Cardiovascular Drugs

Digitalis
Paul J. Hauptman, MD; Ralph A. Kelly, MD

Abstract—Cardiac glycosides have played a prominent role in the therapy of congestive heart failure since William Withering
codified their use in his late 18th century monograph on the efficacy of the leaves of the common foxglove plant (Digitalis
purpurea). Despite their widespread acceptance into medical practice in the ensuing 200 years, both the efficacy and the safety
of this class of drugs continue to be a topic of debate. Moreover, despite the fact that the molecular target for the cardiac
glycosides, the a-subunit of sarcolemmal Na1K1-ATPase (or sodium pump) found on most eukaryotic cell membranes, has
been known for several decades, it remains controversial whether the sympatholytic or positive inotropic effects of these
agents is the mechanism most relevant to relief of heart failure symptoms in humans with systolic ventricular dysfunction.
Herein, we review the molecular and clinical pharmacology of this venerable class of drugs, as well as the manifestations of
digitalis toxicity and their treatment. We also review in some detail recent clinical trials designed to examine the efficacy of
these drugs in heart failure, with a focus on the Digoxin Investigation Group data set. Although, in our opinion, the data on
balance warrant the continued use of these drugs for the treatment of symptoms of heart failure in patients already receiving
contemporary multidrug therapy for this disease, the use of digitalis preparations will inevitably decline with the maturation
of newer pharmacotherapies. (Circulation. 1999;99:1265-1270.)
Key Words: drugs n digitalis n heart failure n pharmacology

C ardiac glycosides have played a prominent role in the

therapy of congestive heart failure since William Withering
codified their use in his classic monograph on the efficacy of the
leaves of the common foxglove plant (Digitalis purpurea) in
1785.1 Nevertheless, throughout this century, a controversy has
Downloaded from http://ahajournals.org by on October 19, 2021
resulting in an increase in the rate of rise of intracavitary
pressure during isovolumic systole at constant heart rate and
aortic pressure that could be demonstrated in normal as well
as failing cardiac muscle. Cardiac glycoside administration
caused the ventricular-function (Frank-Starling) curve of the

existed about whether the risks of digitalis preparations out-
weigh their benefits, particularly in patients with heart failure in
sinus rhythm. In this review, we begin with a brief overview of
the basic and clinical pharmacology of the cardiac glycosides,
followed by an examination of recent clinical trials that have
studied the use of digoxin in patients with moderate to severe
congestive heart failure. The terms “digitalis” or “cardiac gly-
cosides” are used throughout to refer to any of the steroid or
steroid glycoside compounds that exert characteristic positively
inotropic and electrophysiological effects on the heart. In the
1990s, digoxin is by far the most commonly prescribed of these
drugs owing to the ready availability of techniques for measur-
ing its levels in serum, flexibility in routes of its administration,
and its intermediate duration of action. Detailed descriptions of
sources of cardiac glycosides, their chemistry, and structure-
activity relationships are extensively considered in standard
texts.2,3
Mechanism of Action
Positive Inotropic Effect
By the late 1920s, it became clear that digitalis preparations
caused a positive inotropic effect on the intact ventricle,
intact heart to shift upward and to the left, so that more stroke
work would be generated at a given filling pressure. These
effects appear to be sustained during in vivo administration of
digitalis, for periods of weeks to months, without any
evidence of desensitization or tachyphylaxis. It is now gen-
erally believed that digitalis compounds bring about an
increase in the availability of activator Ca21 in heart cells and
that this increase in intracellular Ca21 activity is sufficient to
explain both the inotropic and arrhythmogenic effects of
these drugs.2,3
All cardioactive steroids share the property of being potent
and highly specific inhibitors of the intrinsic membrane
protein Na1K1-ATPase. This enzyme comprises the cellular
“sodium pump,” in which membrane ion translocation is
coupled to the hydrolysis of a high-energy ATP phosphate.
Indeed, Jens Skou was awarded the 1997 Nobel prize in
chemistry for his discovery in the 1960s of the enzymatic
activity he termed the Na1K1-ATPase, which he character-
ized in the giant neurons of shellfish.4 The enzyme is a
heterotrimer consisting of a-, b-, and g-subunits, the
a-subunit of which contains the Na1, K1, and ATP binding
sites of the intact enzyme, and has been highly conserved in

From the Department of Medicine, Division of Cardiology (P.J.H.), Saint Louis University School of Medicine, St. Louis, MO; and the Cardiovascular
Division (R.A.K.), Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass.
