Antiarrhythmic drugs: class actions and proarrhythmia

This page covers how the main antiarrhythmic drugs act, how they cause arrhythmias, how each guideline matches drug to heart substrate, and what to monitor. It uses the held FDA labels for dosing and monitoring of amiodarone, flecainide, sotalol and dronedarone.^{[8][9][10][11]}

• Related topic: Atrial fibrillation.
• Related topic: Cardioversion and anticoagulation timing.
• Related topic: Ventricular tachycardia.
• Related topic: Long QT syndrome and channelopathies.
• Related topic: SVT: AVNRT and AVRT.

Overview and definitions

ESC 2024 AF lists the aims of long-term rhythm control as maintaining sinus rhythm, improving quality of life, slowing AF progression and potentially reducing morbidity related to AF episodes.^[1] It also gives antiarrhythmic drugs a role in patients considered ineligible or unwilling to undergo catheter or surgical ablation.^[1]

In ventricular arrhythmia (VA), ESC 2022 gives these drugs an important role as adjunctive therapy, especially in symptomatic patients.^[3] It adds that no antiarrhythmic drug except beta-blockers has yet shown a reduction in all-cause mortality.^[3]

ESC 2024 AF says all antiarrhythmic drugs may produce serious cardiac adverse effects (proarrhythmia, negative inotropism, hypotension) and extracardiac adverse effects (organ toxicity, predominantly amiodarone).^[1]

Classification: class actions of the core drugs

The FDA labels for flecainide, sotalol, amiodarone and dronedarone place each drug in the Vaughan Williams scheme; ESC 2024 AF and ACC/AHA 2023 text give the class of propafenone and dofetilide.^{[9][10][8][11][1][2]} ACC/AHA 2023 Table 23 lists the ion currents each drug inhibits, and ESC 2022 VA Table 8 adds the ECG effect of flecainide, propafenone, sotalol and amiodarone.^[2][3]

How the drugs act (FDA labels, ACC/AHA 2023 Table 23 and ESC 2022 VA Table 8)

^{[2] [3] [9] [10] [8] [11] [1]}

• Amiodarone (label): like class I drugs it blocks sodium channels at rapid pacing frequencies; like class II drugs it has a noncompetitive antisympathetic action; with prolonged administration it lengthens the action potential (class III); its negative chronotropic effect in nodal tissue is similar to class IV drugs.^[8]
• Sotalol (label): significant beta-blockade occurs at oral doses as low as 25 mg, but significant Class III effects are seen only at daily doses of 160 mg and above.^[10]
• Dofetilide (ACC/AHA 2023 text): poses a high risk for torsades de pointes.^[2]

^{[9] [2] [3] [1] [10] [8] [11]}

How well do they work?

ESC 2024 AF says the long-term effectiveness of antiarrhythmic drugs is limited.^[1] It reports a meta-analysis of 59 randomised controlled trials in which these drugs reduced AF recurrences by 20%–50% compared with no treatment, placebo or drugs for rate control.^[1]

ESC 2024 AF adds that the drugs do not eliminate AF recurrences.^[1] In paroxysmal or persistent AF, a recurrence is not equivalent to treatment failure if episodes are less frequent, briefer or less symptomatic.^[1] When one drug fails, a clinically acceptable response may be achieved with another drug, particularly if from a different class.^[1]

^{[1] [2] [8]}

ESC 2024 AF says the available data suggest no appreciable effect on mortality or other cardiovascular complications, except increased mortality signals for sotalol and amiodarone.^[1] In contrast, it says use within a rhythm control strategy can be associated with reduced morbidity and mortality in selected patients.^[1]

ACC/AHA 2023 reports a Cochrane meta-analysis of 5 randomised studies (1882 patients with AF) that associated sotalol with higher all-cause mortality.^[2] That analysis included patients with advanced heart failure, and the guideline says sotalol may still have a role in patients with preserved heart function; the held text gives no follow-up duration.^[2] In heart failure with reduced ejection fraction, ESC 2026 HF says antiarrhythmic drugs such as amiodarone and dronedarone reduce ventricular arrhythmias but do not prolong survival and may shorten it.^[5]

