties in Refractory Ventricular Tachycardia. Am. J. Cardiol. 1985, 55, 956–962. [Google Scholar] [CrossRef]
  37. Crijns, H.J.; van Gelder, I.C.; Lie, K.I. Supraventricular Tachycardia Mimicking Ventricular Tachycardia during Flecainide Treatment. Am. J. Cardiol. 1988, 62, 1303–1306. [Google Scholar] [CrossRef]
  38. Boriani, G.; Diemberger, I.; Biffi, M.; Martignani, C.; Branzi, A. Pharmacological Cardioversion of Atrial Fibrillation: Current Management and Treatment Options. Drugs 2004, 64, 2741–2762. [Google Scholar] [CrossRef] [PubMed]
  39. Wehling, M. Meta-Analysis of Flecainide Safety in Patients with Supraventricular Arrhythmias. Arzneimittelforschung 2011, 52, 507–514. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  40. Gentzkow, G.D.; Sullivan, J.Y. Extracardiac Adverse Effects of Flecainide. Am. J. Cardiol. 1984, 53, B101–B105. [Google Scholar] [CrossRef]
  41. Hohnloser, S.H.; Dorian, P.; Roberts, R.; Gent, M.; Israel, C.W.; Fain, E.; Champagne, J.; Connolly, S.J. Effect of Amiodarone and Sotalol on Ventricular Defibrillation Threshold: The Optimal Pharmacological Therapy in Cardioverter Defibrillator Patients (OPTIC) Trial. Circulation 2006, 114, 104–109. [Google Scholar] [CrossRef] [PubMed]
  42. Malfatto, G.; Zaza, A.; Forster, M.; Sodowick, B.; Danilo, P.; Rosen, M.R. Electrophysiologic, Inotropic and Antiarrhythmic Effects of Propafenone, 5-Hydroxypropafenone and N-Depropylpropafenone. J. Pharm. Exp. 1988, 246, 419–426. [Google Scholar]
  43. Capucci, A.; Botto, G.; Molon, G.; Spampinato, A.; Favale, S.; Proclemer, A.; Porfilio, A.; Marotta, T.; Vimercati, M.; Boriani, G. The Drug and Pace Health CliNical Evaluation (DAPHNE) Study: A Randomized Trial Comparing Sotalol versus β-Blockers to Treat Symptomatic Atrial Fibrillation in Patients with Brady-Tachycardia Syndrome Implanted with an Antitachycardia Pacemaker. Am. Heart J. 2008, 156, 373.e1–373.e8. [Google Scholar] [CrossRef]
  44. Funck, R.C.; Boriani, G.; Manolis, A.S.; Püererfellner, H.; Mont, L.; Tukkie, R.; Pisapia, A.; Israel, C.W.; Grovale, N.; Grammatico, A.; et al. The MINERVA Study Design and Rationale: A Controlled Randomized Trial to Assess the Clinical Benefit of Minimizing Ventricular Pacing in Pacemaker Patients with Atrial Tachyarrhythmias. Am. Heart J. 2008, 156, 445–451. [Google Scholar] [CrossRef]
  45. Lavalle, C.; Ricci, R.P.; Santini, M. Atrial Tachyarrhythmias and Cardiac Resynchronisation Therapy: Clinical and Therapeutic Implications. Heart 2010, 96, 1174–1178. [Google Scholar] [CrossRef]
  46. Singer, I.; Guarnieri, T.; Kupersmith, J. Implanted Automatic Defibrillators: Effects of Drugs and Pacemakers. Pacing Clin. Electrophysiol. 1988, 11, 2250–2262. [Google Scholar] [CrossRef]
  47. Alboni, P.; Paparella, N.; Cappato, R.; Candini, G.C. Direct and Autonomically Mediated Effects of Oral Flecainide. Am. J. Cardiol. 1988, 61, 759–763. [Google Scholar] [CrossRef]