This review is dedicated to the memory of Richard N. Gorlin, MD, and Thomas W. Smith, MD.
Correspondence to Ralph A. Kelly, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail
rakelly@rics.bwh.harvard.edu
© 1999 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org

1265
 1266 Digitalis
eukaryotes for the establishment and maintenance of trans-
membrane Na1 and K1 gradients (see Reference 5 for a
review).
Another enduring characteristic of Na1K1-ATPase that is
unique among the P-type ATPases is the presence of a
binding site on the extracytoplasmic face of the a-subunit for
the cardiac glycosides. Indeed, the highly selective action of
the cardiac glycosides to bind to the “digitalis binding site”
on Na1K1-ATPase has engendered much speculation about
the possible existence of endogenous ligands, simply because
the amino acid sequence and conformation that form their
binding site have been so highly conserved over many phyla
and millennia. Although intriguing data exist (reviewed in
References 6 through 9), there is as yet no proof that any
“endogenous digitalis” exists that has a well-defined biolog-
ical role in regulating Na1K1-ATPase activity.
Compelling direct evidence supporting cardiac glycoside–
induced increases in intracellular Na1 concentration or activ-
ity ([Na1]i) has now been obtained, and the mechanism of
digitalis-induced positive inotropy is known to involve an
altered balance between intracellular Na1 and Ca21. The
transmembrane Na1 influx occurring with each action poten-
tial, in the presence of diminished outward Na1 pumping due
to digitalis, leads to an increase in intracellular Na1 concen-
tration that in turn increases intracellular Ca21 stores, either
through enhanced Ca21 entry, reduced Ca21 efflux, or both,
effects that are thought to be mediated via Na1-Ca21 ex-
change. Interestingly, recent evidence suggests that the im-
mediate positively inotropic effect of cardiac glycosides,
Downloaded from http://ahajournals.org by on October 19, 2021
measured either in the intact heart in a conscious dog model
or in isometrically contracting papillary muscle strips, is
achieved with remarkable energy transfer efficiency and little
oxygen wasting.10 Finally, Santana and colleagues11 have
recently demonstrated that physiologically relevant (ie, nano-
molar) concentrations of cardiac glycosides can alter the ion
selectivity of voltage-sensitive Na1 channels in sarcolemmal
and T-tubular membranes, permitting Ca21 entry by a mech-
anism they have termed “slip-mode conductance.” The rele-
vance of this finding to the mechanism of action of these
drugs will require further study.
Electrophysiological Effects
As with the positive inotropic effect of these drugs, the major
effect on cardiac rhythm of digitalis preparations is believed
to be due to inhibition of the sodium pump. However, cells in
various parts of the heart show differing sensitivities to
digitalis, and both direct and neurally mediated effects are
now known to occur. Indeed, at therapeutic levels of digoxin,
these drugs decrease automaticity and increase maximum
diastolic potential, effects that can be blocked by atropine,
whereas higher (toxic) concentrations decrease diastolic po-
tentials and increase automaticity.
Similarly, the toxic arrhythmogenic effects of the cardiac
glycosides are due to a combination of direct effects on the
myocardium and neurally mediated increases in autonomic
activity. Both systolic and diastolic [Ca21]i increase during
digitalis-induced arrhythmias, increases that were first in-
ferred from changes in tension, leading to the idea that
intracellular “Ca21 overload” contributes to the observed
arrhythmogenic effects. Spontaneous cycles of Ca21 release
and reuptake then ensue, resulting in afterdepolarizations and
aftercontractions. The afterdepolarization is the result of a
Ca21-activated transient inward current (Iti) and is thought to
be the macroscopic manifestation of Ca21-activated nonspe-
cific cation channels, plus Na1-Ca21 exchange current.