Pathophysiology: how antiarrhythmic drugs cause arrhythmias

Two mechanisms are described below. Drugs that prolong the QT interval can provoke torsades de pointes.^[3] Flecainide, which inhibits the sodium current, slows conduction and widens the QRS in most patients, and in atrial flutter the label reports 1:1 atrioventricular conduction.^[2][9]

QT prolongation and torsades de pointes

ESC 2022 VA says numerous antiarrhythmic drugs, and many drugs with other indications, can prolong the QT interval and provoke torsades de pointes (TdP).^[3] The same passage says they can have negative chronotropic effects, may worsen heart failure and can cause bradycardia.^[3] Hypomagnesaemia and/or hypokalaemia may be associated with TdP.^[3]

• Sotalol label risk factors for TdP: factors such as reduced creatinine clearance, female sex, higher doses, reduced heart rate, and a history of sustained VT/VF or heart failure.^[10]
• Bradycardia (sotalol label): bradycardia itself increases the risk of torsades de pointes.^[10]
• Timing (sotalol label): proarrhythmic events must be anticipated on initiating therapy and with every upward dose adjustment.^[10]
• Timing (ACC/AHA 2023): dofetilide and sotalol confer a relatively high risk of TdP because they prolong the QT interval, and this can occur early during initiation.^[2]
• Amiodarone label: it can exacerbate the presenting arrhythmia in about 2 to 5% of patients, or cause new VF, incessant VT, increased resistance to cardioversion, or polymorphic VT with QTc prolongation (TdP).^[8]
• Amiodarone in the guidelines: ESC 2022 Table 8 lists TdP as infrequent; ESC 2019 SVT says intravenous amiodarone prolongs the QTc but torsades de pointes is rare.^[3][4]

Sodium-channel block, QRS widening and 1:1 flutter

The flecainide label says it slows cardiac conduction in most patients, producing dose-related increases in PR, QRS and QT intervals.^[9] The QT widens by about 8%, but most of that widening (about 60% to 90%) comes from the wider QRS.^[9]

ESC 2024 AF Table 13 says a flecainide infusion should be stopped if the QRS widens by more than 25% or bundle branch block appears.^[1] ESC 2022 VA, in a footnote to its Figure 12, says a QRS increase of more than 25% is not an absolute cut-off but depends on the QRS width before the drug and on individual risk–benefit considerations.^[3]

Slowing the atrial rate can paradoxically speed the ventricle.^[9] The flecainide label reports 1:1 atrioventricular conduction in atrial flutter, as with other Class 1 agents, and says a paradoxical rise in ventricular rate may occur in AF.^[9] It says concomitant negative chronotropic therapy, such as digoxin or beta-blockers, may lower that risk.^[9] ESC 2024 AF says concomitant use of a beta-blocker, diltiazem or verapamil should be considered in patients on flecainide or propafenone, to prevent 1:1 conduction if the rhythm is transformed to atrial flutter (Class IIa, Level C).^[1]

Why the substrate matters

ESC 2024 AF says the risk of proarrhythmia increases in patients with structural heart disease.^[1] The flecainide label adds a negative inotropic effect that may cause or worsen heart failure, particularly with cardiomyopathy, NYHA class III or IV heart failure, or ejection fraction below 30%.^[9] ESC 2022 VA says several drugs increase the risk of VA in Brugada syndrome, and its Table 8 lists Brugada syndrome as a contraindication to flecainide.^[3]

^{[3] [10] [9] [1] [2]}

Clinical presentation: recognising toxicity

The labels and ESC tables describe these patterns.^[8][11][3]

Presentations of drug toxicity

^{[8] [1] [3] [11] [10]}

The two thyroid figures differ by source: the label gives separate rates for hypothyroidism and hyperthyroidism, and ESC 2024 AF gives one combined figure.^[8][1]

Differential diagnosis: a wide or irregular tachycardia on treatment

Start with the ECG pattern. ESC 2019 SVT Table 6 lists SVT with QRS widening due to electrolyte disturbance or antiarrhythmic drugs among the regular wide QRS tachycardias.^[4]

Telling the patterns apart

^{[4] [3]}

ESC 2022 VA says intravenous drugs that slow AV conduction, such as adenosine, beta-blockers and amiodarone, should be avoided when pre-excited AF is the rhythm.^[3]

