
==== Front
Drugs Real World Outcomes
Drugs Real World Outcomes
Drugs - Real World Outcomes
2199-1154
2198-9788
Springer International Publishing Cham

38839728
435
10.1007/s40801-024-00435-0
Original Research Article
Characterizing Utilization and Outcomes of Digoxin Immune Fab for Digoxin Toxicity
http://orcid.org/0000-0003-1939-3126
Sheikh Sophia Sophia.Sheikh@jax.ufl.edu

12
Munson Taylor 1
Garvan Gerard 3
Layton Claire 4
Sollee Dawn 12
Cowdery Colleen 1
Peterson Alexa 1
Rothstein Lindsay Schaack 2
Henson Morgan 1
Gartner Hayley 2
Ujhelyi Michael 5
1 https://ror.org/02y3ad647 grid.15276.37 0000 0004 1936 8091 Department of Emergency Medicine, University of Florida College of Medicine-Jacksonville, Jacksonville, FL USA
2 grid.413116.0 0000 0004 0625 1409 Florida/USVI Poison Information Center-Jacksonville, UF Health Jacksonville, 655 West 8th Street, Jacksonville, FL 32209 USA
3 https://ror.org/02y3ad647 grid.15276.37 0000 0004 1936 8091 Center for Data Solutions, University of Florida College of Medicine-Jacksonville, Jacksonville, FL USA
4 https://ror.org/02y3ad647 grid.15276.37 0000 0004 1936 8091 Integrated Data Repository, University of Florida, Gainesville, FL USA
5 https://ror.org/02y3ad647 grid.15276.37 0000 0004 1936 8091 University of Florida College of Pharmacy, Gainesville, FL USA
5 6 2024
5 6 2024
9 2024
11 3 377388
19 5 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
Background

Digoxin is a widely prescribed drug for congestive heart failure and atrial fibrillation. Digoxin has a narrow therapeutic index and toxicity can develop quite easily. Digoxin immune fab (DIF) is an effective treatment for toxicity, however there are limited studies characterizing its impact on clinical outcomes in real-world clinical practice.

Objectives

The aim of this study was to identify factors and healthcare outcomes associated with digoxin immune fab (DIF) treatment in patients with confirmed/suspected digoxin toxicity.

Methods

An IRB-approved retrospective chart review of digoxin toxic patients (2011–2020) presenting at an academic healthcare system was conducted. Demographic and clinical data were collected. Patients were stratified by DIF treatment versus non-DIF treatment. DIF utilization patterns (appropriate, use when not indicated, or underutilized) were determined using pre-defined criteria. Severe digoxin toxicity was defined as having one or more of the following: mental status disturbances, antiarrhythmic therapy, acute renal impairment or dehydration, serum digoxin concentration (SDC) > 4 ng/mL, or serum K+ > 5 mEq/mL. Logistic multivariable regression analysis evaluated factors associated with DIF use. All statistical analyses were performed in R version 4.1.

Results

Data from 96 patients (non-DIF treated group = 49; DIF treated group = 47) were analyzed. DIF was used appropriately in 70 patients (73%), underutilized in 19 (20%), and administered to 7 (7%) patients when it was not indicated. Several clinical parameters differentiated the DIF from the non-DIF group (p < 0.05) including higher mean SDC (3.41 ± 1.63 vs 2.87 ± 1.17), higher mean potassium (5.33 ± 1.48 vs 4.55 ± 0.87), more toxicity severity (85% vs 49%), and more likely to require cardiac pacing (26% vs 4%). Digoxin toxicity resolved sooner in the DIF group (coefficient − 0.702, 95% CI − 1.137 to − 0.267) (p < 0.01) and they had shorter intensive care unit lengths of stay (12.4 ± 20.3 vs 24.4 ± 28.7 days; p = 0.018). The all-cause mortality rate in patients appropriately managed with DIF therapy versus those patients where DIF was underutilized was 11% and 21%, respectively.

Conclusions

Based on our study population, DIF therapy appears to be beneficial in limiting duration of toxicity and intensive care unit lengths of stay in digoxin toxic patients. Although DIF was appropriately utilized in most cases, there was a relatively high proportion of cases in which DIF treatment was either underutilized or not indicated.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40801-024-00435-0.

