What are the indications for using digoxin in cardiac patients and what is digoxin toxicity?

Digoxin in Cardiac Patients: Indications and Toxicity

Indications for Digoxin Use

Digoxin has two primary indications in cardiac patients: (1) rate control in atrial fibrillation with heart failure and reduced ejection fraction (LVEF <40%), and (2) symptom reduction and decreased hospitalizations in heart failure with reduced ejection fraction despite optimal medical therapy. 1, 2

Heart Failure with Reduced Ejection Fraction (LVEF <40%)

In patients with symptomatic heart failure (NYHA class II-IV) and LVEF <40% in sinus rhythm, digoxin reduces hospitalizations for worsening heart failure by 28% (NNT=13 over 3 years) without affecting mortality. 1

• Digoxin improves ventricular function, patient well-being, and exercise capacity when added to ACE inhibitors/ARBs, beta-blockers, and aldosterone antagonists (Class IIa recommendation, Level of Evidence B). 1, 3
• The drug should be used as adjunctive therapy after optimizing guideline-directed medical therapy, not as monotherapy. 3, 4
• Target serum digoxin concentration is 0.5-0.9 ng/mL, as lower concentrations provide therapeutic benefit with better safety profiles. 3, 4

Atrial Fibrillation with Heart Failure

For patients with atrial fibrillation and LVEF <40%, digoxin is indicated for rate control in addition to, or prior to, a beta-blocker (Class I recommendation, Level of Evidence C). 1, 5, 3

• Add digoxin if ventricular rate is >80 bpm at rest or >110-120 bpm during exercise despite beta-blocker therapy. 1, 5, 3
• Digoxin is useful for initial control of ventricular rate in rapid atrial fibrillation and may be considered in decompensated heart failure patients before initiating a beta-blocker. 1, 6
• Beta-blocker remains the preferred long-term treatment for rate control and provides mortality benefit; digoxin works best in combination with beta-blockers to control heart rate both at rest and during exercise. 1, 5, 3

Atrial Fibrillation Without Heart Failure

• Digoxin controls ventricular rate at rest through vagotonic effects on the AV node but does not adequately control rate during exercise or high adrenergic states. 6, 7
• Use digoxin only in sedentary patients or those who cannot tolerate beta-blockers or calcium channel blockers. 6, 7
• Recent observational studies suggest increased mortality in patients with atrial fibrillation without heart failure taking digoxin, limiting its role in this population. 8

Dosing Strategy

Start with digoxin 0.125 mg daily (or every other day) in elderly patients (>70 years), those with renal impairment, or low lean body mass. 1, 5, 3, 4

• Use 0.25 mg daily only in younger adults with normal renal function. 1, 3
• Loading doses are not necessary in stable outpatients with chronic heart failure. 1, 3
• Higher doses (0.375-0.50 mg daily) are rarely needed and increase toxicity risk without additional benefit. 4

Absolute Contraindications

Do not use digoxin in the following situations: 1, 3

• Second- or third-degree heart block without a permanent pacemaker 1, 3
• Pre-excitation syndromes (Wolff-Parkinson-White syndrome) 1, 3
• Previous evidence of digoxin intolerance 1, 3
• Use caution in suspected sick sinus syndrome 1, 5, 3

Digoxin Toxicity

Clinical Manifestations

Digoxin toxicity manifests differently in adults versus children, with cardiac arrhythmias being the hallmark in both populations. 2

Adults

Cardiac toxicity (50% of adverse reactions): 2

• PR prolongation and ST segment depression (not necessarily toxic) 2
• First-degree, second-degree (Wenckebach), or third-degree heart block (including asystole) 2
• Atrial tachycardia with block 2
• AV dissociation 2
• Accelerated junctional rhythm 2
• Ventricular premature contractions (especially bigeminy or trigeminy), ventricular tachycardia, and ventricular fibrillation 2

Gastrointestinal toxicity (25% of adverse reactions): 2

• Anorexia, nausea, vomiting, and diarrhea 2
• Rarely: abdominal pain, intestinal ischemia, and hemorrhagic necrosis of the intestines 2

CNS toxicity (25% of adverse reactions): 2

• Visual disturbances (blurred or yellow vision) 2
• Headache, weakness, dizziness, apathy, confusion 2
• Mental disturbances (anxiety, depression, delirium, hallucinations) 2

Infants and Children

In pediatric patients, cardiac arrhythmias are the earliest and most frequent manifestation of toxicity, not gastrointestinal or CNS symptoms. 2

• Sinus bradycardia may be the first sign of impending toxicity, especially in infants, even without first-degree heart block. 2
• Most common arrhythmias: conduction disturbances, atrial tachycardia (with or without block), and junctional tachycardia. 2
• Any arrhythmia developing in a child taking digoxin should be assumed to be digoxin-induced until proven otherwise. 2

Risk Factors for Toxicity

Digoxin toxicity commonly occurs with serum levels >2 ng/mL but can occur at lower levels with the following conditions: 4, 9

• Hypokalemia (dramatically increases arrhythmia risk) 1, 5, 4
• Hypomagnesemia 4
• Hypothyroidism 4
• Renal impairment (digoxin is renally eliminated) 1, 5, 7

Drug Interactions Increasing Toxicity Risk

The following medications increase plasma digoxin levels and require dose reduction: 3, 4

• Amiodarone 3, 4
• Verapamil and diltiazem 3, 4
• Quinidine 4
• Spironolactone 4
• Flecainide 4
• Certain antibiotics 3

Mandatory Monitoring Requirements

Serial monitoring of serum electrolytes (especially potassium and magnesium) and renal function is mandatory, as digoxin can cause arrhythmias particularly with hypokalemia. 1, 5, 3, 6

• Check digoxin level early during chronic therapy, but routine serial measurements are not necessary once stable. 1, 3
• Target therapeutic serum concentration: 0.5-0.9 ng/mL (or 0.6-1.2 ng/mL per some guidelines). 3, 4
• Monitor for signs of toxicity: sinoatrial and AV block, arrhythmias, confusion, nausea, anorexia, and visual disturbances. 3

Critical Clinical Pitfalls

• Do not use high doses of digoxin (>0.25 mg daily) for rate control in atrial fibrillation; add beta-blocker or amiodarone instead (if amiodarone is added, reduce digoxin dose). 4
• Digoxin controls resting heart rate but not exercise heart rate in atrial fibrillation, limiting its utility as monotherapy. 1, 6, 7
• In elderly patients, reduced elimination of digoxin necessitates conservative dosing (0.125 mg daily or every other day) and therapeutic monitoring. 4, 7
• The incidence and severity of digoxin toxicity has decreased substantially with modern dosing strategies (lower doses, attention to drug interactions, and monitoring). 2, 4