Digoxin

Additional information

Pharmacokinetics and dosing

The renal clearance of digoxin is reported to be around 12-14% lower in women than men [1, 2]. However, the difference is not considered to be clinically important [2]. As the therapeutic window is narrow, digoxin is mainly eliminated vi the kidneys, and renal clearance generally is lower in women, therapeutic drug monitoring of digoxin and dosage adjustment may be necessary. However, a small retrospective review of medical records (32 men, 35 women) report that the pharmacokinetics of digoxin do not appear to differ by sex [3].

Effects

The mortality risk from digoxin in atrial fibrillation treatment was similar in men and women in a large clinical trial (AFFIRM, 2466 men, 1594 women) [7] and a cohort study (ATIR-CVRN, 15191 men, 12097 women) [8].

A post-hoc subgroup analysis of the Digitalis Investigation Group (DIG) trial (5281 men, 1519 women) showed that digoxin therapy compared with placebo in heart failure was associated with increased all-cause mortality in women, but not in men [4]. This result is controversial because a sub-group analysis of the SOLVD trial (1874 men, 370 women) found no sex difference in survival [5]. However, in this study digoxin was not randomly assigned and the female sample size was very small. A Spanish study of 256 men and 94 women with heart failure also failed to show any sex difference in one-year mortality [6].Explanations for the higher mortality risk in women found in the DIG-trial are unknown, but it has been suggested it was due to higher serum concentrations or an unidentified sex-specific toxicity [4]. A retrospective analysis of the DIG-trial found a beneficial effect of digoxin on morbidity but no excess mortality in women at serum concentration of 0.5-0.9 ng/ml [9]. Based on this, the American Heart Association recommends a target serum concentration of 0.5-0.9 ng/ml, regardless of patient’s sex [10]. In conclusion, the DIG trial is the only large randomized trial showing a sex difference in survival but it is also the only of the above mentioned studies in which the effects of digoxin were compared with a properly constituted placebo group [11].

Analyses of data from the ENGAGE AF-TIMI 48 trial comparing warfarin and edoxaban in atrial fibrillation, digoxin use at baseline (3771 men, 2556 women on digoxin) was independently associated with sudden cardiac death with similar risk in men and women [12].

The effect of digoxin on vasoconstriction does not differ between men and women [13].

Adverse effects

There are conflicting results from studies whether there is an association between treatment with digoxin and the risk of falling. Risk of fracture in elderly patients treated with amiodarone or digoxin was investigated in a population-based nation-wide pharmacoepidemiological case-control study (240 428 men, 258 189 women). Risk of hip and forearm fractures were significantly reduced in both men and women with current use of digoxin [14]. In a prospective study (377 men, 602 women), digoxin treatment was an independent risk factor for falls in men but not in women [15].

In a large Dutch population-based cohort-study (1 389 225 men, 1 598 355 women), women had a 1.4-fold higher risk of digoxin intoxication than men [16].

Reproductive health issues

Regarding teratogenic aspects, please consult the Drugs and Birth Defects Database (in Swedish, Janusmed fosterpåverkan).

Other information

Studies from different countries have shown that women with atrial fibrillation are prescribed digoxin more frequently than men [17, 18].