JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 65, NO. 25, 2015

ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER INC.

ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2015.04.045

Digoxin Use and Subsequent Outcomes Among Patients in a Contemporary Atrial Fibrillation Cohort Larry A. Allen, MD, MHS,* Gregg C. Fonarow, MD,y DaJuanicia N. Simon, MS,z Laine E. Thomas, PHD,z Lucas N. Marzec, MD,* Sean D. Pokorney, MD, MBA,z Bernard J. Gersh, MB, CHB, DPHIL,x Alan S. Go, MD,k Elaine M. Hylek, MD, MPH,{ Peter R. Kowey, MD,# Kenneth W. Mahaffey, MD,** Paul Chang, MD,yy Eric D. Peterson, MD, MPH,z Jonathan P. Piccini, MD, MHS,z for the ORBIT-AF Investigators

ABSTRACT BACKGROUND Although digoxin has long been used to treat atrial fibrillation (AF) and heart failure (HF), its safety remains controversial. OBJECTIVES This study sought to describe digoxin use over time in patients with AF who were stratified by the presence or absence of HF, to characterize the predictors of digoxin use and initiation, and to correlate digoxin use with outcomes. METHODS Longitudinal patterns of digoxin use and its association with a variety of outcomes were assessed in a prospective outpatient registry conducted at 174 U.S. sites with enrollment from June 2010 to August 2011. RESULTS Among 9,619 patients with AF and serial follow-up every 6 months for up to 3 years, 2,267 (23.6%) received digoxin at study enrollment, 681 (7.1%) were initiated on digoxin during follow-up, and 6,671 (69.4%) were never prescribed digoxin. After adjusting for other medications, heart rate was 72.9 beats/min among digoxin users and 71.5 beats/min among nonusers (p < 0.0001). Prevalent digoxin use at registry enrollment was not associated with subsequent onset of symptoms, hospitalization, or mortality (in patients with HF, adjusted hazard ratio [HR] for death: 1.04; without HF, HR: 1.22). Incident digoxin use during follow-up was not associated with subsequent death in patients with HF (propensity adjusted HR: 1.05), but was associated with subsequent death in those without HF (propensity adjusted HR: 1.99). CONCLUSIONS After adjustment for detailed clinical factors, digoxin use in registry patients with AF had a neutral association with outcomes under most circumstances. Because of the multiple conflicting observational reports about digoxin’s safety and possible concerns in specific clinical situations, a large pragmatic trial of digoxin therapy in AF is needed. (J Am Coll Cardiol 2015;65:2691–8) © 2015 by the American College of Cardiology Foundation.

From the *University of Colorado School of Medicine, Aurora, Colorado; yUniversity of California, Los Angeles, California; zDuke Clinical Research Institute, Durham, North Carolina; xMayo Clinic College of Medicine, Rochester, Minnesota; kKaiser Permanente Northern California, Oakland, California; {Boston University School of Medicine, Boston, Massachusetts; #Lankenau Heart Institute and the Jefferson Medical College, Philadelphia, Pennsylvania; **Stanford University School of Medicine, Palo Alto, California; and yyJanssen Scientific Affairs, Raritan, New Jersey. ORBIT-AF is sponsored by Janssen Scientific Affairs, LLC, Raritan, New Jersey. This project was supported in part by funding from the Agency of Healthcare Research and Quality through cooperative agreement number 1U19 HS021092. Dr. Allen is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH) under Award Number K23HL105896. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Dr. Allen has served as a consultant for Amgen, Inc., Janssen Pharmaceuticals, and Novartis. Dr. Fonarow has received research grants or other research support from the NIH and the Agency for Healthcare Research and Quality; has consulted for Novartis, Amgen, Bayer, Gambro, Medtronic, and Janssen Pharmaceuticals; and has received support from the Ahmanson Foundation and the Corday Foundation. Dr. Pokorney has received educational grant support from AstraZeneca; research support from Gilead and Boston Scientific; and modest support from the advisory board of Janssen Pharmaceuticals. Dr. Kowey has been a paid consultant for Johnson & Johnson on multiple projects, including the development of rivaroxaban; has served as a consultant for the American College of Cardiology, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cubist, Eli Lilly, Elsevier, Forest, GlaxoSmithKline, Medtronic, Omthera, Protola Pharma, and

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Digoxin in Atrial Fibrillation: The ORBIT-AF Study

C

ABBREVIATIONS AND ACRONYMS AF = atrial fibrillation CI = confidence interval eGFR = estimated glomerular filtration rate

ardiac glycosides, such as digoxin,

contemporary cohort of patients with AF who were

have been used for decades to treat

stratified by the presence or absence of HF, to char-

patients with atrial fibrillation (AF)

acterize predictors of digoxin use and initiation, and

and those with heart failure (HF) to slow

to clarify the association of digoxin use with heart

atrioventricular nodal conduction and in-

rate, health-related quality of life (HRQOL) measures,

crease cardiac inotropy (1). With the develop-

hospitalization, and survival.

