Author + information
- Received October 26, 1995
- Revision received April 22, 1996
- Accepted May 7, 1996
- Published online October 1, 1996.
- DIRK J. van VELDHUISEN*
- ↵*Address for correspondence: Dr. Dirk J. van Veldhuisen, Department of Cardiology/Thoraxcenter, University Hospital Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands
- WILLEM J. REMME and
- K.I. LIE
Digoxin has been a controversial drug since its introduction >200 years ago. Although its efficacy in patients with heart failure and atrial fibrillation is clear, its value in patients with heart failure and sinus rhythm has often been questioned. In the 1980s, reports of some large-scale trials indicated that digoxin, with or without vasodilators or angiotensin-converting enzyme inhibitors, reduced signs and symptoms of congestive heart failure and improved exercise tolerance. This beneficial influence was mainly found in patients with more advanced heart failure and dilated ventricles, whereas the effect in those with mild disease appeared to be less pronounced. In the last few years, new data have shown that digoxin may also have clinical value in mild heart failure, either when used in combination with other drugs or when administered alone. As neurohumoral activation has increasingly been recognized to be a contributing factor in the disease progression of chronic heart failure, the modulating effects of digoxin on neurohumoral and autonomic status have received more attention. Also, there is evidence that relatively low doses of digoxin may be at least as effective as higher doses and have a lower incidence of side effects. Further, the recognition that the use of digoxin too early after myocardial infarction may be harmful and the development of other drugs, in particular angiotensin-converting enzyme inhibitors, have obviously changed the place of digoxin in the treatment of chronic heart failure. The large-scale survival trial by the Digitalis Investigators Group (DIG), whose preliminary results have recently been presented, has shown that although digoxin has a neutral effect on total mortality during long-term treatment, it reduces the number of hospital admissions and deaths due to worsening heart failure. The potentially new features of the old drug digoxin are discussed in this review.
Ever since 1785, when William Withering  described the use of digitalis in patients with heart failure, this drug has been subject to debate and controversy [2–5]. Although the value of digoxin in patients with heart failure who have atrial fibrillation has generally been recognized, its efficacy in those who have sinus rhythm has often been questioned. Nevertheless, the drug has continued to be widely used in the United States  and Europe, possibly because “old habits die slowly” . Renewed scientific interest emerged, however, when it was found that digitalis had a significant effect on neurohumoral activation and autonomic function in patients with heart failure , an effect that may explain some of its (alleged) favorable properties in this syndrome .
During the last decade, the popularity of digoxin has again increased. This has been partly due to the results of three large scale trials published at the end of the 1980s that did not primarily investigate digoxin itself but used it as a reference drug [8–10]. In these three placebo-controlled trials, which studied >300 patients taking digoxin, the drug was found to cause a statistically significant improvement in exercise time  and left ventricular ejection fraction [8, 10] and to decrease signs and symptoms of heart failure . In the beginning of the 1990s, two other placebo-controlled studies [11, 12] showed a beneficial effect of digoxin on exercise capacity, ejection fraction and clinical variables, both in the presence  and in the absence  of concomitant angiotensin-converting enzyme therapy. However, both studies had a withdrawal design, and the question remains whether their results can be applied to patients in whom digoxin treatment is initiated [3, 13].
In recent years, evidence has accumulated that disease progression in chronic heart failure is related not only to hemodynamic but also to neurohumoral factors . As a consequence, it has become clear that a pronounced beneficial hemodynamic effect of a drug is not necessarily related to a decrease in morbidity and mortality. The autonomic and neurohumoral effects of a drug may in this respect be more predictive , an observation that has also led to renewed interest in digoxin. Other new developments, such as the successful use of lower doses of digoxin, have also contributed to this revived interest. In this review, we discuss recent data on digoxin and place these data against the background of the traditional view of digoxin in the treatment of heart failure. Finally, we briefly discuss the recently presented results of the large mortality trial carried out by the Digitalis Investigators Group: the DIG study.*
1 Importance of Digitalis-Induced Neurohumoral Modulation
Traditionally, heart failure has been considered a hemodynamic disorder and, as a result, drug treatment has primarily attempted to correct hemodynamic abnormalities [14, 17]. However, the concept of the pathophysiology of heart failure has changed during the last 10 years, and recent data strongly support an important role for neurohumoral modulation or inhibition in its treatment. Moreover, the favorable long-term effects of some drugs in heart failure, particularly angiotensin-converting enzyme inhibitors, have for an important part been attributed to their neurohumoral effects [18, 19].
