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CLINICAL STATEMENTS AND GUIDELINES

Circulation. 2024;149:e1–e156. DOI: 10.1161/CIR.0000000000001193 January 2, 2024 e77

Joglar et al 2023 Guideline for the Diagnosis and Management of Atrial Fibrillation

be well-tolerated. A Cochrane database meta-analysis of randomized studies5 reported sotalol to be associated with an increase in all-cause mortality (RR, 2.23 [95% CI, 1.03-4.81]). Low-dose amiodarone is more effective than sotalol and Class IC agents for maintenance of sinus rhythm; but, in view of its adverse effects and multiple drug interactions, is best reserved for patients for whom other antiarrhythmic drugsare ineffective, not preferred, or contraindicated. However, amiodarone and dofetilide are options for maintenance of sinus rhythm for patients with HFrEF, as they are effective,1,2 and most other drugs are contraindicated.

Recommendation-Specific Supportive Text 1.	 In subanalyses of randomized trials, dofetilide1 and amiodarone2 have been shown to be effective for maintenance of sinus rhythm in patients with AF who have HF. Most antiarrhythmic agents, except amiodarone and dofetilide, are contraindicated in patients with HFrEF due to worsening of HF and/ or increased mortality. Sotalol is best avoided in most patients with HFrEF, because most patients with HFrEFare already taking a beta blocker for mortality reduction, and the addition of a second beta blocker (sotalol) is unlikely to be well-tolerated. Therefore, although amiodarone is associated with a wide range of adverse effects and many clinically important drug interactions, amiodarone is often used as a first-line agent for maintenance of sinus rhythm in patients with AF and HFrEF. Dofetilide is also an option for this indication. Patients undergoing initiation or reloading of dofetilide29,30 should be admitted for at least 3 days to a health care facility that can provide calculations of CrCl, continuous electrocardiographic monitoring, and availability of cardiac resuscitation. 2.	 Randomized, controlled studies and a comprehen-

sive Cochrane database analysis have established the efficacy of flecainide3–5 and propafenone5–11 for maintenance of sinus rhythm in patients with AF. In the Flec-SL (Short-term versus long-term antiarrhythmic drug treatment after cardioversion of atrial fibrillation) trial,4 flecainide prevented episodes of paroxysmal AF in 31% of patients over 4 months compared with 9% in the placebo group (0.013). Sustained-release propafenone 425, 325, and 225 mg twice daily extended the median time to the occurrence of AF, AFL, or supraventricular tachycardia (SVT) compared with placebo (>300, 291, and 112 days versus 41 days, P<0.001, for all propafenone doses versus placebo).8 Patients with previous MI or significant structural heart disease (scar or fibrosis) should not take flecainide of propafenone,26,27 and individuals taking flecainide or propafenone should be concomitantly taking an atrioventricular nodal blocking agent to reduce the risk of 1:1 AFL.12 3 Randomized, controlled studies13–15 and a compre-

hensive Cochrane database analysis5 have established the efficacy of dronedarone for maintenance of sinus rhythm in patients with AF. The combined analysis (n=1237) of EURIDIS (European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm) and ADONIS (American-Australian-African Trial with Dronedarone in Atrial Fibrillation or Flutter Patients for the Maintenance of Sinus Rhythm) reported longer median times to AF recurrence in dronedarone groups versus placebo (EURIDIS: 96 versus 41 days; P=0.001; ADONIS 158 versus 59 days; P=0.002).14

4 Randomized, controlled studies and a compre-

hensive Cochrane database analysis5 have established the efficacy of dofetilide for maintenance of sinus rhythm in patients with AF. In the SAFIRE-D (Symptomatic Atrial Fibrillation Investigative Research on Dofetilide) study,1,16 the probability of remaining in sinus rhythm at 1 year was higher in patients receiving dofetilide 500 μg twice daily compared with placebo (0.58 versus 0.25; P<0.001). Patients undergoing initiation or reloading of dofetilide29,30 should be admitted for at least 3 days to a health care facility that can provide calculations of CrCl, continuous electrocardiographic monitoring, and cardiac resuscitation. 5.	 Multiple randomized, controlled studies have

established the efficacy of amiodarone for maintenance of sinus rhythm in AF and have shown amiodarone to be superior to other antiarrhythmic agents. In SAFE-T (Sotalol Amiodarone Atrial Fibrillation Efficacy Trial), amiodarone was superior to sotalol and placebo with respect to median time to recurrence of AF (487 versus 74 versus 6 days, respectively; P<0.001, for amiodarone versus placebo and amiodarone versus sotalol).17 In CTAF (Canadian Trial of Atrial Fibrillation), AF recurrence rates at 16 months were 35% in the amiodarone group and 63% in those randomized to combined propafenone or sotalol (P<0.001).19 However, the adverse effects profile of amiodarone is onerous. Amiodarone is associated with a wide range of adverse effects, including pulmonary fibrosis, hypo- or hyperthyroidism, elevated transaminases, and more rarely hepatotoxicity, photosensitivity, changes in skin pigmentation, peripheral neuropathy, sinus bradycardia, QT interval prolongation and torsades de pointes, corneal microdeposits, and rarely optic neuropathy.24 In addition, amiodarone is associated with many clinically relevant drug interactions.31 Therefore, amiodarone is best reserved for patients who do not respond to other recommended antiarrhythmic agents or for whom other antiarrhythmic drugs are contraindicated.

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