JACC: HEART FAILURE
5, 2016
2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER
EDITORIAL COMMENT
Digoxin for Worsening Chronic
Heart Failure
Underutilized and Underrated*
Andrew P. Ambrosy, MD,a Peter S. Pang, MD, MSC,b Mihai Gheorghiade, MDc
D espite more than 200 years of clinical
experience and a pivotal trial, digoxin, a
puried cardiac glycoside derived from
the foxglove plant, remains the most controversial
drug in contemporary cardiovascular medicine (1,2).
Although the U.S. Food and Drug Administration
approved digoxin in 1997, the guidelines currently
offer only a secondary recommendation (i.e., class IIa)
for digoxin in: 1) patients with HF with reduced
ejection fraction (EF) experiencing persistent symp-
toms despite optimal medical therapy; and 2) as an
adjunct for rate control in patients with atrial brilla-
tion already receiving b-blockers and/or calcium chan-
nel blockers (3). However, there have been no major
advances in the management of patients hospitalized
for worsening chronic HF, and these patients remain
at high risk for early readmission or death despite avail-
able therapies. Thus, there are compelling public
health reasons to reconsider the use of digoxin, a drug
*Editorials published in JACC: Heart Failure reect the views of the au-
thors and do not necessarily represent the views of JACC: Heart Failure or
the American College of Cardiology.
a and that an unknown proportion of patients may
From the Division of Cardiology, Duke University Medical Center,
b
Durham, North Carolina; Department of Emergency Medicine, Indiana
University School of Medicine and the Regenstrief Institute, Indianapolis,
Indiana; and the cCenter for Cardiovascular Innovation, Northwestern
University Feinberg School of Medicine, Chicago, Illinois. Dr. Pang is or
has been a consultant for Janssen, Medtronic, Novartis, Trevena,
scPharmaceuticals, Cardioxyl, Roche Diagnostics, and Relypsa; has
received honoraria from Palatin Technologies; and has received research
support from Roche and Novartis. Dr. Gheorghiade has been a consultant
for Abbott Laboratories, Astellas, AstraZeneca, Bayer HealthCare AG,
CorThera, Cytokinetics, DebioPharm S.A., Errekappa Terapeutici, Glax-
oSmithKline, Ikaria, Johnson & Johnson, Medtronic, Merck & Co.,
Novartis Pharma AG, Otsuka Pharmaceuticals, Palatin Technologies,
Pericor Therapeutics, Protein Design Laboratories, Sano, Sigma Tau,
Solvay Pharmaceuticals, Stealth BioTherapeutics, Takeda Pharmaceu-
tical, and Trevena Therapeutics. Dr. Ambrosy has reported that he has no
relationships relevant to the contents of this paper to disclose.
VOL. 4, NO.
ISSN 2213-1779/$36.00
http://dx.doi.org/10.1016/j.jchf.2016.03.005
that is known to improve signs and symptoms of
congestion as well as reduce HF-related hospitali-
zations and readmissions.
SEE PAGES 348 AND 357
This issue of JACC: Heart Failure features 2 obser-
vational studies exploring real-world practice pat-
terns with digoxin therapy and digoxin toxicity. In
the rst study, Patel et al. (4) utilized data from
the American Heart Associations Get With the
GuidelinesHeart Failure program to assess temporal
trends and clinical characteristics associated with
digoxin use at discharge among patients admitted for
a primary diagnosis of HF. Between January 2005 and
June 2014, digoxin prescription rates at discharge
declined from 33.1% to 10.7% in patients with HF with
reduced EF. Similarly, among patients with HF with
preserved EF, digoxin use decreased from 16.0% to
5.7% over the same timeframe. As might be expected,
digoxin prescription was associated with a history of
atrial brillation and other high-risk clinical features.
The authors appropriately acknowledge that these
ndings cannot be generalized to outpatients with HF
have had undocumented contraindications, in-
tolerances, or drugdrug interactions that may have
impacted clinical decision making.
In the second study, Hauptman et al. (5) performed a
retrospective analysis of the Premier database
describing the management of digoxin toxicity and
clinical outcomes in the modern era. Of 28.5 million
hospitalizations over nearly 5 years, only 24,547 ad-
missions for digoxin toxicity were identied based on
International Classication of Diseases-Ninth Revision
coding for digoxin toxicity and/or Current Procedural
Terminology coding for digoxin immune fab (DIF).
The authors found that DIF was administered in 20%
366 Ambrosy et al.
Digoxin for Worsening Chronic Heart Failure
of patients, and most patients (i.e., 78%) received
DIF within 1 to 2 days of admission. In addition, car-
diovascular specialists were more likely than gener-
alist physicians to treat with DIF, and the use of DIF
was associated with emergency admission, arrhyth-
mias, and acute renal failure/hyperkalemia. Notably,
among patients with digoxin toxicity, there was no
difference in mortality during hospitalization or length
of stay based on DIF treatment status. Weaknesses of
the study include the absence of objective clinical
ndings (i.e., symptoms, physical examination, elec-
trocardiogram, and so on) and digoxin levels to
corroborate the diagnosis of digoxin toxicity as well as
the lack of post-discharge outcomes.
Why has the use of digoxin declined precipitously?
