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(Circulation. 1995;92:1801-1807.)
© 1995 American Heart Association, Inc.

Articles

Effects of Increasing Maintenance Dose of Digoxin on Left Ventricular Function and Neurohormones in Patients With Chronic Heart Failure Treated With Diuretics and Angiotensin-Converting Enzyme Inhibitors

Presented in part at the American Heart Association 65th Scientific Sessions, November 16-19, 1992, New Orleans, La.

Mihai Gheorghiade, MD; Veronica B. Hall, RN; Gordon Jacobsen, MS; Mohsin Alam, MD; Howard Rosman, MD; Sidney Goldstein, MD

From the Divisions of Biostatistics and Cardiovascular Medicine, Henry Ford Heart and Vascular Institute, Detroit, Mich.

Correspondence to Mihai Gheorghiade, MD, Division of Cardiology, Northwestern University Medical School, Chicago, IL 60611.

	Abstract

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Background Despite almost three centuries of use, the appropriate dosage of digitalis in patients with chronic heart failure and normal sinus rhythm has not been well studied.

Methods and Results We studied 22 patients with heart failure who were receiving constant daily doses of digoxin, diuretics, and angiotensin-converting enzyme (ACE) inhibitors. In 18 patients, the oral daily dose of digoxin was increased from a mean of 0.20±0.07 to 0.39±0.11 mg/day corresponding to an increase in the serum digoxin concentration from 0.67±0.22 to 1.22±0.35 ng/mL. Radionuclide and echocardiographic left ventricular ejection fraction; maximal treadmill time; heart failure score; serum concentrations of norepinephrine, aldosterone, atrial natriuretic factor, and antidiuretic hormone; and plasma renin activity were obtained before and after the increase in digoxin dose. Subsequently, 9 patients were randomized to receive digoxin and 9 to receive placebo and radionuclide ejection fraction measured after 12 weeks. With the higher dose of digoxin compared with the lower dose, there was a significant increase in radionuclide ejection fraction from 23.7±9.6% to 27.1±11.8% (P=.007). No significant changes were noted in heart failure score; exercise tolerance; serum concentrations of norepinephrine, atrial natriuretic factor, and antidiuretic hormone; and plasma renin activity. There was, however, an increase in serum aldosterone concentration. Twelve weeks after the patients were randomized to receive digoxin or placebo, there was a significant decrease in ejection fraction (from 29.4±10.4% to 23.7±8.9%) in the placebo group but not in patients who continued to receive digoxin (P=.002).

Conclusions The increase in maintenance digoxin dose, while maintaining serum concentrations within therapeutic range, resulted in a significant increase in left ventricular ejection fraction that was not associated with significant changes in heart failure score, exercise tolerance, and neurohumoral profile.

Key Words: hormones • digoxin • heart failure

	Introduction

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With the increased interest in heart failure as a major cardiovascular health issue, a variety of new therapeutic agents have been investigated.^{1 2} Despite these new agents, digoxin remains an important therapeutic modality in the treatment of chronic heart failure due to systolic dysfunction.³ Recently, a series of studies examined the effect of the use of digoxin in patients with chronic heart failure.^{4 5 6} These studies demonstrated physiological and clinical benefits associated with digoxin therapy compared with placebo, ACE inhibitors,⁵ or other oral inotropic agents.⁶ In addition, the discontinuation of digoxin in patients with stable chronic heart failure treated with diuretics alone⁷ or diuretics and ACE inhibitors⁸ has also been shown to result in clinical and physiological deterioration. These studies refocused our attention on the role of digoxin and demonstrated its beneficial effects when added to ACE inhibitors. They also emphasized the importance of maintenance of digoxin therapy in patients with chronic heart failure.^{7 8}

Despite these recent observations and almost three centuries of digitalis use in humans, a dose–clinical response relationship has not been fully explored.⁹ Studies in animals suggest a direct relationship between digitalis dose and inotropic activity.¹⁰ Also, a dose response was established in patients with chronic atrial fibrillation.^{11 12} However, the optimal dose of digoxin in chronic heart failure has not been well studied in the setting of normal sinus rhythm. The potential importance of the appropriate dose in chronic heart failure is highlighted by the results of the recent vesnarinone trial.¹³ Low-dose vesnarinone, an inotropic agent, had no significant hemodynamic effect except improved survival, whereas a higher dose increased mortality.

