Flecainide: Electrophysiological properties, clinical indications, and practical aspects

Pharmacological Research 148 (2019) 104443

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Invited Review

Flecainide: Electrophysiological properties, clinical indications, and practical aspects

T

⁎

Enrico Paolini, Giulia Stronati, Federico Guerra , Alessandro Capucci Cardiology and Arrhythmology Clinic, Marche Polytechnic University, University Hospital “Umberto I – Lancisi – Salesi”, Ancona, Italy

A R T I C LE I N FO

A B S T R A C T

Keywords: Atrial fibrillation Flecainide Sodium channel Ventricular arrhythmias

Over the last 35 years, flecainide proved itself one of the most commonly used arrhythmic drugs, expanding its original indication for ventricular arrhythmias and results nowadays as the cornerstone of the rhythm control strategy in atrial fibrillation management of patients without structural heart disease. While the increased mortality associated with flecainide in the Cardiac Arrhythmia Suppression Trial (CAST) still casts his shadow over flecainide clinical profile, this compound has subsequently demonstrated safe and is now used successfully for a plethora of indications, including pharmacological cardioversion of atrial fibrillation, cathecolaminergic polymorphic ventricular tachycardia, supraventricular tachyarrhythmias and ventricular pre-excitation. Moreover, the recent marketing of a controlled release formulation, along with the intravenous and immediate release formulations, increased the armamentarium to the clinician’s disposal while improving patients’ compliance. In the present paper, we offer a comprehensive review of the anti-arrhythmic effects of flecainide, detailing its electrophysiological properties, its effects on the conduction system, its clinical use and the major side effects and contraindications in clinical practice.

1. Introduction

2. Electrophysiological properties

Flecainide acetate is a class IC antiarrhythmic drug [1]. Its development started in 1966 [2] and was approved as an antiarrhythmic agent in 1982 in Europe and 1984 in the US thanks to a pilot study by Hodges e Coll. [3]. While surely surprising for today’s standards, flecainide was first approved for suppression and prevention of life threatening ventricular arrhythmias. In fact, such study in 1982 demonstrated that the use of flecainide led to a 96.3% reduction of complex ventricular arrhythmias in 11 hospitalized patients. Over the last 35 years, flecainide expanded its original indication and is now used successfully for a plethora of indications, including supraventricular and ventricular arrhythmias. It became a cornerstone of the rhythm control strategy in atrial fibrillation (AF) management of patients without structural heart disease [4,5]. In the present paper, we offer a comprehensive review of the antiarrhythmic effects of flecainide, detailing its electrophysiological properties, its effects on the conduction system, its clinical use and the major side effects and contraindications in clinical practice.

Flecainide exerts its main pharmacological effect as a potent inhibitor of the sodium channels of the cardiac muscle fibers called Nav1.5 [6]. Nav1.5 is a voltage-gated sodium channel found mainly in the cardiac muscle. It is responsible for the fast upstroke of the action potential (phase 0) and therefore plays an important role in impulse propagation through the heart, starting the so-called “fast depolarization” of the cardiac myocite. The gene that encodes the Nav1.5 is the SCN5A gene, whose mutations are responsible for some of the most known channellopaties, such as the Brugada syndrome and the type 3 long QT syndrome, but are also involved in some form of arrhythmic dilated cardiomyopathy [7]. The SCN5A gene encodes for a large transmembrane protein with four similar domains and a conformational state that can be opened, closed or inactivated (Fig. 1). Flecainide blocks the Nav1.5 channel in its inactivated state [8], therefore reducing the inward flow of sodium in the cell and slowing the physiological recovery of the Nav1.5 from the inactivated conformation to the closed one. Therefore, like all class IC anti-arrhythmic drugs, flecainide reduces the upstroke of the action potential, slowing phase 0 and increasing its

⁎ Corresponding author at: Cardiology and Arrhythmology Clinic, Marche Polytechnic University, University Hospital “Ospedali Riuniti”, Via Conca 71, Ancona, Italy. E-mail address: f.guerra@staff.univpm.it (F. Guerra).

https://doi.org/10.1016/j.phrs.2019.104443 Received 7 February 2019; Received in revised form 3 August 2019; Accepted 3 September 2019 Available online 04 September 2019 1043-6618/ © 2019 Elsevier Ltd. All rights reserved.