In the past, digitalis has been considered a pure positive inotropic agent. As a result, the disappointing results of some large scale trials with positive inotropic agents in the 1980s  led to concern that similar disappointing effects could be expected with digoxin , particularly because the deleterious effects of inotropic drugs appear to be independent of their mechanism of action . In recent years, evidence has emerged that digoxin exerts its inotropic effects mainly at higher doses; at lower doses little inotropic action but more pronounced neurohumoral effects are observed .
Several studies now available have evaluated the neurohumoral and autonomic effects of digoxin. Digitalis appears to modulate sympathetic tone  in a manner similar to that of its hemodynamic effects, which differ between healthy volunteers and patients with heart failure . In heart failure, it will, in general, have a sympathoinhibitory effect, depending on the severity of the disease  and on the dose used [23, 26]. There are several potential explanations for the neuroendocrine inhibitory effects of digitalis in heart failure [6, 7], but the observed improvement or normalization of impaired baroreceptor-mediated mechanisms appears to play an important role [26, 27], although not all studies  support this concept. A reduction of sympathetic tone in heart failure has been demonstrated by directly measuring efferent sympathetic nerve activity in skeletal muscle  or, more easily, by determining plasma norepinephrine concentrations. In two older studies [29, 30] it was shown that digoxin immediately reduced plasma norepinephrine concentrations in patients with heart failure. In the recently published Dutch Ibopamine Multicenter Trial (DIMT), we  showed that this effect was sustained over 6 months of treatment. In a further analysis of these data , this effect was even present in patients with very mild heart failure who received no other drug treatment for their disease. Digoxin may also lower plasma renin levels [25, 29, 32]. This reduction may be a direct renal effect  or secondary to inhibition of sympathetic activity  or caused by activation of atrial natriuretic factor [33, 35], although the latter effect is rather small in humans . Plasma aldosterone has been reported  to decrease with digoxin, but this effect is not very pronounced .
In addition to these neurohormonal actions, effects of digitalis on both cardiopulmonary and arterial baroreceptor function in humans have long been recognized [7, 26, 37–41]. Because baroreceptors modulate sympathetic and parasympathetic (or vagal) activity as a result of stretch of the mechanoreceptors, neurohormonal changes measured in plasma and muscle, as described earlier, are directly related to the effects of digitalis on baroreceptors . Why baroreceptor reflex function is impaired in heart failure and how digitalis improves baroreceptor function in this syndrome have also not been fully elucidated. Several possibilities to explain the latter have been suggested, including 1) a direct receptor effect, 2) an increase in blood pressure, and 3) inhibition of excessive activation of the sodium-potassium adenosine triphosphatase pump [6, 7].
In recent years, analysis of heart rate variability has become a valuable tool to examine (noninvasively) autonomic function in heart failure, and changes in heart rate variability indexes may have some predictive value with regard to the long-term efficacy of drugs in this syndrome . Recently, three studies have examined the effects of digoxin on heart rate variability indexes, both in patients with heart failure [43, 44] and in normal subjects . Krum et al.  studied patients with moderate heart failure, most of whom received background treatment with converting enzyme inhibitors. After 4 to 8 weeks of treatment with rather low doses of digoxin, time domain variables increased significantly and frequency domain variables also improved toward normal, indicating that parasympathetic activity increased substantially whereas sympathetic activity decreased. In another study, Brouwer et al.  examined patients with mild heart failure who had been receiving either low dose diuretic drugs alone or no medication for heart failure. After 3 months, heart rate variability indexes deteriorated slightly in the placebo group but improved significantly in the digoxin group compared with values in the patients receiving placebo. These observations  were essentially the same as those made by Krum et al. , although the effect of digoxin was less pronounced (Fig. 1). Even in normal subjects , digoxin was found to significantly affect heart rate variability measures, particularly the indexes of vagal modulation. In line with the observed effects on sympathovagal balance, digoxin may partly restore the impaired circadian pattern of heart rate variability  that is observed in patients with heart failure . This effect appears to be related to changes in the circadian pattern of circulating plasma norepinephrine after digoxin administration. This finding obviously raises new questions with regard to the well known circadian pattern in the incidence of certain cardiovascular disorders, including sudden death.