BTG Internationalhttp://dx.doi.org/10.13039/100006108 National Center for Advancing Translational Sciences UL1 TR000064 UL1TR001427 issue-copyright-statement© Springer Nature Switzerland AG 2024
==== Body
pmcKey Points

Digoxin immune fab therapy may limit duration of digoxin toxicity and intensive care unit length of stay in digoxin toxicity.	
Digoxin immune fab therapy was appropriately utilized in most of the study population, however there were many patients in which it was underutilized or not indicated.	
Education to improve clinician knowledge on appropriate patient selection for digoxin immune fab therapy may improve recognition and management of digoxin toxicity.	

Background

Digoxin remains a widely prescribed drug for congestive heart failure (CHF) and atrial fibrillation [1]. A recent analysis of the ENGAGE AF-TIMI 48 Trial reported that 30% of CHF patients were treated with digoxin at baseline and 20% of patients without CHF reported digoxin use at trial entry [2]. With such widespread use, digoxin toxicity occurs frequently, upwards of 1% incidence per year [3]. Having a narrow therapeutic index, digoxin is a common medication implicated in emergency department (ED) admissions and has a high proportion of ED visits resulting in medication-related hospitalization [4]. When stratifying for age (< 85 or > 85 years), ED admissions for digoxin toxicity were 3.5-fold greater in the elderly than in the younger cohort [4]. This relatively high index for drug toxicity requires careful therapeutic drug monitoring, particularly in the elderly where digoxin toxicity is associated with increased risk of death [5].

When digoxin toxicity occurs, it must be quickly recognized and managed. In one report, serum digoxin concentrations (SDC) were above the toxic threshold (≥ 2.0 ng/mL) for nearly 96% of estimated ED visits [4]. Toxicity can also be present with lower SDCs [5]. In either case, digoxin toxicity symptoms can be vague and difficult to recognize from other underlying diseases, particularly in chronic digoxin toxicity. Patients with chronic digoxin toxicity are a heterogeneous group of patients with multiple co-morbidities. The complexity of these patients can confound digoxin toxicity diagnosis, potentially delaying appropriate treatment, and lead to worse outcomes.

Fortunately, there is an effective antibody therapy for severe and life-threatening digoxin toxicity—digoxin immune fab antibodies (DIF) [1, 6]. However, studies demonstrating the impacts of DIF on clinical outcomes in real-world healthcare settings are limited [7–11]. There are also limited observational data characterizing DIF’s utilization (appropriate utilization, underutilization, or administration when not indicated) in clinical care. Inappropriate DIF utilization may impact healthcare costs, adverse drug effects and patient outcomes. Given the limited published data, there is a need to characterize utilization of DIF and its impact on patient outcomes. The objectives of this study were to (1) characterize DIF use in confirmed/suspected digoxin toxic patients; (2) identify demographic and clinical factors associated with DIF use; and (3) evaluate the outcomes of patients with confirmed/suspected digoxin toxicity receiving DIF compared with those not receiving DIF.

Methods

Study Design, Settings, and Patient Population

This retrospective chart review was approved by the University of Florida’s Institutional Review Board as an exempt study (IRB study approval number IRB202201650). The University of Florida (UF) Health Integrated Data Repository (IDR) was utilized to identify patients with confirmed or suspected digoxin toxicity. The IDR is a large-scale database that collects and organizes information from across UF Health’s clinical and research enterprises. This clinical data warehouse aggregates data from the university’s various clinical and administrative information systems, including the EpicCare electronic health record system.