ment of alternative treatments for AF (2) and

EHRA = European Heart

HF (3), as well as concerns about digoxin’s

Rhythm Association

potential

HF = heart failure

proarrhythmic

properties

METHODS

and

long-term effects on cardiac remodeling (4),

We used data from the ORBIT-AF (Outcomes Registry

reduced ejection fraction

prescribing digoxin has decreased and is no

for Better Informed Treatment of Atrial Fibrillation)

HR = hazard ratio

longer recommended as first-line therapy

study to assess the use of digoxin and its association

for either disease (3,5). However, there

with outcomes. Details of the ORBIT-AF study design

quality of life

remain unmet needs for the treatment of

have been published previously (17). Briefly, ORBIT-

LVEF = left ventricular ejection

many subgroups of AF patients, including

AF was a U.S.-based, prospective outpatient registry

fraction

those with HF, which has prompted calls

of AF conducted at 176 sites nationwide. The Duke

OR = odds ratio

for renewed use of digoxin in certain clinical

Clinical Research Institute was responsible for ORBIT-

situations (6).

AF site selection and study management. Eligible

HFrEF = heart failure with

HRQOL = health-related

SEE PAGE 2699

patients were 18 years of age and older with electrocardiographically confirmed AF. Enrolling providers

Effectiveness and safety data for digoxin are rela-

included cardiologists, electrophysiologists, and pri-

tively limited. The only large randomized trial of

mary care providers. Site personnel entered infor-

digoxin, the DIG (Digitalis Investigation Group) trial,

mation

showed no effect on mortality, but digoxin did reduce

history, cardiovascular risk factors, AF management

hospitalization among patients with heart failure and

strategy, cardiac imaging, and provider characteris-

a reduced ejection fraction (HFrEF) (7). This trial only

tics into a standardized, web-based collection form.

enrolled patients in sinus rhythm, was conducted

The presence or absence of HF and New York Heart

between 1991 and 1993, and raised safety concerns at

Association (NYHA) functional class were determined

higher serum concentrations and in certain sub-

at baseline by medical record review. Following initial

groups, including women (8–10). A more recent

enrollment, longitudinal information was collected

observational analysis of patients with incident

during clinic visits at approximately 6-month intervals

HFrEF under routine care found that digoxin use was

for up to 36 months, and included information on

independently associated with higher mortality (11).

medication regimens, procedures, hospitalizations,

There are currently no large randomized trials of

quality of life, and vital status. We excluded patients

digoxin in patients with AF. Two post-hoc non-

who were missing information as to whether they were

randomized analyses of data from the large AFFIRM

taking digoxin. Written informed consent was ob-

(Atrial Fibrillation Follow-up Investigation of Rhythm

tained from all study participants. The Duke Institu-

Management) trial came to conflicting conclusions

tional Review Board approved the ORBIT-AF Registry;

(12,13). Post-hoc analysis of other AF trials have

all participating sites obtained approval from local

shown higher mortality associated with digoxin use

institutional review boards before entering patient

(14), as have real-world data from a large incident AF

data.

cohort from the Veterans Administration (15) and 2 large health maintenance organizations (16).

on

demographic

characteristics,

medical

Medication use was collected prospectively at each study visit, including a field specific for

Due to limited and conflicting data, we set out

digoxin. Dose and blood levels were not collected.

to describe digoxin use over time among a large

The follow-up visit date at which digoxin was

Spring Publishing; and has received research grants from Medtronic and St. Jude Medical. Dr. Peterson has received research funding from Janssen Pharmaceuticals, Sanofi, Genentech, Daiichi-Sankyo, Eli Lilly, and AstraZeneca; and has served as a consultant for Boehringer Ingelheim, AstraZeneca, and Janssen Pharmaceuticals. Dr. Piccini has received research grants from ARCA biopharma, Boston Scientific, Gilead, Janssen Pharmaceuticals, ResMed, St. Jude Medical; and has served as a consultant for Bayer, ChanRx, Johnson & Johnson, Medtronic, and Spectranetics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Listen to this manuscript’s audio summary by JACC Editor-in-Chief Dr. Valentin Fuster. Manuscript received January 10, 2015; revised manuscript received March 31, 2015, accepted April 14, 2015.

Allen et al.

JACC VOL. 65, NO. 25, 2015 JUNE 30, 2015:2691–8

Digoxin in Atrial Fibrillation: The ORBIT-AF Study

first reported was defined as the time period of

estimated by the model predicted heart rate, with and

initiation.

without digoxin, with the adjustment variables set

The primary outcome of interest was all-cause

equal to their population average.

death. Additional outcomes of interest included heart

Associations between prevalent digoxin use at

rate, symptoms, HRQOL, all-cause hospitalization, and

baseline and subsequent all-cause death, all-cause

the composite of all-cause hospitalization and death.