2 Digoxin May Be Effective in Both Mild and Advanced Heart Failure
It has always been assumed that the favorable effect of digoxin is more pronounced in—or, rather, would largely be restricted to—patients with moderate to severe heart failure [47–56], and this assumption was confirmed in a meta-analysis of digoxin in 1990 . However, in a subsequent review, Gheorghiade and Zarowitz  pointed out that evidence existed that the drug might also be effective in less advanced heart failure, a finding supported by recent data from our group [25, 31] and from others [59, 60]. In the DIMT study , patients with predominantly mild heart failure were randomized to treatment with digoxin (n = 55), ibopamine (n = 53) or placebo (n = 53). The results showed that digoxin significantly improved exercise time over that achieved with placebo after 6 months. Subanalysis of the data indicated that the drug was indeed relatively more effective in patients with more advanced disease . Nevertheless, digoxin was also effective in patients with mild disease, and when its effects as monotherapy were analyzed (in the 64 patients [40%] who did not receive diuretic drugs at baseline), digoxin was found to be more effective than placebo because it significantly improved exercise time and reduced plasma neurohormones after 6 months (Fig. 2) . These findings are in agreement with data from two other recent studies in patients with mild heart failure in whom the effect of digoxin as monotherapy was evaluated [59, 60]. In the German-Austrian Captopril and Digoxin Study (CADS), Just et al.  studied 222 patients who were randomized to receive digoxin (n = 66), captopril (n = 63) or placebo (n = 67) and were followed up for 2 years. Digoxin significantly improved quality of life and decreased clinical symptoms in comparison with placebo, and more side-effects were observed with captopril than with digoxin. In another study, Kleber and Thyroff-Friesinger  studied 60 patients who were randomized to receive digoxin (n = 22), ibopamine (n = 18) or placebo (n = 20), and these patients were followed up for only 4 weeks. During that study there were no treatment failures in the group receiving digoxin, and quality of life improved in 21 of the 22 patients. In general, digoxin was comparable to ibopamine and significantly more effective than placebo.
3 Digoxin Dosage: Higher Is Not Necessarily Better
Another important issue in the use of digitalis has been establishment of the optimal dose [23, 61]. In the past, when the inotropic effect of the drug was considered of primary importance, relatively high doses were generally used. However, as pointed out earlier, it has gradually become clear that lower doses of digoxin may also be effective and result in less toxicity . In an early postinfarction trial , serum digoxin concentrations were associated with an adverse prognosis, but this association was no longer statistically significant after adjustment for other risk factors. However, in a subanalysis of a large heart failure trial (Prospective Randomized Milrinone Survival Evaluation [PROMISE] study) , high serum digoxin levels (>1.1 ng/ml) were found to be independently related to an adverse prognosis. Some recent “positive” findings [25, 43, 44], such as favorable effects of digoxin on plasma neurohormones and heart rate variability, were observed in patients who were receiving low doses of the drug. In a recent study , when the daily dose of digoxin was increased from 0.20 ± 0.1 mg/day to 0.39 ± 0.1 mg/day (which corresponded to serum levels of 0.7 ± 0.2 ng/ml and 1.2 ± 0.4 ng/ml, respectively), left ventricular ejection fraction increased, but neurohormones did not decrease. Indeed, increasing the digoxin dose to these serum levels may improve left ventricular (systolic) function [64, 65], but lower doses may already be effective in the suppression of neurohormones, an observation that agrees with earlier evidence that low doses of digitalis primarily exert neurohumoral and autonomic effects, whereas high or higher doses mainly have inotropic action . Combined data from the Prospective Randomized Study of ventricular failure and the Efficacy of Digoxin (PROVED) and Randomized Assessment of Digoxin on Inhibitors of the Angiotensin Converting Enzyme (RADIANCE) trials  and from others  suggest that trying to push the digoxin dose to serum levels above ±1.2 ng/ml may be questionable, whereas increasing the dose to levels 1.5 to 2.0 ng/ml is probably unwanted . However, it is difficult to compare serum digoxin concentrations among studies because there is no standardized time after dosing for obtaining serum levels, and several other technical problems may cause additional bias .
If lower doses of digoxin are used, the number of side effects, including serious adverse events, such as arrhythmias, will obviously decrease [68, 69]. This is particularly true in elderly patients, because the incidence of digitalis toxicity is high and recognition of toxicity may be particularly difficult in this group [70, 71]. Moreover, very low doses of the drug may already be effective in these patients .
