Class III antiarrhythmics (marked **D**), particularly amiodarone, are the preferred agents for rhythm control of atrial fibrillation in patients with heart failure with reduced ejection fraction (HFrEF). While amiodarone is classified as a Class III agent (potassium channel blocker that prolongs action potential duration and refractory period), its unique property is that it possesses characteristics of ALL FOUR Vaughan-Williams classes: Class I (sodium channel block), Class II (beta-blockade), Class III (potassium channel block), and Class IV (calcium channel block). This multi-class activity makes it the broadest-spectrum antiarrhythmic available. In HFrEF, other antiarrhythmics are contraindicated due to negative inotropic effects (Class I agents worsen outcomes in structural heart disease; Class IV agents reduce contractility). Amiodarone, despite its extensive toxicity profile requiring careful monitoring (pulmonary, thyroid, hepatic, ocular, dermatologic), remains the most effective and safest choice for rhythm control in this population because its multi-class mechanism provides superior efficacy for both atrial and ventricular arrhythmias without the hemodynamic deterioration seen with other agents. [cite: KD Tripathi 9e Ch 38]
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