Neurally Mediated Actions of Cardiac Glycosides
It is important to understand the role of digitalis glycosides in
modifying the abnormal autonomic nervous system activity
characteristic of advanced heart failure, including altered
baroreflex activity. Mason and Braunwald12 noted .30 years
ago that intravenous ouabain increased mean arterial pres-
sure, forearm vascular resistance, and venous tone in normal
human subjects, probably in part because of direct but
transient effects on vascular smooth muscle. In contrast, as
shown in the Figure, patients with heart failure responded
with a decline in heart rate and other effects that were
consistent with enhanced baroreflex responsiveness. More
recently, Ferguson et al13 demonstrated in patients with
moderate to severe heart failure that infusion of deslanoside,
a rapidly acting cardiac glycoside, increased forearm blood
flow and cardiac index and decreased heart rate concomitant
with a marked decrease in skeletal muscle sympathetic nerve
activity measured as an indicator of centrally mediated
sympathetic nervous system activity. In contrast, dobutamine,
a sympathomimetic drug that increased cardiac output to a
similar degree, did not affect muscle sympathetic nerve
activity in these patients. On the basis of these observations
and those of others (reviewed in detail in Reference 14),
reduced sympathetic nervous system activation may be an
important mechanism contributing to the efficacy of cardiac
glycosides in the treatment of patients with heart failure (and
may occur at blood levels of these drugs that are below those
necessary to achieve a direct inotropic effect).
Clinical Pharmacology
Digoxin Dosing
Although a number of cardiac glycoside preparations remain
available, digoxin is the most commonly prescribed, and its
pharmacology will be described in detail. The reader is
referred to comprehensive texts for a description of the
pharmacology of other cardiac glycosides that remain in
clinical use.3 Digoxin is excreted exponentially, with an
elimination half-life of 36 to 48 hours in patients with normal
renal function, resulting in the loss of about one third of body
stores daily. Renal excretion of digoxin is proportional to the
glomerular filtration rate (and hence to creatinine clearance).
With daily maintenance therapy, a steady state is reached
when daily losses are matched by daily intake. For patients
not previously given digoxin, institution of daily maintenance
therapy without a loading dose results in development of
steady-state plateau concentrations after 4 to 5 half-lives, or 7
to 10 days, in subjects with normal renal function. If the
elimination rate of the drug is prolonged, the length of time
before a steady state is reached on a daily maintenance dose
would also be prolonged proportionately. A patient’s esti-
mated lean body mass should be used in the calculation for
maintenance dosing. Also, recent evidence suggests that the

Downloaded from http://ahajournals.org by on October 19, 2021
Cardiac glycosides and peripheral vascular resistance in heart
failure. A, In a series of pioneering studies, Mason and Braun-
wald12 noted that a 10-minute intravenous infusion of ouabain, a
hydrophilic, rapidly acting cardiac glycoside, into normal sub-
jects increased mean arterial pressure as well as forearm vascu-
lar resistance and venous tone, as shown in this representative
example. However, as shown in B, forearm vascular resistance
Hauptman and Kelly March 9, 1999 1267
steady-state volume of distribution of digoxin (Vdss) is
decreased in chronic renal failure, and therefore loading doses
of digoxin as well as maintenance doses should be decreased
in these patients.15 Digoxin doses in neonates and infants are
substantially larger than those in adults, resulting in relatively
higher serum digoxin concentrations, which are generally
well tolerated. Digoxin does cross the placenta, and fetal
umbilical cord venous blood levels of the drug are similar to
maternal blood levels. There is no contraindication for use of
digoxin during pregnancy or during lactation.
There is usually no need to treat patients with a loading
dose of digoxin except in the setting of certain supraventric-
ular arrhythmias when other drugs useful in treating these
arrhythmias are contraindicated or have not been effective.
This is due to the narrow therapeutic “window” of cardiac
glycosides, which often makes it difficult to judge accurately
an effective loading dose of digoxin that will also minimize
the risk of toxicity. Often, the patients who would benefit
most from the addition of a cardiac glycoside are also those
at greatest risk of exhibiting toxic effects of these drugs (see
below). Because the mechanism of action of the cardiac
glycosides relevant to their beneficial effects in heart failure
patients remains controversial, there is debate about the
appropriate therapeutic range for digoxin. Our analysis of the
consensus to date, based on clinical trial data reviewed below,
would put that range between 0.5 and 1.5 ng/mL.