The IDR was queried for adult patients receiving digoxin therapy between 2011–2020 and having a serum digoxin concentration > 1.8 ng/mL or having confirmed digoxin toxicity (ICD-10 T46.0X1, T46.0X2, T46.0X5, ICD-9 972.1 and E942.1). If an individual patient had more than one inpatient hospitalization fulfilling either criterion, the earliest hospitalization was selected. Exclusion criteria included use of DIF for reasons other than digoxin toxicity, including any diagnosis indicating possible severe pre-eclampsia or a related diagnosis (ICD-10-CM code 642.x). In cases where the serum digoxin concentration was > 1.8 ng/mL without an accompanying diagnostic code confirming toxicity, a manual review of the chart was performed by a physician, clinical toxicologist, or medical toxicologist to determine if symptoms consistent with digoxin toxicity were also present (such as mental status disturbances, cardiac arrhythmias, and hyperkalemia). Patients who were asymptomatic with supratherapeutic digoxin concentrations were excluded from the analysis. Figure 1 depicts the schematic for inclusion of patient encounters identified by the IDR.Fig. 1 Inclusion schematic of patient encounters identified by the IDR. *Encounters associated with serum digoxin concentrations performed as outpatient laboratory testing, documented in outpatient clinic visits or telephone calls. ^Encounters not related to digoxin (examples include mismatch between physician-selected diagnostic code [such as adverse effect of other antidysrhythmic drugs, initial encounter] and final billed diagnostic code [adverse effect of cardiac-stimulant glycosides and drugs of similar action, initial encounter]). DIF digoxin immune fab, EHR electronic health record, IDR University of Florida Integrated Data Repository

Data for this query were derived from two EDs located within a similar geographic area. One ED (site 1) is located within an urban safety-net academic hospital serving a largely indigent socially vulnerable patient population. The other ED (site 2) is located within a large academic tertiary center. During the study period, site 1 had an annual ED volume of 73,308. The average ED patient was 44 years old, 50% were female, 45% self-reported as Black/African American and 46% as White, 33% were on Medicare/Medicaid, and 36% were self-pay/charity pay. Site 2 had an annual ED volume of 62,314. The average ED patient was 45 years old, 52% were female, 20% self-reported as Black/African American and 70% as White, 49% were on Medicare/Medicaid, and 23% were self-pay.

Five independent, non-blinded reviewers performed chart reviews. All chart abstractors were trained prior to data collection, using standardized definitions for each variable and standardized data collection forms. TM then performed a secondary review and SS was available to resolve any conflicting coding. Inter-rater reliability was 99%.

Variables Collected

Demographics and clinical data were collected by manual chart review. Clinical data included whether patient was admitted from emergency department (yes/no); acute digoxin toxicity as suggested by clinical history (yes/no); and severe digoxin toxicity (yes/no) (defined as having at least one of the following—mental status changes/coma; requiring heart rhythm stabilization medications, temporary pacemaker, or external cardioversion; chronic dehydration or acute renal failure; serum digoxin > 4 ng/mL or serum potassium > 5 mEq/mL if serum creatinine is < 2 mg/dL or serum potassium level > 5.5 mEq/mL if serum creatinine is ≥ 2 mg/dL). DIF utilization (yes/no) and DIF date/time of administration were also collected. DIF treatment indications included potentially life-threatening dysrhythmias, progressive bradycardia, second- or third-degree heart block not responsive to atropine, serum potassium > 5.5 mEq/L, acute ingestion of ≥ 10 mg of digoxin, or chronic ingestion leading to steady-state serum concentration of > 6 ng/mL. These criteria were used to categorize DIF utilization as ‘appropriately’ utilized (DIF treatment given only if DIF indications met), ‘not indicated’ (DIF administered but not indicated), or ‘underutilized’ (DIF indicated but not administered) as determined by a clinical/medical toxicologist.

Other variables collected included All Patient Refined Diagnosis-Related Group (APR-DRG) severity score (severity of illness and mortality risk determination that considers comorbidities and admission indication); Charlson Comorbidity Index and estimated 10-year survival; principal diagnosis (digoxin toxicity, ventricular arrhythmia, atrioventricular conduction disturbance, bradycardia, hyperkalemia, altered level consciousness [AMS], acute kidney injury or failure [AKI]); principle diagnosis not digoxin related (CHF, ischemic heart disease [CAD], chronic renal insufficiency [CKD], diabetes mellitus [DM], end-stage renal disease [ESRD], electrolyte disorder other than hyperkalemia); digoxin toxicity was a secondary diagnosis (yes/no); and time to toxicity resolution (defined as time interval when symptoms related to digoxin toxicity resolved) determined by the clinical/medical toxicologist reviewing the medical record.