Bedside assessment before starting a drug

ESC 2022 VA says that in patients who require a potentially arrhythmia-inducing drug, regular ECG and other tests according to the patient’s profile and the drug’s characteristics are recommended (no class or level given).^[3] Its Figure 12 covers evaluation before and during sodium-channel blocking agents, and its Figure 13 covers drugs associated with QT prolongation.^[3] ESC 2022 VA adds that modification of risk factors, when possible, is important for preventing proarrhythmia.^[3]

Baseline checks named in the labels

^{[10] [8] [9] [11]}

ESC 2024 AF also says reversible triggers should be identified and underlying comorbidities treated before starting a drug, to reduce the arrhythmogenic substrate, prevent AF progression and help maintain sinus rhythm.^[1]

Investigations: QT monitoring

The QT thresholds differ by drug and by document, so quote the source when you give a number.^[3][10][11]

QT rules by drug

^{[3] [1] [10] [11] [2]}

• Avoid QT-prolonging combinations: the sotalol label says to avoid other drugs known to cause QT prolongation; the dronedarone label lists QT-prolonging drugs, including Class I and III antiarrhythmics, as contraindicated.^[10][11]
• ESC 2022 VA, Table 8: the sotalol row lists TdP in more than 2% of patients and asks for close monitoring of QT interval and creatinine clearance.^[3]
• Electrolytes: the amiodarone label (low potassium, magnesium or calcium) and the sotalol label (low potassium or magnesium) say these disorders can exaggerate QT prolongation and increase the potential for TdP, so correct them before starting.^[8][10]

Investigations: renal function and dosing

Renal function decides whether some of these drugs can be given at all.^{[10][1][3][2]} The sources do not use the same cut-offs, so the table names each one.^[10][2][3]

Renal rules by drug

^{[10] [2] [3] [1] [9] [11]}

The sotalol label says the risk of TdP can be reduced by adjusting the dose to creatinine clearance and by watching the ECG for excessive QT increases.^[10] ACC/AHA 2023 Table 25 asks for a 12-lead ECG, potassium, magnesium and creatinine-based CrCl at 3–6 months on sotalol, then every 3–6 months, more often with other QT-prolonging drugs or changing kidney function.^[2]

^{[10] [3] [2]}

Investigations: monitoring amiodarone

The amiodarone label reserves the drug for the indicated life-threatening arrhythmias because its use carries substantial toxicity, and it says to use alternative agents first.^[8] ESC 2024 AF asks for careful consideration and monitoring for extracardiac toxicity when amiodarone is used for long-term rhythm control in HFrEF.^[1]

Oral amiodarone monitoring (ACC/AHA 2023 Table 24)

^[2]

The FDA label asks for more at the lung.^[8] It asks for a baseline chest X-ray and pulmonary function tests including diffusion capacity, then repeat history, examination and chest X-ray every 3 to 6 months or if symptoms occur.^[8] It says to consider alternative antiarrhythmic therapy if signs or symptoms of pulmonary toxicity appear.^[8]

• Liver (label): obtain baseline and periodic transaminases; if they exceed three times normal, or double in a patient with an elevated baseline, discontinue or reduce the dose, repeat the tests and treat appropriately.^[8]
• Thyroid (label): monitor before treatment and periodically, particularly in elderly patients and in anyone with thyroid nodules, goitre or other thyroid dysfunction; radioactive iodine is contraindicated in amiodarone-induced hyperthyroidism because of low uptake.^[8]
• Eyes (label): regular ophthalmic examination, including funduscopy and slit-lamp examination; if visual acuity changes or peripheral vision falls, consider stopping and refer promptly; asymptomatic corneal microdeposits alone are not a reason to reduce or stop.^[8]
• Devices (label): chronic antiarrhythmic drugs may change pacing or defibrillation thresholds, so assess thresholds at the start of and during amiodarone treatment.^[8]
• Washout (label): the half-life is 15 to 142 days (desethylamiodarone 14 to 75 days), so adverse reactions and interactions can persist for several weeks after stopping.^[8]

^{[2] [8]}

Management: acute rhythm conversion and resuscitation

ESC 2024 AF calls pharmacological cardioversion an elective procedure in haemodynamically stable patients, and it needs no fasting, sedation or anaesthesia.^[1] The choice of drug is based on the type and severity of concomitant heart disease.^[1] Electrical cardioversion and its anticoagulation timing are covered in Cardioversion and anticoagulation timing.