Because digoxin has hemodynamic¹⁴ and neurohumoral effects,¹⁵ it is important to explore its dose-dependent effects on both left ventricular function and neurohormones. Because to the best of our knowledge this issue has not been previously investigated, we evaluated a subgroup of patients enrolled in a multicenter trial of digoxin withdrawal, RADIANCE.⁸

The objectives of the present study were to evaluate the effects of increased maintenance digoxin dose, within the so-called therapeutic range, on left ventricular function, clinical status, exercise tolerance, and neurohormones in patients with stable chronic heart failure who were receiving constant doses of diuretics and ACE inhibitors.

	Methods

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Study patients included 22 patients who were enrolled in the digoxin-withdrawal study (RADIANCE) at Henry Ford Hospital between September 1989 and November 1990. RADIANCE was a double-blind, randomized, placebo-controlled, parallel multicenter digoxin-withdrawal study.⁸ Inclusion criteria were symptoms of heart failure (dyspnea or fatigue that was exercise induced) associated with a radionuclide left ventricular ejection fraction of 35% plus a left ventricular end-diastolic dimension of 60 as assessed with two-dimensional echocardiography. All patients were in normal sinus rhythm, had subjective and objective evidence of reduced exercise capacity as demonstrated by exertional symptoms, were in NYHA functional class II or III, and an exercise duration (as assessed by a modified Naughton protocol) of 2 to 14 minutes despite treatment for at least 3 months with digoxin, diuretics, and ACE inhibitor. In addition to the RADIANCE inclusion criteria, patients had to have either a serum digoxin concentration of <1.2 ng/mL or be receiving a daily digoxin dose of 0.125 mg. Exclusion criteria were age of <18 years old; blood pressure of >160/95 mm Hg; myocardial infarction within the previous 3 months; exercise limited by angina, lung disease, or claudication; angina requiring continuous treatment; uncorrected primary valvular disease; evidence of obstructive hypertrophic, restrictive, or amyloid cardiomyopathy; active myocarditis; history of supraventricular arrhythmia or sustained ventricular arrhythmia; stroke within the previous 12 months; severe primary, pulmonary, renal, or hepatic disease; uncorrected thyroid disease, or the concurrent current use of other drugs known to affect cardiac function. The protocol was approved by the institutional review board of Henry Ford Hospital, and informed consent was obtained from all study patients.

Study Protocol
Patients who met the criteria for enrollment entered a single-blind phase. While patients were kept on constant doses of diuretics and ACE inhibitors, the digoxin dose was increased by 0.125 mg/day. In one patient, the dose was increased by 0.0625 mg/day. Serum digoxin concentrations were obtained 24 hours after the previous day's dose and immediately before the next study dose. All other studies, including blood tests, were obtained before the next day's dose. Serum digoxin concentrations were monitored, and the dose was increased to achieve either a serum digoxin concentration of >1.2 ng/mL but <2 ng/mL or a daily oral digoxin dose of 0.5 mg. Once this higher concentration or dose (0.5 mg) was achieved, each patient was maintained on this higher dose of digoxin and on a constant dose of diuretics and ACE inhibitors. Severity of heart failure was expressed by a score previously described¹⁶ based on a combination of clinical and radiographic observations, including dyspnea, heart rate, jugular venous distention, rales, and chest radiographic findings. Before the digoxin dose was increased, each patient underwent a maximal treadmill exercise test (with a modified Naughton protocol).¹⁷ To comply with the overall study protocol,⁸ radionuclide angiography was performed for rest left ventricular ejection fraction. A two-dimensional echocardiogram was obtained, and the left ventricle was imaged from the apical four- and two-chamber and parasternal long- and short-axis views. The images were obtained with the patient in a resting state and then immediately after exercise. The preexercise and postexercise images were recorded on a videotape and disk in a digital quad-screen format. The postexercise images were obtained within 1 minute of exercise and reviewed with preexercise images in quad-screen format (Nova Microsonic). The left ventricular and systolic and diastolic cavity volumes were computed from the dimensions and areas obtained from the apical views (both two and four chambers), which were nearly orthogonal to each other according to the recommendations of the American Society of Echocardiography.¹⁸ The left ventricular volumes were calculated using the disk summation method or modified Simpson's rule. All echocardiographic data were interpreted by two echocardiographers (Dr Alam and Dr Rosman) who were blinded to the patients' medication and sequence of echocardiograms.