  48. Hellestrand, K.J.; Nathan, A.W.; Bexton, R.S.; Camm, A.J. Electrophysiologic Effects of Flecainide Acetate on Sinus Node Function, Anomalous Atrioventricular Connections, and Pacemaker Thresholds. Am. J. Cardiol. 1984, 53, B30–B38. [Google Scholar] [CrossRef]
  49. Anderson, J.L.; Lutz, J.R.; Allison, S.B. Electrophysiologic and Antiarrhythmic Effects of Oral Flecainide in Patients with Inducible Ventricular Tachycardia. J. Am. Coll. Cardiol. 1983, 2, 105–114. [Google Scholar] [CrossRef] [Green Version]
  50. Touboul, P.; Atallah, G.; Gressard, A.; Kirkorian, G. Effects of Amiodarone on Sinus Node in Man. Br. Heart J. 1979, 42, 573–578. [Google Scholar] [CrossRef] [Green Version]
  51. Mary-Rabine, L.; Telerman, M. Long Term Evaluation of Flecainide Acetate in Supraventricular Tachyarrhythmias. Acta Cardiol. 1988, 43, 37–48. [Google Scholar]
  52. Shea, P.; Lal, R.; Kim, S.S.; Schechtman, K.; Ruffy, R. Flecainide and Amiodarone Interaction. J. Am. Coll. Cardiol. 1986, 7, 1127–1130. [Google Scholar] [CrossRef] [Green Version]
  53. Coumel, P.; Chouty, F.; Slama, R. Logic and Empiricism in the Selection of Antiarrhythmic Agents: The Role of Drug Combinations. Drugs 1985, 29, 68–76. [Google Scholar] [CrossRef] [PubMed]
  54. Capucci, A.; Piangerelli, 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. Europace 2016, 18, 1698–1704. [Google Scholar] [CrossRef]
  55. Lewis, G.P.; Holtzman, J.L. Interaction of Flecainide with Digoxin and Propranolol. Am. J. Cardiol. 1984, 53, B52–B57. [Google Scholar] [CrossRef]
  56. Trujillo, T.C.; Nolan, P.E. Antiarrhythmic Agents: Drug Interactions of Clinical Significance. Drug Saf. 2000, 23, 509–532. [Google Scholar] [CrossRef] [PubMed]
  57. Holtzman, J.L.; Finley, D.; Mottonen, L.; Berry, D.A.; Ekholm, B.P.; Kvam, D.C.; McQuinn, R.L.; Miller, A.M. The Pharmacodynamic and Pharmacokinetic Interaction between Single Doses of Flecainide Acetate and Verapamil: Effects on Cardiac Function and Drug Clearance. Clin. Pharm. 1989, 46, 26–32. [Google Scholar] [CrossRef]
  58. Brugada, J.; Katritsis, D.G.; Arbelo, E.; Arribas, F.; Bax, J.J.; Blomström-Lundqvist, C.; Calkins, H.; Corrado, D.; Deftereos, S.G.; Diller, G.-P.; et al. 2019 ESC Guidelines for the Management of Patients with Supraventricular TachycardiaThe Task Force for the Management of Patients with Supraventricular Tachycardia of the European Society of Cardiology (ESC). Eur. Heart J. 2020, 41, 655–720. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  59. Brugada, J.; Blom, N.; Sarquella-Brugada, G.; Blomstrom-Lundqvist, C.; Deanfield, J.; Janousek, J.; Abrams, D.; Bauersfeld, U.; Brugada, R.; Drago, F.; et al. Pharmacological and Non-Pharmacological Therapy for Arrhythmias in the Pediatric Population: EHRA and AEPC-Arrhythmia Working Group Joint Consensus Statement. EP Eur. 2013, 15, 1337–1382. [Google Scholar] [CrossRef]
  60. Perry, J.C.; Garson, A. Supraventricular Tachycardia Due to Wolff-Parkinson-White Syndrome in Children: Early Disappearance and Late Recurrence. J. Am. Coll. Cardiol. 1990, 16, 1215–1220. [Google Scholar] [CrossRef] [Green Version]
