Author + information
- Received October 19, 2015
- Revision received December 4, 2015
- Accepted December 10, 2015
- Published online May 1, 2016.
- Nish Patel, MDa,c,
- Christine Ju, MSb,
- Conrad Macon, MDa,
- Udho Thadani, MDc,
- Phillip J. Schulte, PhDb,
- Adrian F. Hernandez, MDb,
- Deepak L. Bhatt, MD, MPHd,
- Javed Butler, MD, MPH, MBAe,
- Clyde W. Yancy, MDf and
- Gregg C. Fonarow, MDg,∗ ()
- aDivision of Cardiology, University of Miami Miller School of Medicine, Miami, Florida
- bDuke Clinical Research Institute, Durham, North Carolina
- cDivision of Cardiology, University of Oklahoma Health Sciences Center and VA Medical Center, Oklahoma City, Oklahoma
- dDivision of Cardiology, Brigham and Woman’s Hospital Heart & Vascular Center and Harvard Medical School, Boston, Massachusetts
- eDivision of Cardiology, Stony Brook School of Medicine, Stony Brook, New York
- fDivision of Cardiology, Northwestern Feinberg School of Medicine, Chicago, Illinois
- gDivision of Cardiology, Ronald Reagan-UCLA Medical Center, Los Angeles, California
- ↵∗Reprint requests and correspondence:
Dr. Gregg C. Fonarow, Ahmanson-UCLA Cardiomyopathy Center, Ronald Reagan UCLA Medical Center, 10833 LeConte Avenue, Room 47-123 CHS, Los Angeles, California 90095-1679.
Objectives The aim of this study was to assess temporal trends and factors associated with digoxin use at discharge among patients admitted with heart failure (HF).
Background Digoxin has class IIa recommendations for treating HF with reduced ejection fraction (HFrEF) in the United States. Digoxin use, temporal trends, and clinical characteristics of HF patients in current clinical practice in the United States have not been well studied.
Methods An observational analysis of 255,901 patients hospitalized with HF (117,761 with HFrEF and 138,140 with preserved EF [HFpEF]) from 398 hospitals participating in the Get With The Guidelines–HF registry between January 2005 and June 2014 was conducted to assess the temporal trends and factors associated with digoxin use.
Results Among 117,761 HFrEF patients, only 19.7% received digoxin at discharge. Digoxin prescriptions decreased from 33.1% in 2005 to 10.7% in 2014 (ptrend < 0.0001). Factors associated with digoxin use in HFrEF included atrial fibrillation (AF) (odds ratio [OR]: 2.14; 95% confidence intervals [CI]: 2.02 to 2.28), history of implantable cardioverter defibrillator use (OR: 1.39; 95% CI: 1.32 to 1.46), chronic obstructive pulmonary disease (OR: 1.13, 95% CI: 1.08 to 1.18), diabetes mellitus (OR: 1.10, 95% CI: 1.06 to 1.14), younger age (OR: 0.96, 95% CI: 0.95 to 0.97), lower blood pressure (OR: 0.96, 95% CI: 0.96 to 0.97), and having no history of renal insufficiency (OR: 0.91, 95% CI: 0.85 to 0.97). Use of digoxin in patients with HFpEF (n = 138,140) without AF was 9.8% in 2005, which decreased to 2.2% in 2014 (ptrend < 0.0001).
Conclusions One in 5 HFrEF patients received digoxin at discharge, with a significant downward temporal trend in use over the study period. Use of digoxin in HFpEF patients without AF was very low and decreased over the study period.
Heart failure (HF) accounts for approximately 1 million admissions as a primary diagnosis each year in the United States (1). Moreover, the readmission rate approaches almost 30% at 90 days (2). Therefore, currently, there is a major focus on reducing HF hospital readmission. The Digitalis Investigator Group (DIG), a large randomized, placebo-controlled trial in patients with HF, showed that digoxin significantly reduced hospitalizations for HF, but it also had no impact on all-cause or cardiovascular mortality (3). Moreover, the DIG pre-specified high-risk subgroup analysis demonstrated that at a 2-year follow up, there was a reduction in all-cause mortality or hospitalization and HF-related mortality for patients with New York Heart Association functional class III/IV symptoms, with left ventricular ejection fractions <25%, and with a cardiothoracic ratio >55% on chest x-rays (4). However, observational studies and post hoc analysis of other subgroups of the DIG trial have reported adverse effects of digoxin on mortality in patients with atrial fibrillation (AF) and those with HF (5–9). Currently, the American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Failure Society of America recommend the use of digoxin, which could be beneficial in patients with current or previous symptoms of HF and reduced left ventricular ejection fraction (HFrEF) to decrease hospitalization for HF (Class IIa; Level of Evidence: B) (10), whereas the European Society of Cardiology (ESC) gives class IIb recommendation for use of digoxin in HFrEF to decrease HF hospitalizations (11).
