Flecainide

Details

Flecainide is a class 1C antiarrhythmic agent that blocks the fast inward Na+ current (INa) and IKr with marked use-dependence and unusually slow Na+ channel unbinding kinetics -- the pharmacodynamic basis for its efficacy in AF. It has been available since 1982 and is recommended as first-line for pharmacological cardioversion and sinus rhythm maintenance in AF patients with structurally normal hearts. Its use was severely curtailed after CAST (1991), which demonstrated excess mortality in post-MI patients; current evidence supports that this risk is specific to structural heart disease and ischaemia, not a class-wide effect in appropriate patients. A mechanistically distinct off-label role exists in CPVT via RyR2 Ca2+ channel open-state blockade.

Key Facts

Mechanism of Action

• INa and IKr blockade: At IC50 1-2 umol/L, flecainide blocks peak Na+ current and IKr. At higher concentrations (IC50 19 umol/L), it inhibits the late Na+ current (INaL) -- INaL is more sensitive than peak INa, enabling selective suppression of pathological late Na+ entry at concentrations with minimal effect on peak INa. (sources/flecainide-af-europace-2011, rating: medium)
• Post-repolarization refractoriness (PRR) -- defining class 1C property: The most clinically important pharmacodynamic feature. Flecainide unbinds from Na+ channels extremely slowly during diastole (time constant >10 s). This prolongs refractoriness beyond the action potential duration -- the drug extends the period during which cells cannot be re-excited even after full repolarization. At atrial rates of 300-600 bpm during AF, PRR is greatly amplified (use-dependence), markedly increasing effective refractory period and terminating re-entrant circuits. (sources/flecainide-af-europace-2011)
• AF termination mechanism: Tachycardia-dependent increase in atrial ERP and wavelength reduces the number of sustainable re-entrant circuits until AF can no longer sustain itself. Alternative (goat model): progressive widening of the temporal excitable gap until AF terminates. (sources/flecainide-af-europace-2011)
• Anti-remodelling rationale: AF-induced rapid Na+ entry → cytosolic Na+ overload → NCX-mediated Ca2+ overload → oxidative stress and structural remodelling. INa blockade attenuates Na+ entry during rapid atrial activation, reducing Ca2+ loading and potentially interrupting the 'AF begets AF' cycle. Preliminary human organotypic atrial tissue data support attenuation of pacing-induced oxidative stress markers and hypertrophic kinase expression. (sources/flecainide-af-europace-2011)
• RyR2 open-state blockade (CPVT mechanism): Flecainide inhibits cardiac ryanodine receptor 2 (RyR2) Ca2+ release channels by open-state blockade, reducing spark Ca2+ mass without causing compensatory SR Ca2+ loading. This prevents diastolic Ca2+ waves that cause triggered delayed afterdepolarizations (DADs) -- the mechanistic basis for its use in CPVT. Distinct from Na+ channel blockade. Whether clinical CPVT efficacy is primarily via this mechanism or via Na+ channel effects remains debated (see Contradictions). (sources/flecainide-af-europace-2011)

Pharmacokinetics

• Oral bioavailability 90-95%; no significant hepatic first-pass metabolism. Half-life 12-27h. Hepatic metabolism via CYP2D6; 85% urinary excretion (inactive metabolites). (sources/flecainide-af-europace-2011, rating: medium)
• Sustained-release capsule formulation available -- lower peak drug concentrations, potentially lower peak QRS widening (safer profile vs immediate-release in some contexts).
• IV dosing: Slow injection 1-2 mg/kg over 10 min (max 150 mg single bolus); infusion 1.2-1.5 mg/kg/h x 1h then 0.12-0.25 mg/kg/h; max cumulative dose 600 mg/24h.
• Oral dosing: Start 50 mg BID in monitored hospital setting; increase 50 mg BID every 4 days. Max 300 mg/day. Dose reduction in significant renal or hepatic impairment.