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in the QRS duration) while the JT interval is prolonged by 4% [4]. For some authors, the widening of the QRS is a visual consequence of the main antiarrhythmic activity of this compound [2]. Furthermore as demonstrated by Kirchhof et al., flecainide may delay the time-dependent recovery of excitability, thereby prolonging in a rate-dependent manner refractoriness beyond repolarization of the action potential to its resting state [9]. This phenomenon is called drug-induced post-repolarization refractoriness and is typical of sodium channelblocking drugs with slow dissociation kinetics (e.g. flecainide or propafenone). Apart from its main activity as an inhibitor of Nav1.5, flecainide shows also other minor effects on cardiac channels. It inhibits potassium channels in a concentration-dependent way, therefore resulting in a further prolongation of the action potential [4]. Flecainide administration also results in a reduction of the intracellular concentration of calcium as the lower concentration of sodium in the cell leads to a slowdown of the sodium calcium antiport [10]. In addition to this, the direct inhibition by flecainide of ryanodine receptor calcium release channels has been recently described [11]. For electrical and mechanical effects of flecainide please see Table 1. 3. Approved formulations for medical use There are currently three drug formulations of the same active principle, two oral (immediate release tablets and modified release capsules) and one intravenous [12]. Flecainide is almost fully absorbed following oral administration and it is not affected by first-pass effect. Its bioavailability is reduced when taken with milk or other dairy products. Gastric pH does not influence the absorption of flecainide and the mean time to reach peak serum concentration is four hours [13]. In healthy subjects, 95% of flecainide is excreted in urine, 30% as unchanged drug and the rest as conjugated. Only 5% of the drug is eliminated in feces. The two main urinary metabolites are meta-0dealkylated flecainide (active) and the meta-0-dealkylated lactam (inactive) [14]. The iso-enzymes CYP2D6 and 1A2 of the cytochrome P450 seem to be involved in the metabolism of flecainide. Plasma clearance can decrease in case of liver failure, cardiac failure, and renal impairment and in case of alkaline urine (pH ≥ 8). Flecainide can be given with special precautions in end-stage renal disease, as haemodialysis eliminates only 1% of unchanged flecainide [14]. The half-life of immediate release flecainide is around 20 h and therefore must be administered twice a day. With regards to the modified release formulation, Tennezè et al. have described a significantly slower half-life only at a dose of 200 mg o.d. [15]. The study concluded that the modified release form of flecainide had similar trough levels when compared to the immediate release compound but with a lower range of plasma concentration and less chance of side effects. In addition to this, higher dosages were necessary to obtain a mean serum concentration similar to the immediate release formulation. It must be noted that the modified release capsules are approved for clinical use

Fig. 1. The Nav1.5 sodium channel in its closed (a), open (b), and deactivated (c) state.

duration without a concomitant prolonging of the repolarization phase. After administration of flecainide at therapeutic levels, the QT interval increases of around 8% (but mainly all the increase is due to an increase

Table 1 Electrical and mechanical effects of flecainide. Electrical effects

Mechanical effects

Slowdown of the conduction within the atria and the ventricles (AH > 15-22% and HV > 25-50%), resulting in PR and QRS prolongation on the ECG Myocardial effective refractory period prolongation Drug-induced post-repolarization refrectoriness

Negative inotropic effect

Action potential prolongation in atrial and ventricular myocytes

Minimal reduction of stroke volume index* Decrease of stroke volume index and cardiac output** Increase in right atrial pressure and wedge pressure**

Reduced probability of delayed afterdepolarizations and triggered activity Reduced automatism of the sinus node Increase in myocardial capture threshold in patients with cardiac implantable electronic devices

* In patients with normal cardiac function. ** In patients with ischaemic heart disease or left ventricle dysfunction. 2

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Table 2 Clinical indications and recommended doses. Indication

Oral formulation (fast release)

Oral formulation (slow release)

Intravenous formulation

Pharmacological cardioversion in patients with atrial fibrillation Rhythm control in patients with paroxysmal or persistent atrial fibrillation Wolff-Parkinson-White syndrome Ectopic atrial tachycardia AV nodal re-entrant tachycardia Atrioventricular re-entrant tachycardia Catecholaminergic polymorphic ventricular tachycardia Diagnostic test to exacerbate type 1 Brugada pattern.

200-300 mg 100-200 mg 100-200 mg 100-200 mg 100-200 mg 100-200 mg 100-200 mg No

– 200 mg o.d. – – – – – –

2 mg/kg – 2 mg/kg 2 mg/kg 2 mg/kg 2 mg/kg 2 mg/kg 2 mg/kg

(pill-in-the-pocket) b.i.d. b.i.d. b.i.d. b.i.d. b.i.d. b.i.d.

in 10 min in in in in in in

10 min 10 min 10 min 10 min 10 min 10 min

with no need of further medical contact. The drug is also safe to be taken as only 7% of patients experienced side effects during follow-up. Current guidelines recommend flecainide as “pill in the pocket” in class IIa, level of evidence B [22]. A cardioversion strategy with the “pill in the pocket” approach could be appropriate even in those patients who present to the emergency department for symptomatic AF and a low number of recurrences, in order to reduce future hospital admissions and postpone the start of regular rhythm control therapy. When ineffective in pharmacological cardioversion, flecainide can still help the physician by increasing the chance of a successful electrical cardioversion. The FLEC-SL trial successfully tested premedication with flecainide before electrical cardioversion and the current European guidelines recommend treatment with flecainide (class IIa, level of evidence B) in order to increase the chances of efficacy of electrical cardioversion and prevent immediate recurrences of AF [23]. While some evidence suggests that the administration of flecainide prior to the procedure correlates to a higher rate of first shock cardioversion compared to placebo [24] it has not been confirmed in other observational studies [25], and randomized clinical trials are still lacking.