Despite the reported beneficial effects of digoxin on HF hospitalizations in the prospective placebo-controlled randomized DIG trial and worsening of symptoms after digoxin withdrawal, some studies have reported that digoxin use has progressively declined (5,12). It is now unclear how the current literature, guidelines, and modern medical therapy have affected the current use of digoxin in patients with HF. Therefore, the goal of this study is to characterize the use of digoxin over the past 10 years among patients hospitalized with HF in the United States. The study also aimed to evaluate the association between different characteristics of patients hospitalized with HFrEF and discharged on digoxin. Changes in the use of digoxin over the past 10 years among patients with HFrEF and in patients with HFpEF were also analyzed, with further comparison of those patients with and without AF.
The American Heart Association’s Get With The Guidelines (GWTG) program is a hospital-based continuous quality improvement program that collects data from participating centers that evaluate the adherence guidelines on stroke, coronary artery disease, and HF. The GWTG-HF registry has been prospectively collecting data from participating centers since 2005. The program enrolls patients who are either admitted with new or decompensated HF or those with new heart HF symptoms during hospitalization, in whom HF is the primary discharge diagnosis. Participating centers submit data on consecutive eligible patients. In participating centers, health care workers are trained to input variables using standardized definitions. Health care information on baseline characteristics, discharge characteristics, medications, medical history, laboratory values, and outcomes at discharge are input into the database. Race/ethnicity is self-reported by the individual patients at registration and not determined by health care personnel.
All of this information is submitted using the GWTG-HF Patient Management Tool (Outcomes Sciences Inc., Cambridge, Massachusetts), which is an internet-based patient management tool. This system performs monitoring for completeness of input information. Only those participating centers with >95% completeness are included in subsequent analyses. All participating institutions had implementation of the GWTG-HF program approved by their institutional review boards. Because this is a quality improvement trial, a waiver for informed consent was granted. The data coordinating center was Outcome Sciences. All data were de-identified, and analysis was performed by the Duke Clinical Research Institute (Durham, North Carolina).
Between January 1, 2005, and June 30, 2014, 282,090 patients were hospitalized with a discharge diagnosis of HF in a total of 403 centers and were enrolled into the GWTG-HF database, and detailed clinical data were prospectively collected. Patients who did not have sex recorded and centers in which <25% of patients had medical history entered in the database were not included in the aforementioned numbers. Patients missing information on digoxin at discharge (n = 14,157), ejection fraction (n = 9,404), and patients who died in-hospital, had discharge status missing, not documented, or left against medical advice (n = 2,628) were excluded. This left 255,901 patients who met the inclusion and exclusion criteria (HFrEF: n = 117,761 [46.0%]; HFpEF: n = 138,140 [54.0%]) (Figure 1). Of the HFrEF patients without a missing medical history, 79,703 (69.6%) did not have a medical history of AF and 34,890 (30.5%) had a history of AF. Of the patients with HFpEF who had a medical history documented, 83,288 (61.8%) did not have a history of AF and 51,593 (38.3%) had a history of AF.
Primary measures and definitions
The primary measure of interest was the prescription rate of digoxin in HFrEF patients at discharge. We also assessed the factors associated with digoxin use and temporal trends in the use of digoxin from 2005 to 2014. In addition, the trend of digoxin use in patients with HFpEF was also analyzed.
We also performed an analysis in which in-hospital deaths were not excluded and rates of in-hospital deaths were analyzed among HFrEF patients with or without digoxin use on admission.
