PERSPECTIVE
NEJM
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After all, in spite of opinion, prejudice or error, Time will fix the real value upon this discovery, and determine whether I have imposed upon myself and others, or contributed to the benefit of science and mankind.
� William Withering, 1785
Since 1785, when Sir William Withering published his treatise on the use of foxglove (see Figure), our perspective on the use of digitalis has continued to change. Withering believed that digitalis had a diuretic effect in patients with a weak and irregular pulse who had edema.
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Only in the early 20th century did digitalis begin to be considered useful in patients with heart failure and normal cardiac rhythm. The hemodynamic effects of digoxin were elucidated in the 1970s, when heart failure was understood to result from diminished function of the left ventricle, which could be ameliorated by decreasing the load on the heart with vasodilators or increasing contractility with inotropic drugs. During this period, three challenges to digoxin therapy were a high incidence of digoxin intoxication, newer promising therapies involving inotropic drugs that had vasodilator properties, and a perceived increase in mortality associated with the use of digoxin in patients who had had myocardial infarctions.
In the 1980s, there was renewed interest in digoxin for several reasons: there was a decrease in the incidence of digoxin intoxication because a lower dose was being used and because it was understood that drug interactions (e.g., with quinidine) could increase serum digoxin levels; newer inotropic drugs were shown to be associated with poorer survival rates; and several trials demonstrated the potential benefit of digoxin in patients with heart failure and normal cardiac rhythm.
In the late 1980s, there was a paradigm shift emphasizing the importance of neurohormonal abnormalities in the progression of heart failure. During this time, it was discovered that digoxin, in addition to improving hemodynamics, had important neurohormonal modulating effects (for example, it reduces plasma renin and norepinephrine levels). In spite of these findings, the importance of digoxin was again questioned with the advent of more specific neurohormonal modulators (angiotensin-converting�enzyme [ACE] inhibitors and beta-blockers). More important, studies of the effect of digoxin on mortality were lacking.
In the mid 1990s, the results of the Randomized Assessment of Digoxin on Inhibitors of the Angiotensin-Converting Enzyme (RADIANCE) trial and the Digitalis Investigation Group (DIG) trial prompted the Food and Drug Administration to approve digoxin under current regulations for the treatment of heart failure. The RADIANCE trial examined the effects of discontinuation of digoxin in stable patients with heart failure who were receiving diuretics and ACE inhibitors. The discontinuation of digoxin was associated with an increase by a factor of five in the rate of worsening heart failure within three months and a decrease in exercise tolerance within that period, in spite of the continuation of therapy with diuretics and ACE inhibitors.
The DIG trial was the first large trial whose main objective was to assess the effect of digoxin therapy on overall mortality in patients with heart failure. The study enrolled 6801 patients who had systolic dysfunction while receiving diuretics and ACE inhibitors, half of whom had not received digoxin therapy. They were randomly assigned to receive a mean daily dose of 0.25 mg of digoxin or placebo. At 37 months after randomization, overall mortality was 35 percent, with no difference between the placebo group and the digoxin group. There was a 12 percent reduction in the rate of death due to pump failure with digoxin that was offset by an increase in the rate of death presumed to result from arrhythmia. Digoxin was associated with a significant reduction in the rate of death or hospitalization for worsening heart failure. Prespecified subgroup analyses suggested that the patients who had the greatest benefit were those who had cardiomegaly on chest radiography, a very low ejection fraction (<0.25), or severe symptoms.
Digoxin has a narrow therapeutic window. In patients with normal cardiac rhythm, the beneficial hemodynamic, neurohormonal, and clinical effects are found with a low dose that results in a serum concentration of approximately 0.7 ng per milliliter. Additional clinical benefits are not seen at higher doses traditionally considered to be therapeutic (with serum concentrations of 1.0 to 1.5 ng per milliliter). These higher doses may only predispose patients to arrhythmias. The DIG trial led to the hypothesis that digoxin may have a bidirectional effect on mortality related to the serum concentration � a beneficial effect at serum concentrations lower than 1.0 ng per milliliter and a detrimental effect at concentrations of 1.0 ng per milliliter or higher. Since digoxin therapy may result in adrenergic stimulation at higher concentrations or in patients with ischemia, the combination of digoxin and beta-blockade may have theoretical advantages. Beta-blockers produce an anti-ischemic, antiadrenergic effect leading to biologic improvement in function, while digoxin maintains hemodynamic compensation.
In this issue of the Journal, Rathore et al. (pages 1403�1411) report the results of a retrospective analysis of data from the DIG trial; they found a 4.2 percent increase in mortality with digoxin therapy in women but no such effect in men. As they acknowledge, a post hoc analysis may result in spurious findings as a result of chance alone or an imbalance in base-line characteristics between the treatment groups. The latter may have been the case, since the serum concentrations at one month were significantly higher in women than in men, and the increase in mortality among women may have been due to the use of a digoxin dose that was too high. Unfortunately, the investigators did not adjust for serum digoxin levels. What the investigators may have demonstrated is that digoxin use in women should be undertaken with greater attention to the appropriate dose. Perhaps the reduction in the rate of hospitalization for heart failure among women could have been achieved without an increase in mortality if a lower dose had been used. We should not abandon a therapy that may help women with heart failure. Rather, we should use a dose that will result in a serum concentration lower than 1.0 ng per milliliter.
Eric J. Eichhorn, M.D.
Medical City Dallas Hospital
Dallas, TX 75230
Mihai Gheorghiade, M.D.
Northwestern University Medical School
Chicago, IL 60611