Blood was collected for evaluation of serum electrolytes, renal function, and neurohumoral studies that included (with the patient at rest in a supine and an upright position and at peak exercise) plasma concentrations of norepinephrine, atrial natriuretic factor, antidiuretic hormone, serum aldosterone, and plasma renin activity. Plasma concentrations of norepinephrine, antidiuretic hormone, and plasma renin activity were analyzed in 16 patients, and plasma concentrations of atrial natriuretic factor and serum aldosterone were analyzed in 15 patients.

All measurements that were obtained at baseline while the patients were receiving maintenance digoxin therapy were repeated at least 2 weeks after the last increase in oral digoxin dose during the dose-adjustment phase. (In one patient, the measurements were repeated 8 days after the last increase in digoxin dose.) During the dose-adjustment period, none of the 18 patients were withdrawn from the study or had other medication changes because of subjective and/or objective evidence of worsening of heart failure. After this single blind segment, nine patients were randomized to receive digoxin and nine to receive placebo as part of the RADIANCE protocol.⁸ Accordingly, the radionuclide left ventricular ejection fraction was measured in the placebo and digoxin groups 12 weeks after randomization while patients were kept on constant doses of diuretics and ACE inhibitors.

Statistical Analysis
All analyses were two-sided, and P<.05 was considered statistically significant. Results are given as mean±1 SD. The one-sample Student's t test was used to evaluate whether the changes from baseline to the increased digoxin dose time point were significantly different from zero in the 18 patients when the underlying distributional assumption of normality was not violated. Otherwise, the nonparametric Wilcoxon signed rank test was used. To analyze these changes relative to their baseline levels, percentage change rather than absolute change was used for all of the study variables except ejection fraction. Absolute change was used for the evaluation of change in ejection fraction because it was already given as a percentage. After randomization of the two groups (digoxin and placebo), ANCOVA was used to test for a group difference in the final ejection fraction levels after adjusting for the increased dose levels at randomization.

	Results

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A total of 22 patients were evaluated in the present study. One patient died while the dose of digoxin was increased (see "Adverse Reactions"). In 3 other patients, the digoxin dose was not increased; 2 of these patients had a serum concentration of >1.2 ng/mL, and the third was receiving 0.25 mg/day. In the remaining 18 patients, the digoxin dose was increased per protocol.⁸ The mean age was 61 years (range, 41 to 79 years). There were 16 men and 2 women. Eight patients had an ischemic and 10 had an idiopathic cardiomyopathy; 10 patients were in NYHA functional class III heart failure, and the remaining were in NYHA functional class II. The mean radionuclide left ventricular ejection fraction was 24±10% while patients were receiving maintenance therapy with digoxin, diuretics, and ACE inhibitors.

The mean oral maintenance digoxin dose at baseline was 0.20±0.07 mg, corresponding to the trough serum digoxin concentration of 0.67±0.22 ng/mL. At baseline, 1 patient was receiving 0.0625 mg/day digoxin, 6 were receiving 0.125 mg/day, and the remaining 11 patients were receiving 0.25 mg/day. Serum creatinine concentration but not age or weight correlated with the digoxin dose (r=-.68; P=.002). Over a mean of 4±3 weeks, the digoxin dose was increased to 0.39±0.11 mg/day, resulting in an average trough serum digoxin concentration of 1.22±0.35 ng/mL (P<.001). In 1 patient, the dosage was increased by 0.065 mg/day; in 7 patients, by 0.125 mg/day; in 8 patients, by 0.25 mg/day; and in 2 patients, by 0.375 mg/day. Three patients were maintained on 0.25 mg/day; 8, on 0.375 mg/day; and 7, on 0.5 mg/day.

