Cardiac glycosides

Note on nomenclature

The most commonly used cardiac glycosides, digoxin and digitoxin, are derived from foxgloves, respectively Digitalis lanata and Digitalis purpurea . For this reason they are generally known as “digitalis.” Most other cardiac glycosides, such as ouabain and proscillaridin, do not come from foxgloves but are nevertheless also commonly called “digitalis.” Thus, the terms “cardiac glycoside” and “digitalis” are used interchangeably.

The cardiac glycosides that have been used therapeutically are listed in Table 1 .

Mechanisms of digitalis toxicity

There is a large amount of evidence that the mechanisms of action of cardiac glycosides are mediated directly or indirectly by inhibition of the sodium/potassium pump enzyme, Na/K-ATPase [ ]. Their toxic effects on the myocardium may be due to excessive inhibition of cardiac Na/K-ATPase, although there is also evidence that effects on the nervous input to the heart may be involved [ ], and it is not clear to what extent such an effect is mediated by inhibition of Na/K-ATPase. However, color vision disturbances associated with cardiac glycosides are due to inhibition of Na/K-ATPase [ ].

Epidemiology of digitalis toxicity

Digitalis toxicity is common, since all cardiac glycosides have a low therapeutic index. Estimates vary widely from study to study, but in large prospective studies of hospital inpatients the frequency of digitalis toxicity has been as high as 29% [ ]. In outpatients the figure may be as high as 16% [ ]. The lower frequency in outpatients may be due partly to poor compliance and partly to digitalis toxicity being a reason for admission to hospital, thus increasing the numbers of toxic inpatients. The risk of toxicity may be lower with digitoxin than with digoxin [ ], but when toxicity occurs it lasts longer, because of the very long half-life of digitoxin.

The overall mortality from digitalis toxicity also varies widely, having been reported as low as 4% and as high as 36% [ ]. However, it varies with dysrhythmias, and for paroxysmal supraventricular tachycardia with block may be as high as 50% [ ].

In a study of serum digoxin concentrations in 1433 patients admitted to hospital, 115 had a raised concentration [ ]. Of the 82 in whom the blood sample had been taken at an appropriate time, 59 had electrocardiographic or clinical features of digoxin toxicity. The patients whose serum digoxin concentrations were over 3.2 nmol/l (2.5 ng/ml) were slightly older (78 versus 73 years) and had higher serum creatinine concentrations (273 versus 123 μmol/l) than those whose plasma concentrations were below 3.1 nmol/l. Of 47 patients with raised digoxin concentrations on admission, 21 were admitted because of digoxin toxicity, and impaired or worsening renal function contributed to high concentrations in 37 patients. A drug interaction was a contributory factor in 10 cases. These results suggest that digoxin toxicity is still very common and confirms the increased risk in elderly patients, patients with renal impairment, and patients taking drugs that may interact with digoxin. Serum potassium concentrations were not reported in this study.

In another study of this sort, serum digoxin concentrations were measured in 2009 patients [ ]. The concentration was over 2.6 nmol/l in 320 cases (9.3%) but in 51 of those the sample had been drawn too soon after the dose. When other results were omitted in cases in which the sampling time was not known, there were 138 evaluable patients, of whom 83 had clinical evidence of digoxin toxicity, an overall incidence of 4.1%. The authors concluded that digoxin toxicity was less common in their series than has previously been reported. There were no differences between the groups in serum potassium, calcium, or magnesium concentrations, but the serum creatinine concentration was significantly higher in those who had definite and possible toxicity. The mean age of the patients was 69 years. It is likely that the differences across studies of this sort are largely due to differences in renal function and age in the population being studied.

