Digoxin for Worsening Chronic Heart Failure

JACC: HEART FAILURE

VOL. 4, NO. 5, 2016

ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 2213-1779/$36.00

PUBLISHED BY ELSEVIER

http://dx.doi.org/10.1016/j.jchf.2016.03.005

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

that is known to improve signs and symptoms of

experience and a pivotal trial, digoxin, a

congestion as well as reduce HF-related hospitali-

purified cardiac glycoside derived from

zations and readmissions.

the foxglove plant, remains the most controversial

SEE PAGES 348 AND 357

drug in contemporary cardiovascular medicine (1,2). Although the U.S. Food and Drug Administration

This issue of JACC: Heart Failure features 2 obser-

approved digoxin in 1997, the guidelines currently

vational studies exploring real-world practice pat-

offer only a secondary recommendation (i.e., class IIa)

terns with digoxin therapy and digoxin toxicity. In

for digoxin in: 1) patients with HF with reduced

the first study, Patel et al. (4) utilized data from

ejection fraction (EF) experiencing persistent symp-

the American Heart Association’s Get With the

toms despite optimal medical therapy; and 2) as an

Guidelines–Heart Failure program to assess temporal

adjunct for rate control in patients with atrial fibrilla-

trends and clinical characteristics associated with

tion already receiving b-blockers and/or calcium chan-

digoxin use at discharge among patients admitted for

nel blockers (3). However, there have been no major

a primary diagnosis of HF. Between January 2005 and

advances in the management of patients hospitalized

June 2014, digoxin prescription rates at discharge

for worsening chronic HF, and these patients remain

declined from 33.1% to 10.7% in patients with HF with

at high risk for early readmission or death despite avail-

reduced EF. Similarly, among patients with HF with

able therapies. Thus, there are compelling public

preserved EF, digoxin use decreased from 16.0% to

health reasons to reconsider the use of digoxin, a drug

5.7% over the same timeframe. As might be expected, digoxin prescription was associated with a history of

*Editorials published in JACC: Heart Failure reflect the views of the authors and do not necessarily represent the views of JACC: Heart Failure or the American College of Cardiology. From the

a

Division of Cardiology, Duke University Medical Center,

atrial fibrillation and other high-risk clinical features. The authors appropriately acknowledge that these findings cannot be generalized to outpatients with HF and that an unknown proportion of patients may

Durham, North Carolina; Department of Emergency Medicine, Indiana

have

University School of Medicine and the Regenstrief Institute, Indianapolis,

tolerances, or drug–drug interactions that may have

b

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,

had

undocumented

contraindications,

in-

impacted clinical decision making. In the second study, Hauptman et al. (5) performed a

scPharmaceuticals, Cardioxyl, Roche Diagnostics, and Relypsa; has

retrospective

received honoraria from Palatin Technologies; and has received research

describing the management of digoxin toxicity and

support from Roche and Novartis. Dr. Gheorghiade has been a consultant

clinical outcomes in the modern era. Of 28.5 million

for Abbott Laboratories, Astellas, AstraZeneca, Bayer HealthCare AG,

analysis

of

the

Premier

database

CorThera, Cytokinetics, DebioPharm S.A., Errekappa Terapeutici, Glax-

hospitalizations over nearly 5 years, only 24,547 ad-

oSmithKline, Ikaria, Johnson & Johnson, Medtronic, Merck & Co.,

missions for digoxin toxicity were identified based on

Novartis Pharma AG, Otsuka Pharmaceuticals, Palatin Technologies,

International Classification of Diseases-Ninth Revision

Pericor Therapeutics, Protein Design Laboratories, Sanofi, Sigma Tau, Solvay Pharmaceuticals, Stealth BioTherapeutics, Takeda Pharmaceu-

coding for digoxin toxicity and/or Current Procedural

tical, and Trevena Therapeutics. Dr. Ambrosy has reported that he has no

Terminology coding for digoxin immune fab (DIF).

relationships relevant to the contents of this paper to disclose.

The authors found that DIF was administered in 20%

366

Ambrosy et al.

JACC: HEART FAILURE VOL. 4, NO. 5, 2016 MAY 2016:365–7

Digoxin for Worsening Chronic Heart Failure

of patients, and most patients (i.e., 78%) received

Although no overall survival benefit was observed

DIF within 1 to 2 days of admission. In addition, car-

in the DIG trial, the effect of digoxin on the mode of

diovascular specialists were more likely than gener-

death is intriguing. In essence, a bidirectional effect

alist physicians to treat with DIF, and the use of DIF

was observed: a decrease in mortality due to pro-

was associated with emergency admission, arrhyth-

gressive pump failure that was offset by an increase

mias, and acute renal failure/hyperkalemia. Notably,

in death due to other cardiovascular causes (9).

among patients with digoxin toxicity, there was no

However, secondary analyses of the DIG database

difference in mortality during hospitalization or length

have raised the hypothesis that digoxin may improve

of stay based on DIF treatment status. Weaknesses of

survival

the study include the absence of objective clinical

including patients with New York Heart Association

findings (i.e., symptoms, physical examination, elec-

functional class III or IV symptoms, an EF <25%,

trocardiogram, and so on) and digoxin levels to

and/or a cardiothoracic ratio >55% (15). Similarly,

corroborate the diagnosis of digoxin toxicity as well as

although there were initially concerns on the basis of

the lack of post-discharge outcomes.

