- Email: [email protected]
Digoxin Toxicity and Use of Digoxin Immune Fab
JACC: HEART FAILURE
VOL.
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
-, NO. -, 2016
ISSN 2213-1779/$36.00
PUBLISHED BY ELSEVIER
http://dx.doi.org/10.1016/j.jchf.2016.01.011
Digoxin Toxicity and Use of Digoxin Immune Fab Insights From a National Hospital Database Paul J. Hauptman, MD,a Steven W. Blume, MS,b Eldrin F. Lewis, MD, MPH,c Suzanne Ward, PHARMD, MBAd
ABSTRACT OBJECTIVES This study was developed to determine contemporary management of digoxin toxicity and clinical outcomes. BACKGROUND Although the use of digoxin in heart failure management has declined, toxicity remains a prevalent complication. METHODS The Premier Perspective Comparative Hospital Database (Premier Inc., Charlotte, North Carolina) was used to retrospectively identify patients diagnosed with digoxin toxicity and/or who received digoxin immune fab (DIF) over a 5-year period (20072011). DIF was evaluated using treatment date, number of vials administered, and total cost. Clinical outcomes included length of stay (total hospitalization; days after DIF), cost of hospitalization, and in-hospital mortality. Exploratory multivariate analyses were conducted to determine predictors of DIF and effect on length of stay, adjusting for patient characteristics and selection bias. RESULTS Digoxin toxicity diagnosis without DIF treatment accounted for 19,543 cases; 5,004 patients received DIF of whom 3086 had a diagnosis of toxicity. Most patients were >65 years old (88%). The predictors of DIF use were urgent/emergent admission, hyperkalemia, arrhythmia associated with digoxin toxicity, acute renal failure, or suicidal intent (odds ratios 1.7, 2.4, 3.6, 2.1, 3.7, respectively; p < 0.0001 for all). The majority (78%) of DIF was administered on days 1 and 2 of the hospitalization; 10% received treatment after day 7. Digoxin was used after DIF administration in 14% of cases. Among patients who received DIF within 2 days of admission, there was no difference for in-hospital mortality or length of stay compared with patients not receiving DIF. CONCLUSIONS Digoxin toxicity diagnoses are clustered in the elderly. One-fifth of cases receive treatment with DIF, most within 2 days of admission. Opportunities exist for improved diagnosis and post-DIF management. Prospective data may be required to assess the impact of DIF on length of stay. (J Am Coll Cardiol HF 2016;-:-–-) © 2016 by the American College of Cardiology Foundation.
D
igoxin remains a therapeutic intervention in
relevant largely as a consequence of the drug’s narrow
both atrial fibrillation and heart failure (HF),
therapeutic window (3,4). The risk factors for digoxin
as described in current clinical practice
toxicity have been amply described (5) and include
guidelines (1,2). Although digoxin use has declined in
advanced patient age (6), renal failure (7), metabolic
HF and meta-analyses have raised questions about
disorders, and drug interactions (8). However, little
efficacy in atrial fibrillation, toxicity remains clinically
is known about hospitalizations related to toxicity
From the aDepartment of Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri; bEvidera, Bethesda, Maryland; cDepartment of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, Massachusetts; and dBTG International Inc., Brentwood, Tennessee. BTG purchased the Premier Perspective hospital database and commissioned Evidera for the data analysis. Mr. Blume was an employee of Evidera at the time of this study, which provides research services to pharmaceutical and device manufacturers; in his salaried position, he worked with a variety of organizations and was precluded from receiving payment or honoraria directly from these organizations. Ms. Ward is Scientific Director for BTG International Inc. Drs. Hauptman and Lewis were unpaid consultants and have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received October 1, 2015; revised manuscript received January 22, 2016, accepted January 25, 2016.
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Use of Digoxin Immune Fab in Digoxin Toxicity
ABBREVIATIONS
including contemporary management and
discharge, or secondary diagnosis) with code 972.1
AND ACRONYMS
resource utilization. Since 1986, antidotal
(poisoning by cardiotonic glycosides and drugs
therapy has been available; however, its use
of similar action—digitalis glycosides, digoxin,
has only been indirectly quantified (9–11).
strophanthins) or code E942.1 (causing adverse
Therefore, the primary objectives of the study
effects in therapeutic use, cardiotonic glycosides,
were to describe patient characteristics, hos-
and drugs of similar action—digitalis glycosides,
pital utilization, and outcomes of patients
digoxin, strophanthins).
APR-DRG = All Patients Refined Disease-Related Group
DIF = digoxin immune fab Dx = coded diagnosis of digoxin toxicity
with digoxin toxicity, and to compare patients
ICD-9-CM = International Classification of Diseases-Ninth
treated with and without digoxin immune
Revision-Clinical Modification
fab (DIF).
hospitalization
HF = heart failure OR = odds ratio
If an individual patient had more than 1 inpatient hospitalization fulfilling either criterion, the earliest was
selected.
Exclusion
criteria
included patient visits for use of DIF for reasons other
METHODS
than digoxin toxicity, including any diagnosis indiA retrospective cohort design was followed using the
cating possible severe pre-eclampsia or a related
Premier Perspective Comparative Hospital Database
diagnosis (ICD-9-CM code 642.x).
(Premier Inc., Charlotte, North Carolina) for the
Patients were assigned to 1 of 2 cohorts, depending
5-year period from 2007 to 2011 (excluding quarter 4).
on their exposure to DIF. The day of exposure to DIF
Premier collects data voluntarily submitted from
and the presence of a diagnosis of digoxin toxicity
more than 450 hospitals including detailed informa-
were also noted to define possible subgroup analyses
tion about day-of-service resource use. Hospital
or covariates.
region, patient, and payer distributions compare well
The following variables were obtained: patient
to national statistics, although they tend to include
demographics (age, gender, race); evidence of acute
larger hospitals (68% of discharges recorded in Pre-
ingestion (e.g., any diagnosis of suicidal intent); prin-
mier are provided by hospitals with more than 300
cipal (discharge) diagnosis (1 per patient; e.g., digoxin
beds, compared to 37% nationally; [12]). The database
toxicity,
contains the data elements available in most hospital
kalemia); admission diagnosis (reliably populated in
or payer datasets including patient demographics,
2009 and after); secondary diagnoses; admission type
marital status, gender, race, diagnosis and procedure
(emergency, urgent, elective); hospital characteris-
codes, length of stay, total cost of inpatient care, and
tics (bed size, teaching status, rural vs. suburban/
a date-stamped log of all billed items, including
urban location and region); admitting physician
medications, laboratory, and diagnostic and thera-
specialty; and month/year of discharge. In addition,
peutic services at the individual patient level.
the APR-DRG group (All Patients Refined Disease-
Member hospitals benchmark their clinical and
arrhythmias,
HF,
renal
failure,
hyper-
Related Group) (3M Health Information Systems,
The
Salt Lake City, Utah) was recorded. APR-DRGs are
underlying data undergo quality checks, and cost
similar to Medicare DRGs, classifying patients to
information is reconciled with the hospitals’ finan-
predict intensity of resource use based on diagnosis
cial statements. The Premier data are subsequently
and key surgical procedure codes but enhanced to
de-identified and rendered Health Insurance Porta-
define separate disease severity and mortality sub-
bility and Accountability Act (HIPAA) compliant to
classes (1 through 4, with 4 being extreme).
financial
performance
against
their
peers.
ensure patient confidentiality (12). STUDY DESIGN. This is a retrospective study designed
to characterize patients with digoxin toxicity and to compare patients with and without treatment with DIF. Inclusion criteria were:
DIF was evaluated using the date of administration, the number of vials administered, and cost. Data related to medications used for treating arrhythmias (potentially as a consequence of digoxin toxicity) were
obtained,
including
anticholinergic
agents
(atropine sulfate) and lidocaine, as well as other
1. Record of administration of DIF (brand names Dig-
potential therapies (magnesium, activated charcoal,
iFab [BTG International Inc., West Conshohocken,
and the placement of a temporary transvenous
Pennsylvania] or DigiBind [formerly manufactured
pacemaker). Use of digoxin after administration of
by GlaxoSmithKline, no longer commercially avail-
DIF was also evaluated by day of administration.
able]; procedure codes Current Procedural Terminology [CPT] J1162 or Q2006); and/or
Clinical outcomes of interest included length of stay (total and in intensive care) measured for both
2. International Statistical Classification of Diseases-
total hospitalization and for days after DIF; cost of
Ninth Revision-Clinical Modification (ICD-9-CM)
hospitalization; and in-hospital mortality. Read-
diagnosis of digoxin toxicity (listed as admitting,
mission and/or subsequent emergency department
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Use of Digoxin Immune Fab in Digoxin Toxicity
visits are limited to the same hospital over a 60-day period.
