What is digoxin?

What is Digoxin?

Digoxin is a cardiac glycoside medication used primarily to treat heart failure with reduced ejection fraction (HFrEF) and to control ventricular rate in atrial fibrillation. 1

Primary Indications

Digoxin has two FDA-approved indications 1:

• Heart Failure: Treatment of mild to moderate heart failure, where it increases left ventricular ejection fraction, improves symptoms and exercise capacity, and reduces heart failure-related hospitalizations without affecting mortality 1
• Atrial Fibrillation: Control of ventricular response rate in patients with chronic atrial fibrillation 1

Mechanism of Action and Clinical Effects

Digoxin works through multiple mechanisms 2:

• Positive inotropic effect: Increases cardiac contractility by inhibiting sodium-potassium ATPase 2
• Neurohormonal modulation: Attenuates activation of neurohormonal systems, which may be its primary mechanism in heart failure rather than its inotropic properties 2
• Vagotonic effect: Slows conduction through the atrioventricular node, controlling ventricular rate in atrial fibrillation 3

Clinical Benefits in Heart Failure

In patients with HFrEF and sinus rhythm, digoxin provides symptom improvement and reduces hospitalizations but does not reduce mortality. 2

The ACC/AHA guidelines give digoxin a Class IIa recommendation (Level of Evidence B) for decreasing hospitalizations in HFrEF patients 2. Clinical trials demonstrate 2:

• Improves symptoms, quality of life, and exercise tolerance in mild to moderate heart failure
• Benefits occur regardless of underlying rhythm (sinus rhythm or atrial fibrillation), etiology (ischemic or nonischemic), or concomitant therapy
• Reduces combined risk of death and hospitalization modestly over 2-5 years
• Reduces heart failure hospitalizations by 28% (NNT=13 over 3 years) 4

Dosing and Administration

Standard dosing is 0.125 to 0.25 mg daily, with lower doses (0.125 mg daily or every other day) required for elderly patients (>70 years), those with impaired renal function, or low lean body mass. 2

Key dosing principles 2, 4:

• No loading doses are necessary for chronic heart failure management 2
• Higher doses (0.375-0.50 mg daily) are rarely needed or used 2
• Target plasma concentration: 0.5 to 0.9 ng/mL (some guidelines suggest up to 1.0 ng/mL) 2, 4
• Lower concentrations (0.5-0.9 ng/mL) prevent worsening heart failure as effectively as higher concentrations with better safety 2, 4

Patient Selection and Timing

Digoxin should be considered in patients with persistent HFrEF symptoms despite guideline-directed medical therapy (GDMT) with diuretics, ACE inhibitors/ARBs, beta-blockers, and aldosterone antagonists. 2

The guidelines suggest several strategies 2:

• Add digoxin to patients with persistent symptoms on GDMT
• Add digoxin early to the initial regimen in patients with severe symptoms
• Delay digoxin until response to neurohormonal antagonists has been defined
• Consider aldosterone antagonists before digoxin in symptomatic patients

For atrial fibrillation with heart failure, digoxin is recommended for rate control, particularly in sedentary patients or those with LVEF <40%. 4, 3

Contraindications and Precautions

Absolute contraindications 2, 4:

• Significant sinus or atrioventricular block without a permanent pacemaker
• Pre-excitation syndromes (Wolff-Parkinson-White syndrome) - digoxin can shorten the refractory period of the accessory pathway and potentially induce ventricular fibrillation 4
• Previous digoxin intolerance 4

Use cautiously in patients taking drugs that depress nodal function or affect digoxin levels (amiodarone, beta-blockers, verapamil, diltiazem) 2

Monitoring Requirements

Mandatory monitoring includes serial serum electrolytes (especially potassium and magnesium) and renal function, as digoxin can cause arrhythmias particularly with hypokalemia. 4

Additional monitoring considerations 2, 4:

• Check digoxin level early during chronic therapy, but routine serial measurements are not necessary once stable 4
• Target therapeutic serum concentration: 0.5-0.9 ng/mL 4
• Toxicity commonly occurs with levels >2 ng/mL but can occur at lower levels with hypokalemia, hypomagnesemia, or hypothyroidism 2

Drug Interactions

Important interactions that increase digoxin levels 2, 4:

• Amiodarone, verapamil, diltiazem, quinidine
• Clarithromycin, erythromycin
• Itraconazole, cyclosporine
• Reduce digoxin dose when adding these agents 4

Adverse Effects

Major side effects include 2:

• Cardiac arrhythmias: Ectopic and re-entrant rhythms, heart block, particularly with hypokalemia 4
• Gastrointestinal: Anorexia, nausea, vomiting 2
• Neurological: Visual disturbances (color vision changes), disorientation, confusion 2, 4

When dosed appropriately with attention to renal function and drug interactions, digoxin is well-tolerated by most patients. 2

Role in Modern Heart Failure Management

Digoxin should be used as part of comprehensive heart failure therapy, not as monotherapy. 4 The magnitude of benefit from GDMT (ACE inhibitors/ARBs, beta-blockers, aldosterone antagonists) far exceeds that of digoxin 4:

• Beta-blockers: 34% mortality reduction, NNT=9 2
• Aldosterone antagonists: 30% mortality reduction, NNT=6 2
• ACE inhibitors/ARBs: 17% mortality reduction, NNT=26 2
• Digoxin: No mortality benefit, reduces hospitalizations 2

If a patient is taking digoxin but not an ACE inhibitor or beta-blocker, digoxin should not be withdrawn, but appropriate neurohormonal antagonist therapy should be instituted. 2

Special Considerations

Digoxin is not indicated as primary therapy for acute decompensated heart failure. 2 Patients should first receive appropriate acute treatment (usually intravenous medications), and digoxin may be initiated after stabilization as part of long-term strategy 2

For atrial fibrillation rate control, beta-blockers are usually more effective than digoxin alone, particularly during exercise. 2 Digoxin works best in sedentary patients or those with heart failure due to its vagotonic mechanism 3