Drug Interactions
Concomitant drug administration may directly alter the phar-
macokinetics of digitalis preparations or indirectly alter their
action on the heart by pharmacodynamic interactions. Quin-
idine reduces both the renal and nonrenal elimination of
digoxin and also decreases its volume of distribution. Recent
evidence indicates that quinidine inhibits digoxin transport
across epithelial cell membranes (particularly in the kidney)
owing to its high affinity for P-glycoprotein, an ATP-
dependent efflux pump encoded by the mdr1a gene.16 Ami-
odarone administration has been found to increase the steady-
state digoxin concentration, and maintenance doses of
digoxin should be decreased by $50%. Newly introduced
drugs will require close surveillance for interactions with
cardiac glycosides.
Examples of pharmacodynamic interactions include con-
comitantly administered diuretic agents that may increase the
incidence of digitalis toxicity both by decreasing the glomer-
ular filtration rate owing to volume depletion and by inducing
a variety of electrolyte disturbances, including hypokalemia,
hypomagnesemia, and (for thiazide diuretics) hypercalcemia.
Also, concurrent administration of some antiarrhythmic
agents may increase the possibility of proarrhythmic events,
and venous tone declined in patients with advanced heart failure
after intravenous ouabain. The response in normal subjects is
likely due in part to a direct effect of cardiac glycosides on pe-
ripheral vascular tone, whereas the rapid, opposite hemodynam-
ic effect in heart failure patients is believed to be due to a
decline in sympathetic nervous system activity, mediated by
enhanced sensitivity of the baroreflex response. Adapted from
Mason and Braunwald,12 with permission.
 1268 Digitalis
an outcome that is often unpredictable in an individual
patient.
Digitalis Toxicity
Electrophysiological Abnormalities
ECG manifestations of digoxin toxicity, such as premature
ventricular contractions, are numerous but, unfortunately, too
nonspecific in most instances to be diagnostic. At higher
doses, junctional pacemakers may begin to discharge at
increasing frequency, resulting in a nonparoxysmal AV
junctional tachycardia. This is recognized clinically as a
paradoxical regularization of the ventricular rate despite
persistent atrial fibrillation. Common supraventricular ar-
rhythmias associated with digitalis toxicity include
tachycardias that originate due to enhanced atrial automatic-
ity. Although there is no single ECG abnormality that is
pathognomonic of digitalis excess, the combination of en-
hanced automaticity and impaired conduction (eg, AV block
accompanied by an accelerated junctional pacemaker) is
highly suggestive of toxicity even in patients whose serum
levels are within the accepted therapeutic range.
The enhanced automaticity of cardiac tissue in response to
toxic levels of cardiac glycosides is increased by hypokale-
mia in experimental animals, whereas the appearance of
delayed afterdepolarizations that could reach threshold is
antagonized by hyperkalemia. However, hyperkalemia may
lead to exacerbation of digitalis-induced conduction delays,
particularly in the AV node. Finally, elevated serum Ca21
Downloaded from http://ahajournals.org by on October 19, 2021
levels increase ventricular automaticity, and this effect is at
least additive to, and perhaps synergistic with, the effects of
digitalis. Administration of intravenous calcium parenterally
to patients to whom digitalis has been given may provoke
lethal ventricular arrhythmias.
Treatment of Digitalis Toxicity
The key to successful treatment is early recognition that an
arrhythmia is related to digitalis intoxication. The more
common manifestations (including occasional ectopic beats,
marked first-degree AV block, or atrial fibrillation with a
slow ventricular response) require only temporary withdrawal
of the drug and ECG monitoring. Ventricular tachycardia due
to digitalis intoxication demands immediate vigorous treat-
ment. Sinus bradycardia, sinoatrial arrest, and second- or
third-degree AV block are often treated effectively with
atropine, although pacing may be required. Administration of
potassium salts is recommended for ectopic ventricular ar-
rhythmias, even when the serum potassium is within the
“normal” range. Hemodialysis is ineffective in the treatment
of digoxin toxicity owing to the drug’s large volume of
distribution (averaging 4 L/kg).
Although several antiarrhythmic drugs have been used in
the treatment of digitalis-induced ventricular arrhythmias, the
first-line treatment for life-threatening digitalis toxicity is
now the administration of digoxin-specific antibody frag-
ments. The widespread availability of Fab fragments of
high-affinity, polyclonal, digoxin-specific antibodies pro-
vides the clinician with a means of rapidly and selectively
reversing digitalis toxicity with little risk of adverse ef-
fects.17–19 A number of patients have now been treated with
antidigoxin Fab fragments on $2 occasions without incident.