Patient characteristics (demographics, medical history, medications before admission, vital signs, and laboratory data) and hospital characteristics were summarized by mean ± SD, median and 25th and 75th percentiles, and count and percentages, for continuous and categorical data, respectively. Characteristics were compared by absolute standardized differences. Cochran-Armitage tests were used to test the trend of digoxin use at discharge across time. Trends of digoxin use were examined for the following subgroups of interest: age above and below the median; sex; race/ethnicity; different geographic region; patients with HF with HFpEF; and patients with and without AF. A multivariable logistic regression model with a generalized estimating equations approach to account for in-hospital clustering was used to examine the association between factors and discharge digoxin use. Patient covariates included in the model were the following: age, sex, race/ethnicity, and insurance; medical history, including smoking, renal insufficiency, peripheral vascular disease, percutaneous coronary intervention, myocardial infarction, hyperlipidemia, implantable cardioverter defibrillator (ICD) or pacemaker, hypertension, diabetes, cerebrovascular accident/transient ischemic attack, chronic obstructive pulmonary disease (COPD), coronary artery bypass graft (CABG), anemia, AF and/or atrial flutter, and ischemic history; vital signs, including systolic blood pressure and heart rate; laboratory tests, including sodium, serum creatinine, ejection fraction, and troponin (abnormal vs. normal). Hospital characteristics included region, teaching status, rural location, number of beds, and percutaneous coronary intervention, CABG, or capable of transplantation. Calendar time, in quarters, was included as a covariate to account for changes over time. If a patient had an unknown medical history status, it was imputed to “no,” because we assumed the field was not filled out when none was applied. Race/ethnicity was based on a two-level variable (non-white vs. white), and missing data were imputed to the most frequent category (white). Multiple imputation, with 25 imputed datasets generated based on fully conditional specification methods, was used to impute all other patient level covariates. Missing hospital characteristics were not imputed, and patients without these data were excluded from the multivariable model (11% of sample). The final presented estimates were based on the combined results over the 25 imputations. Linear associations between continuous factors and digoxin at discharge were assessed, and linear spline transformations were applied if needed. Data were analyzed using SAS version 9.4 (SAS Institute, Cary, North Carolina).
Of the 117,761 patients with HFrEF, 23,237 (19.7%) were prescribed digoxin at discharge. Baseline patient and hospital characteristics overall and stratified by prescription of digoxin at the time of discharge are shown in Table 1. Overall, 19.4% of HFrEF patients received digoxin before admission; 61.2% of those discharged on digoxin received digoxin before admission, whereas 6.3% of those discharged without digoxin received digoxin before admission. Medical history associated with use of digoxin at discharge was AF, having an ICD, and lower brain natriuretic peptide. In contrast, renal insufficiency (serum creatinine >2.0 mg/dl), being on dialysis, and higher blood pressure were less frequently associated with digoxin use at discharge. Concomitant medications at baseline associated with increased use of digoxin at discharge were angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blockers, aldosterone antagonists, and diuretics. The only hospital characteristic with a significant difference between those who were discharged with and without digoxin was the hospital’s region. Hospitals in the South and Midwest used digoxin more, whereas those in the Northeast and West used it less (Table 1).
Table 2 provides GWTG-HF performance measures and quality measures stratified by digoxin use at discharge. Compared with patients not discharged on digoxin, patients discharged on digoxin tended to be discharged with anticoagulation for AF, an aldosterone antagonist, had a cardiac resynchronization therapy defibrillator or a cardiac resynchronization therapy pacemaker placed or prescribed at discharge, and had ICD counseling or ICD placed or prescribed at discharge. However, patients not discharged on digoxin tended to be given a discharge appointment for HF, given influenza vaccine, or given a pneumococcal vaccine compared with patients discharged on digoxin. Table 3 lists the independent patient and hospital characteristics associated with digoxin prescription. After adjustment, digoxin at discharge was associated with younger age, diabetes mellitus, COPD, AF, and higher heart rate. Patients with HFrEF admitted on digoxin with digoxin discontinued before or at discharge compared with patients who continued digoxin were more likely to be older, on dialysis, and with renal insufficiency (Online Table 1).
Digoxin prescription decreased among HFrEF patients from 33.1% in 2005 to 10.7% in 2014 (p < 0.0001) (Table 4). This trend was significant among all age groups, sex, race/ethnicity, different geographic region, and with or without medical history of AF (Figures 2 and 3). Characteristics of patients with HFrEF with and without AF stratified by digoxin use at discharge are shown in Online Tables 2 and 3, respectively. Of note, the rate of digoxin use on admission was similar between HFrEF patients discharged alive and those with in-hospital mortality (19.4% and 19.2%, respectively), and there was no significant difference in in-hospital mortality among HFrEF patients with or without digoxin use on admission (2.8% vs. 2.9%; odds ratio: 0.91, 95% confidence interval: 0.80 to 1.03; p = 0.13).