F I G U R E 1 Derivation of Sample
STATISTICAL ANALYSIS. Descriptive tabular ana-
lyses were conducted presenting each of the preceding study measures for characteristics, treatments, and outcomes by cohort. Patients treated with DIF were further classified by whether a digoxin toxicity diagnosis was recorded. A simple nationwide projection of digoxin toxicity cases and DIF treatments using the Premier database, provided sampling weights was also calculated. Continuous study measures were reported (mean, median, standard deviation, and range; percentiles where data appeared to be skewed). Categorical variables were reported using frequency distributions. Given the large sample sizes, most differences between
cohorts
on
the
basic
2-way
analyses
were statistically significant and p values were uninformative. Given the constraints of this nonrandomized observational study design, exploratory multivariate analyses were conducted to determine predictors of treatment with DIF, as well as the treatment effect of DIF on length of stay, while attempting to adjust for patient characteristics and selection bias. Fixed-effects linear regression models were used to estimate DIF treatment effects for patients within a given APR-DRG, severity level, and utilization of intensive care unit, thereby controlling for unobserved variables related to their condition (13,14); this
DIF ¼ patients who received digoxin immune Fab; non-DIF ¼ patients who did not receive
was especially attractive in the current study because
digoxin immune Fab; Dx ¼ diagnosis.
detailed chart data were not available for incorporation into the model. As a sensitivity analysis, a linear regression without fixed effects and with principal diagnosis, severity indices, and intensive care unit utilization as covariates was also estimated. SAS version 9.2 (SAS Institute Inc., Cary, North Carolina) was the statistical software utilized.
RESULTS
of mortality (33% vs. 17%; on a scale of mild, moderate, major, extreme). Overall, arrhythmia diagnoses accounted for 19% of principal discharge diagnoses (4.8% with atrial fibrillation or flutter). Congestive heart failure and acute renal failure each accounted for 11% of patients, and electrolyte disorders another 4%. Diastolic
PATIENT
AND
PROVIDER
CHARACTERISTICS. A
heart failure ICD-9-CM code 428.3x accounted for
total of 24,547 hospitalizations were identified (of a
15% of the HF diagnoses. In general, diagnoses did
total of 28.5 million hospitalizations over nearly
not differ by cohort, except for a higher portion of
5 years) for which a code was recorded for digoxin
arrhythmia diagnoses among DIF patients than non-
toxicity (n ¼ 19,543), treatment with DIF (n ¼ 1,918),
DIF patients (27% vs. 17%). Admission diagnoses fol-
or both (n ¼ 3,086) (Figure 1).
lowed a similar pattern (data not shown). Secondary
Characteristics of non-DIF and DIF-treated cohorts
diagnoses included arrhythmias in more than 90%,
are shown in Table 1. Patients in both cohorts were
HF in 53%, digoxin toxicity in 90%, and chronic
generally older (31% $85 and 88% $65 years of age)
kidney disease in 61% of patients.
and admitted as emergencies (78%). Race and sex
Three quarters of the admitting physicians of
were similar across cohorts. Patients in the DIF cohort
record in the database were internists, hospitalists,
were more likely than non-DIF patients to be rated as
or family practice physicians (Table 1). Admitting
“extreme” for disease severity (37% vs. 20%), and risk
physicians for the DIF cohort were somewhat more
3
4
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Use of Digoxin Immune Fab in Digoxin Toxicity
and geographic distributions differed little between
T A B L E 1 Patient and Provider Characteristics*
cohorts. ALL N ¼ 24,547 %
Non-DIF N ¼ 19,543 %
DIF N ¼ 5,004 %
DIF TREATMENT. DIF was administered in 5,004
(20%) of patients. After multivariable adjustment, the
Age 85þ yrs
31
32
27
Age 65þ yrs
88
88
86
largest predictors of DIF use were emergency admis-
Race: white
72
72
70
sion (odds ratio [OR] 1.7; p < 0.0001) and coding for
Sex: female
66
65
66
hyperkalemia, arrhythmias associated with digoxin
Admission type: emergency
78
77
80
toxicity, other arrhythmias, acute renal failure, or
Admitted from emergency department
60
61
60
suicidal intent (ORs 2.4, 3.6, 2.0, 2.1, 3.7, respectively;
APR-DRG disease severity: extreme†
24
20
37
Risk of mortality: extreme
20
17
33
Digoxin toxicity diagnosis coded (any position)
92
100
62
Principal diagnosis assigned on discharge
p < 0.0001 for all) (Table 2). Physician generalists were less likely to treat with DIF than cardiovascular specialists (ORs 0.6 to 0.8; p < 0.05). Urban and
Arrhythmias most associated with digoxin toxicity‡
5
4
9
teaching hospitals were slightly less likely than
Other arrhythmias
14
13
18
community nonurban hospitals to use DIF (OR 0.88,
Congestive heart failure
11
11
8
p ¼ 0.01; and OR 0.87, p ¼ 0.04; respectively). Age,
Acute renal failure
11
11
14
sex, and region were not important factors.
Hyperkalemia
1
1
1
Electrolyte disorders other than hyperkalemia
3
4
2
Ischemic cardiac disease
3
3
4
Digoxin toxicity
2
2
3
The majority (78%) of DIF was administered on days 1 and 2 of the hospitalization; 10% received DIF after day 7. Only 6% of patients treated with DIF
CKD 1-3 or hypertensive CKD
1
1
1
were coded as intentional overdose (4% in patients
CKD 4-5, ESRD
0
0
0
not given DIF). The median number of vials used
None of above
50
52
41
per toxicity episode was 3 with 90% of administra-
Arrhythmias most associated with digoxin toxicity‡
17
15
24
also more likely to receive other therapies (activated
Other arrhythmias
75
74
78
charcoal, atropine, lidocaine, or temporary pace-
Congestive heart failure
53
52
56
Acute renal failure
27
24
37
tions 5 or fewer vials. Patients receiving DIF were
Secondary diagnoses
maker) compared with patients not receiving DIF (Table 3).
Hyperkalemia
18
15
27
Electrolyte disorders other than hyperkalemia
45
44
49
Digoxin was administered during the hospitaliza-
Ischemic cardiac disease
48
48
49
tion to a large portion of patients including 31% of
Digoxin toxicity
90
98
59
patients receiving DIF and 14% after receipt of DIF.
CKD 1-3 or hypertensive CKD
32
31
38
CKD 4-5, ESRD
29
27
33
OUTCOMES. The mean length of stay was longer for
None of above
0
0
1
42
43
38
mean cost of DIF was $1,540. Overall costs ($22,328
Admitting physician Internal medicine
patients administered DIF (8.9 days) than for patients who did not receive DIF (6.6 days); in the former, the
Hospitalist
17
17
16
vs. $12,032) and in-hospital mortality (14% vs. 6%)
Family practice
15
15
14
were greater for DIF-treated patients, but 60-day
Cardiovascular
10
9
13
readmission rates (limited to the same hospital)
Nephrology
2
2
2
were equivalent (22% and 23%, respectively; Table 3)
Pulmonary diseases
3
2
4
Other specialty
12
11
12
Institution type
and 180-day readmission rates were somewhat lower for DIF-treated patients (33% vs. 37%, p < 0.0001).