retrospective analyses of the DIG trial that digoxin

in

pre-specified

high-risk

subgroups

Why has the use of digoxin declined precipitously?

might increase mortality in subsets of patients at risk

The safety of digoxin was first challenged in the 1970s

for digoxin toxicity such as women, the elderly, and

on the basis of several retrospective analyses sug-

patients with renal insufficiency, any potential

gesting digoxin therapy might be associated with

detrimental effects on mortality are no longer sig-

increased mortality (6). This prompted the design and

nificant after adjusting for serum digoxin concentra-

conduct of 3 prospective, multicenter, randomized,

tion (SDC) (16–18). In fact, a comprehensive post hoc

double-blinded, placebo-controlled trials: PROVED

analysis including all patients enrolled in the DIG

(Prospective Randomized Study of Ventricular Fail-

main and ancillary trials found that digoxin use

ure and the Efficacy of Digoxin) (7), RADIANCE

among patients with a SDC <1 ng/ml was associated

(Randomized Assessment of [the effect of] Digoxin on

with a robust survival benefit that was consistent

Inhibitors of the Angiotensin-Converting Enzyme)

across age, sex, EF, and comorbid disease states (16).

(8), and the pivotal National Institutes of Health–

As a result, the guidelines have been revised since the

sponsored DIG (Digitalis Investigation Group) (9)

completion of the DIG trial and currently recommend

trials. In aggregate, these landmark studies provide

a lower therapeutic SDC for HF (i.e., <1.0 ng/ml) (3).

a strong evidence basis for the efficacy and safety

More

recently,

the

peer-reviewed

published

of digoxin therapy. In patients with HF with reduced

reports and the popular press have highlighted a

EF, digoxin augments cardiac output (CO) and

number of studies showing potential harm with

reduces pulmonary capillary wedge pressure without

digoxin therapy in both HF and atrial fibrillation.

inducing potentially hazardous increases in heart rate

Notably, 2 independent research teams using differ-

or decreases in blood pressure (10,11). In addition,

ent statistical methods performed secondary analyses

digoxin therapy improves signs and symptoms of HF

of the AFFIRM (Atrial Fibrillation Follow-up Investi-

and functional status (7,8). Similarly, digoxin reduced

gation of Rhythm Management) database and reached

the incidence of all-cause, cardiovascular-related,

diametrically opposed conclusions regarding the

and HF-specific hospitalizations in the DIG trial,

effect of digoxin on mortality (19,20). This highlights

which enrolled 6,800 stable ambulatory HF patients

the inherent limitations of secondary analyses,

with an EF <45% (9). Interestingly, in the DIG ancil-

demonstrating that even with sophisticated statistical

lary trial, which enrolled 988 outpatients with HF

modeling, it may not be possible to comprehensively

with an EF >45%, digoxin use was associated with a

adjust for disease severity and the indication for

trend towards a reduction in hospitalizations for

treatment. In addition, these studies are based on

worsening HF, which approached, but did not reach,

prevalent digoxin use, and substantial differences in

the threshold for significance, perhaps in part due to

clinical characteristics may have emerged in the

the smaller sample size and reduced statistical power

intervening time between drug initiation and data

(12). Although digoxin is known to have a narrow

acquisition. Thus, although existing and future

therapeutic

of

observational datasets may provide useful informa-

digoxin toxicity is low, both in the controlled setting

tion regarding the epidemiology and real-world

of a clinical trial (9) and in the context of everyday

practice patterns with digoxin, definitive conclu-

practice (13,14). For example, in the DIG trial, the

sions regarding its safety based on post hoc analyses

incidence of hospitalization for suspected digoxin

should be interpreted with extreme caution (2).

window,

the

absolute

incidence

toxicity was 2-fold higher in digoxin-treated patients,

In conclusion, there have been no major advances

yet the rate was low overall (i.e., 2.0% vs. 0.9%) (9).

in the pharmacological management of patients

Ambrosy et al.

JACC: HEART FAILURE VOL. 4, NO. 5, 2016 MAY 2016:365–7

Digoxin for Worsening Chronic Heart Failure

hospitalized for worsening chronic HF over the

<1 ng/ml and in certain high-risk groups, digoxin

last 2 decades. These patients remain at high risk

may improve survival. Accordingly, digoxin should

for early readmission or death (21,22). However,

be considered in patients with HF with reduced

digoxin has multiple favorable properties that make it

EF who remain symptomatic despite optimal medical

an ideal therapy for worsening chronic HF (23).

therapy.

Digoxin is the only available inotrope known to increase CO and decrease pulmonary capillary wedge

REPRINT REQUESTS AND CORRESPONDENCE: Dr.

pressure without causing deleterious increases in

Mihai

heart rate or decreases in blood pressure. In addi-

Innovation, Northwestern University Feinberg School

tion, digoxin improves signs and symptoms of HF

of Medicine, 201 East Huron Street, Galter 3-150,

and functional status. Digoxin is known to reduce

Chicago, Illinois 60601. E-mail: m-gheorghiade@

all-cause and HF-specific hospitalizations. At SDCs

northwestern.edu.

Gheorghiade,

Center

for

Cardiovascular

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KEY WORDS digoxin, heart failure, mortality, outcomes, readmissions

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