Electrophysiological Effects on ECG

• Prolongs PR interval 17-29%, widens QRS complex 11-27%. QTc increases only 3-8% -- most apparent QT change is from QRS widening, not ventricular repolarization. JT interval (reflecting true ventricular repolarization) remains largely unchanged. This explains the low TdP risk despite QT prolongation. (sources/flecainide-af-europace-2011, rating: medium)
• Increases endocardial pacing threshold -- pacemaker-dependent patients may require reprogramming after initiation.
• Worsens sinus node recovery time in patients with pre-existing sinus node dysfunction.
• Accessory pathway effects: slows conduction and increases refractoriness in both directions; more pronounced retrograde effect (often causes complete retrograde block when basal refractoriness >270 ms). Safe and effective in WPW-AF.

Clinical Efficacy -- AF Cardioversion

• IV flecainide: SR restoration in up to 95% within 1h in haemodynamically stable patients with acute AF (<48h) and preserved LV function. AHRQ pooled analysis (8 RCTs): conversion rates 52-95%. (sources/flecainide-af-europace-2011, rating: medium)
• Head-to-head RCT: IV flecainide 90% vs propafenone 72% vs amiodarone 64% SR achievement (P=0.008). Flecainide was the most effective cardioverting agent in this comparison.
• Oral loading dose (pill-in-the-pocket): Conversion rate 50-60% at 3h; 75-85% at 6-8h. First dose must be administered in a monitored hospital setting; subsequent self-administration after confirmed safety.
• Pre-electrical cardioversion: IV flecainide pretreatment improves first-shock success (65% vs 30% placebo) and reduces internal cardioversion threshold.
• Guidelines (2006 ACC/AHA/ESC; 2010 ESC): Class I, Level A for cardioversion and SR maintenance in structurally normal hearts.

Clinical Efficacy -- SR Maintenance

• Meta-analysis (60 studies): 65% of patients responsive short-term; 49% long-term. Significantly more patients reported suppression of palpitations (P<0.001), tachycardia, and chest pain vs placebo. Complete freedom from symptoms: 31% flecainide vs 9% placebo. (sources/flecainide-af-europace-2011, rating: medium)

Proarrhythmic Effects

• Class 1C flutter (supraventricular proarrhythmia): Flecainide slows AF to atrial flutter at ~200 bpm but does not slow AV nodal conduction. 1:1 AV conduction can then produce a bizarre wide-QRS tachycardia (superficially resembling VT) at dangerous ventricular rates. An AV nodal blocking drug must always be co-prescribed. Patients should stop exercise if AF recurs. This effect can be converted into a therapeutic opportunity: catheter ablation of the right atrial isthmus (1C flutter circuit) while maintaining flecainide invariably controls AF symptoms. (sources/flecainide-af-europace-2011, rating: medium)
• Ventricular proarrhythmia: Monomorphic sinusoidal wide-QRS VT or polymorphic VT/VF. Risk factors: reduced LV function, ventricular scar, excessive dose, rapid dose escalation. QRS widening is the premonitory marker on the ECG. (sources/flecainide-af-europace-2011)
• CAST and late proarrhythmia: CAST (1991) demonstrated excess mortality in post-MI patients attributed to proarrhythmic interaction of use-dependent Na+ channel blockade with ischaemia, heart failure, and drug accumulation. Late proarrhythmia can occur at any point -- not only on initiation. Patients initially well-selected who subsequently develop CAD or LV dysfunction face ongoing risk. (sources/flecainide-af-europace-2011)

Clinical Safety Data

• Meta-analysis (122 studies, n=4811 SVA patients, mean 241 days): Ventricular arrhythmias <3%; total mortality 0.166% (0.397/100 patient-years). Proarrhythmic episodes lower than control (2.7% vs 4.8%). (sources/flecainide-af-europace-2011, rating: medium)
• Danish registry (n=151,500 first-time AF hospitalisations, 1995-2004): No increased mortality with flecainide in appropriately selected patients. Annualized mortality (per 100 person-years): flecainide 2.54, propafenone 4.25, sotalol 5.29, amiodarone 7.42. (sources/flecainide-af-europace-2011)

Contraindications and Patient Selection

• Absolute contraindications: CAD/prior MI, LVEF <35%, structural cardiomyopathy, Brugada syndrome (flecainide can unmask the Brugada ECG pattern and is used diagnostically in the sodium channel blocker provocation test), 2nd/3rd degree AV block, LBBB, RBBB with left hemiblock, cardiogenic shock, significant renal or hepatic impairment. (sources/flecainide-af-europace-2011, rating: medium)
• Appropriate population: Normal heart, hypertension, or minor heart disease with good LV function -- approximately 80% of PAF patients and 50% of persistent AF patients qualify.
• Monitoring: QRS interval regularly during treatment; exercise stress test at initiation to assess use-dependent QRS widening; regular ECG; pacemaker threshold check if pacemaker-dependent.