Teaching hospital
34
35
31
A sensitivity analysis that restricted the cohort to
Rural hospital
13
13
12
those patients who received DIF within 2 days did not
(355)
(350)
(360)
show a difference for in-hospital mortality or length
(Median number of beds)
of stay compared with the non-DIF patients. Among Values are % of patients, except for median bed number. *p < 0.0001 for all differences >1 percentage point. †APR-DRG indices—mild, moderate, major, extreme (3M Health Information Systems, Salt Lake City, UT). ‡ICD-9 codes 426.0, 426.11, 426.12, 426.13, 427.0, 427.1, 427.41, 427.5, 427.69, 427.81. APR-DRG ¼ All Patients Refined Disease-Related Group; CKD ¼ chronic kidney disease; DIF ¼ received digoxin immune Fab; ESRD ¼ end-stage renal disease; ICD-9 = International Classification of Diseases-Ninth Revision; Non-DIF ¼ did not receive digoxin immune Fab.
patients treated with DIF, those with a digoxin toxicity diagnosis had a much shorter length of stay than those who did not (7.2 days vs. 11.6 days). Regression models adjusting for disease and severity variables, and limiting analysis to patients with a
likely to be specialists than for the non-DIF cohort,
coded diagnosis of digoxin toxicity, estimated that
mostly due to the higher proportion of cardiologists
the effect of DIF on length of stay was a mean
(13% vs. 9%). Attending physician type followed
reduction of 0.3 to 0.7 days. Of those patients read-
a similar pattern (data not shown). Hospital size
mitted, 7% were diagnosed with toxicity or treated
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Use of Digoxin Immune Fab in Digoxin Toxicity
with DIF, regardless of whether they were treated with DIF on their index admission.
T A B L E 2 Predictors of DIF Treatment
NATIONWIDE PROJECTION OF IN-PATIENT CASES AND TREATMENT. A nationwide estimate of the
Effect
Odds Ratio*
95% Confidence Limits
number of digoxin toxicity cases and treatments by
Number of beds
1.00
1.00
1.00
year is shown in Table 4, based on our sample and
Teaching hospital (vs. other)†
0.87
0.77
0.96
Premier-provided sampling weights. Estimated cases
Urban/suburban (vs. rural)†
0.88
0.78
0.99
decreased from 41,000 in 2007 to 35,000 in 2011, while the proportion treated with DIF was essentially unchanged at 21% to 22%.
DISCUSSION Despite reports of decreasing use of digoxin as a treatment for heart failure (3) and uncertainty about
Age group (vs. 65-74 yrs) 0-18
0.39
0.15
1.02
19-24
0.38
0.12
1.21
25-34†
0.35
0.15
0.82
35-44†
0.56
0.33
0.95
45-54
0.80
0.62
1.05
55-64
1.10
0.94
1.28
75-84
0.96
0.86
1.06
85þ†
0.88
0.79
0.99
0.82
0.75
0.89
survival benefit in both HF and atrial fibrillation
Male (vs. female)†
(15–17), toxicity remains an important clinical entity.
Admission type (vs. elective admission)
Contemporaneous
data
about
the
incidence
of
toxicity cases are conflicting (3,18,19). In one report, the incidence of digoxin toxicity did not decline over time, and the percentage of patients receiving DIF
Emergency†
1.73
1.43
2.08
Urgent†
1.24
1.01
1.52
Admission physician specialty (vs. cardiovascular diseases) Pulmonary diseases
1.18
0.92
1.51
Other†
0.75
0.64
0.89
for digoxin toxicity appeared to have increased be-
Nephrology
0.76
0.56
1.05
tween 1996 and 2003 (3). However, Haynes et al.
Internal medicine†
0.70
0.61
0.80
reported that the rate of digoxin toxicity hospital
Hospitalist†
0.71
0.61
0.83
admissions had steadily declined between 1990 and
Family practice†
0.76
0.65
0.89
2004 to 8 per 100,000 population, based on National
Emergency medicine†
0.56
0.38
0.85
Hospital Discharge Survey data (18). Consistent with
Presence of disorders (vs. not present) Digoxin toxicity diagnosis on admission†
1.33
1.22
1.45
Arrhythmia associated with digoxin toxicity†
3.61
2.75
4.75
our study show a continued decrease in the annual
Other arrhythmias†
2.09
1.86
2.36
rate of digoxin toxicity admissions between 2007 and
Acute renal failure†
2.11
1.78
2.48
2011. Recent data on the incidence of toxicity in
Congestive heart failure†
0.60
0.48
0.76
relation to the number of users of digoxin has been
Ischemic cardiac disease
0.81
0.54
1.22
more difficult for researchers to obtain. Referencing 5
Symptoms of malaise or fatigue†
1.14
0.95
1.37
sources from 1990 to 2000, Haynes et al. (18) reported
Hyperkalemia†
2.36
1.75
3.19
Other electrolyte disorders
0.73
0.55
0.97
Suicidal intent
3.74
2.46
5.69
Intentional misuse
1.81
1.49
2.18
these observations, the national projection data in
that the annual incidence of digoxin toxicity is between 4% and 5% per year per user of digoxin. The challenge in this and other reports has been to find commensurate data for both numerator and denominator. For example, although Haynes et al. (18) could
*Shown are odds ratios from multivariable logistic regression. †Significant at p < 0.05 (Wald’s chi-square). DIF ¼ digoxin immune Fab.
estimate the number of hospitalizations for toxicity, the measure of digoxin use was based only on the number of office visits during which time digoxin was mentioned and the number of digoxin scripts per
admission (3). More recently, See et al. (19) found that
100,000 Medicaid beneficiaries.
digoxin toxicity accounted for 1.0% of emergency
In the current report, we estimated 35,000 toxicity
department visits for adverse drug events among
or DIF inpatient discharges in 2011. This number is
patients aged $40 years and 5.9% of hospitalizations
2.4% of the total of 1 million inpatient discharges with
for all adverse drug events among patients $85 years
HF as the primary diagnosis and the 480,000 dis-
of age.
charges with atrial fibrillation as primary (based on
It is possible that under-reporting of digoxin
statistics from the American Heart Association [20]).
toxicity occurs, potentially as a result of lack of
We
(Acute
recognition; another contributing factor may be
Decompensated Heart Failure National Registry)
previously
reported, using
ADHERE
overreliance on laboratory reporting, especially when
data, that 23.5% of those hospitalized for acute
the therapeutic range is inappropriately wide (21).
decompensated HF in 2004 were using digoxin upon
In the DIG (Digitalis Investigation Group) study,
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Use of Digoxin Immune Fab in Digoxin Toxicity
supportive interventions, although low, was also
T A B L E 3 Other Treatments and Outcomes*
greater in patients receiving DIF. Previous studies of
Non-DIF N ¼ 19,543
DIF N ¼ 5,004
DIF/Dx N ¼ 3,086
DIF/No Dx N ¼ 1,918
In-hospital mortality, %
5.7
14.3
10.6
20.2
Length of stay, mean days (SD), median
6.6 (7.1) 5
8.9 (12.4) 6
7.2 (9.7) 5
11.6 (15.6) 7
Intensive care unit use, %
22.2
55.6
51.1
62.9
The fact that 10% of patients who received DIF
60-day hospital readmission, %
23.1
21.6
22.4
20.4
did so after day 7 suggests that some toxicity cases
Outcomes
Cost, mean $ (SD)
12,032 (18,506) 22,328 (35,670) 16,753 (25,023) 31,298 (46,717)
Median $
treatment with DIF have been limited to relatively small series (9–11); low heart rate, acute overdose, and hyperkalemia as well as DIF availability were reported as predictors of use.
failed usual care, were not recognized earlier in the hospital course, or developed during the hospitali-
7,192
12,696
10,951
17,261
Lidocaine, %
17.7
27.3
22.2
35.6
of whether DIF was administered, was long in
Magnesium, %
14.0
23.4
21.4
26.8
contrast to a prior report suggesting a mean of only
Atropine, %
6.2
23.1
22.2
24.5 ns
Activated charcoal
0.4
1.2
1.6
0.4
Temporary pacemaker, %
0.6
4.4
4.2
4.9 ns
zation. Indeed, the mean length of stay, regardless
Other treatments
3.3 days (23). Of some concern, digoxin is not infrequently prescribed after DIF administration. It is unlikely that
*p < 0.0001 for all comparisons except where noted as not significant (ns).