  61. Richardson, C.; Silver, E.S. Management of Supraventricular Tachycardia in Infants. Pediatr. Drugs 2017, 19, 539–551. [Google Scholar] [CrossRef]
  62. Cummings, J.E.; Schweikert, R.A.; Saliba, W.I.; Burkhardt, J.D.; Kilikaslan, F.; Saad, E.; Natale, A. Brief Communication: Atrial–Esophageal Fistulas after Radiofrequency Ablation. Ann. Intern. Med. 2006, 144, 572. [Google Scholar] [CrossRef]
  63. Lewis, J.; Arora, G.; Tudorascu, D.L.; Hickey, R.W.; Saladino, R.A.; Manole, M.D. Acute Management of Refractory and Unstable Pediatric Supraventricular Tachycardia. J. Pediatr. 2017, 181, 177–182. [Google Scholar] [CrossRef] [Green Version]
  64. Tamargo, J.; Le Heuzey, J.-Y.; Mabo, P. Narrow Therapeutic Index Drugs: A Clinical Pharmacological Consideration to Flecainide. Eur. J. Clin. Pharm. 2015, 71, 549–567. [Google Scholar] [CrossRef] [Green Version]
  65. Martínez-Marcos, F.J.; García-Garmendia, J.L.; Ortega-Carpio, A.; Fernández-Gómez, J.M.; Santos, J.M.; Camacho, C. Comparison of Intravenous Flecainide, Propafenone, and Amiodarone for Conversion of Acute Atrial Fibrillation to Sinus Rhythm. Am. J. Cardiol. 2000, 86, 950–953. [Google Scholar] [CrossRef]
  66. Boriani, G. Oral Propafenone To Convert Recent-Onset Atrial Fibrillation in Patients with and without Underlying Heart Disease: A Randomized, Controlled Trial. Ann. Intern. Med. 1997, 126, 621. [Google Scholar] [CrossRef]
  67. Capucci, A.; Boriani, G.; Botto, G.L.; Lenzi, T.; Rubino, I.; Falcone, C.; Trisolino, G.; Della Casa, S.; Binetti, N.; Cavazza, M.; et al. Conversion of Recent-Onset Atrial Fibrillation by a Single Oral Loading Dose of Propafenone or Flecainide. Am. J. Cardiol. 1994, 74, 503–505. [Google Scholar] [CrossRef]
  68. Crijns, H.J.G.M.; Van Wijk, L.M.; Van Gilst, W.H.; Kingma, J.H.; Van Gelder, I.C.; Lie, K.I. Acute Conversion of Atrial Fibrillation to Sinus Rhythm: Clinical Efficacy of Flecainide Acetate. Comparison of Two Regimens. Eur. Heart J. 1988, 9, 634–638. [Google Scholar] [CrossRef]
  69. Boriani, G.; Bifft, M.; Capucci, A.; Botto, G.; Broffoni, T.; Ongari, M.; Trisolino, G.; Rubino, I.; Sanguinetti, M.; Branzi, A.; et al. Conversion of Recent-Onset Atrial Fibrillation to Sinus Rhythm: Effects of Different Drug Protocols. Pacing Clin. Electrophysiol. 1998, 21, 2470–2474. [Google Scholar] [CrossRef] [PubMed]
  70. Capucci, A.; Lenzi, T.; Boriani, G.; Trisolino, G.; Binetti, N.; Cavazza, M.; Fontana, G.; Magnani, B. Effectiveness of Loading Oral Flecainide for Converting Recent-Onset Atrial Fibrillation to Sinus Rhythm in Patients without Organic Heart Disease or with Only Systemic Hypertension. Am. J. Cardiol. 1992, 70, 69–72. [Google Scholar] [CrossRef]
  71. Romano, S.; Fattore, L.; Toscano, G.; Corsini, F.; Coppo, A.; Catanzaro, M.; Romano, A.; Martone, A.; Caccavale, F.; Iodice, E.; et al. Effectiveness and side effects of the treatment with propafenone and flecainide for recent-onset atrial fibrillation. Ital. Heart J. Suppl. 2001, 2, 41–45. [Google Scholar] [PubMed]