^{[1] [2]}

Drugs for sinus rhythm restoration (ESC 2024 AF Table 13)

^{[1] [3]}

ESC 2024 AF reports a meta-analysis in which intravenous vernakalant and flecainide had the highest conversion rate within 4 h.^[1] It says Class IC drugs (flecainide more so than propafenone) convert better within 12 h, while amiodarone acts in a delayed fashion (within 24 h).^[1]

In heart failure, ESC 2026 HF (no class or level given) says amiodarone is recommended in HFrEF requiring pharmacological cardioversion, and that the other antiarrhythmic drugs (propafenone, flecainide and dronedarone) are associated with poorer outcomes in HFrEF and should be avoided.^[5]

• ACC/AHA 2023 Table 22, amiodarone: intravenous 5–7 mg/kg or 300 mg, then 1200–3000 mg by continuous infusion over 24 h; conversion in about 8–12 h; adverse effects include bradycardia, hypotension, QT prolongation, phlebitis and TdP.^[2]
• ACC/AHA 2023 Table 22, oral single doses: flecainide 200 mg if under 70 kg or 300 mg if over 70 kg; propafenone 450 mg if under 70 kg or 600 mg if over 70 kg; conversion in 3–8 h.^[2]
• ACC/AHA 2023 Table 22, ibutilide: 1 mg over 10 min if 60 kg or more, or 0.01 mg/kg over 10 min if under 60 kg; a second equal dose may be given if the arrhythmia does not terminate within 10 min after the end of the first infusion.^[2]

Pill-in-the-pocket

ESC 2024 AF says safe use needs screening to exclude sinus node dysfunction, atrioventricular conduction defects or Brugada syndrome, and prior in-hospital validation of efficacy and safety.^[1] For patients starting pill-in-the-pocket flecainide or propafenone with a concomitant atrioventricular nodal blocking drug, ACC/AHA 2023 says it is reasonable to give the first dose in a facility with continuous ECG monitoring, given the potential for proarrhythmia (COR 2a, LOE B-NR).^[2]

Sustained VT, electrical storm and drug-induced torsades

ESC 2022 VA says intravenous procainamide or amiodarone can be used to terminate haemodynamically tolerated VT of unknown aetiology.^[3] ESC 2019 SVT reports that in the PROCAMIO trial, in patients with well-tolerated wide QRS tachycardia with or without reduced LV ejection fraction, procainamide was associated with fewer major cardiac adverse events and more tachycardia terminations within 40 min than amiodarone.^[4] Its reference list titles that study a randomised comparison of intravenous procainamide versus intravenous amiodarone for tolerated wide QRS tachycardia.^[4] The full VT pathway is in Ventricular tachycardia.

Acute ventricular arrhythmia rows that involve these drugs

^[3]

ESC 2022 VA says intravenous procainamide should not be used in severe heart failure, acute MI or end-stage renal disease.^[3] When a drug-induced arrhythmia is presumed, it says any offending drug needs to be withdrawn and substances known to prolong QT, such as sotalol, should be avoided.^[3] It calls intravenous magnesium an effective therapy for TdP even in the absence of hypomagnesaemia.^[3] Congenital long QT is covered in Long QT syndrome and channelopathies.

Management: long-term drug choice by structural heart disease

ESC 2024 AF says choosing a drug for long-term rhythm control requires careful evaluation of AF type, patient parameters and safety profile.^[1] The ACC/AHA 2023 synopsis (no class or level given) calls antiarrhythmic drugs reasonable for long-term maintenance of sinus rhythm in AF for patients who are not candidates for, or decline, catheter ablation, or who prefer drug therapy.^[2] ESC 2024 AF says combinations of antiarrhythmic drugs are not recommended (no class or level given).^[1]