its use is based on treating worsening of HF after
Non-DIF ¼ did not receive digoxin immune Fab; DIF ¼ received digoxin immune Fab; Dx ¼ diagnosis of digoxin toxicity coded; No Dx ¼ no diagnosis of digoxin toxicity coded; ns ¼ not significant.
antibody administration, although this remains a theoretical explanation. It is possible that quality initiatives will need to be designed and implemented
toxicity was suspected in 11.9% of cases during follow-up, but it led to hospitalization in only 2% (15). However, it is also noteworthy that at least in HF therapeutics, there is increasing recognition that the digoxin’s clinical benefit may be limited to serum concentrations between 0.5 ng/ml and 0.9 ng/ml (22); as a consequence, lower dosing may reduce risk of toxicity, especially in patients who are at risk such as the elderly and patients with renal failure. The recent studies suggesting an increase in mortality with digoxin use in atrial fibrillation with and without HF indicate a need to reassess the role of both digoxin and digoxin levels across multiple indications. Using a large hospital database, we demonstrated that the cohort with toxicity is clinically diverse in terms of coded diagnoses and predominantly elderly, with nearly one-third of patients 85 years of age or older. DIF tends to be prescribed by specialists as opposed to generalists and used in sicker patients as gauged by a number of variables. The use of other
to limit or prevent the reintroduction of digoxin during the index hospitalization with or for digoxin toxicity. Further, we noted that digoxin levels are often measured after DIF, which may not be appropriate unless the assay measures free digoxin alone. It is uncertain whether early use of DIF leads to better outcomes. As an observational study, the ability to clarify factors explaining the difference in length of stay or cost is limited. As expected, disease severity was an important contributing factor to the length of stay and associated cost. As such, a range of multivariable analyses were conducted to attempt to correct for bias. The estimated DIF effect on length of stay was a mean reduction of 0.3 days to 0.7 days if it is assumed that only patients with a coded diagnosis of digoxin toxicity should be compared; otherwise, there was no effect. Approximately 38% of patients receiving DIF did not have a concomitant digoxin toxicity code; these patients had more comorbidities than others receiving DIF, even after multivariable adjustment. One possible explanation is that the sicker the pa-
T A B L E 4 Nationwide Projection of Inpatient Visits and DIF* Treatment by
Year Projected From Sample With Premier Sampling Weights
tient, the greater the importance placed on coding other principal and secondary diagnoses, perhaps for reimbursement and documentation purposes.
Year
Visits With Diagnosis of Digoxin Toxicity or DIF Treatment
Visits With DIF Treatment
Treated With DIF (%)
The additional cost of DIF needs to be weighed against costs associated with nontreatment. In a sta-
2007
41,320
8,839
21
2008
42,842
9,026
21
tistical simulation, DiDomenico et al. demonstrated
2009
39,235
8,165
21
that DIF is associated with cost savings over usual
2010
37,085
7,889
21
supportive care when the digoxin level is greater
2011*
35,369
7,835
22
than 3.5 ng/ml or creatinine clearance is less than
*Q1 to Q3 in sample, projected to full year. DIF ¼ digoxin immune Fab.
22 ml/min; similarly, length of stay is reduced when digoxin levels are >2.3 ng/ml for patients with non–life-threatening toxicity (24). Finally, the use of
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DIF appears to depend at least in part on the specialty
opportunities exist for improved management. Use of
of the attending physician (25) and whether or not
electronic medical record data may facilitate analyses
the ingestion was acute as part of an intentional
that take advantage of laboratory data and as such
overdose; in the current database, the number of such
may allow us to further examine the management of
cases was low. Other variables such as admission
digoxin toxicity and, in particular, the relationship
status of the patient and clinical indicators of severe
between digoxin levels and specific treatments.
toxicity (such as arrhythmias and hyperkalemia) were
Further research is also needed to understand best
also predictors.
practices, appropriate patient selection, and timing
STUDY LIMITATIONS. Our data are limited by lack
for administration of DIF, with prospective data
of long-term outcomes including rehospitalization
collection to assess whether early identification and
(in hospitals other than the initial hospital) and
treatment can lead to shorter lengths of stay and
30-day and longer-term mortality. Therefore, we
improved outcomes.
cannot assess prevalence of repeat toxicity requiring hospitalization. Not all digoxin toxicity is clinically recognized as such. Further, digoxin levels, dosing, outpatient medication use, and renal function are not available in the Premier database, which would
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
Paul J. Hauptman, Division of Cardiology, Saint Louis University Hospital, 3635 Vista Avenue, Saint Louis, Missouri 63110. E-mail: [email protected].
otherwise provide additional insight into the selection and timing of DIF. We cannot account for
PERSPECTIVES
patients who may have experienced digoxin toxicity but were not coded as such; further, subclinical
COMPETENCY IN MEDICAL KNOWLEDGE: Digoxin toxicity
toxicity would not have been identified. We also
remains a prevalent complication. The use of DIF is often associ-
cannot determine digoxin exposure and the risk of
ated with complex presentations. A significant proportion of cases
toxicity on that basis. We were, however, able to
of digoxin toxicity are not treated with DIF. Late administration
make an estimate of the number of digoxin toxicity
of the antidote and reinitiation of digoxin following its use
cases nationwide.
represent potential targets for quality improvement.
CONCLUSIONS
TRANSLATIONAL OUTLOOK: DIF was developed more than
We have shown that digoxin toxicity was often associated with complex hospitalizations and a minority of patients (20%) was treated with DIF. Digoxin was also prescribed in 14% of patients
40 years ago for the treatment of digoxin toxicity and remains the gold-standard approach. Additional study is needed to assess best practices, including evaluation of the impact of early identification and treatment.
following administration of DIF, suggesting that
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5. Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM. Association of serum digoxin con-
10. Lapostolle F, Borron SW, Verdier C, et al. Digoxin-specific fab fragments as single first-line
failure: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. J Am Coll Cardiol 2013;62:e147–239.
centration and outcomes in patients with heart failure. JAMA 2003;289:871–8.
therapy in digitalis poisoning. Crit Care Med 2008;36:3014–8.
6. Shah M, Avgil Tsadok M, Jackevicius CA, Essebag V, Behlouli H, Pilote L. Relation of digoxin use in atrial fibrillation and the risk of all-cause mortality in patients >/¼65 years of age with versus without heart failure. Am J Cardiol 2014; 114:401–6.
11. Schaeffer TH, Mlynarchek SL, Stanford CF, et al. Treatment of chronically digoxin-poisoned patients with a newer digoxin immune fab—a retrospective study. J Am Osteopath Assoc 2010;110:587–92.
2. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association task force on practice guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014;64: e1–76. 3. Hussain Z, Swindle J, Hauptman PJ. Digoxin use and digoxin toxicity in the post-DIG trial era. J Card Fail 2006;12:343–6. 4. Ziff OJ, Lane DA, Samra M, et al. Safety and efficacy of digoxin: systematic review and metaanalysis of observational and controlled trial data. BMJ 2015;351:h4451.
7. Chan KE, Lazarus JM, Hakim RM. Digoxin associates with mortality in ESRD. J Am Soc Nephrol 2010;21:1550–9. 8. Yang EH, Shah S, Criley JM. Digitalis toxicity: a fading but crucial complication to recognize. Am J Med 2012;125:337–43. 9. Lapostolle F, Borron SW, Verdier C, et al. Assessment of digoxin antibody use in patients with elevated serum digoxin following chronic or acute exposure. Intensive Care Med 2008;34: 1448–53.
12. Premier healthcare informatics. Premier capabilities and hospital characteristics. Charlotte, NC: Premier, Inc., 2009. 13. Allison PD. Fixed Effects Regression Methods for Longitudinal Data Using SAS. Cary, NC: SAS Institute, Inc., 2005. 14. Woolridge J. Econometric Analysis of Cross Section and Panel Data. Cambridge, MA: MIT Press, 2010. 15. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997;336:525–33.