Left Ventricular Ejection Fraction
The radionuclide ejection fraction (Table 1) increased from 23.7±9.6% to 27.1±11.8% (P=.007) in patients in whom the digoxin dose was increased. In the three patients in whom the digoxin dose was not increased, the ejection fraction was 16.7±3.1% at baseline and 14.0±5.0% at the follow-up study.

View this table: [in this window] [in a new window]   Table 1. Changes in Radionuclide and Echocardiographic Ejection Fraction Before and After Digoxin Daily Dose Increase in 18 Patients With Chronic Heart Failure in Sinus Rhythm Receiving Diuretics and Angiotensin-Converting Enzyme Inhibitors

The echocardiographic left ventricular ejection fraction (Table 1) at rest increased from 26.1±6.7% to 30.9±9.5% (P=.01) before and after the increase in digoxin dose, respectively. The diastolic volume did not change significantly (218±77 to 208±59 mL; P=.770). The diastolic volume index was 123±47 mL/m² at baseline and 117±38 mL/m² after the dose increase (P=.770). There was a significant decrease in the systolic volume from 169±75 to 151±63 mL (P=.019) and an increase in stroke volume from 48±18 to 57±23 mL (P=.024). The stroke volume index increased from 27±10 to 32±13 mL/m² (P=.024). Immediate after maximal treadmill exercise, the ejection fraction increased from 30.8±8.8% at low digoxin dose to 35.7±12.7% (P=.05) at the increased dose.

After randomization during the double-blinded portion of the protocol, while patients were receiving higher but stable doses of digoxin, nine patients were continued on the same dose of digoxin and nine patients were switched from digoxin to placebo. At 12 weeks, while background therapy with diuretics and ACE inhibitors was kept constant, the radionuclide ejection fraction increased from 24.7±13.2% to 29.5±16.8% in the digoxin group (eight patients) and decreased from 29.4±10.4% to 23.7±8.9% in the placebo group (Table 2). After accounting for the group difference in ejection fraction at increased dose, the 12-week ejection fraction was significantly different between the two groups (ANCOVA, P=.002) (Figure).

View this table: [in this window] [in a new window]   Table 2. Changes in Radionuclide Ejection Fraction in Response to Increased Daily Dose of Digoxin and Then Discontinuation of Digoxin in 9 Patients at 12 Weeks of Follow-up Study

View larger version (15K): [in this window] [in a new window]   Figure 1. Plot of radionuclide left ventricular ejection fraction in 18 patients in whom maintenance digoxin dose was increased and in patients randomized to digoxin (9 patients) or placebo (9 patients).

Exercise Time and Heart Failure Score
Exercise time was not significantly altered by the higher digoxin dose (417±174 seconds at baseline compared with 480±188 seconds at the higher dose; P=.17) (Table 3). Similarly, heart failure scores showed no significant change (2.17±1.34 to 1.72±0.96; P=.82). There also were no significant changes in heart rate, mean blood pressure, body weight, or cardiothoracic ratio after dose adjustment.

View this table: [in this window] [in a new window]   Table 3. Changes in Clinical Variables Including Cardiothoracic Ratio, Exercise Tolerance, and Heart Failure Score Before and After the Increase in Digoxin Dose

Neurohormones
The results of neurohormonal studies are presented in Table 4. Serum norepinephrine concentrations were measured both at rest (supine and upright) and during exercise. There was no significant change in resting supine serum norepinephrine concentrations (419±203 pg/mL at baseline to 428±180 pg/mL; P=.28), standing norepinephrine concentrations (693±335 pg/mL to 669±243 pg/mL; P=.32), or peak exercise norepinephrine concentrations (1146±711 pg/mL to 1016±560 pg/mL; P=.97). There also were no significant changes in plasma renin activity and serum concentrations of atrial natriuretic factor, antidiuretic hormone, creatinine, potassium, or serum urea nitrogen after dose adjustment. There was, however, a significant increase in serum aldosterone from 7.1±3.1 to 10.4±7.1 pg/mL after dose adjustment (P=.02).

