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CLINICAL STATEMENTS AND GUIDELINES

Circulation. 2024;149:e1–e156. DOI: 10.1161/CIR.0000000000001193 January 2, 2024 e79

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

class III or IV HF (shortness of breath on minimal exertion or at rest). More than 40% of the patients had NYHA class II HF at baseline. The investigators reported that, contrary to the study’s hypothesis, the mortality rate was higher in the dronedarone group compared with that in the placebo group (8.1% versus 3.8%; HR, 2.13 [95% CI, 1.07-4.25]; P=0.03). The higher mortality rate was principally associated with worsening HF.

8.3.2 Inpatient Initiation of Antiarrhythmic Agents

Recommendations for Inpatient Initiation of Antiarrhythmic Agents Referenced studies that support the recommendations are summarized in the Online Data Supplement. COR LOE Recommendations

1 A 1 Patients with AF who are initiating, increasing the

dose of, or reinitiating dofetilide therapy should be admitted for a minimum of 3 days to a facility that can provide continuous electrocardiographic monitoring, calculations of CrCl, and cardiac resuscitation, given the potential for proarrhythmia.1–7

2a B-R 2 In patients with AF, it is reasonable to initiate sotalol

therapy in a facility that can provide continuous electrocardiographic monitoring, calculations of CrCl, and cardiac resuscitation, given the potential for proarrhythmia and bradycardia.4,8–10

2a B-NR 3 In patients with AF who are initiating PITP dosing

of flecainide and propafenone with concomitant atrioventricular nodal blocking drugs, it is reasonable to receive the first dose in a facility that can provide continuous electrocardiographic monitoring, given the potential for proarrhythmia.9–13

Synopsis Pharmacological rhythm control is an alternative to catheter ablation in appropriately selected patients. However, many antiarrhythmic agents have a paradoxic risk of proarrhythmia and require close monitoring on initiation. Dofetilide and sotalol confer a relatively high risk of torsades de pointes given they prolong the QT interval, and this can occur early during initiation. As such, patients need to be admitted and closely monitored when starting or reinitiating dofetilide, as well as for increasing the dosage. Many practitioners choose to initiate sotalol in an inpatient setting given it can cause torsades de pointes; furthermore, unlike dofetilide, it can also cause bradyarrhythmia. Amiodarone, flecainide, and propafenone can be started in the outpatient setting. Because PITP with class IC (with concomitant atrioventricular nodal blockers) can cause brady- or tachyarrhythmias, the first attempt during an acute episode of AF may be performed in a monitored environment if a high dose is used. Recommendation-Specific Supportive Text 1.	 Dofetilide, a class III antiarrhythmic drug, is a

selective IKr blocker that also blocks late Na+ current (INaL) and poses a high risk for torsades de pointes. The SAFIRE-D (Symptomatic Atrial Fibrillation Investigative Research on Dofetilide) study investigated dofetilide in cardioverting and maintaining sinus rhythm in 325 patients with AF or AFL who underwent a minimum 3-day hospitalization.1 Of 241 patients randomized to dofetilide, 10 patients had QTc prolongation within the first 3 days, with 2 episodes of torsades de pointes degenerating to VF. In a substudy of the AFFIRM trial, 1 of 12 patients on dofetilide experienced torsades de pointes.3 One retrospective cohort of 378 patients found no significant differences in the incidence of torsades de pointes during inpatient initiation of dofetilide and sotalol (1.3% versus 1.2%).4 One systematic review found a 1% to 10% incidence of torsades de pointes in patients taking dofetilide, highest in patients with HFrEF and taking higher than recommended (or not renally adjusted) doses.14 In 2 randomized RCTs from the DIAMOND (Management of Hyperkalemia in Subjects Receiving Renin-angiotensin-aldosterone System Inhibitor Medications for Heart Failure with Reduced Ejection Fraction) population, in which all patients were hospitalized for at least 3 days after dofetilide was initiated, torsades de pointes occurred in 25 of 762 patients (3.3%)5 and 7 of 749 patients (0.9%),7 respectively, with most occurring within the first 3 days of dosing. In the DIAMOND AF substudy of these trials,6 torsades de pointes occurred in 4 dofetilide-treated patients with AF (1.6%). 2.	 Sotalol is a class III antiarrhythmic with beta-block-

ing properties. Its action potential prolongation (due to the IKr-blocking properties of the d isomer in concert with INaL blockade) predisposes patients to torsades de pointes. One meta-analysis demonstrated that sotalol, compared with placebo or no treatment, was associated with a significantly higher all-cause mortality rate (RR, 2.23; 1882 patients in 5 RCTs) and proarrhythmia (RR, 3.55; 2989 patients in 12 RCTs).18 The SAFE-T trial randomized 665 patients to amiodarone, sotalol, or placebo, all initiated in the outpatient setting (sotalol at 80 mg twice daily for the first week and 160 mg twice daily subsequently).15 Fifteen deaths occurred in the sotalol group, 8 of which were sudden, with a nonsignificant mortality ratio of 1.8 compared with placebo. In 1 retrospective cohort of 120 patients undergoing sotalol initiation as an inpatient, 2 of 7 had torsades de pointes; 20 patients developed significant bradyarrhythmias necessitating dose reductions, and 3 patients required permanent pacing.8 Intravenous sotalol was introduced in the United States in 2015 and reaches therapeutic levels rapidly and with easier dose titration to QTc levels and clinical response. As such, it may be an option for more expedient inpatient initiation (obviating the need for a 3-day initiation period).16

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