In a multicenter survey, conducted between 1988 and 1997, of 28 411 patients, mean age 70 years, admitted to 81 hospitals throughout Italy, 1704 had adverse drug reactions [ ]. In 964 cases (3.4% of all admissions), adverse reactions were considered to be the cause of admission. Of these, 187 were regarded as severe. Gastrointestinal complaints (19%) were the most common, followed by metabolic and hemorrhagic complications (9%). The drugs most often responsible were diuretics, calcium channel blockers, non-steroidal anti-inflammatory drugs, and digoxin. Female sex (OR = 1.30; 95% CI = 1.10, 1.54), alcohol use (OR = 1.39; 95% CI = 1.20, 1.60), and number of drugs (OR = 1.24; 95% CI = 1.20, 1.27) were independent predictors of admission for adverse reactions. For severe adverse reactions, age (for age 65–79, OR = 1.50; 95% CI = 1.01, 2.23; for age 80 and over, OR = 1.53; 95% CI = 1.00, 2.33), co-morbidity (OR = 1.12; 95% CI = 1.05, 1.20 for each point on the Charlson Comorbidity Index), and number of drugs (OR = 1.18; 95% CI = 1.11, 1.25) were predisposing factors. Of the 28 411 patients, about 6700 were taking digoxin, and they suffered 82 adverse effects, either gastrointestinal (n = 28) or unspecified dysrhythmias (n = 44), or presumably both (data not given); of those, 11 were graded as severe (two gastrointestinal and nine dysrhythmias).

Of 603 adults aged 79 years, of whom 59% were women and 18% African-American, 376 patients (62%) were discharged taking digoxin, and 223 (37%) had no indication for its use, based on the absence of left ventricular systolic dysfunction or atrial fibrillation [ ]. After adjustment for various factors, prior digoxin use (OR = 11; 95% CI = 5.7, 23) and pulse over 100/minute (OR = 2.33; 95% CI = 1.1, 4.9) were associated with inappropriate digoxin use. Unfortunately, the authors did not report the frequency of adverse effects, and it is not therefore clear whether patients in whom digoxin is used inappropriately are more or less likely to suffer adverse reactions.

General adverse effects and adverse reactions

Adverse reactions to cardiac glycosides can be cardiac or non-cardiac. They mostly occur through toxicity and are time-independent; susceptibility factors include electrolyte abnormalities (particularly hypokalemia), renal insufficiency, and age.

Frequent non-cardiac reactions include gastrointestinal effects (anorexia, nausea, vomiting, and diarrhea), central nervous system effects (drowsiness, dizziness, confusion, delirium), and less commonly visual effects (color vision abnormalities, photophobia, and blurred vision). Hypersensitivity reactions are rare and include thrombocytopenia and skin rashes. Tumor-inducing effects have not been reported.

Frequent cardiac adverse effects include heart block and ectopic dysrhythmias (ventricular extra beats, other ventricular tachydysrhythmias, and paroxysmal supraventricular tachycardia). The combination of heart block with an ectopic dysrhythmia, for example paroxysmal supraventricular tachycardia with block, is particularly suggestive of toxicity due to cardiac glycosides. Any other dysrhythmia can occasionally be caused by cardiac glycosides.

Of 332 residents of a nursing home, 52 had to be admitted to hospital because of adverse drug reactions [ ]. The drugs most commonly associated with adverse effects were non-steroidal anti-inflammatory drugs (n = 30), psychotropic drugs (n = 14), and digoxin (n = 5).

Individual cardiac glycosides

There are major pharmacokinetic differences among the different cardiac glycosides, the principal difference being between those that are mainly excreted via the kidneys (for example digoxin, metildigoxin, β-acetyldigoxin, ouabain, and k-strophanthin) and those that are mainly excreted via hepatic metabolism (including digitoxin, gitoxin, pengitoxin (16-acetyldigoxin), and gitoformate).

It has also been suggested that there may be some pharmacodynamic differences among different cardiac glycosides [ ], but these may at least partly be determined by differences in tissue distribution.

It is debatable whether any of these differences makes any particular cardiac glycoside preferable to another. The most strongly argued case is that digitoxin is preferable to digoxin in patients with renal insufficiency, since digitoxin is metabolized and digoxin is excreted by the kidneys. However, digitoxin has a much longer duration of action, and if toxicity occurs it will take longer to resolve. Furthermore, determining the effective dose of digitoxin is much more difficult, since there is great interindividual variability in the extent to which digitoxin is metabolized, and hepatic metabolic function cannot be directly measured. Although digoxin excretion also varies from patient to patient, it can at least be gauged by measurement of creatinine clearance. The arguments for and against these preferences have been outlined [ , ] and it is probably best to choose a particular drug according to individual patient requirements.

