Digoxin has been used for decades for the treatment of cardiovascular disease ( CVD ). In 1997, the FDA ( Food and Drug Administration ) approved Digoxin for the treatment of heart failure and atrial fibrillation. The decision was mostly based on the Digitalis Investigation Group ( DIG ) trial, which reported a 28% reduction in hospitalization for congestive heart failure ( CHF ) from Digoxin without any effect on mortality in patients without kidney failure.

On the basis of that and other studies, the National Kidney Foundation Kidney Disease Outcomes Quality Initiative ( KDOQI ) also included Digoxin in its ESRD CVD guidelines for the treatment of cardiomyopathy and atrial fibrillation; however, few studies have been conducted to verify the drug is safe in hemodialysis patients, who are prone to considerable intracellular-extracellular shifts in potassium ( K ) during dialysis that may directly mediate the efficacy and toxicity of the drug.

Exactly how cardiac glycosides should be properly managed and monitored in patients who are on long-term renal replacement therapy ( RRT ) remains unanswered. Researchers at Massachusetts General Hospital ( Boston ) conducted an observational cohort analysis of a large and diverse population of incident dialysis patients to determine the association between mortality and Digoxin in relation to the pharmacodynamic parameters of the drug ( e.g., prescribed Digoxin dosage, serum Digoxin level ) and predialysis serum K level.

In this observational cohort of 120,864 incident hemodialysis patients, the use of Digoxin was associated with an increased risk for death. The mortality effect was significantly potentiated by high serum Digoxin and low serum K levels, which seemed independent of patient characteristics, propensity for treatment, the facility, the physician, disease severity, or time.

Clinically, Digoxin has been used for many years for the treatment of cardiovascular disease. On the basis of several trials in the general population, the drug is sometimes used for the treatment of heart failure and atrial fibrillation, given the unique inotropic and chronotropic properties of Digoxin.
The purported benefits of digoxin may initially seem favourable to the comorbidity profile of dialysis patients, given the high prevalence of atrial fibrillation and hospitalization; however, almost no trials have been conducted to examine whether the hospitalization efficacy, rate control properties, and safety of Digoxin translate to patients who are undergoing long-term renal replacement therapy.

Digoxin directly inhibits the Na/K-ATPase pump in the membrane of the cardiac myocyte, which causes intracellular increases in sodium and a consequent rise in calcium through the sodium-calcium exchanger. A rise in local calcium levels directly prolongs the cardiac action potential and results in a decreased heart rate and an increased binding with troponin C to promote cardiac contractility.

Serum K level and its rapid decline during dialysis may play an important role in the therapeutic effects and toxicity of the drug, because both K and Digoxin compete for the same ATPase-binding site. Hyperkalemia may decrease the effectiveness of Digoxin, whereas hypokalemia can potentiate toxicity.

The study has reported a statistically significant interaction between a low predialysis serum K and a high serum Digoxin level on all-cause mortality consistent with the inhibition of the Na/K-ATPase pump for the biological mechanism of action of Digoxin.

Overall, researchers suggest caution for Digoxin use in the general hemodialysis population, given its prescription was associated with increased mortality in this study.

Since the publication of the DIG study in 1997, data from congestive heart failure registries and trials have demonstrated the progressive decline of Digoxin use in the setting of observational studies that raise potential safety concerns for cardiac glycosides. Most notable, post hoc analyses of the original DIG study reported a significant 4.2% absolute increase in mortality for women and a decreased risk for death when serum levels were maintained at lower, therapeutic concentrations.
Consequently, Digoxin has been progressively reclassified from a class I recommendation in 2001 to a class IIa recommendation in 2005, with explicit cautions in the 2009 American College of Cardiology/American Heart Association guideline that recommend a target serum range of 0.5 to 1.0 ng/dl.

Among patients who were on Digoxin in this retrospective study, the risk for death significantly increased with serum Digoxin levels but not with the prescribed Digoxin dosage.

Digoxin is a drug with a narrow therapeutic/toxic ratio whereby patient-level pharmacokinetics, metabolism, and clearance factors aggregate to introduce variability in drug responsiveness.
For example, Digoxin distributes extensively to peripheral tissue ( average volume of distribution of 785 L ); heavier patients had higher prescribed dosages and lower serum levels. Consequently, targeted serum level therapy with frequent serum-level monitoring seems prudent as a means to achieve the very narrow therapeutic window for the drug.

Several characteristics inherent to the dialysis treatment may explain the study’s finding. The narrow therapeutic index and proarrhythmic qualities of the drug have the potential to limit the overall effectiveness of Digoxin in the end stage renal disease ( ESRD ) population.
Patients who are on long-term renal replacement therapy are subject to recurrent fluid/electrolyte shifts, hypoalbuminuria, and end-organ damage, which may predispose patients with ESRD to adverse reactions from Digoxin.
For example, (1) plasma K concentration drops by approximately 40% during hemodialysis and then rebounds in the postdialytic period ( i.e., transient hypokalemia ), (2) ultrafiltration may temporarily increase serum Digoxin level through its concentration, and (3) uremia has been associated with altered Digitoxin metabolism with a 35% decrease in Digitoxin binding reported during active HD treatment.
Furthermore, responses to dosage corrections are slow because of the extended half-life of the drug.
Overall, the cumulative effect of these factors likely complicates the maintenance of stable/subtoxic Digoxin levels and may increase the risk-benefit ratio of Digoxin use in the ESRD population.

In conclusion, Digoxin should be prescribed with caution to patients who are on long-term hemodialysis. Given the alteration in pharmacokinetic and K shifts seen during dialysis, combined with the potential toxicity and tight therapeutic index of the drug, strict K and Digoxin level management is recommended when patients with ESRD remain on Digoxin until its overall safety is better evaluated through randomized, controlled trials.

Source: Journal of American Society of Nephrology, 2010

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