The safety of digoxin was rst challenged in the 1970s
on the basis of several retrospective analyses sug-
gesting digoxin therapy might be associated with
increased mortality (6). This prompted the design and
conduct of 3 prospective, multicenter, randomized,
double-blinded, placebo-controlled trials: PROVED
(Prospective Randomized Study of Ventricular Fail-
ure and the Efcacy of Digoxin) (7), RADIANCE
(Randomized Assessment of [the effect of] Digoxin on
Inhibitors of the Angiotensin-Converting Enzyme)
(8), and the pivotal National Institutes of Health
sponsored DIG (Digitalis Investigation Group) (9)
trials. In aggregate, these landmark studies provide
a strong evidence basis for the efcacy and safety
of digoxin therapy. In patients with HF with reduced
EF, digoxin augments cardiac output (CO) and
reduces pulmonary capillary wedge pressure without
inducing potentially hazardous increases in heart rate
or decreases in blood pressure (10,11). In addition,
digoxin therapy improves signs and symptoms of HF
and functional status (7,8). Similarly, digoxin reduced
the incidence of all-cause, cardiovascular-related,
and HF-specic hospitalizations in the DIG trial,
which enrolled 6,800 stable ambulatory HF patients
with an EF <45% (9). Interestingly, in the DIG ancil-
lary trial, which enrolled 988 outpatients with HF
with an EF >45%, digoxin use was associated with a
trend towards a reduction in hospitalizations for
worsening HF, which approached, but did not reach,
the threshold for signicance, perhaps in part due to
the smaller sample size and reduced statistical power
(12). Although digoxin is known to have a narrow
therapeutic window, the absolute incidence
digoxin toxicity is low, both in the controlled setting
of a clinical trial (9) and in the context of everyday
practice (13,14). For example, in the DIG trial, the
incidence of hospitalization for suspected digoxin
toxicity was 2-fold higher in digoxin-treated patients,
yet the rate was low overall (i.e., 2.0% vs. 0.9%) (9).
JACC: HEART FAILURE VOL. 4, NO. 5, 2016
MAY 2016:3657
Although no overall survival benet was observed
in the DIG trial, the effect of digoxin on the mode of
death is intriguing. In essence, a bidirectional effect
was observed: a decrease in mortality due to pro-
gressive pump failure that was offset by an increase
in death due to other cardiovascular causes (9).
However, secondary analyses of the DIG database
have raised the hypothesis that digoxin may improve
survival in pre-specied high-risk subgroups
including patients with New York Heart Association
functional class III or IV symptoms, an EF <25%,
and/or a cardiothoracic ratio >55% (15). Similarly,
although there were initially concerns on the basis of
retrospective analyses of the DIG trial that digoxin
might increase mortality in subsets of patients at risk
for digoxin toxicity such as women, the elderly, and
patients with renal insufciency, any potential
detrimental effects on mortality are no longer sig-
nicant after adjusting for serum digoxin concentra-
tion (SDC) (1618). In fact, a comprehensive post hoc
analysis including all patients enrolled in the DIG
main and ancillary trials found that digoxin use
among patients with a SDC <1 ng/ml was associated
with a robust survival benet that was consistent
across age, sex, EF, and comorbid disease states (16).
As a result, the guidelines have been revised since the
completion of the DIG trial and currently recommend
a lower therapeutic SDC for HF (i.e., <1.0 ng/ml) (3).
More recently, the peer-reviewed published
reports and the popular press have highlighted a
number of studies showing potential harm with
digoxin therapy in both HF and atrial brillation.
Notably, 2 independent research teams using differ-
ent statistical methods performed secondary analyses
of the AFFIRM (Atrial Fibrillation Follow-up Investi-
gation of Rhythm Management) database and reached
diametrically opposed conclusions regarding the
effect of digoxin on mortality (19,20). This highlights
the inherent limitations of secondary analyses,
demonstrating that even with sophisticated statistical
modeling, it may not be possible to comprehensively
adjust for disease severity and the indication for
treatment. In addition, these studies are based on
prevalent digoxin use, and substantial differences in
clinical characteristics may have emerged in the
intervening time between drug initiation and data
acquisition. Thus, although existing and future
of observational datasets may provide useful informa-
tion regarding the epidemiology and real-world
practice patterns with digoxin, denitive conclu-
sions regarding its safety based on post hoc analyses
should be interpreted with extreme caution (2).
In conclusion, there have been no major advances
in the pharmacological management of patients
JACC: HEART FAILURE VOL. 4, NO. 5, 2016 Ambrosy et al. 367
MAY 2016:3657 Digoxin for Worsening Chronic Heart Failure

hospitalized for worsening chronic HF over the
last 2 decades. These patients remain at high risk
for early readmission or death (21,22). However,
digoxin has multiple favorable properties that make it
an ideal therapy for worsening chronic HF (23).
Digoxin is the only available inotrope known to in-
crease CO and decrease pulmonary capillary wedge
pressure without causing deleterious increases in
heart rate or decreases in blood pressure. In addi-
tion, digoxin improves signs and symptoms of HF
and functional status. Digoxin is known to reduce
all-cause and HF-specic hospitalizations. At SDCs northwestern.edu.
<1 ng/ml and in certain high-risk groups, digoxin
may improve survival. Accordingly, digoxin should
be considered in patients with HF with reduced
EF who remain symptomatic despite optimal medical
therapy.
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
Mihai Gheorghiade, Center for Cardiovascular
Innovation, Northwestern University Feinberg School
of Medicine, 201 East Huron Street, Galter 3-150,
Chicago, Illinois 60601. E-mail: m-gheorghiade@

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8. Packer M, Gheorghiade M, Young JB, et al. 16. Ahmed A, Rich MW, Love TE, et al. Digoxin and KEY WORDS digoxin, heart failure, mortality,
Withdrawal of digoxin from patients with chronic reduction in mortality and hospitalization in heart outcomes, readmissions