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16. Ouyang AJ, Lv YN, Zhong HL, et al. Metaanalysis of digoxin use and risk of mortality in patients with atrial fibrillation. Am J Cardiol 2015; 115:901–6. 17. Vamos M, Erath JW, Hohnloser SH. Digoxinassociated mortality: a systematic review and meta-analysis of the literature. Eur Heart J 2015; 36:1831–8. 18. Haynes K, Heitjan D, Kanetsky P, Hennessy S. Declining public health burden of digoxin toxicity from 1991 to 2004. Clini Pharm Ther 2008;84: 90–4. 19. See I, Shehab N, Kegler SR, Laskar SR, Budnitz DS. Emergency department visits and hospitalizations for digoxin toxicity: United
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Use of Digoxin Immune Fab in Digoxin Toxicity
States, 2005 to 2010. Circ Heart Fail 2014;7: 28–34. 20. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation 2015;131:e29–322. 21. Hauptman PJ, McCann P, Ramirez Romero JM, Mayo M. Reference laboratory values for digoxin following publication of Digitalis Investigation Group (DIG) trial data. JAMA Int Med 2013;173: 1552–4. 22. Adams KF Jr., Gheorghiade M, Uretsky BF, Patterson JH, Schwartz TA, Young JB. Clinical benefits of low serum digoxin concentrations in heart failure. J Am Coll Cardiol 2002;39:946–53.
23. Gandhi AJ, Vlasses PH, Morton DJ, Bauman JL. Economic impact of digoxin toxicity. Pharmacoeconomics 1997;12:175–81. 24. DiDomenico RJ, Walton SM, Sanoski CA, Bauman JL. Analysis of the use of digoxin immune fab for the treatment of non-life-threatening digoxin toxicity. J Cardiovasc Pharmacol Ther 2000;5:77–85. 25. Kirrane BM, Olmedo RE, Nelson LS, MercurioZappala M, Howland MA, Hoffman RS. Inconsistent approach to the treatment of chronic digoxin toxicity in the United States. Hum Exp Toxicol 2009;28:285–92.
KEY WORDS antidote, digoxin, outcomes, toxicity
VOL.
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
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ISSN 2213-1779/$36.00
PUBLISHED BY ELSEVIER
http://dx.doi.org/10.1016/j.jchf.2016.01.011
Digoxin Toxicity and Use of Digoxin Immune Fab Insights From a National Hospital Database Paul J. Hauptman, MD,a Steven W. Blume, MS,b Eldrin F. Lewis, MD, MPH,c Suzanne Ward, PHARMD, MBAd
ABSTRACT OBJECTIVES This study was developed to determine contemporary management of digoxin toxicity and clinical outcomes. BACKGROUND Although the use of digoxin in heart failure management has declined, toxicity remains a prevalent complication. METHODS The Premier Perspective Comparative Hospital Database (Premier Inc., Charlotte, North Carolina) was used to retrospectively identify patients diagnosed with digoxin toxicity and/or who received digoxin immune fab (DIF) over a 5-year period (20072011). DIF was evaluated using treatment date, number of vials administered, and total cost. Clinical outcomes included length of stay (total hospitalization; days after DIF), cost of hospitalization, and in-hospital mortality. Exploratory multivariate analyses were conducted to determine predictors of DIF and effect on length of stay, adjusting for patient characteristics and selection bias. RESULTS Digoxin toxicity diagnosis without DIF treatment accounted for 19,543 cases; 5,004 patients received DIF of whom 3086 had a diagnosis of toxicity. Most patients were >65 years old (88%). The predictors of DIF use were urgent/emergent admission, hyperkalemia, arrhythmia associated with digoxin toxicity, acute renal failure, or suicidal intent (odds ratios 1.7, 2.4, 3.6, 2.1, 3.7, respectively; p < 0.0001 for all). The majority (78%) of DIF was administered on days 1 and 2 of the hospitalization; 10% received treatment after day 7. Digoxin was used after DIF administration in 14% of cases. Among patients who received DIF within 2 days of admission, there was no difference for in-hospital mortality or length of stay compared with patients not receiving DIF. CONCLUSIONS Digoxin toxicity diagnoses are clustered in the elderly. One-fifth of cases receive treatment with DIF, most within 2 days of admission. Opportunities exist for improved diagnosis and post-DIF management. Prospective data may be required to assess the impact of DIF on length of stay. (J Am Coll Cardiol HF 2016;-:-–-) © 2016 by the American College of Cardiology Foundation.
D
igoxin remains a therapeutic intervention in
relevant largely as a consequence of the drug’s narrow
both atrial fibrillation and heart failure (HF),
therapeutic window (3,4). The risk factors for digoxin
as described in current clinical practice
toxicity have been amply described (5) and include
guidelines (1,2). Although digoxin use has declined in
advanced patient age (6), renal failure (7), metabolic
HF and meta-analyses have raised questions about
disorders, and drug interactions (8). However, little
efficacy in atrial fibrillation, toxicity remains clinically
is known about hospitalizations related to toxicity
From the aDepartment of Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri; bEvidera, Bethesda, Maryland; cDepartment of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, Massachusetts; and dBTG International Inc., Brentwood, Tennessee. BTG purchased the Premier Perspective hospital database and commissioned Evidera for the data analysis. Mr. Blume was an employee of Evidera at the time of this study, which provides research services to pharmaceutical and device manufacturers; in his salaried position, he worked with a variety of organizations and was precluded from receiving payment or honoraria directly from these organizations. Ms. Ward is Scientific Director for BTG International Inc. Drs. Hauptman and Lewis were unpaid consultants and have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received October 1, 2015; revised manuscript received January 22, 2016, accepted January 25, 2016.
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Use of Digoxin Immune Fab in Digoxin Toxicity
ABBREVIATIONS
including contemporary management and
discharge, or secondary diagnosis) with code 972.1
AND ACRONYMS
resource utilization. Since 1986, antidotal
(poisoning by cardiotonic glycosides and drugs
therapy has been available; however, its use
of similar action—digitalis glycosides, digoxin,
has only been indirectly quantified (9–11).
strophanthins) or code E942.1 (causing adverse
Therefore, the primary objectives of the study
effects in therapeutic use, cardiotonic glycosides,
were to describe patient characteristics, hos-
and drugs of similar action—digitalis glycosides,
pital utilization, and outcomes of patients
digoxin, strophanthins).
APR-DRG = All Patients Refined Disease-Related Group
DIF = digoxin immune fab Dx = coded diagnosis of digoxin toxicity
with digoxin toxicity, and to compare patients
ICD-9-CM = International Classification of Diseases-Ninth
treated with and without digoxin immune
Revision-Clinical Modification
fab (DIF).
hospitalization
HF = heart failure OR = odds ratio
If an individual patient had more than 1 inpatient hospitalization fulfilling either criterion, the earliest was
selected.
Exclusion
criteria
included patient visits for use of DIF for reasons other
METHODS
than digoxin toxicity, including any diagnosis indiA retrospective cohort design was followed using the
cating possible severe pre-eclampsia or a related
Premier Perspective Comparative Hospital Database
diagnosis (ICD-9-CM code 642.x).
