What is the indication and dosage of digoxin (Digitalis glycoside) in cardiology according to the American College of Cardiology (ACC) 2023 guideline?

Digoxin Indications in Cardiology According to ACC 2023 Guidelines

Digoxin has two primary indications in cardiology: (1) reducing hospitalizations in symptomatic heart failure with reduced ejection fraction (HFrEF) despite guideline-directed medical therapy (Class 2b, Level B-R), and (2) adjunctive rate control in atrial fibrillation, particularly when combined with beta-blockers (listed as a pharmacological rate control option). 1

Primary Indications and Level of Evidence

Heart Failure with Reduced Ejection Fraction (HFrEF)

Class 2b Recommendation (Level B-R): In patients with symptomatic HFrEF despite GDMT (or who are unable to tolerate GDMT), digoxin might be considered to decrease hospitalizations for HF. 1

• The 2022 ACC/AHA/HFSA Heart Failure Guideline specifically states digoxin has no mortality benefit—neither beneficial nor harmful—but modestly reduces the combined risk of death and hospitalization. 1
• The primary evidence comes from the DIG trial (Digitalis Investigation Group), which enrolled patients with NYHA class II-III HF and showed treatment with digoxin for 2-5 years had no effect on mortality but reduced hospitalizations. 1
• Digoxin should only be considered after optimization of neurohormonal antagonists (ACE inhibitors/ARBs, beta-blockers, mineralocorticoid receptor antagonists, SGLT2 inhibitors). 1
• Target serum digoxin concentration is 0.5-0.9 ng/mL, as concentrations above 1.0 ng/mL offer no additional benefit and may increase mortality risk. 1, 2

Atrial Fibrillation Rate Control

Listed as a pharmacological rate control agent in the 2023 ACC/AHA/ACCP/HRS Atrial Fibrillation Guideline, but not as first-line therapy. 1

• Beta-blockers are superior to digoxin for rate control, particularly during exercise, and should be the preferred initial agent. 1, 3
• Digoxin is most appropriate as an adjunctive agent for rate control, not monotherapy, especially in patients with concomitant heart failure. 1, 3
• Digoxin monotherapy is ineffective for exercise-induced tachycardia due to its vagotonic mechanism, which is overcome by increased sympathetic tone during activity. 1, 4
• The combination of digoxin with beta-blockers or non-dihydropyridine calcium channel blockers provides superior rate control both at rest and during exercise. 1, 4

Dosing Recommendations from ACC Guidelines

Standard Maintenance Dosing

• 0.125-0.25 mg daily for most adults under age 70 with normal renal function. 1, 5
• 0.125 mg daily for patients over age 70, with impaired renal function, or low lean body mass. 1, 5
• 0.0625 mg daily (or every other day) for patients with marked renal impairment. 1, 5
• Higher doses (0.375-0.50 mg daily) are rarely needed or recommended for heart failure management. 1

Intravenous Dosing for Acute Rate Control in AF

• Initial IV bolus: 0.25-0.5 mg over several minutes. 1
• Repeat doses of 0.25 mg may be given every 60 minutes as needed. 1
• Maintenance: 0.0625-0.25 mg daily orally after acute control achieved. 1

Critical Dosing Considerations

• No loading doses are necessary for chronic heart failure management—gradual accumulation with maintenance dosing is preferred. 1, 5
• Steady-state serum concentrations are achieved in approximately 5 half-lives (1-3 weeks depending on renal function). 5
• The dose must be adjusted based on creatinine clearance, age, and lean body weight. 5

Contraindications and Precautions

Absolute Contraindications

• Significant sinus or second/third-degree AV block without a permanent pacemaker. 1, 3
• Pre-excitation syndromes (e.g., Wolff-Parkinson-White with AF/atrial flutter), as digoxin can facilitate rapid conduction down the accessory pathway. 1, 3

Use with Extreme Caution

• Patients taking other AV nodal blocking agents (beta-blockers, calcium channel blockers, amiodarone). 1, 3
• Hypokalemia, hypomagnesemia, or hypothyroidism, which increase the risk of toxicity even at therapeutic levels. 1
• Renal impairment, as digoxin is renally eliminated and accumulation occurs rapidly. 1, 5

Drug Interactions Requiring Dose Reduction

Reduce digoxin dose by 50% when initiating amiodarone or dronedarone, and by 30-50% with verapamil, quinidine, clarithromycin, erythromycin, itraconazole, cyclosporine, or propafenone. 1, 2

Monitoring Requirements

Therapeutic Drug Monitoring

• Target serum concentration for heart failure: 0.5-0.9 ng/mL. 1, 2
• Target serum concentration for atrial fibrillation: 0.6-1.2 ng/mL (though lower is preferred). 2, 6
• Toxicity commonly occurs at levels >2 ng/mL, but can occur at lower levels with electrolyte abnormalities. 1
• Sample digoxin levels at least 6-8 hours after the last dose to allow tissue equilibration. 5

When to Check Digoxin Levels

• When adding interacting medications (amiodarone, verapamil, etc.). 2, 6
• When signs of toxicity appear (cardiac arrhythmias, GI symptoms, neurological symptoms). 2, 6
• In patients with changing renal function. 2, 6
• Routine monitoring is not necessary once a stable dose is established in the absence of clinical changes. 6

Concurrent Laboratory Monitoring

• Serum potassium and magnesium should be monitored regularly, as deficiencies increase toxicity risk. 1, 2, 6
• Renal function (creatinine clearance) should be assessed, particularly in elderly patients. 1, 2, 6

Common Pitfalls and Clinical Pearls

Major Pitfalls to Avoid

• Do not use digoxin as first-line therapy for atrial fibrillation rate control—beta-blockers are superior. 1, 3
• Do not use loading doses in stable outpatients with heart failure—they are unnecessary and increase toxicity risk. 1, 5
• Do not exceed 0.25 mg daily in most patients with chronic AF—if rate control is inadequate, add a beta-blocker rather than increasing digoxin. 2
• Do not ignore drug interactions—proactively reduce digoxin dose by 50% when starting amiodarone. 2, 6

Clinical Pearls

• Digoxin is particularly useful in patients with hypotension limiting beta-blocker use, as it does not lower blood pressure. 2
• In patients with advanced CKD, start with 0.0625 mg daily or every other day and monitor levels closely. 2, 5
• The DIG trial showed increased mortality at plasma concentrations exceeding 1.2 ng/mL, so lower targets are safer. 1
• Digoxin improves symptoms and exercise tolerance in heart failure but provides no mortality benefit, unlike ACE inhibitors, beta-blockers, and MRAs. 1, 7

Signs of Digoxin Toxicity

Cardiac Manifestations

• Ventricular arrhythmias (ectopic beats, ventricular tachycardia). 1, 2
• AV block of varying degrees. 1, 2
• Sinus bradycardia or sinus pauses. 1

Non-Cardiac Manifestations

• Gastrointestinal: anorexia, nausea, vomiting (often earliest signs). 1, 2
• Neurological: visual disturbances (yellow-green halos), confusion, disorientation. 1, 2