Long-term maintenance of sinus rhythm in AF: rows by drug

^{[1] [2]}

• ACC/AHA 2023, dofetilide: reasonable without significant baseline QT prolongation or uncorrected hypokalaemia or hypomagnesaemia, with dose selection based on kidney function and close monitoring of QT, potassium, magnesium and kidney function (COR 2a, LOE A).^[2]
• ESC 2024 AF: a beta-blocker, diltiazem or verapamil should be considered with flecainide or propafenone to prevent 1:1 conduction if the rhythm becomes atrial flutter (Class IIa, Level C).^[1]
• ESC 2024 AF: antiarrhythmic drug therapy is not recommended with advanced conduction disturbances unless antibradycardia pacing is provided (Class III, Level C).^[1]
• ACC/AHA 2023 supportive text: most antiarrhythmic agents, except amiodarone and dofetilide, are contraindicated in HFrEF because of worsening heart failure and/or increased mortality; sotalol is best avoided in HFrEF because most patients already take a beta blocker.^[2]
• ACC/AHA 2023 synopsis: low-dose amiodarone is more effective than sotalol and Class IC agents, but its adverse effects and drug interactions mean it is best reserved for when other drugs are ineffective, not preferred or contraindicated.^[2]

^{[1] [2]}

Long-term doses and where to start

Long-term oral doses as each source states them

^{[1] [9] [10] [11] [2] [8]}

In AF, ACC/AHA 2023 says amiodarone, flecainide and propafenone can be started in the outpatient setting.^[2] For sotalol in patients with AF, it says initiation in a facility that can provide continuous ECG monitoring, CrCl calculation and cardiac resuscitation is reasonable, given the potential for proarrhythmia and bradycardia (COR 2a, LOE B-R).^[2] Its supportive text says patients starting or reloading oral sotalol should be admitted for at least 3 days to such a facility.^[2] The sotalol label says to hospitalise patients being initiated or re-initiated for at least 3 days, or until steady state, with resuscitation and continuous ECG monitoring available.^[10]

For dofetilide, ACC/AHA 2023 says patients with AF who are initiating, increasing or reinitiating it should be admitted for at least 3 days to such a facility, given the potential for proarrhythmia (COR 1, LOE A).^[2] The flecainide label says that for sustained VT, whatever the cardiac status, flecainide should be started in hospital with rhythm monitoring.^[9]

Ventricular arrhythmia: long-term rows

Long-term ventricular arrhythmia rows that involve these drugs

^[3]

ESC 2022 VA says amiodarone carries severe systemic toxicity and, for idiopathic arrhythmias, should be used only if ablation or other drugs fail or cannot be used.^[3] It adds that flecainide has a more favourable adverse effect profile regarding organ toxicity, but increased mortality has previously been shown in patients with MI.^[3] ESC 2026 HF says that, unlike antiarrhythmic drugs such as amiodarone, ICDs reduce mortality in cardiac arrest survivors and in sustained ventricular arrhythmias, regardless of LVEF or heart failure.^[5]

Specific scenarios

Pre-excited AF

ESC 2024 AF says patients with Wolff–Parkinson–White syndrome and AF are at risk of fast ventricular rates from conduction over the accessory pathway, potentially leading to ventricular fibrillation and sudden death.^[1] ESC 2019 SVT reports paroxysmal AF in 50% of patients with WPW, and it may be the presenting arrhythmia.^[4] Accessory-pathway re-entry is covered in SVT: AVNRT and AVRT.

ESC 2019 SVT says any AV node-modulating agent (adenosine, verapamil, diltiazem, beta-blockers or digoxin) should be avoided in pre-excited AF because it may contribute to a risk of ventricular fibrillation.^[4] It adds that intravenous amiodarone may not be as safe as previously thought, because enhanced pathway conduction and ventricular fibrillation have been reported, and that procainamide appears to be safer in this setting.^[4]

^{[4] [2]}

• ESC 2024 AF (no class or level given): immediate electrical cardioversion for haemodynamically compromised pre-excited AF; avoid AV node-modulating drugs; pharmacological cardioversion can be attempted with ibutilide or flecainide, while propafenone needs caution because of its AV-node effects; amiodarone should be avoided because of its delayed action.^[1]
• ESC 2019 SVT, chronic therapy: digoxin, beta-blockers, diltiazem, verapamil and amiodarone are not recommended and are potentially harmful in pre-excited AF (Class III, Level B).^[4]
• ESC 2022 VA Table 8: pre-excited AF is listed as a contraindication to adenosine.^[3]
• ESC 2024 AF Table 12 footnote (no class or level given): all rate control drugs are contraindicated in Wolff–Parkinson–White syndrome, and so is intravenous amiodarone.^[1]
• ESC 2019 SVT on Class Ic drugs: use them with caution, as they exert an effect on the AV node.^[4]