Digoxin in Supraventricular Tachycardia
As reviewed above, the principal mechanism by which
cardiac glycosides slow the ventricular response in supraven-
tricular tachycardias is by decreasing sympathetic nervous
system activity (particularly in patients with heart failure) and
by enhancing parasympathetic nervous system activity. The
role of digoxin in paroxysmal atrial fibrillation, a condition in
which the drug has limited efficacy, has been superseded by
the introduction of newer, more efficacious, and safer drugs
over the past 2 decades. The only patients with supraventric-
ular tachycardia for whom cardiac glycosides remain useful
adjunctive therapy are those with atrial fibrillation (acute and
chronic) and symptomatic ventricular systolic dysfunction.
Even in this population, digoxin is typically sufficient for
ventricular rate control only in patients with relatively well-
compensated heart failure at rest (ie, in the absence of
markedly enhanced sympathetic nerve system activity).
Safety and Efficacy in Heart Failure: The
Clinical Trial Data
Relevance of Serum Digoxin Levels
Recent data from some clinical trials, reviewed below,
suggest that the sympatholytic effects of digoxin may occur at
serum drug concentrations below those necessary to achieve
a classic positively inotropic effect (note that we term these
actions of digoxin a “sympatholytic” effect and avoid the
commonly used, but overly vague and often incorrect, appel-
lation “neurohormonal antagonist,” because many factors
included under this umbrella, such as angiotensins, endothe-
lins, and inflammatory cytokines, to name a few, are neither
neurally derived nor hormones in the conventional sense).
Gheorghiade et al20 showed that increasing the dose from a
mean of 0.2 to 0.39 mg/d (corresponding to an increase in
serum levels from 0.67 to 1.22 ng/mL) resulted in an increase
in ejection fraction but no further change in exercise tolerance
or decline in venous norepinephrine levels, a conclusion
supported by at least several additional small clinical trials
(eg, Reference 21; reviewed in Reference 14).
The possibility that digoxin could exhibit several mecha-
nisms of action over the range of serum concentrations
achieved clinically could explain why patients with high
digoxin levels (.1.1 ng/mL) had a higher mortality in a
clinical trial designed to study the effect of milrinone on
survival in heart failure patients (the Prospective RandOm-
ized MIlrinone Survival Evaluation [PROMISE]), an effect
that was independent of ejection fraction.22 Therefore, judi-
cious use of digitalis requires recognition of concomitant
medications or disease states that could affect digoxin phar-
macokinetics, as well as early recognition of potential toxic-
ity, both of which remain essential for safe and effective
dosing of this class of agents.23
Smaller Clinical Trials in Patients With
Heart Failure
A number of short- and long-term controlled and uncontrolled
clinical trials have suggested that digoxin results in an impres-

Relative Risk Reduction in Hospitalizations With Digoxin Therapy
Digoxin
(n53397), n (%)
Reason for hospitalization
Total cardiovascular 1694 (49.9)
Worsening heart failure 910 (26.8)
Suspected digoxin 67 (2.0)
toxicity
No. of patients hospitalized 2184 (64.3)
No. of hospitalizations 6356
Adapted from the Digitalis Investigation Group.27
sive array of benefits (reviewed in References 14 and 24).
PROVED (Prospective Randomized study Of Ventricular fail-
ure and Efficacy of Digoxin)25 and RADIANCE (Randomized
Assessment of Digoxin on Inhibitors of ANgiotensin-
Converting Enzyme)26 were 2 prospective, multicenter, placebo-
controlled trials that examined the effects of withdrawal of
digoxin in patients with stable mild-to-moderate heart failure (ie,
New York Heart Association [NYHA] class II or III) and
systolic ventricular dysfunction (ie, a left ventricular ejection
fraction #0.35). All patients studied were in sinus rhythm; target
serum digoxin concentration in both studies during the baseline
run-in phase was 0.9 to 2.0 ng/mL; and in RADIANCE, patients
in the trial also received concurrent therapy with an ACE
inhibitor. When patients were randomly assigned either to
continue active digoxin therapy or to withdraw from active
therapy and receive a matching placebo, 40% of patients in
Downloaded from http://ahajournals.org by on October 19, 2021
PROVED and 28% of patients in RADIANCE who received
placebo noted a significant worsening of heart failure symptoms
compared with 20% and 6%, respectively, of patients who
continued to receive active drug. This absolute risk reduction of
20% in digoxin-treated patients constituted a substantial treat-
ment effect. However, neither of these trials had the statistical
power to detect an effect of digoxin therapy on the survival of
patients with heart failure, an end point for which efficacy had
already been established for the use of selected vasodilators in
this disease.