only for the rhythm management of AF. The half-life of intravenous flecainide at therapeutic dosages (0.5−2 mg/Kg) is between 7–18 hours. [14] 4. Clinical indications 4.1. Sinus rhythm restoration Flecainide can be used for many clinical indications. The approved ones are listed in Table 2. The most frequent use of flecainide is for pharmacological cardioversion of persistent or paroxysmal AF. Sinus rhythm is achieved through a reduction of the action potential duration and a concomitant increase in atrial refractoriness, leading to the termination of the re-entry circuit [2]. On the other hand, the preservation of sinus rhythm after a documented episode of AF (the so-called “rhythm control strategy”) cannot be explained by the use-dependent inhibition of the sodium channels: it could, however, be due to the inhibition of the potassium and, indirectly, of the calcium currents. According to the latest guidelines of the European Society of Cardiology [16], flecainide is recommended (class of recommendation I, level of evidence A), together with propafenone and vernakalant, for pharmacological cardioversion of AF in patients with no structural heart disease. The intravenous dosage is 1.5–2 mg/Kg (maximum 150 mg) to be diluted in 100 ml of glucose solution 5% in at least 10 min. If ineffective, some authors describe the possibility of administering 1.2–1.5 mg/Kg/h for the first hour and then to start an infusion at the rate of 0.12-0.25 mg/kg/h for the following hours, up to a maximum of 24 h [4]. Other authors suggest a simplified protocol that includes a bolus of 1.5–2 mg/Kg (maximum 150 mg) plus an infusion at a rate of 0.007 mg/kg/min in order to obtain the pharmacological expected effect after the first three hours [5]. In case of oral administration, the dose of flecainide is of 200–300 mg in one single dose as soon as AFrelated symptoms start [17]. The efficacy of flecainide in restoring sinus rhythm depends on patient’s characteristics, mode of administration, dosage, and time from AF onset, therefore the reported conversion rates vary between 55% and 92%. Nonetheless, flecainide is traditionally described as one of the most effective drugs for AF cardioversion [5,18,19]. Moreover, intravenous administration of flecainide offers a very short time to conversion to sinus rhythm [4]. The mean time to cardioversion is 2–4 h with intravenous administration to a maximum of 8 h when the drug is given orally [17]. This is especially important in an emergency setting as after 48 h the thromboembolic risk is increased and therefore cardioversion is contraindicated unless further tests (such as transesophageal echocardiography) are carried out. It must be noted, however, that the absence of adverse events during the intravenous administration of flecainide does not correlate to the incidence of adverse events during oral administration [20]. Alboni et al. described how in patients previously cardioverted with intravenous flecainide, home self-administration of the drug has proven to be effective in restoring sinus rhythm [21]. If taken within 10 min from symptoms’ onset, 94% of palpitations cease within four hours,

4.2. Rhythm control strategy Flecainide can be used for rhythm control in symptomatic patients, lone AF, and before ablation procedure, given that the patient does not have ischaemic heart disease or heart failure, in accordance with the ESC guidelines (class I, level of evidence A). The dose of the drug administered to obtain rhythm control is variable: we can currently find on the American and European market formulations as low as 25 mg b.i.d. up to a maximum of 100 mg b.i.d. To this day, many trials have studied the effects of antiarrhythmic drugs in recurrent AF. However, many of them have small sample sizes, test different therapeutic schemes, and are hardly comparable between each other. Moreover, many such trials used only symptomatic or incidentally-diagnosed recurrences of AF as an endpoint, not taking into consideration all asymptomatic and short episodes, which are however very frequent and hold the same prognostic value [26]. The 2015 review on antiarrhythmic drugs of the Cochrane Database [19] shows the efficacy of chronic treatment with flecainide acetate compared to control patients, with an Odds Ratio better than propafenone and second only to amiodarone (Fig. 2). An older meta-analysis on 60 studies showed that 65% of patients respond successfully to a short term treatment and 49% to a long term one [27], therefore indicating that flecainide is more efficient than propafenone, amiodarone and dronedarone in terms of rhythm control, although no head to head comparisons are available. The PITAGORA was a multicentre, prospective, randomized, single blinded study that compared amiodarone and IC drugs in maintaining sinus rhythm in patients with a pacemaker indication for sinus node disease and AF [28]. It was planned as a non-inferiority study and the primary endpoint was a composite of death, permanent AF, hospitalization for cardiovascular cause, necessity of electrical cardioversion and change in antiarrhythmic medication. Only flecainide was 3

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Fig. 2. Indirect comparisons between flecainide, class I anti-arrhythmic drugs and amiodarone. Data taken from [19].

(flecainide), group C (metoprolol). The primary endpoint was the recurrence of AF, either symptomatic or diagnosed during routine ECGs. Follow-up was 12 months. Out of 173 patients, 80 were randomised to group A, 72 to group B and 21 to group C. Enrolment in the metoprololonly group was stopped prematurely due to a high number of recurrences registered during the first ad interim analysis (76.2%). In this trial, the combination therapy significantly reduced AF recurrences after one year by 20% (relative risk reduction of 30%). With regards to the two types of AF (permanent and paroxysmal) the estimated time free from recurrence was similar, even though patients with persistent AF had an overall higher risk profile. In addition to this, it was found that the patients with persistent AF randomized to the combination group experienced fewer recurrences compared to those randomized to group B. A similar, but not significant, trend was registered for patients with paroxysmal AF. The combined therapy proved itself safe: in group A, one patient interrupted the therapy due to fatigue and another one due to worsening of his renal function. Similarly, in group B, one patient ceased treatment because of dermatotoxicity and another one due to fatigue. No episodes of atrial flutter conducted 1:1 were reported. Other forms of tachyarrhythmias were registered, but they did not lead to treatment withdrawal. The authors therefore concluded that the combination treatment could be as effective and safe as the flecainide alone in preventing recurrences in patients with persistent AF. Another prospective study investigated the efficacy and safety of amiodarone in association with flecainide [32]. Dual antiarrhythmic therapy was started in patients awaiting ablation, in patients who had already undergone ablation but suffered from frequent symptomatic recurrences, and in patients with recurrent paroxysmal AF refractory to antiarrhythmic therapy. All patients underwent treatment with amiodarone for at least four months and started flecainide at the lowest dose of 25 mg b.i.d., titrated to 50 mg b.i.d. Seventy-five percent of patients showed an improvement of the AF-related symptoms in the first year and 60% during the second year. No syncopal episodes or deaths were documented. However, among those patients who declared a symptomatic relief, 37% had to stop the combination therapy. In conclusion, it is clear how the combined therapy with an antiarrhythmic and a rate-lowering drug can be both safe and effective. On the other hand, simultaneous administration of drugs from different Vaughan-Williams classes can be burdened by a plethora of side effects, and is not recommended by some experts [13], while there is a known contraindication to the use of different class I drugs together [16].