(Premier Inc., Charlotte, North Carolina) for the
Patients were assigned to 1 of 2 cohorts, depending
5-year period from 2007 to 2011 (excluding quarter 4).
on their exposure to DIF. The day of exposure to DIF
Premier collects data voluntarily submitted from
and the presence of a diagnosis of digoxin toxicity
more than 450 hospitals including detailed informa-
were also noted to define possible subgroup analyses
tion about day-of-service resource use. Hospital
or covariates.
region, patient, and payer distributions compare well
The following variables were obtained: patient
to national statistics, although they tend to include
demographics (age, gender, race); evidence of acute
larger hospitals (68% of discharges recorded in Pre-
ingestion (e.g., any diagnosis of suicidal intent); prin-
mier are provided by hospitals with more than 300
cipal (discharge) diagnosis (1 per patient; e.g., digoxin
beds, compared to 37% nationally; [12]). The database
toxicity,
contains the data elements available in most hospital
kalemia); admission diagnosis (reliably populated in
or payer datasets including patient demographics,
2009 and after); secondary diagnoses; admission type
marital status, gender, race, diagnosis and procedure
(emergency, urgent, elective); hospital characteris-
codes, length of stay, total cost of inpatient care, and
tics (bed size, teaching status, rural vs. suburban/
a date-stamped log of all billed items, including
urban location and region); admitting physician
medications, laboratory, and diagnostic and thera-
specialty; and month/year of discharge. In addition,
peutic services at the individual patient level.
the APR-DRG group (All Patients Refined Disease-
Member hospitals benchmark their clinical and
arrhythmias,
HF,
renal
failure,
hyper-
Related Group) (3M Health Information Systems,
The
Salt Lake City, Utah) was recorded. APR-DRGs are
underlying data undergo quality checks, and cost
similar to Medicare DRGs, classifying patients to
information is reconciled with the hospitals’ finan-
predict intensity of resource use based on diagnosis
cial statements. The Premier data are subsequently
and key surgical procedure codes but enhanced to
de-identified and rendered Health Insurance Porta-
define separate disease severity and mortality sub-
bility and Accountability Act (HIPAA) compliant to
classes (1 through 4, with 4 being extreme).
financial
performance
against
their
peers.
ensure patient confidentiality (12). STUDY DESIGN. This is a retrospective study designed
to characterize patients with digoxin toxicity and to compare patients with and without treatment with DIF. Inclusion criteria were:
DIF was evaluated using the date of administration, the number of vials administered, and cost. Data related to medications used for treating arrhythmias (potentially as a consequence of digoxin toxicity) were
obtained,
including
anticholinergic
agents
(atropine sulfate) and lidocaine, as well as other
1. Record of administration of DIF (brand names Dig-
potential therapies (magnesium, activated charcoal,
iFab [BTG International Inc., West Conshohocken,
and the placement of a temporary transvenous
Pennsylvania] or DigiBind [formerly manufactured
pacemaker). Use of digoxin after administration of
by GlaxoSmithKline, no longer commercially avail-
DIF was also evaluated by day of administration.
able]; procedure codes Current Procedural Terminology [CPT] J1162 or Q2006); and/or
Clinical outcomes of interest included length of stay (total and in intensive care) measured for both
2. International Statistical Classification of Diseases-
total hospitalization and for days after DIF; cost of
Ninth Revision-Clinical Modification (ICD-9-CM)
hospitalization; and in-hospital mortality. Read-
diagnosis of digoxin toxicity (listed as admitting,
mission and/or subsequent emergency department
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visits are limited to the same hospital over a 60-day period.
F I G U R E 1 Derivation of Sample
STATISTICAL ANALYSIS. Descriptive tabular ana-
lyses were conducted presenting each of the preceding study measures for characteristics, treatments, and outcomes by cohort. Patients treated with DIF were further classified by whether a digoxin toxicity diagnosis was recorded. A simple nationwide projection of digoxin toxicity cases and DIF treatments using the Premier database, provided sampling weights was also calculated. Continuous study measures were reported (mean, median, standard deviation, and range; percentiles where data appeared to be skewed). Categorical variables were reported using frequency distributions. Given the large sample sizes, most differences between
cohorts
on
the
basic
2-way
analyses
were statistically significant and p values were uninformative. Given the constraints of this nonrandomized observational study design, exploratory multivariate analyses were conducted to determine predictors of treatment with DIF, as well as the treatment effect of DIF on length of stay, while attempting to adjust for patient characteristics and selection bias. Fixed-effects linear regression models were used to estimate DIF treatment effects for patients within a given APR-DRG, severity level, and utilization of intensive care unit, thereby controlling for unobserved variables related to their condition (13,14); this
DIF ¼ patients who received digoxin immune Fab; non-DIF ¼ patients who did not receive
was especially attractive in the current study because
digoxin immune Fab; Dx ¼ diagnosis.
detailed chart data were not available for incorporation into the model. As a sensitivity analysis, a linear regression without fixed effects and with principal diagnosis, severity indices, and intensive care unit utilization as covariates was also estimated. SAS version 9.2 (SAS Institute Inc., Cary, North Carolina) was the statistical software utilized.
RESULTS
of mortality (33% vs. 17%; on a scale of mild, moderate, major, extreme). Overall, arrhythmia diagnoses accounted for 19% of principal discharge diagnoses (4.8% with atrial fibrillation or flutter). Congestive heart failure and acute renal failure each accounted for 11% of patients, and electrolyte disorders another 4%. Diastolic
PATIENT
AND
PROVIDER
CHARACTERISTICS. A
heart failure ICD-9-CM code 428.3x accounted for
total of 24,547 hospitalizations were identified (of a
15% of the HF diagnoses. In general, diagnoses did
total of 28.5 million hospitalizations over nearly
not differ by cohort, except for a higher portion of
5 years) for which a code was recorded for digoxin
arrhythmia diagnoses among DIF patients than non-
toxicity (n ¼ 19,543), treatment with DIF (n ¼ 1,918),
DIF patients (27% vs. 17%). Admission diagnoses fol-
or both (n ¼ 3,086) (Figure 1).
lowed a similar pattern (data not shown). Secondary
Characteristics of non-DIF and DIF-treated cohorts
diagnoses included arrhythmias in more than 90%,
are shown in Table 1. Patients in both cohorts were
HF in 53%, digoxin toxicity in 90%, and chronic
generally older (31% $85 and 88% $65 years of age)
kidney disease in 61% of patients.
and admitted as emergencies (78%). Race and sex
Three quarters of the admitting physicians of
were similar across cohorts. Patients in the DIF cohort
record in the database were internists, hospitalists,
were more likely than non-DIF patients to be rated as
or family practice physicians (Table 1). Admitting
“extreme” for disease severity (37% vs. 20%), and risk
physicians for the DIF cohort were somewhat more
3
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Use of Digoxin Immune Fab in Digoxin Toxicity
and geographic distributions differed little between
T A B L E 1 Patient and Provider Characteristics*
cohorts. ALL N ¼ 24,547 %
Non-DIF N ¼ 19,543 %
DIF N ¼ 5,004 %
DIF TREATMENT. DIF was administered in 5,004
(20%) of patients. After multivariable adjustment, the
Age 85þ yrs
31
32
27
Age 65þ yrs
88
88
86
largest predictors of DIF use were emergency admis-
Race: white
72
72
70
sion (odds ratio [OR] 1.7; p < 0.0001) and coding for
Sex: female
66
65
66
hyperkalemia, arrhythmias associated with digoxin
Admission type: emergency
78
77
80
toxicity, other arrhythmias, acute renal failure, or
Admitted from emergency department
60
61
60
suicidal intent (ORs 2.4, 3.6, 2.0, 2.1, 3.7, respectively;
APR-DRG disease severity: extreme†
24
20
37
Risk of mortality: extreme
20
17
33
Digoxin toxicity diagnosis coded (any position)
92
100
62
Principal diagnosis assigned on discharge
p < 0.0001 for all) (Table 2). Physician generalists were less likely to treat with DIF than cardiovascular specialists (ORs 0.6 to 0.8; p < 0.05). Urban and
Arrhythmias most associated with digoxin toxicity‡
5
4
9
teaching hospitals were slightly less likely than
Other arrhythmias
14
13
18
community nonurban hospitals to use DIF (OR 0.88,
Congestive heart failure
11
11
8
p ¼ 0.01; and OR 0.87, p ¼ 0.04; respectively). Age,
Acute renal failure
11
11
14
sex, and region were not important factors.