The Digitalis Investigation Group Trial
A number of lingering controversies over the role of digoxin
were to be resolved by the large multicenter Digitalis Investiga-
tion Group (DIG) trial, composed of 2 studies in a total of 302
centers in the United States and Canada.27,28 The “main” trial
required patients to be in sinus rhythm, with documented left
ventricular ejection fraction #0.45 and heart failure as deter-
mined by preset signs, symptoms, or radiographic criteria. Prior
or ongoing therapy with digoxin was admissible; therefore, in
effect, the DIG trial was in fact partly a digoxin-withdrawal trial.
The use of ACE inhibitors was not mandated but “strongly
encouraged”; additional drugs could be added at the discre-
tion of the investigator, and follow-up was established at 4
weeks, 4 months, and then every subsequent 4 months. The
primary end point was all-cause mortality, and secondary end
points were mortality due to cardiovascular causes, mortality
due to worsening heart failure, and hospitalization due to
worsening heart failure or other causes. Among the 6800
patients enrolled in this main trial, there were no differences
Hauptman and Kelly March 9, 1999 1269
Placebo Absolute Relative Risk
(n53403), n (%) Difference, % (95% CI) P
1850 (54.4) 24.5 0.87 (0.81–0.93) ,0.001
1180 (34.7) 27.9 0.72 (0.66–0.79) ,0.001
31 (0.9) 1.1 2.17 (1.42–3.32) ,0.001
2282 (67.1) 22.8 0.92 (0.87–0.98) 0.006
6777
in baseline characteristics between active-drug and placebo
group, including demographics, cause of heart failure, ejec-
tion fraction, dose of digoxin (or placebo) used, or use of
ACE inhibitors, nitrates, or diuretics.
After a mean follow-up of 37 months (range, 28 to 58
months), there were no differences in all-cause or cardiovas-
cular mortality. There was a trend toward a reduction in death
from heart failure, with a relative risk of 0.88 (95% CI, 0.77
to 1.01). The pivotal difference between the digoxin and
placebo groups is to be found in the decreased risk of
hospitalization for heart failure, with a relative risk for
patients taking digoxin of 0.72 (95% CI, 0.66 to 0.79)
(Table). This effect was sufficiently large that it remained
statistically significant when combined with the mortality end
points. The reduction in relative risk was greater for patients
with ejection fractions ,25% and for patients with more
advanced symptoms, as measured by NYHA classification.
The heart failure survival and hospitalization curves appear to
separate early after randomization, especially in the patient
subgroup in which digoxin was withdrawn, supporting the
conclusions reached in PROVED25 and RADIANCE.26
Open-label digoxin was given to more patients taking
placebo than digoxin (22.0% versus 14.2%). In the subgroup
of patients with recorded digoxin levels, .88% were within
the prescribed therapeutic range of 0.5 to 2.0 ng/mL at 1
month. Overall, there were nearly 10% fewer total cardiovas-
cular hospitalizations (1694 or 49.9% versus 1850 or 54.4%)
as well as fewer hospitalizations for each digoxin-treated
patient. In addition, the reduction in risk of death or need for
hospitalization due to worsening heart failure was the same
for patients taking digoxin at the time of randomization and
those not previously treated with the drug.
Despite these encouraging results, an increase in deaths
from other cardiac causes was noted in the group randomized
to receive digoxin. This category included deaths presumed to
result from tachyarrhythmias or bradyarrhythmias without
worsening heart failure, as well as deaths due to atheroscle-
rotic coronary disease, low-output states, and cardiac surgery.
Out-of-hospital death presumed to be due to an arrhythmia
was not a prespecified end point, and no data have been
published from the trial for this separate group.