demonstrated to be non-inferior to amiodarone. Moreover, in the PITAGORA trial, amiodarone and IC drugs had similar efficacy in preventing AF episodes longer than 10 min or one day, while amiodarone seemed better in preventing AF episodes longer than a week [28]. Regardless of the guidelines recommendations, class IC drugs appear to be under used in everyday clinical practice, possibly due to an over perception of the severity of the side effects. A retrospective study on the American database “Thomas Reuters MarketsScan Commercial Claims and Encounters” documented an overall excessive use of amiodarone compared to IC drugs, while these latter were preferred in females, in patients with a history of atrial flutter, in patients with a known history of AF and in patients already treated with verapamil or diltiazem [29]. On the other hand, these drugs were avoided or scarcely used in older hospitalised patients, in patients with diabetes and in patients under anticoagulant treatment. Such a trend was observed both before and after the introduction on the market of dronedarone. The same retrospective study also underlined that flecainide also had a lower discontinuation rate (40%) when compared to amiodarone (52%) and dronedarone (69%) over a 5-year follow-up. According to the current guidelines, rate control medications are often associated with antiarrhythmic therapy in order to hamper or slow AF natural progression. In 2003, the VAPARAF study investigated the effects of verapamil in association with antiarrhythmic therapy [30]. Three hundred and sixty-three patients were enrolled in this multicentre, prospective, randomized study. The patients were divided in four groups: group A (amiodarone four weeks prior to cardioversion), group F (flecainide three days prior to the cardioversion), group A + V (amiodarone four weeks prior to cardioversion and verapamil were administered; verapamil three days prior to the cardioversion), group F + V (both flecainide and verapamil three days prior to the cardioversion). All patients who presented a recurrence within 3 months were crossed over to another group and a second electrical cardioversion was planned after 48 h. The study concluded that verapamil added to flecainide significantly reduced the recurrences of AF with no significant increase in side effects and no increased withdrawals. A more recent study conducted at our clinic investigated the efficacy of combined treatment with flecainide and metoprolol in patients with paroxysmal and permanent AF [31]. The hypothesis that the two drugs might have a synergistic action comes from the pathophysiological basis according to which Nav1.5 inward current could be modulated by beta-adrenergic receptors through a the cGMP pathway. One hundred and seventy three patients naïve for antiarrhythmic therapy were consecutively enrolled and randomized into three groups right after electrical cardioversion: group A (flecainide and metoprolol), group B: 4

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in order to cause a retrograde block, which is complete when the cycle is less than 270 ms. A meta-analysis described how flecainide administration may determine a success rate of 72% in the acute setting in patients with atrioventricular re-entry tachycardia and 83% in patients with atrioventricular node re-entry tachycardia [27]. In case of longterm treatment, the efficacy rates have been registered to be respectively of 70% and 78%. With regards, to atrial ectopic tachycardia, 86% of patients responded to flecainide in the acute setting and 95% during chronic treatment. With regards to the possibility of using combination therapy in supraventricular tachycardia (i.e flecainide plus other rhythm or rate control drugs), little data is available in literature and it mainly refers to pediatric population. As described in paragraph 7.3, in fact, flecainide is the first line drug in pediatric patients affected by ventricular or supraventricular arrhythmias and its combinations with other drugs such as sotalol has been described to be effective in refractory supraventricular tachycardia [40]. Moreover, flecainide has also been described in combination with amiodarone and either esmolol or propranolol in neonates and infants with incessant supraventricular tachycardia [41].

4.2.1. Treatment duration The FLEC SL trial was a prospective, randomized, double-blind study, which evaluated recurrences with daily ECG and Holter monitoring [23]. The primary endpoint was the time to recurrence of persistent AF or all-cause mortality. Three treatment regimens were compared: no antiarrhythmic drug treatment; treatment with flecainide (200–300 mg per day) for four weeks; and flecainide (200–300 mg per day) for 6 months. The shorter treatment duration proved itself to be non-inferior compared to the longer one. In addition to this, a post hoc analysis of those patients who did not reach the primary endpoint after one month showed that the longer treatment period was superior to the shorter one and both were superior to placebo after four weeks of therapy. 4.2.2. Controlled release formulations As the patient compliance tends to decrease with the increase of number of pills taken during the day, a modified release formulation of the drug was developed in order to overcome the b.i.d. administration of flecainide acetate. Such a formulation requires once a day administration and was recently approved for maintaining sinus rhythm in patients with persistent or paroxysmal AF [12]. A French study demonstrated a similar efficacy between the immediate release and the controlled release formulations [33]. In addition to this, the safety of the modified release formulation was investigated in another study based on the maximum variation of the length of the QRS compared to baseline [34]. The increase in the QRS duration was < 15% in 71.8% of patients and ≥ 25% in 18.8% of patients, but only in three patients the duration was above 120 msec. A prospective, randomized study analysed the length of the QRS and the plasma concentration of the active principle for both formulations at baseline and after 8 weeks [35]. It concluded that the two formulations were comparable in terms of pharmacodynamics and that the QRS length varied during the day with the immediate release formulation but not with the modified release one. Although from a safety point of view the two formulations were comparable, it is possible that avoiding the fluctuations on QRS length could reduce the incidence of side effects, but at the same time reduce the anti-arrhythmic effect of flecainide itself, due to a lower batmotropic effect.