  72. Khan, I.A. Oral Loading Single Dose Flecainide for Pharmacological Cardioversion of Recent-Onset Atrial Fibrillation. Int. J. Cardiol. 2003, 87, 121–128. [Google Scholar] [CrossRef]
  73. Chevalier, P.; Durand-Dubief, A.; Burri, H.; Cucherat, M.; Kirkorian, G.; Touboul, P. Amiodarone versus Placebo and Class Ic Drugs for Cardioversion of Recent-Onset Atrial Fibrillation: A Meta-Analysis. J. Am. Coll. Cardiol. 2003, 41, 255–262. [Google Scholar] [CrossRef] [Green Version]
  74. Alboni, P.; Botto, G.L.; Baldi, N.; Luzi, M.; Russo, V.; Gianfranchi, L.; Marchi, P.; Calzolari, M.; Solano, A.; Baroffio, R.; et al. Outpatient Treatment of Recent-Onset Atrial Fibrillation with the “Pill-in-the-Pocket” Approach. N. Engl. J. Med. 2004, 351, 2384–2391. [Google Scholar] [CrossRef] [Green Version]
  75. Valembois, L.; Audureau, E.; Takeda, A.; Jarzebowski, W.; Belmin, J.; Lafuente-Lafuente, C. Antiarrhythmics for Maintaining Sinus Rhythm after Cardioversion of Atrial Fibrillation. Cochrane Database Syst. Rev. 2019. [Google Scholar] [CrossRef]
  76. Salvage, S.C.; Chandrasekharan, K.H.; Jeevaratnam, K.; Dulhunty, A.F.; Thompson, A.J.; Jackson, A.P.; Huang, C.L.-H. Multiple Targets for Flecainide Action: Implications for Cardiac Arrhythmogenesis. Br. J. Pharm. 2018, 175, 1260–1278. [Google Scholar] [CrossRef] [Green Version]
  77. Andrade, J.G.; MacGillivray, J.; Macle, L.; Yao, R.J.R.; Bennett, M.; Fordyce, C.B.; Hawkins, N.; Krahn, A.; Jue, J.; Ramanathan, K.; et al. Clinical Effectiveness of a Systematic “Pill-in-the-Pocket” Approach for the Management of Paroxysmal Atrial Fibrillation. Heart Rhythm. 2018, 15, 9–16. [Google Scholar] [CrossRef] [Green Version]
  78. Alboni, P.; Botto, G.L.; 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. Heart 2010, 96, 546–549. [Google Scholar] [CrossRef]
  79. Echt, D.S.; Ruskin, J.N. Use of Flecainide for the Treatment of Atrial Fibrillation. Am. J. Cardiol. 2020, 125, 1123–1133. [Google Scholar] [CrossRef] [Green Version]
  80. Climent, V.E.; Marín, F.; Mainar, L.; Gómez-Aldaraví, R.; Martínez, J.G.; Chorro, F.J.; Román, P.; Sogorb, F. Effects of Pretreatment with Intravenous Flecainide on Efficacy of External Cardioversion of Persistent Atrial Fibrillation. Pacing Clin. Electrophysiol. 2004, 27, 368–372. [Google Scholar] [CrossRef]
  81. Boriani, G.; Biffi, M.; Capucci, A.; Bronzetti, G.; Ayers, G.M.; Zannoli, R.; Branzi, A.; Magnani, B. Favorable Effects of Flecainide in Transvenous Internal Cardioversion of Atrial Fibrillation. J. Am. Coll. Cardiol. 1999, 33, 333–341. [Google Scholar] [CrossRef] [Green Version]
  82. Chimienti, M.; Cullen, M.T.; Casadei, G. Safety of Flecainide versus Propafenone for the Long-Term Management of Symptomatic Paroxysmal Supraventricular Tachyarrhythmias. Eur. Heart J. 1995, 16, 1943–1951. [Google Scholar] [CrossRef]