Hence, despite the comprehensive data set that emerges from
the DIG trial, our ability to resolve all outstanding controversies
with digoxin using the DIG trial data set is limited. The question
of an “ideal” (ie, most efficacious and least toxic) serum digoxin
 1270 Digitalis
level remains unresolved. Furthermore, in an ancillary study of
the DIG trial, a subgroup of 581 patients from both the main and
secondary studies (ejection fraction #0.45 and .0.45, respec-
tively) completed 6-minute corridor walk tests and a variety of
quality-of-life questionnaires at enrollment and at 1, 4, and 12
months. No statistically significant differences were detected
between the digoxin and placebo groups (Rekha Garg, MD;
personal communication; 1998), although it is possible that this
substudy was underpowered to detect meaningful differences
among the most symptomatic patients.
Finally, any assessment of the likelihood that digoxin will
remain a mainstay of standard heart failure therapy29,30 is further
complicated by the emergence of agents that act directly to
suppress the activity of the sympathetic nervous system in heart
failure, particularly the b-adrenergic antagonists. It is unlikely
that another study will be performed to resolve the outstanding
clinical issues in the post-DIG trial era. The effort and costs
required to enroll patients in a non–industry-sponsored trial of a
generically available drug with sufficient power are prohibitive.
Furthermore, as standard drug therapy for heart failure improves,
a larger number of patients will be required to show an effect on
survival. In the setting of the maturation of newer therapies that
focus on survival as the important outcome, the likelihood is that
the digitalis debate, as well as the usage of this venerable class
of drugs, will fade in intensity, albeit without a clear declaration
of victory by proponents or detractors.
Acknowledgments
Dr Kelly is supported by grants HL-36141 and HL-52320 from the
Downloaded from http://ahajournals.org by on October 19, 2021
National Institutes of Health. The authors thank Dr Rekha Garg for
helpful discussions regarding the data from the DIG trial.
References
1. Withering W. An account of the foxglove and some of its medical uses,
with practical remarks on dropsy, and other diseases. In: Willius FA,
Keys TE, eds. Classics of Cardiology. New York, NY: Dover Publi-
cations Inc; 1941;1:231–252.
2. Eisner DA, Smith TW. The Na-K pump and its effectors in cardiac
muscle. In: Fozzard HA, Haber E, Katz AM, Morgan HE, eds. The Heart
and Cardiovascular System. New York, NY: Raven Press; 1991:863–902.
3. Kelly RA, Smith TW. Pharmacological treatment of heart failure. In:
Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 9th
ed. New York, NY: McGraw-Hill; 1996:809 – 838.
4. Skou JC. The Na,K-pump. In. Fleischer S, Fleischer B, eds. Methods in
Enzymology. San Diego, Calif: Academic Press; 1988;156:1–28.
5. Geering K. Na, K-ATPase. Curr Opin Nephrol Hypertens. 1997;6:
434 – 439.
6. Blaustein MP. Endogenous ouabain: role in the pathogenesis of hyper-
tension. Kidney Int. 1996;49:1748 –1753.
7. Hollenberg NK, Graves SW. Endogenous sodium pump inhibition:
current status and therapeutic opportunities. Prog Drug Res. 1996;
46:9 – 42.
8. Hamlyn JM, Hamilton BP, Manunta P. Endogenous ouabain, sodium
balance and blood pressure: a review and a hypothesis. J Hypertens.
1996;14:151–167.
9. Kelly RA, Smith TW. Endogenous cardiac glycosides. Adv Pharmacol.
1994;25:263–288.
10. Hasenfuss G, Mulieri LA, Allen PD, Just H, Alpert NR. Influence of
isoproterenol and ouabain on excitation-contraction coupling, cross-
bridge function, and energetics in failing human myocardium. Circu-
lation. 1996;94:3155–3160.
11. Santana LF, Gomez AM, Lederer WJ. Ca21 flux through promiscuous
cardiac Na1 channels: slip-mode conductance. Science. 1998;279:
1027–1033.
12. Mason DT, Braunwald E. Studies on digitalis, X: effects of ouabain on
forearm vascular resistance and venous tone in normal subjects and in
patients in heart failure. J Clin Invest. 1964;43:532–543.
13. Ferguson DW, Berg WJ, Sanders JS, Roach PJ, Kempf JS, Kienzle MG.
Sympathoinhibitory responses to digitalis glycosides in heart failure
patients: direct evidence from sympathetic neural recordings. Circulation.
1989;80:65–77.
14. Hauptman PJ, Kelly RA. Digitalis glycosides. In: Hosenpud, Greenberg
BH, eds. Congestive Heart Failure: Pathophysiology, Diagnosis and
Comprehensive Approach to Therapy. Baltimore, Md: Williams &
Wilkins. In press.