4.4. Ventricular tachycardia The treatment of ventricular tachycardia and ventricular ectopic beats represented the first historical clinical indication for flecainide. Unfortunately, the CAST study was prematurely stopped for increased mortality in patients taking flecainide or encainide (see also chapter 5.2) [42]. In patients with previous myocardial infarction, history of ventricular ectopic beats or non-sustained ventricular arrhythmias and impaired left ventricular ejection fraction, flecainide significantly increased the risk of arrhythmia-related (HR 2.64; 95%CI: 1.60–4.36) and all-cause mortality (2.38; 95%CI: 1.59-3.57). It is worth mentioning that 53% of all patients enrolled had a left ventricular ejection fraction≥0.40 [2]. According to current guidelines, flecainide can be used in patients with normal systolic function and no ischemic heart disease for the prevention of ventricular arrhythmias, both alone and in combination with potassium-channel blockers. Intravenous use of flecainide or procainamide can be considered in selected patients with no structural heart disease in order to restore sinus rhythm, if the electrical cardioversion is not feasible or not accepted by the patient [43]. In addition to this, two studies by Ermakov et al. have described combination therapy with flecainide and sotalol/metoprolol or flecainide, sotalol and mexiletine as both effective and safe in refractory ventricular tachycardia associated with right ventricular cardiomyopathy and no LV dysfunction [44,45].

4.3. Supraventricular tachycardia and ventricular pre-excitation Flecainide has been proven to reduce the recurrences of supraventricular arrhythmias. This could be related to the inhibition of the potassium and calcium currents (negative batmotropic effect) and subsequent reduction of cellular excitability. In clinical practice, a betablocker is usually used as a first line therapy in atrioventricular nodal re-entry tachycardia [36]. However, if beta-blockers are not effective or contraindicated, flecainide represents a feasible alternative. Concerning pre-excitation syndromes such as Wolff-ParkinsonWhite (WPW), class IC drugs were indicated by the European guidelines up until the last update of 2016. Intravenous flecainide in generally more effective on the accessory pathway rather than on the atrioventricular node and the His-Purkinje system. [37] Flecainide is shown to block anterograde conduction in 40% of cases and retrograde conduction in 50% of cases, vastly prolonging refractoriness of the accessory pathway in the other patients. Moreover, flecainide increases the atrial cycle length in patients with AF and WPW and decreases the ventricular response during high-frequency AF episodes, thus lowering the chances of degenerating into ventricular fibrillation [38]. Chronic administration of flecainide is able to prevent AF induction in nearly 50% of patients with WPW during an electrophysiological study, and vastly decreases symptomatic AF recurrences [39]. Nowadays, the most recent guidelines emphasize the need to obtain rate control rather than rhythm control so intravenous propafenone, procainamide and ajmaline are preferred to amiodarone and flecainide. The aim is to slow retrograde conduction within the accessory pathway

4.5. Cathecolaminergic polymorphic ventricular tachycardia (CPVT) This arrhythmia is due to a mutation of the type 2 ryanodine receptor (RyR) calcium release channels genes and less frequently of the calsequestrin (type 2 sarcoplasmatic binding protein CASQ2) gene. In 60% of patients affected, a mutation of the two genes leading to corrupted protein is noted. The electrophysiological effect is a leak of calcium by the ryanodine channel with a concomitant accumulation of cytosolic calcium. The antiport calcium-sodium is then activated, leading to delayed depolarizations and triggered activities, which can cause ventricular arrhythmias especially during increased adrenergic tone [8]. Flecainide, especially when combined to beta-blockers, is able to reduce the calcium accumulation in the cytosol, reducing delayed depolarization [46]. The antagonising effect of flecainide is performed directly on the RyR calcium channel and indirectly on the sodium currents via both the Nav1.5 channel and the antiport. A multicentre retrospective study reported a 76% reduction of CPTV episodes during physical activity with no side effect registered [47]. More specifically, in 8 out of 33 patients, the reduction was partial while in 14 ventricular 5

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of triggering ventricular fibrillation during the test [59]. The sensibility and specificity of the flecainide test are proportional to the pre-test selection of patients. The FINGER multicentre trial showed how the incidence of arrhythmic events during follow up in patients who were initially asymptomatic was 0.8% in patients with a spontaneous type 1 pattern and 0.4% in patients with an induced type 1 pattern [60]. In addition to this, in the PRELUDE trial no asymptomatic patients with induced type 1 pattern experienced arrhythmias during the 3 year follow up [61]. The guidelines recommend the test to be carried out only in those patients with clinical suspect of Brugada syndrome (cardiac arrest or syncope) and with no ECG pattern type1 as a positive test without clinical suspect has no positive predictive value for future arrhythmias [43]. Similarly, performing the test on patients who already have a spontaneous type 1 Brugada pattern does not add any diagnostic information. While surely diagnostic, the clinical usefulness and the prognostic value of the flecainide test is still to be defined.