Among patients with HFpEF, use of digoxin at hospital discharge was 9.5% and significantly less than that compared with patients with HFrEF (p < 0.0001). Characteristics of HFpEF patients with and without digoxin use at discharge are shown in Online Table 4. Use of digoxin in patients with HFpEF was 16.0% in 2005, which decreased to 5.7% in 2014 (p < 0.0001). Among patients with HFpEF, the use of digoxin differed by the presence or absence of AF. Among patients with HFpEF and a medical history of AF, digoxin use was 27.5% in 2005, which decreased to 10.6% in 2014 (p < 0.0001). Its use in HFpEF without AF was infrequent; only 9.8% in 2005, which decreased to 2.2% in 2014 (p < 0.0001).
This study evaluated the trends in digoxin use over the past 10 years in a large hospital based database of 117,761 patients hospitalized with HFrEF and 138,140 patients hospitalized with HFpEF. The most remarkable finding of this study was the rapid decrease in digoxin use in patients with HFrEF over the past 10 years. There was a 68% relative and 22% point absolute decrease in the prescription of digoxin at hospital discharge over a 10-year period, between 2005 and 2014, and this decrease was significant among all groups evaluated in this study. Although use of digoxin was significantly lower among patients with HFpEF, there was also a substantial decrease over time in use.
The DIG trial was a large randomized clinical trial with 6,800 study participants with systolic HF in sinus rhythm that evaluated the effect of digoxin versus placebo in an outpatient setting using hard clinical endpoints (3). The study demonstrated a statistically significant reduction in incidence of hospitalization for HF with digoxin, but it did not show any difference in mortality (3). It is noteworthy that the DIG trial was conducted before beta-blockers were proved to reduce mortality and morbidity in HF. However, most patients enrolled in outcome trials of beta-blockers received digoxin. Moreover, small, randomized, placebo-controlled withdrawal trials in patients with HFrEF showed that exercise performance decreased when digoxin was withdrawn, whether the patients were on angiotensin-converting enzyme inhibitors or not (13). In addition, a meta-analysis that evaluated the use of digoxin in 13 randomized clinical trials in subjects with systolic HF in sinus rhythm showed no effect on long-term mortality, but these trials again demonstrated a significant reduction in clinical symptoms and incidence of hospitalizations (14). A more modern but retrospective observational study demonstrated a decrease in re-admission in subjects with decompensated systolic HF when they were discharged with a prescription for digoxin (15).
Despite this positive impact on HF re-hospitalization, several observational studies have shown decreased use of digoxin in patients with HFrEF. A study from the ADHERE (Acute Decompensated Heart Failure National Registry) trial showed a reduction in digoxin use from 51% in the first quarter of 2002 to 38% in last quarter of 2004 (16). A study from the Veteran Affairs health system database demonstrated a 58% decrease in use of digoxin between 2002 and 2011 in the treatment of AF (17). Another study that evaluated pharmacotherapy in AF demonstrated a drop in use of digoxin for rate control of 41% from 1999 to 2003 (18). A Canadian study that evaluated pharmacotherapy in AF demonstrated similar findings of a decrease in prescription of digoxin from 53.4% in 1998 to 26.2% in 2006 (12). Although the indication for use of digoxin in some of these studies was different from that in our study, they all showed a generalized decrease in the overall use of digoxin.
In 2002, a post hoc analysis of the DIG trial was published, suggesting that among women, digoxin use was associated with increased all-cause mortality (9). More recently, there have been several observational studies that have shown increased mortality with the use of digoxin. An analysis of the TREAT-AF (Retrospective Evaluation and Assessment of Therapies in AF) study showed that digoxin use was independently associated with increased mortality (5). Another retrospective analysis of the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) study also showed an increase in mortality with digoxin use (19). A retrospective cohort study that evaluated the use of digoxin in those with systolic HF from the Kaiser Permanente health care system also showed an increased mortality associated with the use of digoxin (8). Although these observational studies are concerning, there has not been a randomized clinical trial that has shown increased mortality in the overall enrolled population with the use of digoxin. However, these studies have undoubtedly caused concerns over digoxin for prescribing physicians, contributing to its declining use. Moreover, relatively weak recommendation in AHA/ACC and ECS Guidelines, along with the little attention that digoxin use has received at major scientific meetings, which often emphasize newer medications and devices, may also have contributed to a declining use of digoxin to treat HFrEF.
In our study, we also identified several factors associated with digoxin use in multivariable analysis. ICD or pacemaker use, AF, low ejection fraction, COPD, normal renal function, and diabetes mellitus were associated with the use of digoxin. In contrast, older age, renal insufficiency, hypertension, smoking, ischemic cardiomyopathy, and anemia were associated with a decreased use of digoxin. These findings suggest cautious use of digoxin with avoidance of digoxin in patient populations who are more susceptible to digoxin toxicity and using digoxin in patient populations who may potentially benefit the most.