Herbal formulations

Numerous plants worldwide contain cardiac glycosides that have been used both therapeutically as herbal formulations and for the purposes of self-poisoning. Details are given in Table 2 .

• A 59-year-old man developed third-degree atrioventricular block after using an extract of Nerium oleander transdermally to treat psoriasis [ ]. A fatality due to drinking a herbal tea prepared from N. oleander leaves, erroneously believed to be eucalyptus leaves, has been reported [ ].

Poisoning from ingestion of the seeds of Thevetia peruviana (yellow oleander) can be treated with oral multiple-dose activated charcoal, which reduce mortality [ ]. The lack of efficacy of activated charcoal in one trial [ ] was probably due to failure to select the patients that were most likely to benefit [ ]. Fab fragments of antidigoxin antibody have also been used to treat oleander intoxication, for example in a 7-year-old child [ ] and a 44-year-old man [ ], but in a randomized controlled trial did not affect mortality [ ]. A retrospective study suggested that the antibody fragments might reduce mortality [ ], but was confounded by the simultaneous introduction of activated charcoal.

In a Turkish case, the ingestion of two bulbs or Urginea maritima as a folk remedy for arthritic pains was sufficient to result in fatal poisoning [ ].

Observational studies

Hospital admissions because of digoxin toxicity became significantly less common from 1991 to 2004 in the USA and UK; in the former this was associated with a reduction in the use of digoxin, but in the latter there was no such change; however, in both countries the number of prescriptions written for a dose of at least 250 micrograms fell [ ].

Of 2 987 580 hospital admissions in the Netherlands during 2001–4 there were 1286 cases of digoxin intoxication (0.04%) [ ]. The incidence rate for admission related to digoxin intoxication was 49 per 100 000 prescriptions (95% CI = 46, 51), corresponding to 1.94 admissions per 1000 treatment years. Women had a 1.4-fold higher risk of intoxication than men (95% CI = 1.3, 1.6). The age- and sex-adjusted relative risk of death in patients with digoxin intoxication compared with those admitted for other reasons was 0.7 (95% CI = 0.5, 0.8).

Placebo-controlled studies

Post-hoc analyses of the Digoxin Investigation Group (DIG) study continue to appear. In 988 ambulatory patients with chronic heart failure in sinus rhythm and ejection fractions over 45% randomly assigned to digoxin (n = 492) or placebo (n = 496)., 102 (21%) in the digoxin group and 119 patients (24%) in the placebo group (HR = 0.82; 95% CI = 0.63, 1.07) experienced the primary combined outcome of heart failure hospitalization or heart failure mortality during a mean follow-up period of 37 months [ ]. Digoxin had no effect on all-cause or cause-specific mortality or on all-cause or cardiovascular hospitalization. Digoxin was associated with a trend toward a reduction in hospitalizations resulting from worsening heart failure (HR = 0.79; 95% CI = 0.59, 1.04) but also with a trend toward an increase in hospitalizations for unstable angina (HR = 1.37; 95% CI = 0.99, 1.91). The likeliest conclusion from these results is that digoxin does not alter outcomes in this group of patients.

Cardiovascular

Nervous system

Toxic effects of digitalis on the nervous system occur relatively often. Although in severe toxicity the incidence may be as high as 65% [ ], in most series it has been below 25% [ ]. In 8220 patients aged at least 65 years, the crude relative risk of nervous system dysfunction of unspecified types was about 2.0 (95% CI = 1.7, 2.5) among the 16.5% who were taking digoxin; co-morbidity and the number of out-patient medical services did not affect the risk [ ].

Anorexia, nausea, and vomiting are mediated by the central nervous system. Other common nervous system effects of digitalis include confusion, dizziness, drowsiness, bad dreams, restlessness, nervousness, agitation, and amnesia.

Epilepsy occurs rarely and can be accompanied by electroencephalographic changes [ ].

