Flecainide –

An Underrated Antiarrhythmic Drug

EFFICACY OF FLECAINIDE
IN ATRIAL AND
VENTRICULAR
ARRYTHMIAS
Atrial Fibrillation
• Atrial fibrillation (AF), most common type of cardiac arrhythmia is
characterized by complete disorganization of atrial electric activity and
consequent loss of atrial systole with a characteristic and easily
recognizable electrocardiographic pattern.

• According to data available, its prevalence is 1%, with the incidence

increasing with age ranging from 9% in individuals aged 75 years to
22% in those aged 80 years.
CATECHOLAMINERGIC
POLYMORPHIC
VENTRICULAR TACHYCARDIA
(CPVT)
• Catecholaminergic polymorphic ventricular tachycardia (CPVT), a
sporadic cardiac ion channelopathy, noted in children, adolescents and
young adults is a heterogenous disease without apparent structural heart
disease.

• It is characterized by normal resting ECG, and ventricular events

associated with triggering factors that include exercise, acute
emotion,stress‐induced or adrenergically mediated premature
ventricular contractions (PVCs), polymorphic ventricular tachycardia
(PVT), and/or bidirectional VT (BVT), with recurrent character and heart
rate (HR) >120 bpm.
Diagnosis of CPVT
According to Heart Rhythm Society consensus statement, CPVT is diagnosed

• In the presence of a structurally normal heart and coronary arteries,

normal ECG, and unexplained exercise or catecholamine induced BVT,
polymorphic PVCs or VT in individuals <40 years of age
• In patients with pathogenic mutation
• In family members of a CPVT index case with a normal heart who
manifests exercise induced PVCs or BVT/PVT
• In any young person with unexplained syncope, unexplained seizures, or
SCD/SCA
FLECAINIDE IN VENTRICULAR
TACHYARRHYTHMIAS AND ATRIAL FIBRILLATION
• Flecainide, an 1C antiarrhythmic drug has been indicated for the
suppression of sustained ventricular tachycardia and acute cardioversion of
atrial fibrillation and for sinus rhythm maintenance.

• It is recommended as one of the first-line antiarrhythmic drugs in such

patients.
• Furthermore, results from various studies recommend its use in
preventing ventricular tachyarrhythmias in patients with
catecholaminergic polymorphic ventricular tachycardia associated both
with ryanodine receptor and calsequestrin mutations

• Since flecainide is characterized by a relatively high success rate in

restoring sinus rhythm and a short median time to restore the rhythm,
it has been considered as a potential alternative to propafenone and
amiodarone. Evidence had shown superiority of flecainide with a 90%
conversion rate in the first 12 hours as compared to 72% and 64% for
propafenone and amiodarone, respectively.
Pharmacokinetics of flecainide
• Bioavailability - 90%.
• It does not undergo hepatic first pass metabolism.
• Its plasma peak levels are achieved after 2-3 h and steady state levels
within 3-5 d.
• Its half-life remains unaffected by dose and ranges from 7 to 23 hours;
half-life being increased in patients with ventricular ectopic beats
(mean 20 h) due to reduced renal function.
• Flecainide levels are higher in cardiac tissues compared to plasma and
its therapeutic plasma levels range between 0.2 and 1.0 mg/mL.
• Flecainide is metabolized by liver cytochromes CYP2D6 and CYP1A2
and then eliminated in urine.
Mechanism of action of flecainide in patients
with atrial fibrillation to regulate sinus rhythm
• Due to presence of oxidative stress during atrial fibrillation, significant
structural changes in the atria cause remodeling of the myocardial fibers and
mitochondrial dysfunction.
• Furthermore, inflammatory adhesion molecules associated with oxidative
stress such as nuclear factor kappa β (NFκB), reactive oxygen species and
glycogen, are associated with impairment of cellular physiology, thus
accelerating apoptotic process and cellular protein decomposition.
• Moreover, there is intracellular Ca2+ accumulation that aids in ischemia and
cellular dysfunction.
• This increase in intracellular Ca2+ accumulation is diminished by flecainide by
blocking Na+ channels, thus reducing oxidative stress process and further atrial
remodeling
Antiarrhythmic mechanisms of flecainide in
Catecholaminergic polymorphic ventricular
tachycardia
• In CPVT, due to defective leaking ryanodine receptor (RYR) 2 channels,
there is diastolic calcium release from the sarcoplasmic reticulum
which results in calcium overload due to sympathetic activation.