^{[4] [2]}

Atrial flutter on a Class IC drug

ESC 2024 AF Table 13 says flecainide must not be used to convert atrial flutter.^[1] In its long-term antiarrhythmic drug rows, ESC 2024 AF says that in AF patients treated with flecainide or propafenone, a beta-blocker, diltiazem or verapamil should be considered to prevent 1:1 conduction if the rhythm is transformed to atrial flutter (Class IIa, Level C).^[1] ACC/AHA 2023 says patients taking flecainide or propafenone should also take an atrioventricular nodal blocker to reduce the risk of 1:1 flutter.^[2]

Conduction disease, sinus node disease and Brugada syndrome

• ESC 2024 AF: antiarrhythmic drug therapy is not recommended with advanced conduction disturbances unless antibradycardia pacing is provided (Class III, Level C).^[1]
• Amiodarone label contraindications: cardiogenic shock; sick sinus syndrome, second- or third-degree AV block, or bradycardia leading to syncope without a functioning pacemaker; hypersensitivity including iodine.^[8]
• Flecainide label contraindications: pre-existing second- or third-degree AV block, or right bundle branch block with a left hemiblock (bifascicular block), unless a pacemaker is present; cardiogenic shock; hypersensitivity.^[9]
• Sotalol label contraindications: sinus bradycardia, sick sinus syndrome, or second- and third-degree AV block unless a functioning pacemaker is present; congenital or acquired long QT; cardiogenic shock or decompensated heart failure; serum potassium under 4 mEq/L; bronchial asthma or related bronchospastic conditions; hypersensitivity; and, for AF or flutter, a baseline QT interval over 450 msec.^[10]
• Dronedarone label contraindications on conduction include second- or third-degree AV block or sick sinus syndrome (except with a functioning pacemaker), bradycardia under 50 bpm, and QTc over 500 ms or PR interval over 280 ms; the full list is under complications below.^[11]
• Brugada syndrome: ESC 2024 AF Table 13 says flecainide should not be used, and ESC 2022 VA Table 8 lists Brugada syndrome as a contraindication to flecainide and propafenone.^[1][3]

Hyperthyroidism

ESC 2024 AF Table 13 lists amiodarone in hyperthyroidism as only if no other option (risk of thyrotoxicosis).^[1] ESC 2022 VA Table 8 lists hyperthyroidism as a precaution for amiodarone.^[3]

Complications and pitfalls

Dronedarone in heart failure or permanent AF

The Multaq label carries a boxed warning.^[11] It says dronedarone doubles the risk of death in symptomatic heart failure with recent decompensation requiring hospitalisation or NYHA class IV heart failure.^[11] It says dronedarone doubles the risk of death, stroke and heart failure hospitalisation in permanent AF.^[11]

• Contraindicated (label): permanent AF (sinus rhythm will not or cannot be restored); symptomatic heart failure with recent decompensation requiring hospitalisation or NYHA class IV symptoms; second- or third-degree AV block or sick sinus syndrome (except with a functioning pacemaker); bradycardia under 50 bpm.^[11]
• Also contraindicated (label): strong CYP3A inhibitors, such as ketoconazole, itraconazole, voriconazole, cyclosporine, telithromycin, clarithromycin, nefazodone and ritonavir; erythromycin; drugs or herbal products that prolong the QT interval and might increase the risk of torsade de pointes, including Class I and III antiarrhythmics; liver or lung toxicity from previous amiodarone; QTc over 500 ms or PR interval over 280 ms; severe hepatic impairment; hypersensitivity to the drug or its excipients.^[11]
• Rhythm checks (label): monitor cardiac rhythm no less often than every 3 months; cardiovert patients found in AF if clinically indicated, or stop dronedarone.^[11]
• Start in sinus rhythm (label): only in patients in sinus rhythm who are receiving appropriate antithrombotic therapy.^[11]
• Heart failure on treatment (label): if heart failure develops or worsens and needs hospitalisation, discontinue dronedarone.^[11]
• Liver and lung (label): hepatocellular injury including acute liver failure needing transplant, and interstitial lung disease including pneumonitis and pulmonary fibrosis, have been reported after marketing; consider periodic hepatic enzymes, especially in the first 6 months, although it is not known whether routine periodic monitoring will prevent severe liver injury.^[11]