Fig. 3. Most common non-cardiac side effects. Data taken from [4].

tachycardia was completely abolished after flecainide administration. This result was then confirmed in a sub analysis conducted only the patients undergoing optimal beta-blocking treatment. A prospective randomized trial carried out on 14 pediatric patients undergoing betablocker therapy showed a complete suppression of CPVT episodes in 85% of patients after flecainide administration, with no significant differences in terms of side effects between flecainide and placebo [48]. The same efficacy was confirmed in patients with CPTV with no known gene mutation [49]. The latest update of the American guidelines on the treatment of ventricular arrhythmias describes the use of flecainide in patients with CPTV as class of recommendation I, level of evidence evidence B in symptomatic patients or if arrhythmias are still registered despite maximum tolerated beta-blocker dose [50].

5. Practical aspects 5.1. Side effects The Cochrane database analysis on all antiarrhythmic drugs [19] describes the safety of flecainide in patients with no contraindication as being the only drug which did not determine any deaths in the studies taken into account (along with propafenone) and the drug that was interrupted the most because of side effects (Fig. 2). With regards to side effects associated with the immediate release formulation, noncardiac ones are the most frequent, they start at initiation of treatment, and are often transient. The only exception is peripheral neuropathy, which, although rare, only appears after prolonged treatment. Rare and with no demonstrated cause effect are hypertransaminasemia, liver failure, cholestasis, and blood dyscrasias. Please see Fig. 3 for a list of the most frequent side effects associated with flecainide. A meta-analysis of 122 studies including 4811 patients with supraventricular tachyarrhythmias showed a lower incidence of hypotension, diarrhoea, headache, nausea, proarrhythmic episodes and angina, when compared to controls [62]. On the contrary, effects on the central nervous system and visual disturbances were significantly increased in the patients treated with flecainide. About the modified release formulation, reported side effects are mainly gastro-intestinal intolerance, respiratory disturbances, central nervous system disturbances, peripheral neuropathy and musculoskeletal disorders. As previously stated, flecainide in combination with metoprolol was effective in reducing AF recurrences and it decreased side effects, and improved quality of life scores [31]. A real life, observational, retrospective study described, in 112 patients with paroxysmal or persistent AF, an increase of long-term mortality linked with the use of flecainide with a mortality standardized ratio for all causes of 1.57 and 4.16 for cardiovascular deaths [63].

4.6. Diagnostic test for type 1 Brugada pattern Malfunctioning of the Nav1.5 channel is correlated to two different channellopathies: Brugada syndrome and type 3 long QT syndrome [43]. In Brugada syndrome, there is a loss of function of the channel with a subsequent reduction of the inward sodium current, while in the long QT syndrome there is an increase in the inward sodium due to an increased activity of the late sodium inward currents secondary to the inability of the Nav 1.5 to remain inactivated [51]. It is therefore unclear how some patients might have both a QT prolongation and an elevation of the ST segment in the right precordial leads, as if in an “overlap syndrome” [8]. Hence, although apparently appropriate, the use of flecainide in the type 3 long QT syndrome could have a pro arrhythmic effect, therefore pushing the current guidelines to recommend mexiletine instead of flecainide in these patients. The use of flecainide is however described as a diagnostic tool for Brugada syndrome: a 10 min 2 mg/Kg infusion can cause a reduction in the velocity of the action potential, which is added to the decreased conduction of the action potential related to the disease itself. This test allows the clinician to notice a Brugada type 1 pattern on the ECG. The test is positive if an ST elevation > 2 mm with a convex morphology in the right precordial leads is noted. In addition to this, during the infusion of flecainide, three prognostic aspects should be taken into account: coved aspect of the ST segment in the peripheral leads [52], T wave alternation in any lead [53], and S wave in lead I [54], while the induction of ventricular arrhythmias has an uncertain prognostic meaning. Initially, ajmaline at a 1 mg/Kg dosage was proposed instead of flecainide because of a reported diagnostic superiority, possibly due to the inhibition of the transient outward currents drug mediated [55,56]. However, nowadays the use of flecainide has increased in clinical practice and the diagnostic sensibility is similar to that of the ajmaline [57,58], so much so that flecainide is recommended as a class of recommendation IIa, level of evidence B in such cases [50]. Ajmaline seems to have higher sensibility but lower specificity, with a higher risk

5.2. Pro-arrhythmia and systolic dysfunction Flecainide, as all class Ic drugs, can have negative inotropic effects and be proarrhythmic potentially inducing both bradycardia and tachycardia. These side effects, albeit serious, are rare and can be prevented by an accurate patient selection and vigilant monitoring. Salerno et al described how small variations in flecainide serum concentration could lead to severe arrhythmias, and potentially fatal toxic levels (> 700–1000 ng/ml) should be avoided [64]. The most serious side effects were in fact described as concentration-dependant. Therefore, patients at risk for important variations in the serum concentration of the drug, such as patients with liver failure or renal impairment, should undergo periodic monitoring [13]. Most of the relevant pro-arrhythmic side effects usually start within 14 days from start, so it is 6

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investigated by a prospective, randomized trial. Therefore, flecainide contraindication is not based on solid evidences, although burdened by ethical limitations that impede further studies. We would like to underline the fact that no evidence is available regarding patients with subcritical coronary heart disease and no previous myocardial infarct or inducible ischaemia and patients with heart failure with preserved ejection fraction. The anti-arrhythmic drugs used in these categories of patients are very few and burdened by side effects, which often lead to interrupting the treatment.

generally considered as good clinical practice to monitor PR interval, corrected QT interval, and QRS width. Nonetheless, some authors have reported on how the classic ECG alterations subside after 21 days of chronic treatment even in patients with maintained serum concentrations and conserved anti-arrhythmic efficacy. Therefore, they hypothesized a clinical dissociation between flecainide anti-arrhythmic properties and ECG changes, casting doubts on the real usefulness of monitoring [65]. One patient out of three might develop a first-degree AV block after starting flecainide. This block, if asymptomatic, does not represent an indication to stop the treatment or undergo further tests. Second or third-degree atrioventricular blocks represent an indication to withdraw flecainide, unless the patient if already implanted with a pacemaker for another indication. Other potential arrhythmic effects are transient asystole (especially common during cardioversion in patients pre-treated with flecainide due to the drug action on the recovery time of the sinus node) and organization of AF into an atrial flutter with a 1:1 conduction. This latter complication is especially feared for its increased ventricular response, which is around 300 bpm, although available evidences describe a prevalence of less than 2% in all patients treated with flecainide [5,63]. As already mentioned, it must be noted that atrial flutter with a 1:1 conduction can be avoided by the concomitant use of beta-blockers or calcium channel antagonists. As stated above, the initial clinical indication of flecainide was the suppression of ventricular tachycardia and the reduction of ventricular ectopic beats. The 10th of August 1989, preliminary data from the CAST trial were published [42]. The aim of the trial was to demonstrate the efficacy of flecainide, encainide, and moricizine in terms of arrhythmic death reduction in patients with ischemic cardiomyopathy. Unfortunately, the study was interrupted prematurely by the safety board due to the high mortality rate in the group flecainide/encainide. The trial continued to be carried out as CAST II comparing placebo with moricizine but was again interrupted for an excess of mortality in the experimental group. The results of the CAST trial shocked the scientific community worldwide and provided the definitive evidence for the contraindication of flecainide acetate in patients with ischaemic cardiac disease or with reduced systolic function. Myocardial ischaemia might increase the pro arrhythmic effects of the drug as the reduced conduction velocity caused by the drug, in the context of heterogeneity of conduction secondary to the ischaemia and the increase in the drug concentration in the ischaemic areas, can lead to toxic effects. Flecainide is therefore contraindicated in patients with previous myocardial infarction even with preserved ejection fraction. In addition, the drug should not be used in case of proved inducible ischaemia. All contraindications at the start and during treatment with flecainide are described in Table 3. It is important to underline how the isolated inotropic effect in patients with no ischemic heart disease or heart failure has not been

5.3. Overdose As flecainide is a drug with narrow therapeutic index, over dosage is usually fatal and there is no specific antidote. Overdose symptoms comprehend dizziness, tremor, ataxia, pulmonary oedema, bradypnoea, visual disturbances, photophobia, hypotension, bradyarrhythmias, syncope, ventricular tachycardia, new bundle branch block, acute cardiac failure, pulseless electrical activity, and sudden cardiac death. Overdose patients are usually treated with support therapy. However, sodium bicarbonate infusion at high concentrations competes with the bond between flecainide and sodium channels and can reduce the side effects of the drug [64]. In case of bradyarrhythmias, the implantation of a temporary pacemaker might be needed. 5.4. Treatment management Prior to the initiation of treatment with flecainide, even before cardioversion, patients should be assessed to exclude ischemic cardiac disease or Brugada syndrome. A prospective observational study investigated the safety of pharmacological cardioversion with 300 mg of flecainide in 106 patients with recent onset of atrial fibrillation and at least one cardiovascular risk among reduced ejection fraction, heart failure, and PROCAM score > 41,associated with a 10 year risk of MI of 5% [66]. No ventricular arrhythmias, atrial flutter or bradyarrhythmias were observed a part from sinus bradycardia or a sinus pause of 2–4 s immediately after the cardioversion. In case of long-term treatment with flecainide, it is possible that patients develop an organic cardiac disease, including ischaemic cardiac disease, during the treatment period. Therefore, all patients treated with flecainide should be educated in recognising heart failure and ischemic heart disease symptoms such as angina, dyspnoea for physical stress, syncope or dizziness [5]. 6. Pharmacological interactions Flecainide should not be administered with other IC antiarrhythmic drugs. In addition to this, association with other anti-arrhythmic drugs should be carried out only after careful evaluation of risks and benefits. Regarding the association with beta-blockers and calcium-channel

Table 3 Contraindications. Absolute

Relative

Structural heart disease: Ischemic heart disease (previous acute coronary syndrome, instrumentally inducible ischemia) Heart failure Impaired left ventricular function Cardiogenic shock Hemodynamically significant valvular heart disease Conduction disturbances: Sick sinus syndrome Second or third degree atrioventricular block Left bundle branch block Bi-fascicular block (right bundle branch block + left anteriore hemiblock) Intra-ventricular aspecific conduction delay (QRS > 120 msec) Brugada Syndrome

Previous history of impaired left ventricular dysfunction Electrolytes imbalance Hypersensitivity to the active substance or to the excipients Impossibility to monitor the patient after intake Severe chronic kidney disease (eGFR < 35 ml/min/1.73 m2) Excess of extracardiac adverse effects

7

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7.3. Pediatric population

Table 4 Pharmacological interactions. Patient monitoring

Consider therapy modification

Avoid combination

alfuzosin carbonic anhydrase ihibitors chloroquine ciprofloxacin moderate CYP2D6 inhibitors darunavir etravirine PEG-interferon a2b sodium bicarbonate sodium lactate tromethamine verapamil

amiodarone bupropion gadobutrol QTc-prolonging agents strong CYP2D6 inhibitors

dronedarone indinavir lopinavir lumefantrine mizolastine pimozide quinine ritonavir terfenadine tetrabenazine thioridazine tipranavir ziprasidone

Flecainide is the recommended first line therapy drug for the treatment of supraventricular and ventricular arrhythmias in the paediatric population, in particular for foetuses, infants and children with normal cardiac anatomy and preserved ventricular function. As recommended by the last consensus statement, flecainide should be used for the following indications [67]: - Acute termination of regular narrow QRS tachycardia when both vagal manoeuvres and adenosine fail. This is especially true in patients under the year of age or with contraindication to verapamil and diltiazem; - Chronic prophylactic treatment of narrow QRS tachycardia; - Idiopathic ventricular beats, when symptomatic and not controlled with propranolol; - As a second line therapy in idiopathic monomorphic ventricular tachycardia, with propranolol and amiodarone as first choices; - WPW syndrome (orthodromic or antidromic tachycardia or pre-excited atrial fibrillation; - Prevention of ventricular arrhythmias in type 3 long QT syndrome; - Treatment and prevention of CPVT when not adequately controlled with beta-blockers.

blockers, both substances have a negative inotropic effect, which should always be taken into account. When flecainide is associated with digoxin, concentration of the glycoside could increase by 13–19% within 6 h from administration therefore leading to a possible toxic effect. To conclude, tobacco stimulates CYP450 and increases flecainide turnover [14]. In Table 4 we reported all possible drug interaction with flecainide.

Table 5 synthetizes the recommended doses for each indication. On a note, although the CAST trial [42] demonstrated an important proarrhythmic effect in adults with previous myocardial infarction and left ventricular depression, these findings could not be translated to the paediatric population. Despite its larger use in the paediatric population with congenital heart disease de-facto, the discordant results on safety emerged from retrospective studies bring out the need for further larger studies to validate its use in that population [68]. Finally, flecainide (even in combination with digoxin) is recommended as first line treatment of foetal supraventricular tachyarrhythmias, both in short and long V-A interval [69].

7. Special populations 7.1. Hepatic and renal impairment Patients with liver failure or renal impairment risk drug overdose [12]. More specifically the half-life of the drug is prolonged in proportion to the level of renal impairment. Flecainide is scarcely dialysed. It is therefore contraindicated in patients with end stage renal disease and liver failure. 7.2. Pregnancy

8. Conclusions

Flecainide has been shown to have a teratogenic effect on animals. As there is currently no specific evidence, the drug can be used in pregnancy only if the benefit outweighs the risk for the foetus. In fact, flecainide is bound to plasma proteins and therefore can cross the placenta and be excreted in breast milk. Some case reports have described safety in the treatment of foetal supraventricular tachyarrhytmias, especially with trans-placenta administration and monitoring of the mother plasma levels [10].

To conclude, flecainide can be used of a plethora of indications in the acute and chronic treatment of many arrhythmias including atrial fibrillation, other supraventricular arrhythmias, CPVT, and ventricular tachycardia. Moreover, its effectiveness can be further increased by combination therapy with other anti-arrhythmic drugs, a strategy that is commonly used in many clinical scenarios. Flecainide-related side

Table 5 Recommended doses and indications in paediatric population. Arrhythmia

Acute termination

Atrioventricular nodal re-entrant tachycardia (AVNRT)* Junctional ectopic tachycardia Permanent junctional reciprocating tachycardia*** Atrioventricular re-entrant tachycardia (AVRT)WPW syndrome and recurrent SVT*** Preexcited AF WPW syndrome and single or infrequent SVT Focal/Multifocal atrial tachycardia*** Atrial flutter** Symptomatic ventricular extra beats Idiopathic ventricular tachycardia Right ventricular outflow tract tachycardia LQT3 syndrome CPVT

1,5−2 mg/kg 1,5−2 mg/kg 1,5−2 mg/kg 1,5−2 mg/kg

diluted diluted diluted diluted

Prophylactic treatment in in in in

H2O H2O H2O H2O

over over over over

5 5 5 5

min min min min

3 mg/kg p.o. when necessary (pill in the pocket) 1,5−2 mg/kg diluted in H2O over 5 min 1,5−2 mg/kg diluted in H2O over 5 min

2–7 mg/kg 2–7 mg/kg 2–7 mg/kg 2–7 mg/kg

p.o. p.o. p.o. p.o.

b.i.d. b.i.d. b.i.d. b.i.d.

2–7 mg/kg p.o. b.i.d. 2–7 mg/kg p.o. b.i.d.

1,5−2 mg/kg diluted in H2O over 5 min 1,5−2 mg/kg diluted in H2O over 5 min 2–7 mg/kg p.o. b.i.d. 2–7 mg/kg p.o. b.i.d.

* Given the high prevalence of atrial flutter in infants and the difficulties to manage the sympathetic tone, when flecainide is chosen to stop atrioventricular nodal tachycardia (AVNRT), it should be combined with propranolol or another beta blocking agent, to reduce the risk of 1:1 conduction. ** always added to digoxin. *** also in combination with sotalol (range: 100–250 mg/m2/day) when refractory to flecainide alone. 8

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effects are well known, and can be managed with relatively ease by experienced physicians. Further evidences are needed in order to tell if controlled-release formulation has the safe efficacy and safety as the classic formulation for atrial fibrillation and for chronic prophylaxis of other arrhythmias as well. Moreover, it is time to gather data regarding flecainide safety in specific populations, such as heart failure with preserved ejection fraction, reversible forms of systolic dysfunction, and non-obstructive coronary atherosclerosis.

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Declaration of Competing Interest All authors declare they have no conflicts of interest. References

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