Other reported effects include transient global amnesia [ ], trigeminal neuralgia [ , ], nightmares [ ], organic brain syndrome (including impairment of long-term and short-term memory) [ ], impairment of learning and memory [ ], and a clinical syndrome resembling herpes encephalitis [ ].

Accidental administration of digoxin intrathecally has reported in three cases in which ampoules containing digoxin were thought to have been confused with ampoules containing lidocaine, because they looked alike [ ]. In one case, paresthesia and paralysis of the lower limbs occurred up to the umbilical level; the patient, a 21-year-old man, was conscious but agitated, tachycardic, and hypertensive, with abdominal distension, urinary retention, and absent leg reflexes. He recovered spontaneously.

• Progressive stupor has been reported in an 85-year-old woman with mild renal insufficiency who was given digoxin 0.25 mg/day [ ]. The plasma digoxin concentration was 7.8 nmol/l. She recovered within 2 weeks after digoxin withdrawal, consistent with the likely half-life of digoxin. A 24-hour electrocardiogram showed one period of asystole for 4 seconds, but that is unlikely to have explained her symptoms.

Chorea has occasionally been reported in adults taking digitalis [ ], and also in a child [ ].

• A 7-year-old girl with severe congenital heart disease who was given digoxin 0.125 mg bd developed chorea and had a serum digoxin concentration of 3.8 ng/ml. When digoxin was withheld and the serum concentration fell to 1.5 ng/ml her symptoms resolved. They recurred 4 days after rechallenge when her digoxin concentration was 2.5 mg/ml and again resolved after it had fallen to 1.3 mg/ml.

The authors hypothesized that digoxin caused chorea by virtue of an estrogenic effect in the basal ganglia, similar to the effect that is occasionally produced by oral contraceptives.

Sensory systems

Psychiatric

Acute psychosis and delirium can occur in digitalis toxicity, particularly in elderly people [ ], and can be accompanied by visual or auditory hallucinations [ , ].

• Acute delirium occurred in a 61-year-old man whose serum digitoxin concentration was 44 ng/ml [ ].

Digitalis toxicity can occasionally cause depression [ ].

• A 77-year-old woman developed extreme fatigue, anorexia, psychomotor retardation, and social withdrawal 1 month after starting to take digoxin 0.5 mg/day for congestive heart failure [ ]. She did not respond to intravenous clomipramine 25 mg/day for 7 months. Her serum digoxin concentration was 3.2 ng/ml. Digoxin was withdrawn, and 12 days later, when her serum digoxin concentration was 0.5 ng/ml, she had improved, but was left with a memory disturbance, which was attributed to background dementia.

Endocrine

Digitalis has effects on sex hormones. It causes increased serum concentrations of follicle-stimulating hormone (FSH) and estrogen and reduced concentrations of luteinizing hormone (LH) and testosterone [ ]. These effects are probably not related to any direct estrogen-like structure of digitalis (despite structural similarities), but rather to an effect involving the synthesis or release of sex hormones. There are three possible clinical outcomes of these effects.

Metabolism

In three patients with diabetes mellitus, withdrawal of digoxin improved blood glucose control, implying that digoxin had impaired glucose tolerance [ ]. The authors conceded that the effect might have occurred coincidentally, but in one case glucose tolerance deteriorated again after rechallenge. Insulin increases the cellular uptake of glucose and stimulates the sodium/potassium pump, and it may be that inhibition of the sodium/potassium pump by digoxin has the opposite effect.

In 14 patients with morbid obesity, who were being given digoxin in the hope that reduced production of cerebrospinal fluid, with the consequent reduction in pressure, might be associated with weight reduction, the dosage of digoxin (Lanacrist 0.13 mg, equivalent to 0.065 mg of digoxin) was titrated to produce a minimum serum digoxin concentration of 1.0 nmol/l [ ]. One patient was already diabetic, and five developed fasting blood glucose concentrations greater than 5.0 mmol/l on three consecutive occasions, with accompanying glycosuria. Another had fasting blood glucose concentrations of 6.0–8.5 mmol/l. There was a significant relation between the dose of digoxin and the risk of impaired glucose tolerance. However, the diabetes mellitus did not abate after digoxin withdrawal, and since all these patients were obese, the occurrence of diabetes was probably coincidental.

