What are the risks associated with digoxin (digitalis glycoside) therapy?

From the Guidelines

Digoxin therapy carries significant risks, including toxicity, which can be life-threatening, and its use should be carefully monitored, especially in patients with kidney dysfunction, electrolyte imbalances, and those taking interacting medications, as stated in the 2013 ACCF/AHA guideline 1. The most concerning risk is digoxin toxicity, which can occur when blood levels exceed the narrow therapeutic range. Symptoms of toxicity include nausea, vomiting, visual disturbances, confusion, and cardiac arrhythmias. Some key points to consider when using digoxin include:

• Patients with kidney dysfunction are at higher risk for toxicity as digoxin is primarily eliminated by the kidneys.
• Electrolyte imbalances, particularly hypokalemia, hypomagnesemia, and hypercalcemia, can potentiate digoxin toxicity even at therapeutic levels.
• Drug interactions pose another significant risk, as medications like amiodarone, verapamil, and certain antibiotics can increase digoxin levels.
• Elderly patients are especially vulnerable to adverse effects due to decreased renal function and lower muscle mass. Regular monitoring of digoxin levels, renal function, and electrolytes is essential, particularly after dose adjustments or when starting interacting medications, as recommended by the 2013 ACCF/AHA guideline 1. Some of the major adverse effects of digoxin include:
• Cardiac arrhythmias, such as ectopic and re-entrant cardiac rhythms and heart block.
• Gastrointestinal symptoms, such as anorexia, nausea, and vomiting.
• Neurological complaints, such as visual disturbances, disorientation, and confusion. The concomitant use of certain medications, such as clarithromycin, dronedarone, erythromycin, amiodarone, itraconazole, cyclosporine, propafenone, verapamil, or quinidine, can increase serum digoxin concentrations and may increase the likelihood of digoxin toxicity, as noted in the 2013 ACCF/AHA guideline 1. Therefore, the dose of digoxin should be reduced if treatment with these drugs is initiated, and patients should be educated to recognize early signs of toxicity and report them immediately, as prompt intervention can prevent serious complications, as stated in the 2013 ACCF/AHA guideline 1.

From the FDA Drug Label

Calcium, particularly when administered rapidly by the intravenous route, may produce serious arrhythmias in digitalized patients. Potassium-depleting are a major contributing factor to digitalis toxicity. Concomitant use of digoxin and increases the risk of cardiac arrhythmias. Due to the considerable variability of these interactions, the dosage of digoxin should be individualized when patients receive these medications concurrently.

The risks associated with digoxin therapy include:

• Serious arrhythmias due to calcium administration or potassium depletion
• Digitalis toxicity due to various drug interactions
• Cardiac arrhythmias when used concomitantly with other medications
• Advanced or complete heart block when combined with beta-adrenergic blockers or calcium channel blockers
• Increased risk of toxic reactions in patients with impaired renal function, particularly in the elderly population 2

From the Research

Digoxin Risks

The use of digoxin, a digitalis glycoside, in the management of chronic heart failure and atrial fibrillation is associated with several risks. These risks can be broadly categorized into:

• Cardiac risks
• Non-cardiac risks
• Drug interactions

Cardiac Risks

Cardiac risks associated with digoxin therapy include:

• Arrhythmias, such as bradycardia, ventricular tachycardia, and ventricular fibrillation 3, 4
• Heart block, which can be exacerbated by concomitant use of other agents that depress sinus or atrioventricular nodal function 3
• Increased risk of digitalis toxicity, which can occur at therapeutic doses, especially in patients with renal impairment, hypokalemia, hypomagnesemia, or hypothyroidism 3, 5

Non-Cardiac Risks

Non-cardiac risks associated with digoxin therapy include:

• Gastrointestinal disorders, such as nausea and vomiting 6
• Neuropsychological disorders, such as confusion and hallucinations 6
• Electrolyte imbalances, such as hyperkalemia and hypokalemia 5, 6

Drug Interactions

Digoxin interacts with several drugs, which can increase the risk of toxicity or reduce its efficacy. These drugs include:

• Macrolides, which can increase digoxin levels by inhibiting P-glycoprotein 6
• Amiodarone, which can increase digoxin levels and potentiate its cardiac effects 3, 6
• Nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin-converting-enzyme (ACE) inhibitors, and angiotensin II receptor antagonists, which can increase the risk of renal impairment and digoxin toxicity 6
• Sucralfate, acarbose, and cytotoxic agents, which can reduce digoxin plasma concentrations 6

Special Populations

Special consideration is needed when using digoxin in certain populations, such as:

• Older adults (≥ 65 years), who may be more susceptible to digoxin toxicity due to age-related changes in renal function and body composition 7
• Patients with renal impairment, who may require dose adjustments to avoid toxicity 3, 5
• Patients with light-chain (AL) amyloidosis, who may be at increased risk of digoxin toxicity due to cardiac and renal involvement 4