Use in CPVT

• Flecainide is first add-on therapy after beta-blockers in CPVT (~30% of patients require add-on therapy). ESC 2022 upgraded it to Class I (ICD + beta-blockers + flecainide) after aborted cardiac arrest. (sources/channelopathies-jaha-2025, rating: high; sources/VA-SCD-ESC-2022, rating: very high)
• Variant-specific response: p.R420W, p.S2246L, p.C2277R respond well; p.G357S and p.G2337V appear non-responsive in registry data (Chang 2025). (sources/RYR2-CPVT-CircEP-2025, rating: very high)
• See entities/CPVT and entities/RYR2 for full variant-specific data and mechanism debate.

Contradictions / Open Questions

• CAST reinterpretation -- proarrhythmia specific to structural disease or class-wide risk? This review attributes CAST excess mortality to proarrhythmia in post-MI structural disease, not a class-wide effect. This interpretation is widely accepted but mechanistic certainty is incomplete -- late proarrhythmia in CAST could not be fully separated from patient selection, CAD progression, and drug accumulation. The Danish registry (n=151,500) supports safety in appropriately selected AF patients but was retrospective and non-randomised. (sources/flecainide-af-europace-2011, rating: medium)
• RyR2 blockade vs Na+ channel mechanism in CPVT: Three competing lines of evidence: (1) Liu 2011 -- flecainide prevents arrhythmias without affecting Ca2+ homeostasis (Na+ channel mechanism); (2) Kryshtal 2021 -- direct RyR2 inhibition demonstrated; (3) Bannister 2016 -- no direct RyR2 channel effect. The Hilliard 2010 data (cited in this review) showed open-state RyR2 blockade reducing spark Ca2+ mass in a CPVT mouse model. Clinical CPVT efficacy is well-established but the primary mechanism is unresolved. (sources/flecainide-af-europace-2011, sources/RYR2-CPVT-CircEP-2025)
• Industry COI and promotional framing: This review was funded by Meda Pharmaceuticals with significant author financial relationships. The rehabilitative framing of flecainide post-CAST is scientifically supported but the review presents selective evidence -- no head-to-head comparison with ablation as a competing strategy, and comparative efficacy table (Table 2) relies on indirect comparisons without direct RCTs. (sources/flecainide-af-europace-2011)
• 2011 data gap -- catheter ablation: The review recommends flecainide as first-line rhythm control but was published before catheter ablation was established as Class I/A for paroxysmal AF (ESC 2024, AHA 2023). In 2024 guidelines, PVI is preferred over antiarrhythmic drugs as first-line for paroxysmal AF in many patients, substantially limiting the position of flecainide in current clinical algorithms.

Connections

• Related to entities/Atrial-Fibrillation -- primary indication; cardioversion and SR maintenance
• Related to entities/Amiodarone -- cardioversion head-to-head (flecainide superior); structural disease comparison
• Related to entities/Dronedarone -- both Class IC-alternative agents for structurally normal hearts; dronedarone lacks CAST concern but has HF contraindication
• Related to entities/CPVT -- first add-on after beta-blockers; Class I post-arrest (ESC 2022)
• Related to entities/RYR2 -- open-state Ca2+ channel blockade; variant-specific response data
• Related to entities/Brugada-Syndrome -- absolute contraindication; used diagnostically in sodium channel blocker provocation test
• Related to concepts/Drug-Induced-Arrhythmia -- class 1C flutter; CAST proarrhythmia
• Related to concepts/Cardiac-Action-Potential -- PRR mechanism
• Related to concepts/Antiarrhythmic-Drugs
• Related to concepts/Pharmacological-Provocation-Testing -- sodium channel blocker provocation for Brugada

Sources

• Related to sources/flecainide-af-europace-2011