4 Digoxin Should Be Given With Caution After Myocardial Infarction
Several large retrospective studies have examined the effect of digitalis in acute myocardial infarction [62, 73, 74]. Although these studies generally show that patients treated with digitalis fared worse than those who were not, their findings are limited by the fact that most patients who were taking digitalis were doing so because they suffered from more severely impaired left ventricular function . Nevertheless, a recent large scale study  that corrected for all confounding factors (such as left ventricular function) also found a relative risk of 1.8 in multivariate analysis associated with digoxin use.
Unfortunately, only a few small prospective studies on the value of digoxin after acute myocardial infarction are available. In two older studies, digoxin was found not to affect preload or afterload  or to improve hemodynamics . In another study , digoxin improved hemodynamics but only in patients with heart failure. In a recent investigation , digoxin had an adverse effect on ventricular remodeling after anterior myocardial infarction, but it increased ejection fraction. This finding has been reported before , but its clinical relevance is unclear.
There are several reasons why digitalis might not be beneficial in acute myocardial infarction [82–84]. It may increase myocardial oxygen consumption  by augmenting contractility , by increasing intramyocardial tension and by inducing peripheral or coronary  vasoconstriction. Also, it may provoke or aggravate myocardial ischemia, leading to ventricular arrhythmias and death, and it may increase infarct size . Because myocardial stunning or hibernation may be present for weeks after infarction, use of digoxin should in general be avoided in the (sub)acute phase after infarction, unless there is strong indication for its administration such as rapid atrial fibrillation. In the past, heart failure in the acute phase of myocardial infarction was often treated with digoxin [82, 83], but this is no longer the general practice. One factor may be that digoxin may aggravate the clinical condition in the setting of cardiogenic shock  and, therefore, dobutamine or dopamine is now often used instead. In addition, the positive results of recent large scale trials with angiotensin-converting enzyme inhibitors in this setting [89, 90] have also played a role in this change.
5 Other Possible Factors in the Declining Role of Digoxin in Heart Failure
Other factors may also have been involved in the declining role of digoxin in heart failure in the late 1970s and early 1980s. At that time, angiotensin-converting enzyme inhibitors became available for the treatment of heart failure. These agents were soon found to significantly reduce morbidity and mortality, both in severe , but also in less advanced [92, 93] heart failure, and they are currently the cornerstone of heart failure treatment. In many patients with mild to moderate heart failure, these drugs, rather than digoxin , are used in combination with diuretic drugs, and many physicians are now even inclined to initiate medical treatment with these drugs alone, as monotherapy. Because only angiotensin-converting enzyme inhibitors have been shown to favorably affect the natural history of heart failure, it has been stated  that digoxin should be reserved for patients who remain symptomatic after treatment with angiotensin-converting enzyme inhibitors and diuretic drugs.
Another important, often neglected factor is the fact that digoxin is a very inexpensive drug. As a result, pharmaceutical companies have not been enthusiastic to start major trials with this drug. Thus, the large scale digoxin survival trial, the DIG study, is sponsored by the National Institutes of Health in conjunction with Department of Veterans Affairs Cooperative Studies Program [16, 96]. It is ironic, as mentioned earlier, that many important data on digoxin have been gained from studies that were primarily aimed at investigating new compounds and were sponsored by the companies manufacturing these compounds [8, 10, 25, 59]. The low cost of digoxin obviously has a positive side, and a recent health care analysis  showed that discontinuation of digoxin in patients with stable heart failure leads to increased economic costs.
6 Effects of Digoxin on Mortality in Patients With Heart Failure
Until recently, only retrospective and uncontrolled data were available concerning the effect of digoxin on mortality in patients with chronic heart failure. For this reason, the large scale DIG trial was designed and sponsored by the National Institutes of Health in conjunction with the Department of Veterans Affairs Cooperative Studies Program [16, 96, 98]. In this double-blind, parallel group comparison, patients with heart failure and sinus rhythm were randomized to receive digoxin or placebo in addition to other medication. Patients were required to have current or past evidence of signs and symptoms of heart failure and a left ventricular ejection fraction ≤0.45. In a parallel, separate smaller study (±1,000 patients) the effects in those with an ejection fraction >0.45 were studied. The primary end point of the study was the effect of digitalis on total mortality; secondary end points included a (first) hospital admission for worsening heart failure or other causes, cardiovascular mortality, death due to worsening heart failure and (presumed) arrhythmias, and effects on quality of life. The dose of digoxin during the study was based on an algorithm that included age, gender, weight and renal function. Recruitment for the study started in early 1991, and by the end of 1995, almost 8,000 patients had been enrolled in the United States and Canada.