Collected laboratory, procedure, medications, and vital sign data included serum digoxin concentration (ng/mL), serum potassium, and heart rate at time of toxicity; external cardioversion/pacing (yes/no); permanent pacemaker placement (yes/no); mechanical ventilation (yes/no); administration of magnesium, lidocaine, amiodarone, atropine, kayexalate, and catecholamines.

The primary outcome included time to toxicity resolution and secondary outcomes of hospital admission, intensive care unit (ICU) admission, hospital length of stay (LOS), ICU LOS, APR-DRG severity, all-cause 60-day readmissions, and all-cause mortality during admission. Hospital LOS captured all time spent in the hospital, including the ICU when applicable.

Data Analysis

Demographic and clinical data were summarized descriptively for the overall study group as well as by DIF indication categories (appropriate utilization, not indicated, underutilized). Patients were stratified by whether they received DIF treatment or not. Univariate regressions were performed to compare demographic and clinical outcome differences between treatment groups. Both logistic and linear regressions were used to test the effect of DIF treatment on time to toxicity resolution (linear regression, log transformed), ICU admission (logistic regression), ICU LOS (linear regression, log transformed), all-cause 60-day readmission (logistic regression), and all-cause mortality during admission (logistic regression); while controlling for gender, race, age, SDC, severe digoxin toxicity designation, Charlson comorbidity estimated 10-year survival and APR-DRG score. All statistical analyses on the data set were performed in R version 4.1. Sample size calculations were performed using the R pwr package version 1.3-0 [12].

Results

A total of 796 unique patient encounters were identified by the IDR. Of these, 700 encounters were excluded after chart review, leaving 96 that met study inclusion criteria (30% from site 1; 70% from site 2) (Fig. 1). To model time to resolution of toxicity (primary study outcome) using multivariable linear regression, our study cohort size of 96 allowed detection of a moderate effect size of 0.25 with at least 80% power assuming a 0.05 level of significance.

Figure 2 displays temporal trends in digoxin toxicity and administrations of DIF. Data from 96 patients (non-DIF treated group = 49; DIF treated group = 47) were analyzed (Table 1). The study cohort was predominantly elderly (71 years old, SD 16.4), White (70%), female (66%), with a mean potassium of 4.93 (SD 1.27) and mean SDC of 3.13 (SD 1.43), with 53% presenting in acute toxicity, and 67% meeting study definition of severe toxicity. The average number of vials given was 3.7 (range 2–10). There were 12 (12%) deaths during hospital admission.Fig. 2 Temporal trends in digoxin toxicity and digoxin immune fab antibody administrations (2011–2020)

Table 1 Comparison of demographic, clinical factors and outcomes in digoxin toxic patients stratified by digoxin immune fab (DIF) treatment