Several limitations of our study merit consideration. GWTG-HF is a voluntary registry, and despite having a broad array of hospitals participating from all parts of the country, these findings may not be generalizable to patients and hospitals that are not represented. Residual measured and unmeasured confounding may affect some of these findings. Moreover, there is the possibility of false positive findings caused by multiple comparisons. Because the GWTG-HF registry captures only in-hospital data, we could not determine what proportions of patients were subsequently prescribed digoxin as an outpatient. A proportion of patients not treated with digoxin may have had undocumented contraindications, intolerances, or drug interactions. The database does not track serum digoxin level and toxicity associated with its use, which could have influenced clinical decision-making. Data collection was dependent on the accuracy and completeness of data abstraction from medical chart review.
In conclusion, among patients hospitalized with HF from 2005 to 2014 in U.S. hospitals participating in GWTG-HF, the use of digoxin at hospital discharge decreased progressively. These reductions in use were observed in patients with HFrEF and HFpEF, who were with and without AF. Randomized, placebo-controlled outcome trials will be necessary to address whether digoxin provides incremental benefit to contemporary guideline-directed medical therapies to assess whether this declining use is appropriate and enhancing patient safety, or whether it may be depriving patients with HFrEF of an important medication to reduce HF hospitalizations and improve quality of life.
COMPETENCY IN PRACTICE-BASED LEARNING: The AHA/ACC and the Heart Failure Society of America recommend that use of digoxin can be beneficial in patients with current or previous symptoms of HF and HFrEF to decrease hospitalization for HF (class IIa; Level of Evidence: B).
COMPETENCY IN MEDICAL KNOWLEDGE: There is a significant downward temporal trend in the use of digoxin in patients with HFrEF over the past decade.
TRANSLATIONAL OUTLOOK: Randomized, sufficiently powered, placebo-controlled outcome trials are necessary to address whether digoxin provides incremental benefit to contemporary guideline-directed medical therapies to assess whether this declining use is appropriate and enhancing patient safety, or whether it may be depriving patients with HFrEF of an important medication to reduce HF hospitalizations and improve quality of life.
The Get With The Guidelines–Heart Failure (GWTG-HF) program is provided by the American Heart Association. GWTG-HF is sponsored, in part, by Amgen Cardiovascular and has been funded in the past through support from Medtronic, GlaxoSmithKline, Ortho-McNeil, and the American Heart Association Pharmaceutical Roundtable.
Dr. Hernandez has received honoraria from Amgen, Gilead, Janssen, Merck & Co., Inc., and Novartis; and research funding from Amgen, AstraZeneca, BMS, GlaxoSmithKline, Janssen, Novartis, and Portola; Dr. Bhatt is a member of the Advisory Board for Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; a member of the Board of Directors for Boston VA Research Institute, Society of Cardiovascular Patient Care; is the Past Chair of the American Heart Association Get With The Guidelines Steering Committee; a member of the Data Monitoring Committees for Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, and the Population Health Research Institute; has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), and WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor); has received research funding from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi Aventis, and The Medicines Company; has been a site co-investigator for Biotronik, St. Jude Medical; has been a trustee for American College of Cardiology; and has performed unfunded research for FlowCo, PLx Pharma, and Takeda; Dr. Butler has received honoraria from Travena Inc., and Takeda and research funding from the National Institute of Health; Dr. Yancy has received research funding from the Patient Centered Outcomes Research Institute; Dr. Fonarow has received honoraria from Amgen, Boston Scientific, Johnson & Johnson, The Medicines Company, Medtronic, Novartis, and Takeda; has received research funding from Gambro, Medtronic, the National Heart, Lung, and Blood Institute, and the National Institute of Health/ National Institute of Allergy and Infectious Diseases; and has been a consultant for Medtronic, Novartis, Amgen, and Janssen. The other authors have reported that they have no relationships relevant to the discussion of this paper to disclose.
- Abbreviations and Acronyms
- American College of Cardiology
- atrial fibrillation
- American Heart Association
- chronic obstructive pulmonary disease
- European Society of Cardiology
- Get With The Guideline
- heart failure
- heart failure with preserved ejection fraction
- heart failure with reduced ejection fraction
- implantable cardioverter defibrillator
- Received October 19, 2015.
- Revision received December 4, 2015.
- Accepted December 10, 2015.
- American College of Cardiology Foundation
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