  83. Gulizia, M.; Mangiameli, S.; Orazi, S.; Chiarandà, G.; Piccione, G.; Di Giovanni, N.; Colletti, A.; Pensabene, O.; Lisi, F.; Vasquez, L.; et al. A Randomized Comparison of Amiodarone and Class IC Antiarrhythmic Drugs to Treat Atrial Fibrillation in Patients Paced for Sinus Node Disease: The Prevention Investigation and Treatment: A Group for Observation and Research on Atrial Arrhythmias (PITAGORA) Trial. Am. Heart J. 2008, 155, 100.e1–100.e9. [Google Scholar] [CrossRef]
  84. Kirchhof, P.; Camm, A.J.; Goette, A.; Brandes, A.; Eckardt, L.; Elvan, A.; Fetsch, T.; van Gelder, I.C.; Haase, D.; Haegeli, L.M.; et al. Early Rhythm-Control Therapy in Patients with Atrial Fibrillation. N. Engl. J. Med. 2020, 383, 1305–1316. [Google Scholar] [CrossRef]
  85. The AFFIRM Investigators. Relationships Between Sinus Rhythm, Treatment, and Survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study. Circulation 2004, 109, 1509–1513. [Google Scholar] [CrossRef] [PubMed]
  86. Forleo, G.B.; Della Rocca, D.G.; Lavalle, C.; Mantica, M.; Papavasileiou, L.P.; Ribatti, V.; Panattoni, G.; Santini, L.; Natale, A.; Biase, L.D. A Patient with Asymptomatic Cerebral Lesions During AF Ablation: How Much Should We Worry? J. Atr. Fibrillation 2016, 8, 1323. [Google Scholar] [CrossRef]
  87. Patel, K.; Natale, A.; Yang, R.; Trivedi, C.; Romero, J.; Briceno, D.; Mohanty, S.; Alviz, I.; Natale, V.; Sanchez, J.; et al. Is Transesophageal Echocardiography Necessary in Patients Undergoing Ablation of Atrial Fibrillation on an Uninterrupted Direct Oral Anticoagulant Regimen? Results from a Prospective Multicenter Registry. Heart Rhythm. 2020, 17, 2093–2099. [Google Scholar] [CrossRef]
  88. Romero, J.; Ogunbayo, G.; Elayi, S.C.; Darrat, Y.; Rios, S.A.; Diaz, J.C.; Alviz, I.; Cerna, L.; Gabr, M.; Chernobelsky, E.; et al. Safety of Catheter Ablation for Atrial Fibrillation in the Octogenarian Population. J. Cardiovasc. Electrophysiol. 2019, 30, 2686–2693. [Google Scholar] [CrossRef]
  89. Della Rocca, D.G.; Mohanty, S.; Mohanty, P.; Trivedi, C.; Gianni, C.; Al-Ahmad, A.; Burkhardt, J.D.; Gallinghouse, G.J.; Hranitzky, P.; Sanchez, J.E.; et al. Long-term Outcomes of Catheter Ablation in Patients with Longstanding Persistent Atrial Fibrillation Lasting Less than 2 Years. J. Cardiovasc. Electrophysiol. 2018, 29, 1607–1615. [Google Scholar] [CrossRef]
  90. Mohanty, S.; Trivedi, C.; Gianni, C.; Della Rocca, D.G.; Morris, E.H.; Burkhardt, J.D.; Sanchez, J.E.; Horton, R.; Gallinghouse, G.J.; Hongo, R.; et al. Procedural Findings and Ablation Outcome in Patients with Atrial Fibrillation Referred after Two or More Failed Catheter Ablations. J. Cardiovasc. Electrophysiol. 2017, 28, 1379–1386. [Google Scholar] [CrossRef]
  91. Freemantle, N.; Lafuente-Lafuente, C.; Mitchell, S.; Eckert, L.; Reynolds, M. Mixed Treatment Comparison of Dronedarone, Amiodarone, Sotalol, Flecainide, and Propafenone, for the Management of Atrial Fibrillation. Europace 2011, 13, 329–345. [Google Scholar] [CrossRef]