View this table: [in this window] [in a new window]   Table 4. Changes in Neurohormones, Serum Potassium, and Renal Function Before and After the Increase in the Maintained Digoxin Dose

Adverse Reactions
During follow-up, despite constant doses of diuretics and ACE inhibitors two patients developed hypokalemia that responded to oral potassium supplementation. Another patient developed symptomatic nonsustained ventricular tachycardia at a serum digoxin concentration of 0.9 ng/mL during a daily digoxin dose of 0.375 mg. In this third patient, mexiletine therapy was instituted, and digoxin was continued and later increased to 0.5 mg/day PO. With the patient receiving mexiletine and this higher dose of digoxin, repeat Holter monitoring failed to demonstrate ventricular tachycardia. One additional patient developed exertional angina during the study and responded to nitrates. Two other patients died during the study: one during the dose-increase period and another after randomization while receiving digoxin therapy. This first patient who died had ischemic heart disease and was receiving 0.25 mg/day of digoxin, resulting in a serum digoxin concentration of 0.6 mg/mL. The dosage was increased to 0.375 mg/day. At 8 days after the increase in digoxin dose, the serum concentration was 0.8 ng/mL; at 22 days, it was 0.9 ng/mL. Five days after the last measurement of the serum digoxin concentration, the patient was brought to the emergency department with an evolving myocardial infarction, underwent cardiac catheterization, and died during attempted percutaneous transluminal coronary angioplasty while in cardiogenic shock. The second patient had an idiopathic dilated cardiomyopathy and was receiving 0.25 mg digoxin and had a serum concentration of 0.6 ng/mL. The dosage was increased to 0.375 mg/day, resulting in a serum concentration of 1.1 ng/mL, 14 days after the dose increase. The patient died 21 days after randomization; the death was sudden and unexpected. Neither of these patients showed evidence of digoxin intoxication before death.

	Discussion

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Results of the present study indicate that in patients in sinus rhythm with chronic systolic heart failure who are receiving constant doses of diuretics and ACE inhibitors, an increase in the dose of digoxin within a relatively narrow range of serum concentration results in an increase in left ventricular ejection fraction at rest and immediately after maximal treadmill exercise. This improvement in left ventricular ejection fraction was not associated with significant changes in neurohumoral measurements, except for an increase in serum aldosterone concentrations. The improvement in ejection fraction with the higher doses of digoxin was not associated with a significant improvement in heart failure score or exercise tolerance. In the RADIANCE study,⁸ which was a study of a similar but larger number of patients, the withdrawal of digoxin was associated with a decrease in left ventricular ejection fraction and a significant increase in functional class and exercise tolerance. There are several possibilities that may account for the lack of improvement in exercise capacity in our study: Because exercise tolerance and heart failure score were evaluated while patients were receiving different doses of digoxin therapy, it is possible that the lower dose was as effective as the higher dose in improving exercise performance, as shown by Young et al.¹⁹ It is also possible that the beneficial effects from digoxin on exercise tolerance and functional class are observed after a longer treatment period. The mean observation period in our study was 4 weeks compared with 12 weeks in the RADIANCE study. In RADIANCE, the development of overt heart failure was delayed and appeared to be continuously increasing over the 12 weeks after digoxin was discontinued. Because digitalis in chronic heart failure has both inotropic and vasodilatory effects,¹⁵ it is not clear from our study whether the increase in ejection fraction was related to an increase in cardiac contractility, to a decrease in afterload, or to both. Because the stroke volume increased significantly without a significant change in end-diastolic volume or blood pressure, it is possible that the increase in the ejection fraction was mostly related to the inotropic properties of the drug. However, a reduction in end-systolic volume can also result from decreased left ventricular outflow resistance. Thus, the relative contribution of possible reduction of afterload cannot be excluded.

