What are additional (plus one) Class (C) rhythm control agents?

Additional (Plus One) Class C Rhythm Control Agents

Beyond the first-line rhythm control agents (flecainide, dofetilide, propafenone, and ibutilide), additional Class C level evidence supports the use of amiodarone, sotalol, procainamide, and quinidine for rhythm control in atrial fibrillation, with agent selection critically dependent on underlying cardiac structure and comorbidities. 1

Primary Additional Rhythm Control Agents

Amiodarone

• Most versatile additional agent with Class I, II, III, and IV antiarrhythmic properties, making it effective across multiple mechanisms 2
• Oral loading (600 mg/day) can restore sinus rhythm and is highly effective for maintenance of sinus rhythm 1
• Particularly valuable in structural heart disease (post-CABG, valve surgery, heart failure) because it does not cause hypotension and has minimal negative inotropic effects 1
• IV amiodarone (300 mg over 1 hour, then 10-50 mg/h) is more effective for rate control than acute cardioversion 1
• Major limitation: potential acute pulmonary toxicity in post-cardiac surgery patients whose lungs have been exposed to physical insults 1
• Long-term concerns: thyroid dysfunction, pulmonary fibrosis, hepatic toxicity, corneal deposits, and skin discoloration 1

Sotalol

• Oral-only formulation in the United States with Class III antiarrhythmic activity plus nonselective beta-blocking properties 1
• Similar efficacy to other Class III agents (except amiodarone) for conversion and maintenance of sinus rhythm 1
• Provides excellent rate control if atrial fibrillation recurs due to beta-blocking effects 1
• Minimal data exist for efficacy specifically in post-cardiac surgery atrial fibrillation 1
• Risk of torsades de pointes requires monitoring, especially with renal insufficiency, electrolyte abnormalities, or bradycardia 1

Ibutilide

• IV-only formulation with efficacy similar to Class IA drugs and sotalol 1
• Slightly more efficacious for atrial flutter conversion than atrial fibrillation 1
• Useful pretreatment for patients with previous lack of response to electrical cardioversion 1
• Class I recommendation for pharmacological cardioversion when contraindications are absent 1

Dofetilide

• Oral-only formulation demonstrating efficacy for restoration and maintenance of sinus rhythm in coronary artery disease and heart failure 1
• Not proven effective in post-cardiac surgery patients, with some evidence of toxicity 1
• Requires dose adjustment in renal insufficiency and mandatory 3 days of in-hospital monitoring during initiation due to ventricular arrhythmia risk 1
• Class I recommendation for pharmacological cardioversion when contraindications are absent 1

Class IA Agents (Limited Role)

Procainamide

• Only Class IA agent available in both IV and oral formulations in the United States 1
• Sparse data support use for restoration or maintenance of sinus rhythm post-cardiac surgery 1
• Limited by hypotension with IV administration and should be avoided in renal insufficiency 1
• Risk of ventricular arrhythmias (torsades de pointes) with all Class IA agents 1

Quinidine and Disopyramide

• Oral formulations only for patients able to absorb medications postoperatively 1
• Very limited evidence for post-cardiac surgery atrial fibrillation 1
• Complicated by ventricular arrhythmias and QT prolongation 1

Critical Safety Considerations

Contraindicated Agents

• Class IC agents (flecainide, propafenone) are contraindicated in patients with coronary artery disease, prior myocardial infarction, or structural heart disease due to increased mortality demonstrated in the CAST trial 3, 4
• Flecainide specifically associated with significantly increased mortality in patients with coronary artery disease and ventricular ectopy 1
• Not recommended for chronic atrial fibrillation due to risk of 1:1 atrioventricular conduction and paradoxical ventricular rate acceleration 4

Proarrhythmic Risk Management

• All antiarrhythmic drugs carry proarrhythmic risk ranging from increased PVCs to ventricular tachycardia, ventricular fibrillation, or torsades de pointes 1, 3, 4
• Replenish electrolytes before initiating therapy: maintain potassium ≥4.0 mEq/L and adequate magnesium levels 1
• Monitor continuously with telemetry and immediate defibrillator access when starting antiarrhythmic drugs during atrial fibrillation 1
• Conversion to sinus rhythm frequently associated with sinus pause, creating high-risk setting for torsades de pointes 1

Agent Selection Algorithm by Cardiac Status

Structurally normal hearts:

• First choice: Class IC agents (flecainide, propafenone) have lowest proarrhythmic risk and organ toxicity 5
• Alternative: Sotalol, dofetilide with attractive safety profiles 5

Hypertrophied hearts:

• Avoid Class III/IA agents due to enhanced torsades de pointes risk 5
• Consider amiodarone with low proarrhythmic risk but monitor for organ toxicity 5

Ischemic heart disease or fibrosis:

• Avoid all Class I agents due to greatly increased risk of sustained ventricular fibrillation/flutter 5
• Amiodarone is preferred due to safety in structural heart disease 1

Heart failure:

• Amiodarone or dofetilide are appropriate choices 1
• Avoid Class IC agents entirely 1