  92. Kirchhof, P.; Andresen, D.; Bosch, R.; Borggrefe, M.; Meinertz, T.; Parade, U.; Ravens, U.; Samol, A.; Steinbeck, G.; Treszl, A.; et al. Short-Term versus Long-Term Antiarrhythmic Drug Treatment after Cardioversion of Atrial Fibrillation (Flec-SL): A Prospective, Randomised, Open-Label, Blinded Endpoint Assessment Trial. Lancet 2012, 380, 238–246. [Google Scholar] [CrossRef]
  93. Della Rocca, D.G.; Tarantino, N.; Trivedi, C.; Mohanty, S.; Anannab, A.; Salwan, A.S.; Gianni, C.; Bassiouny, M.; Al-Ahmad, A.; Romero, J.; et al. Non-pulmonary Vein Triggers in Nonparoxysmal Atrial Fibrillation: Implications of Pathophysiology for Catheter Ablation. J. Cardiovasc. Electrophysiol. 2020, 31, 2154–2167. [Google Scholar] [CrossRef]
  94. Allot, E.; Denjoy, I. Comparison of the Safety and Efficacy of Flecamide versus Propafenone in Hospital Out-Patients with Symptomatic Paroxysmal Atrial Fibrillation/Flutter. Am. J. Cardiol. 1996, 77, 66A–71A. [Google Scholar] [CrossRef]
  95. Naccarelli, G.V.; Dorian, P.; Hohnloser, S.H.; Coumel, P. Prospective Comparison of Flecainide versus Quinidine for the Treatment of Paroxysmal Atrial Fibrillation/Flutter. Am. J. Cardiol. 1996, 77, 53A–59A. [Google Scholar] [CrossRef]
  96. Carunchio, A.; Fera, M.S.; Mazza, A.; Burattini, M.; Greco, G.; Galati, A.; Ceci, V. A comparison between flecainide and sotalol in the prevention of recurrences of paroxysmal atrial fibrillation. G. Ital. Cardiol. 1995, 25, 51–68. [Google Scholar]
  97. Van Wijk, L.M.; den Heijer, P.; Crijns, H.J.; van Gilst, W.H.; Lie, K.I. Flecainide Versus Quinidine in the Prevention of Paroxysms of Atrial Fibrillation. J. Cardiovasc. Pharmacol. 1989, 13, 32. [Google Scholar] [CrossRef]
  98. Henthorn, R.W.; Waldo, A.L.; Anderson, J.L.; Gilbert, E.M.; Alpert, B.L.; Bhandari, A.K.; Hawkinson, R.W.; Pritchett, E.L. Flecainide Acetate Prevents Recurrence of Symptomatic Paroxysmal Supraventricular Tachycardia. The Flecainide Supraventricular Tachycardia Study Group. Circulation 1991, 83, 119–125. [Google Scholar] [CrossRef] [Green Version]
  99. Pritchett, E.L.C. Propafenone Treatment of Symptomatic Paroxysmal Supraventricular Arrhythmias: A Randomized, Placebo-Controlled, Crossover Trial in Patients Tolerating Oral Therapy. Ann. Intern. Med. 1991, 114, 539. [Google Scholar] [CrossRef]
  100. Blomström-Lundqvist, C.; Scheinman, M.M.; Aliot, E.M.; Alpert, J.S.; Calkins, H.; Camm, A.J.; Campbell, W.B.; Haines, D.E.; Kuck, K.H.; Lerman, B.B.; et al. ACC/AHA/ESC Guidelines for the Management of Patients with Supraventricular Arrhythmias—Executive Summary. J. Am. Coll. Cardiol. 2003, 42, 1493–1531. [Google Scholar] [CrossRef] [Green Version]
  101. Crijns, H.J.G.M.; den Heijer, P.; van Wijk, L.M.; Lie, K.I. Successful Use of Flecainide in Atrial Fibrillation with Rapid Ventricular Rate in the Wolff-Parkinson-White Syndrome. Am. Heart J. 1988, 115, 1317–1321. [Google Scholar] [CrossRef]
  102. Pandozi, C.; Galeazzi, M.; Lavalle, C.; Ficili, S.; Russo, M.; Santini, M. Navx-Guided Cryoablation of Atrial Tachycardia Inside the Left Atrial Appendage. Indian Pacing Electrophysiol. J. 2011, 10, 556–561. [Google Scholar]
