Therapeutic Range of Digoxin
Regardless of the issues of digoxin clinical safety discussed, a major concern with the use of digoxin is avoiding toxicity from increased serum levels. The DIG trial noted that digoxin may decrease the high risk of hospitalization for patients with CHF with decreased EF. A significant linear association between all-cause mortality and serum digoxin concentration was found. The highest risk of all-cause mortality was associated with a high serum concentration of 1.6–2.0 ng/ml (adjusted HR 1.33; 95% CI 1.12–1.58; p = 0.001). On the other hand, the lowest serum digoxin concentrations of 0.5–0.7 ng/ml were associated with the lowest and significantly decreased all-cause mortality risk (adjusted HR 0.77; 95% CI 0.67–0.89; p < 0.001). The findings appeared consistent with a therapeutic benefit for digoxin in patients with CHF with decreased EF at a serum digoxin concentration range of 0.5–0.7 ng/ml. The DIG trial reported that the benefit of digoxin in men with CHF and an EF ≤ 45% appeared to be optimum at a serum digoxin level of 0.5–0.8 ng/ml. Unfortunately, many laboratory report forms cite the normal serum digoxin range as 0.5–2.0 or 0.8–2.0 ng/ml, whereas it appears appropriate to list the upper therapeutic range as 1.0 ng/ml.[105,106]
As noted, the therapeutic range for the use of digoxin and other digitalis cardiac glycosides is very narrow, and this narrow therapeutic range and the frequent usage in elderly patients contribute significantly to toxicity problems. The majority of digoxin toxicity cases in the elderly appear to be associated with inappropriately high doses, especially in the setting of renal insufficiency, multiple prescriptions, poor counseling of patients, transcription problems, female sex, and lean body mass. The decreased use of digoxin means digoxin toxicity has become uncommon, but this means it may be overlooked when it does occur. The use of anti-digoxin antibody Fab fragments is the standard of care, especially with severe accidental digitalis intoxication and suicide attempts, but randomized clinical trials to prove the benefit of such treatments are lacking. In addition, a survey of various physicians indicated that the use of anti-digoxin antibody Fab fragments is disparate: cardiologists 67%, emergency physicians 82%, and toxicologists 91.5%. In addition to the highly effective anti-digoxin antibody Fab fragments, other standards of care include a temporary pacemaker for high-grade atrioventricular block, appropriate antiarrhythmics for ventricular arrhythmias, maintenance of good acid–base status, attention to serum magnesium levels, reversal of CHF if possible, attention to any clinical myocardial ischemia, and maintenance of serum potassium ≥ 4.0 mEq/l. However, of note regarding antiarrhythmics is a report of three cases of AF with rapid ventricular response and severely decreased EF. Amiodarone was given, along with a beta blocker plus digitalis; following amiodarone loading and with a prolonged mean QTc in all patients, a torsade de pointes tachycardia developed. Activated charcoal has no proven benefit in digoxin toxicity and should not be used. In addition, extracorporeal treatments have no proven benefit for digoxin toxicity and should generally not be attempted. However, beneficial off-label use in digoxin toxicity has been reported with a filter approved by the US FDA for the removal of beta-2 microglobulin during hemodialysis. Digoxin has been reported to account for up to 50% of preventable adverse drug reactions. Multiple adverse drug interactions affect the geriatric patient, and unfavorable interactions between macrolide antibiotics and digoxin were notable in a review of 17 studies. A meta-analysis of cardiovascular drugs associated with falls in the elderly found that digoxin contributed to an increased risk of falling.
Plasma levels of the electrolyte potassium are important in avoiding digitalis toxicity. Hypokalemia (including that induced by a diuretic) and digitalis both inhibit the myocardial Na+/K+-ATPase, with a resultant decrease of the intracellular concentration of potassium, leading to various cardiac arrhythmias. To worsen the situation further, the myocardial uptake of digitalis is significantly increased in the presence of low plasma potassium and, in addition, hypokalemia decreases the renal excretion of digoxin, further augmenting digitalis toxicity. An elevated potassium level is also harmful and has been associated with increased digitalis fatalities, especially when bradycardia and hyperkalemia occur simultaneously with the use of digoxin. Magnesium deficiency has also been associated with digoxin toxicity, even at what would be considered low serum digoxin concentrations. Obviously, in addition to careful monitoring to assure serum digoxin levels < 1.0 ng/ml, careful attention must be paid to avoid significant potassium and magnesium electrolyte abnormalities.
Anti-digoxin antibody Fab fragments (Digibind®) for the treatment of digitalis toxicity are already discussed in Sect. 7.1, but further comment in a defined section of the review is warranted. The development of the radioimmunoassay for digoxin by Smith and coworkers as discussed by Lewis in 1969 enabled a new understanding of the clinical pharmacology of digoxin, and the subsequent development of anti-digoxin antibody Fab fragments as specific toxicity antidotes contributed dramatically to the safe use of digitalis. Unfortunately, antibody use for toxicity is insufficient; a study of 838 patients with increased serum digoxin or digitoxin concentrations found that Fab fragment-treated patients had a much lower mortality (6%; 4/67) than untreated toxicity patients (15%; 117/770). Fortunately, there is evidence of cross-reactivity with antidigoxin antibody Fab fragments to benefit treatment of digitoxin toxicity. Use of Fab fragments should also occur in severe poisoning from ingestion of foxglove plant leaves.
Interaction of Digitalis With Antiarrhythmic Drugs
The PALLAS (Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy) trial studied 3236 patients aged ≥ 65 years with permanent AF for at least 6 months and at increased risk for major cardiovascular events. The study was stopped because of a detectable increased incidence of cardiovascular events in the dronedarone group versus placebo, including arrhythmic death, stroke, and CHF hospitalization. The authors noted that dronedarone increased the serum digoxin level by 33% in PALLAS, and almost one-third of the patients studied were taking digoxin. It was concluded that dronedarone should not be used in patients with permanent AF at increased risk for major cardiovascular events. In a substudy of PALLAS, Hohnloser et al. found an increased association of dronedarone with arrhythmias and cardiovascular death but not the occurrence of CHF in patients taking digoxin. In an experimental study with rabbits, Frommeyer et al. found that the perfused isolated simulated CHF hearts of rabbits that had been on chronic oral dronedarone showed an increased incidence of ventricular fibrillation in association with the application of ouabain. The authors noted that ouabain resulted in a significant shortening of ventricular repolarization and that their study may be of value in interpreting the PALLAS trial results.
Am J Cardiovasc Drugs. 2018;18(6):427-440. © 2018 Adis Springer International Publishing AG