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CLINICAL STATEMENTS AND GUIDELINES

Circulation. 2024;149:e1–e156. DOI: 10.1161/CIR.0000000000001193 January 2, 2024 e63

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

7.2.2 Long-Term Rate Control

Recommendations for Long-Term Rate Control Referenced studies that support the recommendations are summarized in the Online Data Supplement. COR LOE Recommendations

1 B-NR 1 In patients with AF, beta blockers or nondihydropyri-

dine calcium channel blockers (diltiazem, verapamil) are recommended for long-term rate control with the choice of agent according to underlying substrate and comorbid conditions.1,2

2a B-NR 2 For patients with AF in whom measuring serum

digoxin levels is indicated, it is reasonable to target levels <1.2 ng/mL.3–6

2a B-R 3 In patients with AF and HF symptoms, digoxin is

reasonable for long-term rate control in combination with other rate-controlling agents, or as monotherapy if other agents are not preferred, not tolerated, or contraindicated.7–9

3: Harm C-LD 4 In patients with AF and LVEF <40%, nondihydro-

pyridine calcium channel–blocking drugs should not be administered given their potential to exacerbate HF.10,11

3: Harm B-R 5 In patients with permanent AF who have risk factors

for cardiovascular events, dronedarone should not be used for long-term rate control.12

Synopsis Both nondihydropyridine calcium channel blockers (verapamil and diltiazem) and beta blockers are effective for long-term rate control. These agents are useful in ventricular rate control in the absence of preexcitation. Digoxin may be useful in patients with limited tolerability to other agents, or as adjunct therapy in patients with a difficult to control ventricular rate. Limited data exist comparing various rate control agents, especially in the setting of chronic rate control. Selection of specific agents should consider patient-specific characteristics (ie, HFrEF, reactive airway disease) and response (Figure 18).

Recommendation-Specific Supportive Text 1.	 One prospective, randomized, investigator-blinded,

crossover study compared the effect of 4 ratereducing once-daily drug regimens on the ventricular heart rate and arrhythmia-related symptoms in patients with permanent AF. The 24-hour mean heart rate was 96±12 bpm at baseline (no treatment), 75±10 bpm with diltiazem, 81±11 bpm with verapamil, 82±11 bpm with metoprolol, and 84±11 bpm with carvedilol. All drugs significantly reduced the heart rate compared with baseline.13 In a retrospective cohort study, investigators used a database from 2 urban emergency departments to identify consecutive patients with emergency department discharge diagnoses of AF. A total of 259 consecutive patients were enrolled, with 100 receiving calcium channel blockers and 159 receiving beta blockers. Baseline demographics and comorbidities were similar. Twenty-seven percent of patients taking beta blockers were admitted, 31.0% of patients taking calcium channel blockers were admitted, and there were no significant differences in emergency department length of stay, adverse events, or 7- or 30-day emergency department revisits. A follow-up analysis of the AFFIRM study examined the difference in all hospitalization and all-cause mortality in participants treated with a single rate-control agent at baseline. No difference was found among those participants receiving beta blockers, nondihydropyridine calcium channel blockers, or digoxin.2

2 Seminal work investigating digoxin toxicity was

based on a small series of patients, where toxicity was determined by electrocardiographic abnormalities.14 Toxicity was seen when serum digoxin concentrations exceeded 2.0 ng/mL, and almost certainly at levels >3.0 ng/mL. Based on this small study, the narrow therapeutic range of digoxin is usually cited as 0.8 to 2.0 ng/mL, with substantial variation across institutional laboratories and published references.15,16 However, 3 post hoc analyses of the DIG (Digitalis Investigation Group) trial suggested that safe use of digoxin is seen at lower serum concentrations.4–6 Serum digoxin concentrations of 0.5 to 0.9 ng/mL were associated with significantly lower all-cause mortality rates and hospitalizations compared with concentrations ≥1.0 ng/mL.3 Another analysis suggested that serum digoxin concentrations >1.2 ng/mL may be harmful, particularly in women.7 A post hoc analysis comparing patients with AF taking digoxin with propensity score-matched controls suggested that patients with serum digoxin concentrations <0.9 ng/mL had no increased risk of death, concentrations of 0.9 to 1.1 ng/mL had a nonsignificant increased risk of death, and serum digoxin concentrations ≥1.2 ng/mL were associated with a significant (56%) increased risk of death.4 Serum digoxin concentrations of 0.5 to 0.8 ng/mL seem safest in terms of benefit without adverse effects in patients with HFrEF.17

3 Digoxin may have added efficacy as rate control

in conjunction with beta blockers in patients with AF. A small RCT of 47 patients with persistent AF and concomitant HFrEF compared the effects of digoxin alone, carvedilol alone, and their combination.10 Combination therapy was significantly associated with better rate control and symptom relief than monotherapy with either agent. The RATE-AF trial randomized 160 patients with persistent AF and concomitant HFrEF to digoxin and bisoprolol.11 No significant differences in the primary endpoint of QOL were noted at 6 months with either agent. Several secondary outcomes, including N-terminal pro-brain natriuretic peptide level, were significantly lower in the digoxin group, without a

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