Hematologic

Thrombocytopenia has been reported in patients taking digitoxin, acetyldigoxin, and digoxin [ ]. Cardiac glycosides inhibit Na/K-ATPase, causing changes in intracellular calcium concentration. Increased intracellular calcium is a key event in platelet activation, and there is evidence that cardiac glycosides activate platelets in vitro, albeit in high concentrations [ , ]. Platelet and endothelial functions have been studied in 30 patients with non-valvular atrial fibrillation, 16 of whom were taking digoxin (mean plasma digoxin concentration 1.2 nmol/l) [ ]. Digoxin significantly increased platelet CD62P expression and platelet–leukocyte conjugates and markedly increased EMP62E and EMP31, markers of endothelial activation. After adjusting for potential confounders (including age, congestive heart failure, coronary artery disease, ejection fraction, antiplatelet drugs, β-blockers, and calcium channel blockers), the differences persisted. The authors concluded that if digitalis activates endothelial cells and platelets it could predispose to thrombosis and vascular events. However, there is no evidence that that happens clinically.

There have been rare reports of eosinophilia in patients taking cardiac glycosides [ ].

Gastrointestinal

Gastrointestinal symptoms are common in digitalis toxicity. These include anorexia, nausea, and vomiting [ ], probably as a result of stimulation of the chemoreceptor trigger zone in the brain.

Diarrhea occurs occasionally [ ].

Dysphagia has been rarely reported [ , ].

Other rare events include intestinal ischemia [ , ], and hemorrhagic intestinal necrosis [ ].

• A 79-year old woman with a serum digoxin concentration of 4.9 ng/ml had a mesenteric infarction [ ]. At postmortem no other causes were discovered.

• An 84-year-old woman developed abdominal pain in association with symptoms of digitalis toxicity while taking digitoxin 0.07 mg/day and other drugs, including furosemide [ ]. Her serum potassium concentration was 2.9 mmol/l and the serum digitoxin concentration was 32 ng/ml (usual target range 13–25). She had first-degree heart block, incomplete left bundle branch block, and typical ST segment changes. All medications were withdrawn and the hypokalemia was corrected with intravenous potassium. Abdominal X-ray and ultrasonography showed paralytic ileus and she died 48 hours later. At autopsy there was hemorrhagic congestion of the heart, lungs, and other organs, and the intestines were edematous and hemorrhagic, with submucosal edema, necrotic ulceration, and intramural bleeding. There was no thromboembolism.

The authors attributed this effect to digitoxin toxicity. Verapamil, diltiazem, and antidigoxin antibody fragments have all been reported to be beneficial in mesenteric ischemia induced by cardiac glycosides. Intestinal ischemia responds to verapamil and to antidigoxin antibody [ ].

Non-occlusive mesenteric ischemia secondary to digitalis is rare but has again been reported, in a 76-year-old woman with digoxin intoxication (serum concentration 6.0 μg/l) [ ]. Non-occlusive acute mesenteric ischemia has also been demonstrated in another case, that of a 68-year-old man, in whom ultrasonography was diagnostic [ ].

Necrotic enterocolitis might have been related to digoxin toxicity in a neonate [ ]. However, the authors did not highlight this in their report, but instead emphasized that digitalis intoxication in neonates may present with vomiting and no cardiac signs of toxicity.

Death

In a retrospective, non-randomized study of 484 patients, 90 of whom were taking digoxin, there was an increased death rate (RR = 2.12, CI = 1.21, 3.74) in those taking digoxin [ ]. In another non-randomized, retrospective analysis of the effects of digoxin in patients with acute myocardial infarction there was a higher rate of mortality in the 243 patients taking digoxin compared with the 1743 patients who were not [ ]. The results of these studies are reminiscent of the results of previous similar retrospective analyses. However, the prospective DIG study clearly showed no increase in mortality [ ], and the results of these later non-randomized retrospective studies should be ignored.

