Discussion
muscle mass, lower skeletal muscle mass, skeletal muscle mass, overdose, toxicity, heart failure, adverse drug reactions, impaired renal function
ADVERSE EFFECTS, REGRESSION, HEART FAILURE, ADVERSE DRUG REACTIONS, IMPAIRED RENAL FUNCTION
Although the cardiac glycoside digitoxin has been in clinical use for decades, little data are available enabling simple and safe dose titration of digitoxin, especially in patients with HFrEF. DIGIT-HF is the only sizeable randomized clinical trial investigating the effect of digitoxin within a prespecified range of serum concentrations on clinical outcomes in HFrEF [The only larger data source available up to now demonstrating a relationship between serum concentrations of cardiac glycoside and outcomes in patients with heart failure is the DIG trial. DIG investigated the effect of digoxin vs. placebo on outcomes in patients in sinus rhythm and LVEF < 45% [Adverse effects and toxicity of cardiac glycosides are very rare at serum concentrations in the lower therapeutic range (for digoxin: 0.5–0.9 ng/ml or 0.65–1.15 mmol/L; for digitoxin 8–18 ng/ml or 10.5–23.6 mmol/l), but have been described at serum concentrations > 2.0 ng/ml of digoxin and > 30 ng/ml of digitoxin [Because of their different pharmacokinetic properties, digitoxin represents the pharmacologically more stable cardiac glycoside compared to digoxin, especially in patients with impaired renal function [In the current analysis, we identified eGFR, BMI, and in particular female sex as factors associated with the necessity of a digitoxin dose reduction in the derivation cohort chosen from the DIGIT-HF population. The strong association with female sex in multivariable regression models might reflect the lower skeletal muscle mass of women compared to men, associated with a reduced compartment and overall digitoxin distribution volume resulting in higher digitoxin serum concentrations in women compared to men for a defined digitoxin dose [The next most significant factor associated with the necessity of a digitoxin dose reduction was BMI. BMI, in general, positively correlates with total skeletal muscle mass. Therefore, the observed negative association between BMI and necessity for digitoxin dose reduction reflects, similar as for female sex, the relationship between the compartment and overall volume of digitoxin distribution, which is higher in patients with a higher BMI resulting in the need for higher digitoxin doses to achieve therapeutic serum concentrations.Unexpectedly, we also identified a significant negative association between eGFR and necessity of digitoxin dose reduction. The causal relationship is not clear, because digitoxin elimination is entirely compensated by extrarenal (entero-hepatic) clearance even in patients with impaired renal function and digitoxin serum concentrations are constant even if renal function is markedly impaired [Specifically, the correlation between age and eGFR is -0.55 in our data set, which is substantial. Guided by our aim to maximize the probability of detecting all patients who need a dose reduction, we added age to the score and detected in the analysis and the validation set each three more patients for a dose reduction, which increased score sensitivity (data not shown). Therefore, and taking into account knowledge for the need of digitoxin dose reduction because of reduced muscle mass and, therefore, smaller volume of digitoxin distribution in the elderly [The intention of this analysis was to develop a score that faciliatates the dosing decision when treatment with digitoxin needs to be started in HFrEF patients. The components of the score are readily available and with high validity in clinical routine. Female sex, high age, low BMI, and impaired renal function fulfilled these criteria. From the clinical perspective and patient safety, a dosing score should, in particular, prevent overdosing of digitoxin, because digitoxin serum concentrations exceeding the therapeutic range might cause grave side effects or even toxicity. Also, the long half-life of digitoxin leads to prolonged elimination times rendering overdose a significant clinical problem of digitoxin. Therefore, a respective dosing score should have high sensitivity to detect the need of a dose,reduction from 0.07.mg to 0.05 mg o.d. in the present population, which would encourage to start with the low dose of 0.05 mg digitoxin o.d. in clinical practice. Specificity of the score on the other hand is negligible, because we would recommend measurement of digitoxin serum concentration after 6 weeks to check whether a dose of 0.05 mg digitoxin o.d. was sufficient to reach serum concentrations within the therapeutic range. Based on the digitoxin dosing score, all women, and all patients ≥ 75 years or with a BMI < 27 kg/mOur prospective trial data support a retrospective analysis of adverse drug reactions in Germany, indicating adverse drug reactions because of overdosing with digitoxin particular in patients < 70 kg, > 80 years, and women [Based on recent analyses, cardiac glycosides still may be an important option for the treatment of patients suffering from HFrEF [