15. Cheng JWM, Charland SL, Shaw LM, Kobrin S, Goldfarb S, Stanek EJ,
Spinler SA. Is the volume of distribution of digoxin reduced in patients with
renal dysfunction? Determining digoxin pharmacokinetics by fluorescence
polarization immunoassay. Pharmacotherapy. 1997;17:584–590.
16. Fromm MF, Kim RB, Stein CM, Wilkinson GR, Roden DM. Inhibition of
P-glycoprotein-mediated drug transport: a unifying mechanism to explain
the interaction between digoxin and quinidine. Circulation. In press.
17. Kelly RA, Smith TW. Antibody therapies for drug overdose. In: Austen
KF, Burakoff SJ, Rosen FS, Strom TR, eds. Therapeutic Immunology.
Boston, Mass: Blackwell Scientific; 1996;27:353–362.
18. Antman EM, Wenger TL, Butler VP Jr, Haber E, Smith TW. Treatment
of 150 cases of life-threatening digitalis intoxication with digoxin-
specific Fab antibody fragments: final report of a multicenter study.
Circulation. 1990;81:1744 –1752.
19. Hickey AR, Wenger TL, Carpenter VP, Tilson HH, Hlatky MA, Furberg
CD, Kirkpatrick CH, Strauss HC, Smith TW. Digoxin immune Fab
therapy in the management of digitalis intoxication: safety and efficacy
results of an observational surveillance study. J Am Coll Cardiol. 1991;
17:590 –598.
20. Gheorghiade M, Hall VB, Jacobsen G, Alam M, Rosman H, Goldstein S.
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. Circulation.
1995;92:1801–1807.
21. Slatton ML, Irani WN, Hall SA, Marcoux LG, Page RL, Grayburn PA,
Eichhorn EJ. Does digoxin provide additional hemodynamic and
autonomic benefit at higher doses in patients with mild to moderate heart
failure and normal sinus rhythm? J Am Coll Cardiol. 1997;29:
1206 –1213.
22. Yusuf S, Garg R, Held P, Gorlin R. Need for a large randomized trial to
evaluate the effect of digitalis on morbidity and mortality in congestive
heart failure. Am J Cardiol. 1992;69:64G–70G.
23. Borron SW, Bismuth C, Muszynski J. Advances in the management of
digoxin toxicity in the older patient. Drugs Aging. 1997;10:18 –33.
24. Rahimtoola SH, Tak T. The use of digitalis in heart failure. Curr Probl
Cardiol. 1996;21:787– 853.
25. Uretsky BF, Young JB, Shahidi E, Yellen LG, Harrison MC, Jolly MK,
on behalf of the PROVED Investigative Group. Randomized study
assessing the effect of digoxin withdrawal in patients with mild to
moderate chronic congestive heart failure: results of the PROVED trial.
J Am Coll Cardiol. 1993;22:955–962.
26. Packer M, Gheorghiade M, Young JB, Costantini PJ, Adams KF, Cody
RJ, Smith LK, Van Voorhees L, Gourley LA, Jolly MK, for the
RADIANCE study. Withdrawal of digoxin from patients with chronic
heart failure treated with angiotensin-converting-enzyme inhibitors.
N Engl J Med. 1993;329:1–7.
27. The Digitalis Investigation Group. The effect of digoxin on mortality and
morbidity in patients with heart failure. N Engl J Med. 1997;336:
525–533.
28. The Digitalis Investigation Group. Rationale, design, implementation,
and baseline characteristics of patients in the DIG trial: a large, simple,
long-term trial to evaluate the effect of digitalis on mortality in heart
failure. Control Clin Trials. 1996;17:77–97.
29. Konstam M, Dracup K, Baker D, Bottorff MB, Brooks NH, Dacey RA,
Dunbar SB, Jackson AB, Jessup M. Heart Failure: Evaluation and Care
of Patients with Left Ventricular Systolic Dysfunction: Clinical Practice
Guideline No. 11. Rockville, Md: US Dept of Health and Human
Services, Agency for Health Care Policy and Research; June 1994.
AHCPR publication 94-0612.
30. ACC/AHA Task Force. Heart failure guidelines. J Am Coll Cardiol.
1995;26:1376 –1398.