What are the preferred anti-arrhythmic (arrhythmia) drugs?

Preferred Anti-Arrhythmic Drugs

The preferred anti-arrhythmic drug depends primarily on the presence or absence of structural heart disease, with flecainide, propafenone, and sotalol recommended first-line for patients without structural heart disease, while amiodarone and dofetilide are the only safe options for patients with heart failure or significant left ventricular dysfunction. 1

Selection Based on Cardiac Substrate

Patients WITHOUT Structural Heart Disease (No or Minimal Heart Disease)

For patients with structurally normal hearts, flecainide, propafenone, and sotalol are the first-line agents because they are well-tolerated, essentially devoid of extracardiac organ toxicity, and have the lowest proarrhythmic risk in this population. 1

• These class IC agents (flecainide, propafenone) and class III agent (sotalol) have demonstrated equal efficacy in preventing AF recurrences in comparative trials 2
• Dronedarone is also a first-line option in this population, particularly for reducing cardiovascular hospitalizations in patients with non-permanent AF and cardiovascular risk factors 1
• Beta-blockers should be considered first-line for adrenergically-mediated AF 1, 3
• If first-line agents fail or cause side effects, second-line choices include amiodarone, dofetilide, disopyramide, procainamide, and quinidine 1

Patients WITH Heart Failure

Amiodarone and dofetilide are the ONLY antiarrhythmic drugs proven safe in patients with heart failure and are the mandatory first-line choices in this population. 1

• Randomized trials have specifically demonstrated the safety of amiodarone and dofetilide (given separately) in patients with congestive heart failure 1
• All other antiarrhythmic drugs carry unacceptable proarrhythmic risk in heart failure patients 1
• Dofetilide reduced AF incidence and hospital readmissions for heart failure without increasing mortality in the DIAMOND CHF trial 4
• Amiodarone should be the drug of choice in patients with severe heart failure 1

Patients WITH Coronary Artery Disease (CAD)

Sotalol is the preferred first-line agent in stable CAD patients because it combines beta-blocking activity with antiarrhythmic efficacy and has less long-term toxicity than amiodarone. 1

• Beta-blockers may be considered first, though data on their efficacy for maintaining sinus rhythm after cardioversion are not convincing 1
• Amiodarone is a reasonable alternative, particularly if the patient also has heart failure 1
• Dofetilide may be considered as a second-line agent in stable CAD patients, particularly post-myocardial infarction 1, 2
• Flecainide and propafenone are absolutely contraindicated in CAD patients due to increased risk of life-threatening ventricular arrhythmias 1, 3
• Quinidine, procainamide, and disopyramide are third-line choices 1

Patients WITH Hypertensive Heart Disease

Without Left Ventricular Hypertrophy (LVH)

Flecainide and propafenone are first-line choices because they do not prolong the QT interval, offering a safety advantage over drugs that cause QT prolongation. 1

• If these agents fail or cause side effects, amiodarone, dofetilide, and sotalol are appropriate second-line choices 1
• Disopyramide, procainamide, and quinidine are third-line agents 1

With Marked Left Ventricular Hypertrophy (Wall Thickness ≥1.4 cm)

Amiodarone becomes the mandatory first-line agent when marked LVH is present because hypertrophied myocardium is at increased risk for torsade de pointes with QT-prolonging drugs. 1

• Patients with LVH are at increased risk of developing torsade de pointes related to early ventricular afterdepolarizations 1
• Amiodarone prolongs the QT interval but carries a very low risk of ventricular proarrhythmia despite this effect 1
• Sotalol is thought to be associated with increased proarrhythmia in LVH patients 1
• Dronedarone may be an option, though definitive data in marked LVH are lacking 1

Special Clinical Scenarios

Vagally-Mediated AF

• Disopyramide or flecainide are preferred initial agents due to their anticholinergic properties 1, 3

Adrenergically-Induced AF

• Beta-blockers or sotalol are the suggested first-line agents 1, 3

Recurrent Paroxysmal AF

• The same substrate-based algorithm applies as above 1
• Rate control and thromboembolism prevention are appropriate regardless of rhythm control strategy 1

Critical Safety Considerations

Proarrhythmic Risk Hierarchy

Class IC drugs (flecainide, propafenone) must NEVER be used in patients with structural heart disease, CAD, or ischemia due to dramatically increased risk of sustained ventricular fibrillation/flutter. 3, 5

• In ischemia or conditions with impaired cell contact (fibrosis, infiltration), proarrhythmic risk with class I drugs is greatly increased 5
• Drugs that prolong the QT interval (class IA and III agents) carry increased torsade de pointes risk in hypertrophied hearts 1, 5
• Beta-blockers have the lowest proarrhythmic risk and are the only antiarrhythmics proven to reduce sudden arrhythmic death 3, 6

Amiodarone Considerations

Amiodarone is the most effective antiarrhythmic for maintaining sinus rhythm but should generally be reserved for second-line use due to extracardiac toxicity, except in heart failure or marked LVH where it becomes first-line. 1

• Amiodarone is more effective than sotalol, propafenone, and flecainide for maintaining sinus rhythm 1
• Its extracardiac toxicity profile (pulmonary, thyroid, liver) relegates it to second-line therapy in patients without structural heart disease 1, 3
• Amiodarone has a very long half-life (up to 100 days), making it less suitable for short-term therapy 3

Dofetilide-Specific Requirements

Dofetilide requires mandatory inpatient initiation with creatinine clearance calculation and serial QTc monitoring due to dose-dependent torsade de pointes risk. 4

• Creatinine clearance must be calculated before the first dose, with dose adjustment for CrCl 40-60 mL/min (250 mcg twice daily) 4
• QTc must be measured 2-3 hours after each dose for the first 5 doses 4
• Dofetilide is contraindicated if baseline QTc >500 ms or if CrCl <20 mL/min 4
• 76% of torsade de pointes episodes occur within the first 3 days of therapy 4

Drug Interactions Requiring Dose Adjustment

• Amiodarone increases digoxin levels by 70% after one day; reduce digoxin dose by approximately 50% 7
• Amiodarone increases warfarin effect by 100% after 3-4 days; reduce warfarin dose by one-third to one-half 7
• Amiodarone increases quinidine levels by 33% and procainamide levels by 55%; reduce doses by one-third 7
• Flecainide and propafenone can convert AF to atrial flutter with rapid ventricular response; pre-administer beta-blockers, verapamil, or diltiazem to prevent this 3