A post hoc re-analysis of the data from the DIG study suggested that mortality might be increased in patients with higher plasma digoxin concentrations. If this were true, it would suggest that lower digoxin concentrations (0.5–0.8 ng/ml) would be associated with a reduced death rate and this has again been hypothesized [ ].

Evidence that that is in fact so has come from another retrospective analysis of the Digitalis Investigation Group (DIG) study, in which continuous multivariable analysis showed a significant linear relation between serum digoxin concentration and mortality, with no effect of sex [ ]. The hazard ratios (HR) for mortality varied with serum concentration, with reduced mortality at serum concentrations of 0.5–0.9 ng/ml (HR = 0.81; 95% CI = 0.71, 0.92) and increased mortality at concentrations of 1.2–2.0 ng/ml (HR = 1.21; CI = 1.05, 1.40). However, digoxin reduced the risk of hospitalization at all serum concentrations.

In 345 patients with heart failure randomized to either digoxin (n = 175) or captopril ( n = 170) and followed for a median of 4.5 years the death rate at 48 months was lower with captopril (21%) than with digoxin (32%), although this did not reach conventional significance [ ]. Since there was no placebo group for comparison it is not clear whether digoxin altered mortality in this study. Of the numerous adverse effects that were reported, the only one that differed between the two treatments was cough, which was significantly more frequent with captopril. In the absence of a placebo comparison it is impossible to say whether any of the other adverse effects were drug-related.

Despite the fact that the prospective study called DIG clearly showed that there was no increase in mortality in patients in taking long-term digoxin therapy [ ], retrospective, non-randomized studies continue to be reported [ , ]. In 180 patients with idiopathic dilated cardiomyopathy the overall mortality was 19% in those taking digoxin and 10% in those not taking digoxin [ ]. However, when the use of digoxin was adjusted for several predictive variables it no longer predicted cardiac death. This finding is reassuring, but results of studies like this, whatever their results, should be ignored, in view of the evidence that is currently available from the one large prospective, randomized study.

When interpreting the evidence presented in other accounts of the association between drug therapy and death it is important to remember that the current evidence suggests that digoxin does not cause excess mortality. For example, digoxin was the second most commonly encountered medication in an investigation of 2233 deaths reported to an American County Medical Examiner’s office, with a medication history available in 775 cases [ ]. Furosemide was mentioned 181 times, digoxin 131 times, and glyceryl trinitrate 103 times. All other drugs were mentioned less than 100 times each. The authors suggested that the presence of digoxin at a death scene should suggest heart failure or a cardiac dysrhythmia, but they did not go further and stress that in such a case digoxin need not necessarily be implicated in the death. Postmortem diagnosis of digoxin toxicity is exceptionally difficult, but measurement of digoxin in the vitreous fluid can be helpful.

In a survey of 2 312 203 deaths in the USA in 1995, 206 (0.009%) were attributed to adverse drug reactions on death certificates [ ]. At the same time in the MedWatch program, 6894 deaths were reportedly attributed to adverse drug reactions, representing 6.3% of the 108 735 reports of adverse drug reactions. In the death certificate study 18 deaths were attributed to cardiac glycosides and in the MedWatch survey 15 deaths. This compares with figures of 289 and 782 from antimicrobial drugs, 449 and 280 from hormones, and 947 and 477 from drugs that affect the constituents of the blood (for example anticoagulants).

Sex-based differences in the effect of digoxin have been explored in a post-hoc analysis of the data from the DIG) study [ , ]. There was an absolute difference of 5.8% (95 CI = 0.5, 11) between men and women in the effect of digoxin on the case fatality rate from any cause. Women who were randomly assigned to digoxin had a significantly higher fatality rate than women who were randomly assigned to placebo (33% versus 29%), while the fatality rate was similar among men randomly assigned to digoxin or placebo (35% versus 37%). However, serum digoxin concentrations were higher in the women at 1 month, and this may have contributed to the increased risk of death [ ].

