Cardiac Glycoside Therapy

Introduction to Digitoxin and Digoxin

• Digitoxin is primarily metabolized in the liver and less dependent on renal function for elimination, according to the European Society of Cardiology 1
• Digoxin is primarily eliminated through renal excretion and highly dependent on renal function, as stated by the European Society of Cardiology and the American Heart Association 1, 2

Sex Differences in Digoxin Pharmacokinetics

• Women have higher serum digoxin concentrations than men due to reduced volume of distribution and lower renal clearance of digoxin, as reported by the American College of Clinical Pharmacology 2
• Women may also have possibly reduced expression of Na+,K+-ATPase compared to men, which can affect digoxin concentrations, according to the American College of Clinical Pharmacology 2
• The optimal therapeutic range for women with heart failure may be lower (0.5-0.9 ng/mL), as evidenced by post-hoc analysis of the DIG trial, and supported by the American Heart Association 2

Digoxin Therapy and Outcomes

• Post-hoc analysis of the DIG trial showed a higher risk of death associated with digoxin in women but not in men, as reported by the American College of Cardiology 2
• At low serum digoxin concentrations (0.5-0.9 ng/mL), mortality reduction was observed in men but not in women, according to the American College of Cardiology 2
• The DIG trial showed no effect on all-cause mortality, but a 28% relative risk reduction for hospitalization due to worsening heart failure, and an absolute risk reduction of 7.9% for heart failure hospitalizations, as reported by the European Society of Cardiology (ESC) 3

Risk Factors for Digoxin Toxicity

• Female sex is a risk factor for digoxin toxicity, as stated by the American College of Clinical Pharmacology 2
• Digoxin should be started at 0.125-0.25 mg daily, with lower doses (0.125 mg daily or every other day) used in patients over 70 years, those with impaired renal function, or low lean body mass, as recommended by the American Heart Association (AHA) and European Society of Cardiology (ESC) 4, 5
• Serum concentration of digoxin should be maintained between 0.5-1.2 ng/mL, as suggested by the European Society of Cardiology (ESC) and American Heart Association (AHA) 3, 5

Contraindications and Interactions

• Digoxin is contraindicated in bradyarrhythmias, second- or third-degree AV block, sick sinus syndrome, carotid sinus syndrome, Wolff-Parkinson-White syndrome, hypertrophic obstructive cardiomyopathy, hypokalemia, and hypercalcemia, as noted by the American College of Cardiology and European Society of Cardiology (ESC) 3, 1
• Beta-blockers are contraindicated in patients with significant bradyarrhythmias, advanced AV block without a pacemaker, or severe asthma, as recommended by the European Heart Journal 1
• Amiodarone, diltiazem, verapamil, certain antibiotics, and quinidine can increase plasma digoxin levels, as reported by the European Society of Cardiology (ESC) 3

Combination Therapy with Beta-Blockers

• Beta-blockers are usually more effective when added to digoxin in controlling ventricular response, particularly during exercise, as recommended by the European Society of Cardiology (ESC) 5
• For long-term rate control, a beta-blocker, either alone or in combination with digoxin, is preferred, as recommended by the European Society of Cardiology (ESC) 3
• In heart failure, beta-blockers should generally be initiated before digoxin, as recommended by the European Society of Cardiology (ESC) and American Heart Association (AHA) 3, 6
• The following table summarizes the effects of digoxin and beta-blockers:

2, 7, 1, 3, 8, 4

• Beta-blockers have a beneficial effect on mortality in heart failure with reduced ejection fraction, with a 34% reduction in mortality, as noted by the European Heart Journal 7

Monitoring and Toxicity

• Serial monitoring of serum electrolytes and renal function is mandatory due to risk of arrhythmias, particularly in the context of hypokalemia, as recommended by the European Society of Cardiology (ESC) 3
• Digoxin toxicity can manifest as sinoatrial and AV block, atrial and ventricular arrhythmias (especially with hypokalemia), confusion, nausea, anorexia, and visual disturbances, according to the European Society of Cardiology (ESC) 3