Class IC drugs after myocardial infarction

The flecainide label describes CAST as a long-term, multicentre, randomised, double-blind study.^[9] It enrolled patients with asymptomatic non-life-threatening ventricular arrhythmias who had an MI more than six days but less than two years before.^[9] Excess mortality or non-fatal cardiac arrest occurred with flecainide: 16/315 (5.1%) against 7/309 (2.3%) with matched placebo, over an average 10 months of treatment.^[9]

ACC/AHA 2023 describes CAST as randomised, double-blind and placebo-controlled, with class IC flecainide and encainide associated with higher mortality after recent MI; most patients also had LVEF below 50%.^[2] The label says applying CAST to other populations, such as those without recent MI, is uncertain.^[9] It still considers Class 1C risks generally unacceptable in patients without life-threatening ventricular arrhythmias, even when symptoms are unpleasant.^[9]

Drug interactions

Interactions named in the held sources

^{[2] [3] [8] [10]}

Other pitfalls

• Combining antiarrhythmic drugs: ESC 2024 AF says combinations are not recommended (no class or level given).^[1]
• Intravenous amiodarone may cause phlebitis: ESC 2024 AF Table 13 advises a large peripheral vein, avoiding intravenous use beyond 24 h, and preferably a volumetric pump.^[1]
• Stopping sotalol: the label says to reduce the dose gradually over 1 to 2 weeks when stopping long-term treatment, particularly in ischaemic heart disease, if possible, and to monitor the patient.^[10]
• New heart failure on sotalol: the label says new or worse heart failure may occur during initiation or uptitration because of its beta-blocking effects.^[10]
• Flecainide in chronic AF: the label says its use in chronic AF has not been adequately studied and is not recommended, and it should not be used after recent MI.^[9]

Prognosis and follow-up

ESC 2022 VA says no antiarrhythmic drug except beta-blockers has yet shown a reduction in all-cause mortality.^[3] The sotalol label says it has not been shown to enhance survival in life-threatening ventricular arrhythmias.^[10] The flecainide label says there is no evidence from controlled trials that it favourably affects survival or the incidence of sudden death.^[9]

ACC/AHA 2023 Table 25 asks for AST and ALT within the first 6 months of dronedarone, to detect possible hepatotoxicity early.^[2] Its Table 24 sets the amiodarone schedule, and the dronedarone label asks for rhythm checks at least every 3 months.^[2][11]

Special populations

Pregnancy

Antiarrhythmic drugs in pregnancy (ESC 2025)

^[6]

ESC 2025 says amiodarone can cause foetal abnormalities, bradycardia and thyroid dysfunction, so routine use in pregnancy is contraindicated, but it may be given as a single dose in emergencies such as VT storm.^[6] It places no restriction on amiodarone in cardiac arrest.^[6] It says anti-arrhythmic drugs such as flecainide and sotalol are not associated with foetal harm in structurally normal hearts, although sotalol’s beta-blocker effect needs foetal growth monitoring.^[6]

ACC/AHA 2023 says drugs with a history of safe use in pregnancy (for example flecainide and sotalol) are reasonable for maintaining sinus rhythm in pregnant individuals with AF and no structural heart disease (COR 2a, LOE C-LD).^[2] With structurally normal hearts and haemodynamically stable AF, it says pharmacological cardioversion with agents with a history of safe use in pregnancy, such as intravenous procainamide, may be considered (COR 2b, LOE C-LD).^[2] The amiodarone and dronedarone labels both warn of possible fetal harm.^[8][11]

Heart failure with reduced ejection fraction

ESC 2026 HF says intravenous amiodarone or digoxin may be considered in haemodynamically unstable HFrEF with AF to stabilise the patient and control heart rate acutely (Class IIb, Level C).^[5] ACC/AHA 2023 says that in AF and heart failure with rapid ventricular rates, when beta blockers or calcium channel blockers are contraindicated or ineffective, intravenous amiodarone is reasonable for acute rate control (COR 2a, LOE B-NR).^[2] Its footnote says to consider the risk of cardioversion and stroke when amiodarone is used for rate control.^[2]