Preliminary analysis of the results  showed that digoxin had no effect on total mortality during a mean follow-up period of >3 years. However, the number of hospital admissions and the number of deaths due to worsening heart failure were significantly reduced by digoxin, whereas the incidence of presumed arrhythmic deaths and deaths due to myocardial infarction tended to increase. Although there was some suggestion that the reduction in risk of worsening heart failure achieved by digoxin was most pronounced in patients with a lower ejection fraction, the reduction was not significantly different between patients with relatively preserved and patients with relatively impaired left ventricular function.
This latter observation would support the hypothesis that digoxin might be effective not only in advanced, but also in milder stages of heart failure, as discussed earlier. The majority of patients were taking 0.25 mg/day of digoxin, and almost 30% of patients had a serum digoxin level >1.0 ng/ml. However, no data were presented concerning the influence of digoxin dose or serum levels on clinical outcome. Results of quality of life assessment were not yet available.
The use of digoxin in patients with heart failure and sinus rhythm has been controversial for >200 years. Many of the positive data on digoxin have been gained from withdrawal trials and have therefore often been criticized. Several prospective, double-blind randomized studies published in the last few years have shed new light on the value and place of digoxin in the treatment of patients with heart failure and sinus rhythm. Furthermore, preliminary results of DIG, the large scale mortality trial, have yielded important new information about this drug. The main finding from that study to date is that digoxin has a neutral effect on total mortality in patients with heart failure. However, the drug has significantly reduced the number of deaths due to worsening heart failure and related hospital admissions, data that suggest that it may slow progression of the disease. Although the final data have not been published, the results do not clearly point in one direction, and it is therefore likely that the controversy regarding this drug will continue. From these newer data and from other developments with regard to the insights into the pathophysiology and treatment of heart failure, several issues concerning the value and use of digoxin have become clear.
1) In light of the generally accepted importance of neurohumoral activation in the pathophysiology of heart failure, the recently recognized positive neurohumoral effects of digoxin (including its influence on baroreceptor function and heart rate variability) seem promising. 2) Although digoxin appears to be most effective in advanced heart failure, several new studies show that it may also be of value in patients with milder stages of the disease. In the latter, however, it is by definition more difficult to show a significant drug effect, and studies in this patient group should thus be conducted with larger sample sizes and a longer follow-up period, as has been done with angiotensin-converting enzyme inhibitors . 3) Relatively high doses of digoxin have traditionally been used, but recent data suggest that lower doses may be effective as well. When lower doses are used, fewer side effects will occur, and the subjective well-being of the patient may improve. 4) Patients with a new or fairly recent myocardial infarction should, in general, probably not be treated with digoxin, and the drug should be used with some caution in patients who have heart failure after infarction. Because digoxin has often been administered to these patients in the past, the negative results of some reported trials may be partly explained by this factor. Finally, other factors may be involved in the declining role of digoxin in heart failure, including the increased use of angiotensin-converting enzyme inhibitors, and the low cost of digoxin, which makes research with this compound less attractive to pharmaceutical companies.
A.1 Abbreviations and Acronyms
DIG = Digitalis Investigators Group
DIMT = Dutch Ibopamine Multicenter Trial
↵* Gorlin R, Garg R. The effects of digitalis on mortality and hospitalizations in patients with heart failure. Presented at the 45th Annual Scientific Session of the American College of Cardiology, Orlando, Florida, March 1996.
- Received October 26, 1995.
- Revision received April 22, 1996.
- Accepted May 7, 1996.
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- 1 Importance of Digitalis-Induced Neurohumoral Modulation
- 2 Digoxin May Be Effective in Both Mild and Advanced Heart Failure
- 3 Digoxin Dosage: Higher Is Not Necessarily Better
- 4 Digoxin Should Be Given With Caution After Myocardial Infarction
- 5 Other Possible Factors in the Declining Role of Digoxin in Heart Failure
- 6 Effects of Digoxin on Mortality in Patients With Heart Failure
- 7 Summary
- Appendix A