• Flecainide blocks the RYR2 channels, thus directly aiming the molecular
defect
Recommendations
Evidence based efficacy of Flecainide-
Atrial Fibrillation
Trial 1
A study was done to evaluate the safety of class 1C antiarrhythmic drugs
(AAD) in patients with atrial fibrillation with stable coronary artery
disease (CAD). It included 24315 patients who were divided in two
populations

• Atrial fibrillation patients with CAD based upon AAD class (flecainide, n
= 1,114, vs class-3 AAD,n = 1,114)
• Atrial fibrillation patients who had undergone a percutaneous coronary
intervention or coronary artery bypass graft (flecainide, n = 150, and
class-3 AAD, n = 1,453).
End points included heart failure (HF) hospitalization, ventricular
tachycardia (VT), mortality and major adverse cardiovascular events
(MACE) at 3 years. Findings of the study were:

• Significantly lower rates of mortality (9.1% vs 19.3%, p<0.0001), HF

hospitalization (12.5% vs 18.3%, p<0.0001), MACE (22.9% vs 36.6%,
p<0.0001), and VT (5.8% vs 8.5%, p=0.02) were noted in the flecainide
group for population 1 at 3 years (Figure 4)

• Adverse events were lower in the flecainide compared to the class-3

AAD group for mortality (20.9% vs 25.8%, p=0.26), HF hospitalization
(24.5% vs 26.1%, p=0.73), VT (10.9% vs 14.7%, p=0.28) and MACE
(44.5% vs 49.5%, p=0.32) in population 2 at 3 years, though the rates
were nonsignificant
Trial 2
A study was conducted to evaluate the effect of oral flecainide controlled
release on quality of life and treatment compliance of patients with
symptomatic, paroxysmal or persistent atrial fibrillation. It included 679
patients who were administered 200 mg flecainide once a day.
Findings of the study were:
• Significant decrease in the Canadian Cardiovascular Society Severity of
Atrial Fibrillation (CCS-SAF) scale score was reported with flecainide
controlled release at the end of the study as compared with baseline (1.32
vs 1.64; Figure 5)
Flecainide CR significantly reduced the CCS-SAF score both in paroxysmal atrial fibrillation
(1.27 vs 1.61, p<0.0001) as well as in persistent atrial fibrillation patients (1.63 vs 1.84,
p=0.017)

• Only 0.6% of patients experienced a total of 6 adverse events during the study period
• About 93.6% of patients responded well to the treatment signifying a high compliance
rate.

This proportion of patients had not missed any dose during the study period.

Conclusively, flecainide controlled release administration is associated with significant

improvement in quality-of-life in both paroxysmal as well as persistent atrial fibrillation
patients, with an excellent safety profile and associated patient compliance.
Evidence based efficacy of Flecainide-
CPVT
Trial 1
In a study done to evaluate the efficacy and safety of flecainide in patients
with CPVT, relevant data was searched on Cochrane Library, PubMed,
Embase, and Web of Science. Seven retrospective cohort studies and 1
randomized controlled trial were selected. Findings of the study were:
• Significant reduction in risk of arrhythmic events was noted with
flecainide monotherapy as compared to standard therapy in CPVT
patients with and without genetic mutations
• In those with genetic mutations, combination of flecainide with β-blocker
was associated withreduced incidence of symptomatic events as
compared to β-blocker monotherapy
• Flecainide efficacy was accounted to be due to marked reduction in
peak heart rates during exercise

• No significant difference was noted between flecainide and β-blockers

in terms of drug safety.

Conclusively, flecainide is an effective and safe anti-arrhythmic agent.

Flecainide monotherapy can be considered as a good alternative for
catecholaminergic polymorphic ventricular tachycardia patients with β-
blocker intolerance.
Trial 2
A single-blind, placebo-controlled, randomized clinical crossover trial was
conducted to evaluate the efficacy of flecainide used as an adjunct to
conventional treatment with maximally tolerated β-blockers in the
treatment of CPVT. It included 13 patients with CPVT who were
randomized to receive either flecainide 100 mg/day every 12 hourly or
placebo for 3 months.
After 1-week washout, patients were crossed over to placebo or flecainide
for 3 months.
Primary end point was VT or appropriate implantable cardioverter
defibrillator therapy, and the secondary end point was the degree of
ventricular arrhythmias induced on exercise testing.
Findings of the study were:
• Significant reduction was observed in median ventricular arrhythmia
score during exercise by flecainide (0 vs 2.5) as compared to placebo
(Figure 6, Table 2)
• Complete suppression was observed in 11 of 13 patients (85%)
• Serious adverse events did not differ between the flecainide and
placebo arms.

Conclusively, flecainide is effective in reducing ventricular arrythmias

during exercise in patients with CPVT and persistent exercise-induced
ectopy despite a maximally tolerated β-blocker dose.