In another post-hoc analysis of the data from the DIG study the patients who had been randomized to digoxin were divided into three groups, according to serum digoxin concentration, 0.5–0.8 ng/ml, 0.9–1.1 ng/ml, and 1.2 ng/ml and over [ ]. Higher concentrations were associated with higher all-cause fatality rates: 30%, 39%, and 48% respectively.

Both of these studies suggest that lower serum concentrations of digoxin (0.5–1.0 ng/ml) may be beneficial for routine therapy of heart failure than have traditionally been recommended (0.8–2.0 ng/ml), and this has been discussed in a brief review [ ].

Pregnancy

Digoxin has been used to cause fetal death before termination of pregnancy [ ]. However, in a double-blind study in 126 women who had terminations by dilatation and evacuation at 20–23 weeks gestation intra-amniotic injection of digoxin 1 mg did not alter blood loss or pain; nor did it reduce difficulties with or the complications of the procedure [ ]. Significantly more women vomited after intra-amniotic digoxin. Digoxin given by this route is slowly absorbed into the systemic circulation, with a peak plasma concentration of 0.8 ng/ml at 11 hours [ ].

Fetotoxicity

Digoxin crosses the placenta and enters the neonatal circulation [ ]. It has therefore been used, for example, to improve fetal cardiac function [ ]. In normal circumstances there seem to be no adverse effects on the neonate, and neonatal plasma concentrations are below those generally considered to be therapeutic. There has been one report of fatal toxicity in the fetus of a woman who took an overdose of digitoxin [ ].

Age

Sex

Post-hoc analysis of the results of the DIG study suggested that digoxin may adversely affect survival in women but not in men. Among patients with left ventricular dysfunction enrolled in the Studies of Left Ventricular Dysfunction (SOLVD) with left ventricular ejection fractions of 0.35 and below, there was no interaction between sex and digitalis treatment in respect of survival, and there was no significant difference in the hazard ratios for men and women taking digitalis with respect to all-cause mortality, cardiovascular mortality, heart failure mortality, or dysrhythmic death with worsening heart failure [ ]. The authors concluded that there was no evidence of a difference between men and women in the effect of digitalis on survival. This has been confirmed by a reanalysis of the data from the Digitalis Investigation Group (DIG) study [ ].

Evidence of sex differences in the response to digoxin has been sought in two studies in Sweden [ ], following the observation that in the DIG study women who were randomly assigned to digoxin had a significantly higher fatality rate than women who were randomly assigned to placebo (33% versus 29%), while the fatality rate was similar among men randomly assigned to digoxin or placebo (35% versus 37%). In the first study, in which 363 women and 257 men were compared, the women were taking significantly smaller doses of digoxin (0.16 versus 0.18 mg/day), but had significantly higher trough steady-state serum digoxin concentrations, both unadjusted (1.48 versus 1.26 nmol/l) and adjusted for age, dose, and serum creatinine (1.54 versus 1.20 nmol/l); furthermore, significantly more women had serum digoxin concentrations above 2.5 nmol/l (OR = 4; 9%% CI = 1.6, 10). In the second study the authors searched the Swedish national register of adverse drug reactions and found that there were significantly more reports of adverse reactions to digoxin in women (165 versus 112) and significantly more serious reactions (30 versus 9), despite similar numbers of prescriptions. These data support the suggestion that women may be more susceptible to the adverse effects of digoxin than men.

In an analysis of adverse drug reactions in four German pharmacovigilance centers, which resulted in hospitalization of 3092 patients in 2000–2004, 314 patients were admitted because of adverse effects associated with cardiac glycosides. The incidence of adverse reactions was 1.9 (CI = 1.0, 3.3) per 1000 patients exposed to cardiac glycosides per 3 months exposure. More women were affected than men (244 versus 70) and oral digitoxin was involved in 296 (228 women). Women received significantly higher body weight-related doses of digitoxin and had significantly higher digitoxin plasma concentrations than men. Doses were high (over 1 microgram/kg/day) in 71% of the women but in only 29% of the men. Those who had adverse reactions to cardiac glycosides had a significantly lower body weight and were significantly older than patients with other adverse drug reactions.

Other susceptibility factors

Several factors increase patient susceptibility to digitalis intoxication. They can be considered in two groups [ ].