There are little data on the hemodynamic effects associated with different doses of digitalis preparations. Klein et al¹⁰ correlated the electrical and mechanical changes in the dog heart during progressive digitalization. Their study demonstrated a progressive linear increase in contractility (dP/dt)P in response to increasing doses of digitalis preparations until ventricular tachycardia occurred. These observations were in agreement with the findings of Williams et al²⁰ that the inotropic action exerted by digitalis increases progressively until toxic arrhythmias appear. Carliner et al²¹ studied systolic time intervals in eight patients with coronary artery disease, hypertension, or both without heart failure in response to oral digoxin doses of 0.25 mg/day or 0.5 mg/day for alternate 2-week periods without a loading dose. A positive inotropic response was noted with both doses, but a greater positive inotropic effect was noted with the 0.5-mg dose. Hoeschen and Cuddy²² studied 21 patients without overt heart failure in whom the daily dose was increased from 0.25 mg (serum concentration, 0.56 ng/mL) to 0.5 mg (serum concentration, 1.18 ng/mL), and they observed an improvement in ventricular function as estimated by systolic time intervals. Belz et al²³ studied groups of healthy male volunteers. Some received oral digoxin of doses of 0.1, 0.2, 0.3, 0.4, 0.5, or 0.6 mg/day for 7 days after the loading doses. Although there was a progressive increase in contractility assessed by systolic time intervals in response to escalating doses, a plateau was reached at the higher doses. Similar results in a group of ischemic patients were reported by Buch and Waldorff.²⁴ Lampe et al²⁵ examined 15 patients and found that the shortening of the systolic time intervals was maximum at a serum concentration of 1 ng/mL.

Ware et al²⁶ suggested that the maximal improvement in ejection fraction in elderly patients with heart failure was observed when serum concentrations were between 0.4 to 1.0 ng/mL. Arnold et al²⁷ found that acute intravenous administration of additional doses of 0.25 or 0.5 mg in patients with severe heart failure on maintenance therapy with digoxin and a serum concentration of 1.1 ng/mL did not significantly enhance the hemodynamic response either at rest or during exercise.

Our results are in keeping with other investigations of the effects of digoxin therapy on left ventricular ejection fraction. In the Digoxin-Captopril study⁵ of patients with mild-to-moderate heart failure receiving diuretic therapy, which compared the initiation of digoxin with ACE inhibitor therapy, a significant increase in ejection fraction was observed in patients in whom digoxin was initially withdrawn for 2 weeks, followed by the reinstitution of the drug to achieve a serum concentration of >0.7 ng/mL.⁵ In that study, in which the average digoxin dosage was adjusted between 0.125 and 0.375 mg/day, the ejection fraction increased from 26% before digoxin therapy to 30% after 12 weeks of digoxin therapy.⁵

In addition to its inotropic effects, digoxin appears to have neuroendocrine effects in patients with heart failure.¹⁵ Because elevated serum norepinephrine concentrations have been associated with reduced survival²⁸ and an increase in serum concentration during therapy has been associated with an increase in mortality,²⁹ we assessed the neurohumoral changes during incremental doses of digoxin. During acute¹⁴ or chronic therapy,³⁰ digoxin decreased the norepinephrine serum concentrations and improved the autonomic dysfunction.^{31 32} There are no studies that examined the digoxin dose-dependent effects on neurohormones. In the present study, it appears that despite a significant increase in left ventricular ejection fraction, no significant changes in norepinephrine serum concentrations were observed. It is possible that the neuroendocrine attenuation occurs only with low-dose digoxin. The DIMT study group³⁰ showed that a low dose of digoxin caused a significant decrease in serum norepinephrine concentration at 6 months of follow-up compared with placebo. Because digoxin has both sympathoinhibitory³³ and sympathoexcitatory effects³⁴ that are dose dependent,³⁵ it is possible that the low dose attenuates the neurohumoral activation without improving the hemodynamics, whereas a higher dose improves hemodynamics without having a modulating effect on neurohormones. The sympathoinhibitory or sympathoexcitory effects may also be related to differences in severity of left ventricular dysfunction in different patient groups.