  103. Pritchett, E.L.C.; DaTorre, S.D.; Platt, M.L.; McCarville, S.E.; Hougham, A.J. Flecainide Acetate Treatment of Paroxysmal Supraventricular Tachycardia and Paroxysmal Atrial Fibrillation: Dose-Response Studies. J. Am. Coll. Cardiol. 1991, 17, 297–303. [Google Scholar] [CrossRef]
  104. Katritsis, D.G.; Boriani, G.; Cosio, F.G.; Hindricks, G.; Jaïs, P.; Josephson, M.E.; Keegan, R.; Kim, Y.-H.; Knight, B.P.; Kuck, K.-H.; et al. European Heart Rhythm Association (EHRA) Consensus Document on the Management of Supraventricular Arrhythmias, Endorsed by Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS), and Sociedad Latinoamericana de Estimulación Cardiaca y Electrofisiologia (SOLAECE). EP Eur. 2017, 19, 465–511. [Google Scholar] [CrossRef]
  105. Gianni, C.; Sanchez, J.E.; Mohanty, S.; Trivedi, C.; Della Rocca, D.G.; Al-Ahmad, A.; Burkhardt, J.D.; Gallinghouse, G.J.; Hranitzky, P.M.; Horton, R.P.; et al. Isolation of the Superior Vena Cava from the Right Atrial Posterior Wall: A Novel Ablation Approach. Ep Eur. 2018, 20, e124–e132. [Google Scholar] [CrossRef] [PubMed]
  106. Pietersen, A.H.; Hellemann, H. Usefulness of Flecainide for Prevention of Paroxysmal Atrial Fibrillation and Flutter. Am. J. Cardiol. 1991, 67, 713–717. [Google Scholar] [CrossRef]
Jcm 10 01456 g001 550
Figure 1. Current evidence on the use of flecainide. Structural heart disease is any abnormality, or defect, of the heart muscle or the heart valves.
Figure 1. Current evidence on the use of flecainide. Structural heart disease is any abnormality, or defect, of the heart muscle or the heart valves.
Jcm 10 01456 g001
Table
Table 1. Recommended dose of flecainide in supraventricular arrhythmias (SVT).
Table 1. Recommended dose of flecainide in supraventricular arrhythmias (SVT).
SVTRecommended DoseAdministration Route
Atrial Fibrillation
(Restoration of sinus rhythm)		200–300 mg
2 mg/kg		Oral
Intravenous
Atrial Fibrillation
(Maintenance of sinus rhythm)		100–200 mg bid
200 mg once daily		Oral
AVNRT/AVRT50–150 mg bidOral
Focal Atrial Tachycardia50–150 mg bidOral
AVNRT: atrioventricular nodal reentrant tachycardia; AVRT: atrioventricular reentrant tachycardia.
Table
Table 2. Management of adverse events due to flecainide.
Table 2. Management of adverse events due to flecainide.
Adverse EventIncidenceIndication
Drug induced Brugada<1%Discontinue
QRS increased more than 40 ms or wider than 130 ms<1%Discontinue
QRS increased more than 20 ms1–2%Reduce Dosage
Bradyarrhythmia, sinus pause, AV block1–2%Discontinue
Hypotension3–5% (mostly with IV)Reduce Dosage
1:1 atrial flutter3–5%Discontinue and consider ablate CTI dependent-flutter
Worsening heart failure<1%Discontinue
Extracardiac effects (dizziness, tremor, nausea)1–2%Reduce Dosage
AV: atrioventricular; CTI: cavotricuspid isthmus; IV: intravenous.
Table
Table 3. Reversion rate of recent-onset atrial fibrillation to sinus rhythm.