hospitalization, cardiovascular hospitalization, and

Symptoms were measured using the European Heart

onset of symptoms were assessed in unadjusted and

Rhythm Association (EHRA) score of AF-related

adjusted analysis. According to the pre-specified

symptoms (18). HRQOL was assessed by the Atrial

analysis plan, primary analyses were stratified a pri-

Fibrillation Effect on Quality-of-Life questionnaire

ori by the presence or absence of HF. Time to first

in a subset of patients at baseline, and at 12 and

reported symptoms was measured at 6-month visit

24 months (19).

intervals, and a discrete time Cox model was used for

STATISTICAL

ANALYSIS. Characteristics

between

this outcome only; otherwise, exact event dates were

patients were described as frequency and percent for

used. The potential for clustering of patient outcomes

categorical

(interquartile

within a site was handled by adding a random effect

ranges) for continuous variables. The characteristics

for site (multivariable Cox frailty model). Models

were compared using the chi-square test for cate-

were adjusted for all covariates listed in Online

variables

and

median

gorical variables and the Wilcoxon rank sum test for

Table 3, which were determined to have: 1) partic-

continuous variables. The cohort was divided into

ular clinical relevance, determined a priori; or 2) a

those taking digoxin at study enrollment (prevalent

statistically significant association with any of the

use), those initiated on digoxin during follow-up

outcomes under evaluation, as previously identified

(incident use), and those not on digoxin at any time

by backward selection with stay criteria of 0.05. The

during the study. Characteristics among the groups

same set of covariates was used for adjustment of all

were compared using Pearson chi-square tests for

outcomes. Adjusted associations for outcomes were

categorical variables and Wilcoxon rank sum tests for

displayed as HRs (95% CI).

continuous variables.

Associations between incident digoxin use in

To examine factors associated with prevalent

follow-up and subsequent all-cause death, all-cause

digoxin use, a multivariable hierarchical logistic

hospitalization, and cardiovascular hospitalization

regression model was constructed using backward

were assessed through propensity score matching

selection for the binary outcome of digoxin use at

between patients initiated on digoxin at follow-up. It

baseline (see the covariates in Online Table 1 [54 pre-

was unusual to have subsequent follow-up in subjects

specified clinical and demographic characteristics

who initiated digoxin at the final follow-up period

and a random effect for the enrolling site] followed by

(30 to 36 months); therefore, digoxin initiation was

the inclusion criterion of p < 0.05 final model cova-

restricted to occur between 6 and 24 months. Anal-

riates in Online Table 2a). Prevalent digoxin users at

yses were conducted separately for patients with and

baseline were excluded from this model. Because

without HF. Each case (incident digoxin use) was

digoxin use was measured at 6-month visit intervals, a

matched to 3 control subjects (noninitiators) using

second multivariable, discrete time Cox frailty model

sequential stratification matching (20), which identi-

was constructed for the time to the first report of

fied matches from the same point in follow-up at

digoxin initiation (final model covariates in Online

which digoxin was initiated and used all available

Table 2b). Patients were censored from the risk set

covariate information up to that point (including HF

when they were lost to follow-up (mainly due to stag-

status). The criteria for matching was a single pro-

gered entry into the cohort). A third discrete time Cox

pensity score, obtained from a logistic regression

frailty model was constructed for digoxin discontinu-

model for digoxin initiation. Matching was conducted

ation among prevalent digoxin users (final model

sequentially, starting at 6 months and moving for-

covariates in Online Table 2c). Results were presented

ward through follow-up. At each visit, patients who

as odds ratios (ORs) and/or hazard ratios (HRs) with

initiated digoxin were matched to other subjects

corresponding 95% confidence intervals (CIs) and

who were still under follow-up at the same time, but

p values.

who had not yet started digoxin. The criteria for

Baseline heart rate was compared for baseline

identifying a match was “closeness” on a single pro-

digoxin use using a linear regression model that

pensity score value calculated at each visit. To be

accounted for other rate control medications (i.e.,

considered a match, patients had to have a difference

beta-blockers, verapamil, diltiazem, sotalol, and

in propensities no greater than a caliper of 20% of a

amiodarone). The adjusted mean heart rate was

SD. Standardized differences were used to evaluate

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JACC VOL. 65, NO. 25, 2015 JUNE 30, 2015:2691–8

Digoxin in Atrial Fibrillation: The ORBIT-AF Study

the success of propensity matching at achieving bal-

compared with 32.6% of patients who never received

ance. Outcomes assessment began immediately after

digoxin.

the time period of initiation, and the model was fit

Factors independently associated with digoxin use

using stratified Cox regression, stratified on the

at baseline included the following: rate control

matched pair (21).

strategy and absence of previous ablation; permanent

Pre-defined secondary analyses were performed

AF; worse HF functional class and LVEF; sinus node

in patient subgroups with renal function (esti-

dysfunction; larger left atria; lower diastolic blood

mated glomerular filtration rate [eGFR]

Digoxin Use and Subsequent Outcomes Among Patients in a Contemporary Atrial Fibrillation Cohort.

Although digoxin has long been used to treat atrial fibrillation (AF) and heart failure (HF), its safety remains controversial...
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