We observed an increase in aldosterone concentration in response to a higher digoxin dose. Other investigators have shown that acute administration of digoxin decreased the serum aldosterone concentration.^{36 37} It is not clear why the serum aldosterone concentration increased during chronic digoxin therapy. Although it is possible that digoxin has a direct effect on the aldosterone release, other investigators have shown that aldosterone serum concentration did not change with chronic digoxin therapy.³⁰

The ANF serum concentration did not change during the study. Although the ANF serum concentration correlates with hemodynamic measurements,^{38 39} it is not clear whether hemodynamic improvement in response to therapy results in a decrease in ANF serum concentrations.⁴⁰

We were interested to determine whether digoxin can further alter plasma renin activity, particularly when the chronic use of digoxin results in a decrease in plasma renin activity.³¹ Our patients were studied while receiving constant doses of ACE inhibitors and diuretics, and they failed to show a change in plasma renin activity.

It appears that the majority of patients in the United States who are receiving chronic digoxin therapy for systolic heart failure are maintained on 0.25 mg/day digoxin, which usually corresponds to a relatively low serum concentration. However, in the past, for a number of years, the recommended daily dose of digoxin in the United States was 0.5 mg/day. Our study suggests that patients maintained on therapeutic doses of ACE inhibitors, diuretics, and digoxin therapy may increase their resting ejection fraction in response to a small increase in the daily digoxin dose, resulting in a serum concentration that is within therapeutic range. This higher dose, resulting in a serum concentration of approximately 1.2 ng/mL, was used in the RADIANCE⁸ and PROVED⁷ studies without serious adverse effects. We also have shown that this modest increase does not activate the neuroendocrine system. Further research on dose-related effects of digoxin in patients with chronic heart failure is needed because, although digoxin is one of the most commonly prescribed drugs in the United States (12 million prescriptions in 1986), the most appropriate dose to achieve maximal clinical benefits without increasing the risk of intoxication is not known. In addition, the ongoing Digitalis Investigation Group mortality trial is not addressing the dose-related effect of digoxin on mortality.⁴¹ The importance of the appropriate dose is highlighted by the recent vesnarinone trial,¹³ which showed that a low dose of an oral inotrope that had no detectable hemodynamic effect resulted in improved survival, yet a higher dose adversely affected survival.

Study Limitations
The initial portion of the present study was not randomized or double-blinded, and the number of patients studied was small. It is possible that the increased ejection fraction may have been related to the time change in left ventricular ejection fraction noted in other heart failure trials. However, in these trials the changes in ejection fraction were not significant, and the fact that the ejection fraction decreased when digoxin was discontinued suggests that the improvement in left ventricular function was related to an increase in serum digoxin concentration.

Conclusions
In patients with stable heart failure and sinus rhythm who are receiving diuretics and ACE inhibitors, an increase in the dose of digoxin within therapeutic range was associated with an increase in left ventricular ejection fraction. This increase in left ventricular ejection fraction was not associated with neuroendocrine activation. We suggest that patients receiving maintenance oral digoxin therapy with a low serum digoxin concentration should have the dose increased if they continue to have symptomatic heart failure despite maximal tolerated doses of diuretics and ACE inhibitors. This recommendation is supported by the recent trials that have shown a beneficial clinical effect from digoxin at a serum concentration of 0.9 to 2 ng/mL (mean, 1.2 ng/mL). It should be recognized, however, that the risk of developing digoxin intoxication is related to the dose used. Larger randomized trials should examine the effects of different doses of digoxin on clinical status, neurohormones, and survival.

	Selected Abbreviations and Acronyms

 

ACE = angiotensin-converting enzyme RADIANCE = Randomized Assessment of Digoxin on Inhibitors of the Angiotensin Converting Enzyme NYHA = New York Heart Association ANF = atrial natriuretic factor<\/.>

	Acknowledgments

 
This work was supported by a grant from Burroughs Wellcome, Co, Research Triangle Park, NC.

Received February 21, 1995; revision received April 30, 1995; accepted May 3, 1995.

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