Older adults, children and device patients

• Older adults (amiodarone label): monitor thyroid function before and periodically during treatment, particularly in elderly patients.^[8]
• Children (flecainide label): in children with structural heart disease, flecainide has been associated with cardiac arrest and sudden death; it should be started in hospital with rhythm monitoring.^[9]
• Pacemakers (flecainide label): it increases endocardial pacing thresholds and may suppress ventricular escape rhythms; check the threshold before starting, after one week and regularly thereafter.^[9]
• Pacemakers and ICDs (amiodarone label): chronic antiarrhythmic drugs may affect pacing or defibrillation thresholds.^[8]
• Kidney disease: see the renal table above; sotalol, flecainide, dofetilide, propafenone and dronedarone carry renal rules in the held sources.^{[10][1][2][3][11]}

Evidence, guidelines and regional differences

The two AF guidelines grade the same drugs differently.^[1][2] Quote the body, year and class together at the viva.

^{[1] [2]}

Trials named in the held sources

^{[9] [2] [11] [2] [11]}

Pre-excited AF across documents

ESC 2019 SVT does not recommend intravenous amiodarone in haemodynamically stable pre-excited AF (Class III, Level B).^[4] ACC/AHA 2023 lists amiodarone among AV nodal blocking drugs contraindicated in pre-excited AF, because of the risk of precipitating VF or haemodynamic deterioration (COR 3: Harm, LOE B-NR).^[2] ESC 2024 AF, in narrative without a class, says amiodarone should be avoided because of its delayed action.^[1]

ANZ practice

The 2018 NHFA/CSANZ AF guideline was written to assist Australian practitioners managing adults with AF.^[7] Its summary abstract covers acute and chronic arrhythmia management with antiarrhythmic therapy.^[7] That abstract states that cardioversion remains first-line for acute rhythm control when clinically indicated, and that flecainide is preferable to amiodarone for acute and chronic rhythm control.^[7] Only the abstract of this summary is held, and the full guideline (PMID 30077228) is not held as text in its version of record, so no NHFA/CSANZ recommendation strength or patient selection criteria are given here.^[7] No NHFA/CSANZ antiarrhythmic drug guideline newer than 2018 was found for this topic; the 2023 CSANZ position statement on AF ablation was found, but its text is not held. The FDA labels are used for dosing and monitoring; Australian TGA product information was not held for this topic.

Currency

ESC 2026 HF adds narrative, without a class, that amiodarone is recommended in HFrEF requiring pharmacological cardioversion.^[5] Among the guidelines checked for this topic, ESC 2024 AF, ESC 2022 VA, ESC 2019 SVT and ACC/AHA 2023 AF are the newest documents of their bodies on these questions, and ESC 2026 HF and ESC 2025 pregnancy were checked for newer rows. The 2025 EHRA practical compendium of antiarrhythmic drugs and the 2026 HRS/PACES scientific statement were found but are consensus documents without class rows and are not held as text for this topic.

Exam pearls

References11ShowHide

1. [1]Van Gelder IC, et al. 2024 ESC Guidelines for the management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J, 2024.PMID 39210723
2. [2]Joglar JA, et al. 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation, 2024.PMID 38033089
3. [3]Zeppenfeld K, et al. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J, 2022.PMID 36017572
4. [4]Brugada J, 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.PMID 31504425
5. [5]Køber L, et al. 2026 ESC Guidelines for the management of heart failure. Eur Heart J, 2026.PMID 42661420
6. [6]De Backer J, et al. 2025 ESC Guidelines for the management of cardiovascular disease and pregnancy. Eur Heart J, 2025.PMID 40878294
7. [7]Brieger D, et al. National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand: Australian clinical guidelines for the diagnosis and management of atrial fibrillation 2018. Med J Aust, 2018.PMID 30067936
8. [8]RemedyRepack Inc. AMIODARONE HYDROCHLORIDE TABLET — prescribing information. DailyMed, 2026.Source
9. [9]Amneal Pharmaceuticals of New York LLC FLECAINIDE ACETATE tablet — prescribing information. DailyMed, 2026.Source
10. [10]Legacy Pharma USA, Inc. BETAPACE (sotalol hydrochloride) tablet; BETAPACE AF (sotalol hydrochloride) tablet — prescribing information. DailyMed, 2024.Source
11. [11]Sanofi-Aventis U.S. LLC MULTAQ (dronedarone) tablet, film coated — prescribing information. DailyMed, 2025.Source