Table 3. Reversion rate of recent-onset atrial fibrillation to sinus rhythm.
StudyPopulation in Flecainide ArmAF DurationFlecainideReversion RateAdverse Event
Martínez-Marcos et al. [65]50≤2 dIntravenous (2 mg/kg followed by 1 mg/kg at 8 h if not in sinus rhythm)1 h → 58%
8 h → 82%
12 h → 90%		Transient junctional
rhythm: 4%
Atrial flutter: 2%
Symptomatic hypotension:2% Paresthesia: 4%
Total: 12%
Capucci et al. [67]58≤7 dSingle oral dose (300 mg)3 h → 59%
8 h → 78%		Transient junctional rhythm:1.7%
Atrial flutter: 3.4%
Crijns et al. [68]13≤24 hIntravenous (2 mg/kg up to 150 mg)3 h → 77%-
Boriani et al. [69]69≤7 dSingle oral dose (300 mg)1 h → 13%
3 h → 57%
8 h → 75%		-
Capucci et al. [70]22≤7 dSingle oral dose (300 mg)8 h → 91%
24 h → 95%		no
Romano et al. [71]138≤3 dIntravenous1 h → 73%
3 h → 80%
6 h → 86%
24 h → 90%		-
Table
Table 4. Flecainide for maintenance of sinus rhythm.
Table 4. Flecainide for maintenance of sinus rhythm.
Authorn. PatientType of AFCompared TreatmentEndpoint of AF RecurrenceResults
Chimienti et al. [82]200ParoxysmalFlecainide
vs.
Propafenone		Palpitation recurrence on days 15, 30, 90, 180, 270, 360No difference between flecainide and propafenone
Gulizia et al. [83]176 with PMKParoxysmalIc AAD
vs.
Amiodarone		Time to first occurrence of death, atrial cardioversion, cardiovascular hospitalization or change of AADIC AAD non inferior to Amiodarone.
Similar AT recurrences
Naccarelli et al. [95]239ParoxysmalFlecainide
vs.
Quinidine		AF recurrence at 12 monthsFlecainide similar efficacy to quinidine but better tolerated
Allot et al. [94] 97ParoxysmalFlecainide
vs.
Propafenone		AF recurrence at 12 monthsFlecainide similar efficacy to propafenone
Carunchio et al. [96]66ParoxysmalFlecainide
vs.
Sotalolo
vs.
Placebo		AF recurrence at 1, 3, 6 and 12 monthsFlecainide similar efficacy to sotalol and superior to placebo
van Wijk et al. [97]26ParoxysmalFlecainide
vs.
Quinidine		AF recurrence during 3-months follow-up periodFlecainide superior to quinidine
AAD: antiarrhythmic drug, AF: atrial fibrillation; AT: atrial tachycardia; PMK: pacemaker.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Lavalle, C.; Magnocavallo, M.; Straito, M.; Santini, L.; Forleo, G.B.; Grimaldi, M.; Badagliacca, R.; Lanata, L.; Ricci, R.P. Flecainide How and When: A Practical Guide in Supraventricular Arrhythmias. J. Clin. Med. 2021, 10, 1456. https://doi.org/10.3390/jcm10071456

AMA Style

Lavalle C, Magnocavallo M, Straito M, Santini L, Forleo GB, Grimaldi M, Badagliacca R, Lanata L, Ricci RP. Flecainide How and When: A Practical Guide in Supraventricular Arrhythmias. Journal of Clinical Medicine. 2021; 10(7):1456. https://doi.org/10.3390/jcm10071456

Chicago/Turabian Style

Lavalle, Carlo, Michele Magnocavallo, Martina Straito, Luca Santini, Giovanni Battista Forleo, Massimo Grimaldi, Roberto Badagliacca, Luigi Lanata, and Renato Pietro Ricci. 2021. "Flecainide How and When: A Practical Guide in Supraventricular Arrhythmias" Journal of Clinical Medicine 10, no. 7: 1456. https://doi.org/10.3390/jcm10071456

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop