Flecainide

Article Author:
Karuppiah Arunachalam
Article Editor:
Talal Alzahrani
Updated:
5/21/2019 7:44:23 PM
PubMed Link:
Flecainide

Indications

Flecainide acetate is an oral class Ic antiarrhythmic drug (AAD) which blocks cardiac Na+ channels and was approved by the FDA in 1984. Flecainide is used in paroxysmal supraventricular tachycardia (PSVT’s), including atrioventricular nodal re-entrant tachycardia (AVNRT), AV re-entrant tachycardia (AVRT) and atrial fibrillation/atrial flutter in patients who do not have structural heart disease. Flecainide is also an option in treating life-threatening ventricular arrhythmias. 

Mechanism of Action

Flecainide acts on the fast-inward Na+ ion channel and has a high affinity to activated or open Na+ channels. It prolongs the depolarization and increases refractoriness due to slow release from its binding site. It potently acts on the His-Purkinje system. It also works by inhibiting IKr channels, delaying potassium rectifier current resulting in prolongation of action potential duration in both ventricular and atrial muscle fibers. Flecainide is shown to block ryanodine receptor opening, which reduces calcium release from sarcoplasmic reticulum resulting in after depolarization and triggered activity. Hence, indications for flecainide include catecholaminergic polymorphic ventricular tachycardia (CPVT).

Administration

ACC/AHA/HRS guidelines 2014 recommends a total daily dose of 400 mg orally. Initiating dose for paroxysmal atrial fibrillation/paroxysmal atrial flutter/PSVT is 50 mg every 12 hours; increase by 50 mg twice daily at 4-day intervals. No dosage changes are necessary for liver disease as per the manufacturer. With renal disease and CrCl less than 35ml/min/1.73m, caution is necessary when increasing dose at 4-day intervals.

Breastfeeding considerations:

Flecainide is present in breast milk; relative Infant dose is 8% when maternal dosing is 200mg/day. The relative infant dosing is calculated using the highest average breast milk concentration in comparison to the maternal dosage. Breastfeeding is acceptable as long as relative infant dosing is under 10%.

Pharmacodynamics and pharmacokinetics:

Oral bioavailability is nearly 100% but decreases when administered with milk. It is 40% protein bound, and half-life elimination varies across age groups. In newborns: less than 28 hours, 3 months: 11 to 12 hours, 12 months: 6 hours. In children: 8 hours, adolescents 12 to 15 years: approximately 11 hours, adults: 12 to 24 hours. It takes 1 to 6 hours to peak in serum after administration. Excreted in urine 30% and feces 5%.[1][2][3]

Adverse Effects

Cardiac toxicity:

Flecainide has a proarrhythmic effect with an increased incidence of mortality and non-fatal cardiac arrest in patients with a history of myocardial infarction and asymptomatic premature ventricular contractions (PVCs)/non-sustained ventricular tachycardia (NSVT). Flecainide prolongs depolarization and can slow conduction in the AV node, His-Purkinje system. These changes can result in prolonged PR interval, first-degree heart block, and second-degree heart block. Preexisting sinus node disease can result in profound bradycardia. It does not affect repolarization so exerts a mild effect on QT interval. Flecainide has a negative inotropic effect on cardiac muscles. Therefore, its use in heart failure patients is contraindicated. Flecainide has the potential to convert atrial fibrillation into atrial flutter with 1 to 1 conduction and also ventricular tachyarrhythmias, so beta-blockers or calcium channel blockers should be used concurrently.[2][4]

Contraindications

According to AHA/ACC/HRS 2017 guidelines, flecainide is contraindicated in patients with structural heart disease. Other contraindications include hypersensitivity, documented second or third degree AV block, sick sinus syndrome, bundle branch block, cardiogenic shock, acquired/congenital QT prolongation with a history of torsades de pointes, and concurrent intake of ritonavir.

Monitoring

Narrow therapeutic index:

There are an increased response and a steep relationship between dose and concentration. Plasma levels require monitoring in patients with severe renal failure or severe hepatic disease. Drug overdose could be fatal with flecainide. Dosing should be adjusted based on clinical response.[5]

Monitoring parameters:

In patients with renal failure or hepatic impairment, it is prudent to monitor EKG, blood pressure, periodic serum trough concentration. Therapeutic trough concentration is between 0.2 to 1 mcg/ml.  Lower trough concentration is sufficient in pediatric patients.

Enhancing Healthcare Team Outcomes

In this section, we will discuss evidence-based use and outcomes associated with flecainide in various clinical settings.

CAST trial (Cardiac Arrhythmia Suppression Trial):

Initially, it was thought to be effective in the treatment of PVCs/NSVT after myocardial infarction to reduce the incidence of sudden death. However, multicenter randomized placebo-controlled trial on patients after myocardial infarction, use of flecainide was associated with increased mortality due to fatal arrhythmias. So, flecainide is considered in patients without coronary artery disease and left ventricular dysfunction. Currently, contraindications to flecainide include patients with left ventricular hypertrophy, ischemic heart disease, HOCM, high degree AV block, and complete heart block.[6]

PITAGORA trial:

A multicenter single-blind prospective randomized trial compared amiodarone with class IC (propafenone and flecainide) in patients with atrial fibrillation and pacemaker due to sinus node disease for maintaining sinus rhythm as a goal. Flecainide was found to be non-inferior and also equal efficacious in preventing episodes more than 10 mins or 1 day.[7]

Pill in the pocket approach:

According to the NEJM study published in 2004, flecainide is one of the drugs apart from propafenone used in outpatient or emergency room setting to treat symptomatic atrial fibrillation. In some patients oral prophylaxis or catheter ablation may not be feasible, a single dose of antiarrhythmic at the time of onset of symptoms is appropriate. The dose of flecainide was 300 mg for patients more than 70 kg or 200 mg otherwise. Around 165 patients were followed for 2 years, 94% of patients were successfully treated after the onset of symptoms within 2 hours. Recurrences were treated up to 84 percent. The number of emergency room visits and hospitalizations were significantly lower during the study period compared to the year before the treatment period.[8]

Acute cardioversion in emergency departments:

Based on recent meta-analyses, IV flecainide is superior to other antiarrhythmics like ibutilide, amiodarone, sotalol, propafenone, and procainamide. Eleven randomized controlled trials were analyzed and found that flecainide had high efficacy with cardioversion within 2 hours. No statistically significant difference in proarrhythmic behavior compared to placebo or other antiarrhythmics.[9]

Effect on atrial remodeling:

Structural changes in atria occur due to atrial fibrillation leading to myocardial remodeling and mitochondrial dysfunction due to oxidative stress. Atrial activation rapidly leads to intracellular calcium accumulation due to Na+/Ca2+ exchanger during atrial fibrillation. Flecainide inhibits intracellular Ca2+ accumulation by which reduced atrial remodeling and oxidative stress.[10]

Fetal tachycardia:

Flecainide is proven to be of use in the transplacental treatment of fetal tachycardia. Flecainide was found to be superior to digoxin and sotalol in termination of fetal tachycardia, especially supraventricular tachycardia. The placental transfer is not affected in hydrops fetalis.[11]

Catecholaminergic polymorphic ventricular tachycardia:

As discussed above, flecainide inhibits cardiac ryanodine receptors in open state which is responsible for the release of calcium leading to CPVT. Flecainide suppresses 76% of exercise-induced ventricular arrhythmias in 33 genotype-positive patients. It is also found to be efficacious in suppressing ventricular tachyarrhythmias in genotype negative patients.[12]

Practical aspects before and during initiation of flecainide:

1. Exercise stress test before initiating to rule out coronary artery disease and during the treatment when there is resting QRS prolongation

2. EKG to monitor for QRS prolongation, the dose should be reduced to half the initial dose if QRS increases by 25%

3. Screen for sinus and AV node disease

4. Concurrent use of negative chronotropic agents like beta blockers

Pharmaceutical therapy with flecainide requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level V]


References

[1] Holmes B,Heel RC, Flecainide. A preliminary review of its pharmacodynamic properties and therapeutic efficacy. Drugs. 1985 Jan;     [PubMed PMID: 3882390]
[2] Roden DM,Woosley RL, Drug therapy. Flecainide. The New England journal of medicine. 1986 Jul 3;     [PubMed PMID: 3520324]
[3] Conard GJ,Ober RE, Metabolism of flecainide. The American journal of cardiology. 1984 Feb 27;     [PubMed PMID: 6364769]
[4] Andrikopoulos GK,Pastromas S,Tzeis S, Flecainide: Current status and perspectives in arrhythmia management. World journal of cardiology. 2015 Feb 26;     [PubMed PMID: 25717355]
[5] Tamargo J,Le Heuzey JY,Mabo P, Narrow therapeutic index drugs: a clinical pharmacological consideration to flecainide. European journal of clinical pharmacology. 2015 May;     [PubMed PMID: 25870032]
[6] Echt DS,Liebson PR,Mitchell LB,Peters RW,Obias-Manno D,Barker AH,Arensberg D,Baker A,Friedman L,Greene HL, Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. The New England journal of medicine. 1991 Mar 21;     [PubMed PMID: 1900101]
[7] Gulizia M,Mangiameli S,Chiarandà G,Spadola V,Di Giovanni N,Colletti A,Bulla V,Circo A,Pensabene O,Vasquez L,Vaccaro I,Grammatico A, Design and rationale of a randomized study to compare amiodarone and Class IC anti-arrhythmic drugs in terms of atrial fibrillation treatment efficacy in patients paced for sinus node disease: the PITAGORA trial. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2006 Apr;     [PubMed PMID: 16627459]
[8] Alboni P,Botto GL,Baldi N,Luzi M,Russo V,Gianfranchi L,Marchi P,Calzolari M,Solano A,Baroffio R,Gaggioli G, Outpatient treatment of recent-onset atrial fibrillation with the     [PubMed PMID: 15575054]
[9] Intravenous Flecainide for Emergency Department Management of Acute Atrial Fibrillation., Markey GC,Salter N,Ryan J,, The Journal of emergency medicine, 2018 Mar     [PubMed PMID: 29269083]
[10] Iwai T,Tanonaka K,Inoue R,Kasahara S,Motegi K,Nagaya S,Takeo S, Sodium accumulation during ischemia induces mitochondrial damage in perfused rat hearts. Cardiovascular research. 2002 Jul;     [PubMed PMID: 12062717]
[11] Alsaied T,Baskar S,Fares M,Alahdab F,Czosek RJ,Murad MH,Prokop LJ,Divanovic AA, First-Line Antiarrhythmic Transplacental Treatment for Fetal Tachyarrhythmia: A Systematic Review and Meta-Analysis. Journal of the American Heart Association. 2017 Dec 15;     [PubMed PMID: 29246961]
[12] van der Werf C,Kannankeril PJ,Sacher F,Krahn AD,Viskin S,Leenhardt A,Shimizu W,Sumitomo N,Fish FA,Bhuiyan ZA,Willems AR,van der Veen MJ,Watanabe H,Laborderie J,Haïssaguerre M,Knollmann BC,Wilde AA, Flecainide therapy reduces exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. Journal of the American College of Cardiology. 2011 May 31;     [PubMed PMID: 21616285]