Hyperkalemia
1
1
1
Electrolyte disorders other than hyperkalemia
3
4
2
Ischemic cardiac disease
3
3
4
Digoxin toxicity
2
2
3
The majority (78%) of DIF was administered on days 1 and 2 of the hospitalization; 10% received DIF after day 7. Only 6% of patients treated with DIF
CKD 1-3 or hypertensive CKD
1
1
1
were coded as intentional overdose (4% in patients
CKD 4-5, ESRD
0
0
0
not given DIF). The median number of vials used
None of above
50
52
41
per toxicity episode was 3 with 90% of administra-
Arrhythmias most associated with digoxin toxicity‡
17
15
24
also more likely to receive other therapies (activated
Other arrhythmias
75
74
78
charcoal, atropine, lidocaine, or temporary pace-
Congestive heart failure
53
52
56
Acute renal failure
27
24
37
tions 5 or fewer vials. Patients receiving DIF were
Secondary diagnoses
maker) compared with patients not receiving DIF (Table 3).
Hyperkalemia
18
15
27
Electrolyte disorders other than hyperkalemia
45
44
49
Digoxin was administered during the hospitaliza-
Ischemic cardiac disease
48
48
49
tion to a large portion of patients including 31% of
Digoxin toxicity
90
98
59
patients receiving DIF and 14% after receipt of DIF.
CKD 1-3 or hypertensive CKD
32
31
38
CKD 4-5, ESRD
29
27
33
OUTCOMES. The mean length of stay was longer for
None of above
0
0
1
42
43
38
mean cost of DIF was $1,540. Overall costs ($22,328
Admitting physician Internal medicine
patients administered DIF (8.9 days) than for patients who did not receive DIF (6.6 days); in the former, the
Hospitalist
17
17
16
vs. $12,032) and in-hospital mortality (14% vs. 6%)
Family practice
15
15
14
were greater for DIF-treated patients, but 60-day
Cardiovascular
10
9
13
readmission rates (limited to the same hospital)
Nephrology
2
2
2
were equivalent (22% and 23%, respectively; Table 3)
Pulmonary diseases
3
2
4
Other specialty
12
11
12
Institution type
and 180-day readmission rates were somewhat lower for DIF-treated patients (33% vs. 37%, p < 0.0001).
Teaching hospital
34
35
31
A sensitivity analysis that restricted the cohort to
Rural hospital
13
13
12
those patients who received DIF within 2 days did not
(355)
(350)
(360)
show a difference for in-hospital mortality or length
(Median number of beds)
of stay compared with the non-DIF patients. Among Values are % of patients, except for median bed number. *p < 0.0001 for all differences >1 percentage point. †APR-DRG indices—mild, moderate, major, extreme (3M Health Information Systems, Salt Lake City, UT). ‡ICD-9 codes 426.0, 426.11, 426.12, 426.13, 427.0, 427.1, 427.41, 427.5, 427.69, 427.81. APR-DRG ¼ All Patients Refined Disease-Related Group; CKD ¼ chronic kidney disease; DIF ¼ received digoxin immune Fab; ESRD ¼ end-stage renal disease; ICD-9 = International Classification of Diseases-Ninth Revision; Non-DIF ¼ did not receive digoxin immune Fab.
patients treated with DIF, those with a digoxin toxicity diagnosis had a much shorter length of stay than those who did not (7.2 days vs. 11.6 days). Regression models adjusting for disease and severity variables, and limiting analysis to patients with a
likely to be specialists than for the non-DIF cohort,
coded diagnosis of digoxin toxicity, estimated that
mostly due to the higher proportion of cardiologists
the effect of DIF on length of stay was a mean
(13% vs. 9%). Attending physician type followed
reduction of 0.3 to 0.7 days. Of those patients read-
a similar pattern (data not shown). Hospital size
mitted, 7% were diagnosed with toxicity or treated
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with DIF, regardless of whether they were treated with DIF on their index admission.
T A B L E 2 Predictors of DIF Treatment
NATIONWIDE PROJECTION OF IN-PATIENT CASES AND TREATMENT. A nationwide estimate of the
Effect
Odds Ratio*
95% Confidence Limits
number of digoxin toxicity cases and treatments by
Number of beds
1.00
1.00
1.00
year is shown in Table 4, based on our sample and
Teaching hospital (vs. other)†
0.87
0.77
0.96
Premier-provided sampling weights. Estimated cases
Urban/suburban (vs. rural)†
0.88
0.78
0.99
decreased from 41,000 in 2007 to 35,000 in 2011, while the proportion treated with DIF was essentially unchanged at 21% to 22%.
DISCUSSION Despite reports of decreasing use of digoxin as a treatment for heart failure (3) and uncertainty about
Age group (vs. 65-74 yrs) 0-18
0.39
0.15
1.02
19-24
0.38
0.12
1.21
25-34†
0.35
0.15
0.82
35-44†
0.56
0.33
0.95
45-54
0.80
0.62
1.05
55-64
1.10
0.94
1.28
75-84
0.96
0.86
1.06
85þ†
0.88
0.79
0.99
0.82
0.75
0.89
survival benefit in both HF and atrial fibrillation
Male (vs. female)†
(15–17), toxicity remains an important clinical entity.
Admission type (vs. elective admission)
Contemporaneous
data
about
the
incidence
of
toxicity cases are conflicting (3,18,19). In one report, the incidence of digoxin toxicity did not decline over time, and the percentage of patients receiving DIF
Emergency†
1.73
1.43
2.08
Urgent†
1.24
1.01
1.52
Admission physician specialty (vs. cardiovascular diseases) Pulmonary diseases
1.18
0.92
1.51
Other†
0.75
0.64
0.89
for digoxin toxicity appeared to have increased be-
Nephrology
0.76
0.56
1.05
tween 1996 and 2003 (3). However, Haynes et al.
Internal medicine†
0.70
0.61
0.80
reported that the rate of digoxin toxicity hospital
Hospitalist†
0.71
0.61
0.83
admissions had steadily declined between 1990 and
Family practice†
0.76
0.65
0.89
2004 to 8 per 100,000 population, based on National
Emergency medicine†
0.56
0.38
0.85
Hospital Discharge Survey data (18). Consistent with
Presence of disorders (vs. not present) Digoxin toxicity diagnosis on admission†
1.33
1.22
1.45
Arrhythmia associated with digoxin toxicity†
3.61
2.75
4.75
our study show a continued decrease in the annual
Other arrhythmias†
2.09
1.86
2.36
rate of digoxin toxicity admissions between 2007 and
Acute renal failure†
2.11
1.78
2.48
2011. Recent data on the incidence of toxicity in
Congestive heart failure†
0.60
0.48
0.76
relation to the number of users of digoxin has been
Ischemic cardiac disease
0.81
0.54
1.22
more difficult for researchers to obtain. Referencing 5
Symptoms of malaise or fatigue†
1.14
0.95
1.37
sources from 1990 to 2000, Haynes et al. (18) reported
Hyperkalemia†
2.36
1.75
3.19
Other electrolyte disorders
0.73
0.55
0.97
Suicidal intent
3.74
2.46
5.69
Intentional misuse
1.81
1.49
2.18
these observations, the national projection data in
that the annual incidence of digoxin toxicity is between 4% and 5% per year per user of digoxin. The challenge in this and other reports has been to find commensurate data for both numerator and denominator. For example, although Haynes et al. (18) could
*Shown are odds ratios from multivariable logistic regression. †Significant at p < 0.05 (Wald’s chi-square). DIF ¼ digoxin immune Fab.
estimate the number of hospitalizations for toxicity, the measure of digoxin use was based only on the number of office visits during which time digoxin was mentioned and the number of digoxin scripts per
admission (3). More recently, See et al. (19) found that
100,000 Medicaid beneficiaries.
digoxin toxicity accounted for 1.0% of emergency
In the current report, we estimated 35,000 toxicity
department visits for adverse drug events among
or DIF inpatient discharges in 2011. This number is
patients aged $40 years and 5.9% of hospitalizations
2.4% of the total of 1 million inpatient discharges with
for all adverse drug events among patients $85 years
HF as the primary diagnosis and the 480,000 dis-
of age.
charges with atrial fibrillation as primary (based on
It is possible that under-reporting of digoxin
statistics from the American Heart Association [20]).
toxicity occurs, potentially as a result of lack of
We
(Acute
recognition; another contributing factor may be
Decompensated Heart Failure National Registry)
previously
reported, using
ADHERE
overreliance on laboratory reporting, especially when
data, that 23.5% of those hospitalized for acute
the therapeutic range is inappropriately wide (21).
decompensated HF in 2004 were using digoxin upon
In the DIG (Digitalis Investigation Group) study,
5
Hauptman et al.
6
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Use of Digoxin Immune Fab in Digoxin Toxicity
supportive interventions, although low, was also
T A B L E 3 Other Treatments and Outcomes*
greater in patients receiving DIF. Previous studies of
Non-DIF N ¼ 19,543
DIF N ¼ 5,004
DIF/Dx N ¼ 3,086
DIF/No Dx N ¼ 1,918
In-hospital mortality, %
5.7
14.3
10.6
20.2
Length of stay, mean days (SD), median
6.6 (7.1) 5
8.9 (12.4) 6
7.2 (9.7) 5
11.6 (15.6) 7
Intensive care unit use, %
22.2
55.6
51.1
62.9
The fact that 10% of patients who received DIF
60-day hospital readmission, %
23.1
21.6
22.4
20.4
did so after day 7 suggests that some toxicity cases
Outcomes
Cost, mean $ (SD)
12,032 (18,506) 22,328 (35,670) 16,753 (25,023) 31,298 (46,717)
Median $
treatment with DIF have been limited to relatively small series (9–11); low heart rate, acute overdose, and hyperkalemia as well as DIF availability were reported as predictors of use.
failed usual care, were not recognized earlier in the hospital course, or developed during the hospitali-
7,192
12,696
10,951
17,261
Lidocaine, %
17.7
27.3
22.2
35.6
of whether DIF was administered, was long in
Magnesium, %
14.0
23.4
21.4
26.8
contrast to a prior report suggesting a mean of only
Atropine, %
6.2
23.1
22.2
24.5 ns
Activated charcoal
0.4
1.2
1.6
0.4
Temporary pacemaker, %
0.6
4.4
4.2
4.9 ns
zation. Indeed, the mean length of stay, regardless
Other treatments
3.3 days (23). Of some concern, digoxin is not infrequently prescribed after DIF administration. It is unlikely that
*p < 0.0001 for all comparisons except where noted as not significant (ns).
its use is based on treating worsening of HF after
Non-DIF ¼ did not receive digoxin immune Fab; DIF ¼ received digoxin immune Fab; Dx ¼ diagnosis of digoxin toxicity coded; No Dx ¼ no diagnosis of digoxin toxicity coded; ns ¼ not significant.
antibody administration, although this remains a theoretical explanation. It is possible that quality initiatives will need to be designed and implemented
toxicity was suspected in 11.9% of cases during follow-up, but it led to hospitalization in only 2% (15). However, it is also noteworthy that at least in HF therapeutics, there is increasing recognition that the digoxin’s clinical benefit may be limited to serum concentrations between 0.5 ng/ml and 0.9 ng/ml (22); as a consequence, lower dosing may reduce risk of toxicity, especially in patients who are at risk such as the elderly and patients with renal failure. The recent studies suggesting an increase in mortality with digoxin use in atrial fibrillation with and without HF indicate a need to reassess the role of both digoxin and digoxin levels across multiple indications. Using a large hospital database, we demonstrated that the cohort with toxicity is clinically diverse in terms of coded diagnoses and predominantly elderly, with nearly one-third of patients 85 years of age or older. DIF tends to be prescribed by specialists as opposed to generalists and used in sicker patients as gauged by a number of variables. The use of other
to limit or prevent the reintroduction of digoxin during the index hospitalization with or for digoxin toxicity. Further, we noted that digoxin levels are often measured after DIF, which may not be appropriate unless the assay measures free digoxin alone. It is uncertain whether early use of DIF leads to better outcomes. As an observational study, the ability to clarify factors explaining the difference in length of stay or cost is limited. As expected, disease severity was an important contributing factor to the length of stay and associated cost. As such, a range of multivariable analyses were conducted to attempt to correct for bias. The estimated DIF effect on length of stay was a mean reduction of 0.3 days to 0.7 days if it is assumed that only patients with a coded diagnosis of digoxin toxicity should be compared; otherwise, there was no effect. Approximately 38% of patients receiving DIF did not have a concomitant digoxin toxicity code; these patients had more comorbidities than others receiving DIF, even after multivariable adjustment. One possible explanation is that the sicker the pa-
T A B L E 4 Nationwide Projection of Inpatient Visits and DIF* Treatment by
Year Projected From Sample With Premier Sampling Weights
tient, the greater the importance placed on coding other principal and secondary diagnoses, perhaps for reimbursement and documentation purposes.
Year
Visits With Diagnosis of Digoxin Toxicity or DIF Treatment
Visits With DIF Treatment
Treated With DIF (%)
The additional cost of DIF needs to be weighed against costs associated with nontreatment. In a sta-
2007
41,320
8,839
21
2008
42,842
9,026
21
tistical simulation, DiDomenico et al. demonstrated
2009
39,235
8,165
21
that DIF is associated with cost savings over usual
2010
37,085
7,889
21
supportive care when the digoxin level is greater
2011*
35,369
7,835
22
than 3.5 ng/ml or creatinine clearance is less than
*Q1 to Q3 in sample, projected to full year. DIF ¼ digoxin immune Fab.
22 ml/min; similarly, length of stay is reduced when digoxin levels are >2.3 ng/ml for patients with non–life-threatening toxicity (24). Finally, the use of
JACC: HEART FAILURE VOL.
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Hauptman et al.
- 2016:-–-
Use of Digoxin Immune Fab in Digoxin Toxicity
DIF appears to depend at least in part on the specialty
opportunities exist for improved management. Use of
of the attending physician (25) and whether or not
electronic medical record data may facilitate analyses
the ingestion was acute as part of an intentional
that take advantage of laboratory data and as such
overdose; in the current database, the number of such
may allow us to further examine the management of
cases was low. Other variables such as admission
digoxin toxicity and, in particular, the relationship
status of the patient and clinical indicators of severe
between digoxin levels and specific treatments.
toxicity (such as arrhythmias and hyperkalemia) were
Further research is also needed to understand best
also predictors.
practices, appropriate patient selection, and timing
STUDY LIMITATIONS. Our data are limited by lack
for administration of DIF, with prospective data
of long-term outcomes including rehospitalization
collection to assess whether early identification and
(in hospitals other than the initial hospital) and
treatment can lead to shorter lengths of stay and
30-day and longer-term mortality. Therefore, we
improved outcomes.
cannot assess prevalence of repeat toxicity requiring hospitalization. Not all digoxin toxicity is clinically recognized as such. Further, digoxin levels, dosing, outpatient medication use, and renal function are not available in the Premier database, which would
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
Paul J. Hauptman, Division of Cardiology, Saint Louis University Hospital, 3635 Vista Avenue, Saint Louis, Missouri 63110. E-mail: [email protected].
otherwise provide additional insight into the selection and timing of DIF. We cannot account for
PERSPECTIVES
patients who may have experienced digoxin toxicity but were not coded as such; further, subclinical
COMPETENCY IN MEDICAL KNOWLEDGE: Digoxin toxicity
toxicity would not have been identified. We also
remains a prevalent complication. The use of DIF is often associ-
cannot determine digoxin exposure and the risk of
ated with complex presentations. A significant proportion of cases
toxicity on that basis. We were, however, able to
of digoxin toxicity are not treated with DIF. Late administration
make an estimate of the number of digoxin toxicity
of the antidote and reinitiation of digoxin following its use
cases nationwide.
represent potential targets for quality improvement.
CONCLUSIONS
TRANSLATIONAL OUTLOOK: DIF was developed more than
We have shown that digoxin toxicity was often associated with complex hospitalizations and a minority of patients (20%) was treated with DIF. Digoxin was also prescribed in 14% of patients
40 years ago for the treatment of digoxin toxicity and remains the gold-standard approach. Additional study is needed to assess best practices, including evaluation of the impact of early identification and treatment.
following administration of DIF, suggesting that
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KEY WORDS antidote, digoxin, outcomes, toxicity