	No DIF (49, 51%)	DIF (47, 49%)	Overall (96, 100%)	p value	
Demographics	
 Age, years (mean ± SD)	70.8 ± 17.6	70.5 ± 15.1	70.7 ± 16.4	0.700	
 Gender	
  Males	15 (31)	17 (36)	32 (33)	0.662	
  Females	34 (69)	29 (62)	63 (66)		
 Race	
  White	33 (67)	34 (72)	67 (70)	0.481	
  Black/African American	11 (22)	12 (26)	23 (24)		
  Other/unknown	5 (10)	1 (2%)	5 (5)		
 Ethnicity	
  Hispanic	3 (6)	2 (4)	5(5)	1.000	
  Non-Hispanic	44 (90)	44 (94)	88 (92)		
  Unknown	2 (4)	1 (2)	3 (3)		
  Charlson comorbidity estimated 10-year survival (mean ± SD)	32.3 ± 36.2	33.7 ± 32.7	33.0 ± 34.3	0.722	
Toxicity characteristics	
 Acute digoxin toxicity	
  Yes	30 (61)	21 (45)	51 (53)	0.156	
  No	19 (39)	26 (55)	45 (47)		
 Severe digoxin toxicity	
  Yes	24 (49)	40 (85)	64(67)	<0.0001	
  No	25 (51)	7 (15)	32 (33)		
 Serum digoxin concentrations, ng/mL (mean ± SD)	2.87 ± 1.17	3.41 ± 1.63	3.13 ± 1.43	0.012	
 Serum potassium mEq/mL (mean ± SD)	4.55 ± 0.879	5.33 ± 1.48	4.93 ± 1.27	0.009	
 Heart rate, beats/min	
  ≤ 50	15 (31)	25 (53)	40 (42)	0.055	
  > 50	34 (69)	21 (45)	55 (57)		
Diagnostic codes	
 Primary diagnosis of digoxin toxicity	
  Yes	11 (22)	43 (91)	54 (56)	< 0.0001	
  No	38 (78)	4 (9)	42 (44)		
 Kidney injury or failure	
  Yes	15 (31)	16 (34)	31 (32)	0.888	
  No	34 (69)	31 (66)	65 (68)		
 Altered level of consciousness	
  Yes	10 (20)	12 (26)	22 (23)	0.723	
  No	39 (80)	35 (74)	74 (77)		
 Dehydration	
  Yes	2 (4)	2 (4)	4 (4)	1.000	
  No	47 (96)	45 (96)	92 (96)		
 Fatigue/generalized weakness	
  Yes	3 (6)	1 (2)	4 (4)	0.617	
  No	46 (94)	46 (98)	92 (96)		
 Heart block or arrhythmia		
  Yes	39 (80)	33 (70)	72 (75)	0.409	
  No	10 (20)	14 (30)	24 (25)		
 Visual changes	
  Yes	1 (2)	1 (2)	2 (2)	1.000	
  No	48 (98)	46 (98)	94 (98)		
 Nausea/vomiting	
  Yes	5 (10)	5 (11)	10 (10)	1.000	
  No	44 (90)	42 (89)	86 (90)		
 Hyperkalemia	
  Yes	7 (14)	13 (28)	20 (21)	0.173	
  No	42 (86)	34 (72)	76 (79)		
Medications and procedures	
 DIF utilization	
  Underutilized	19 (39)	0 (0)	19 (20)	< 0.0001	
  Appropriate utilization	30 (61)	40 (85)	70 (73)		
  Not indicated	0 (0)	7 (15)	7 (7)		
 Medicationsa	
  Yes	25 (51)	31 (66)	56 (58)	0.135	
  No	24 (49)	16 (34)	40 (42)		
   Magnesium	17 (35)	12 (25)	29 (30)		
   Lidocaine	1 (2)	5 (11)	6 (6)		
   Amiodarone	15 (31)	4 (9)	19 (20)		
   Atropine	4 (8)	15 (32)	19 (20)		
   Kayexalate	8 (16)	11 (23)	19 (20)		
   Catecholamines	12 (24)	13 (28)	25 (26)		
 Temporary pacing	2 (4)	12 (26)	14 (15)	0.003	
Health care utilization and other outcomes	
 APR-DRG severity (mean ± SD)	296 ± 255	336 ± 277	315 ± 267	0.432	
 Admitted from emergency department					
  Yes	39 (80)	43 (91)	82 (85)	0.173	
  No/unknown	10 (20)	4 (9)	14 (15)		
 Hospital length of stay, days (mean ± SD)	16 ± 22.6	14.3 ± 24.9	15.2 ± 23.7	0.654	
 ICU admission					
  Yes	16 (33)	33 (70)	49 (51)	0.105	
  No	33 (67)	14 (30)	47 (49)		
 ICU length of stay, days (mean ± SD)	24.4 ± 28.7	12.4 ± 20.3	17.2 ± 24.5	0.019	
 Time to toxicity resolution (log, days) (mean ± SD)b	1.1 ± 0.4	0.6 ± 1.1	0.9 ± 1	0.028	
 Mechanical ventilation					
  Yes	11 (22)	9 (19)	19 (20)	0.803	
  No	38 (78)	38 (81)	76 (79)		
 Death during admission					
  Yes	7 (14)	5 (11)	12 (12)	0.817	
  No	42 (86)	42 (89)	84 (88)		
 60-day readmission					
  Yes	8 (16)	8 (17)	16 (17)	1.000	
  No	41 (84)	39 (83)	80 (83)		
Significant p-values are indicated in bold. Means and standard deviation values are reported as means ± standard deviation

APR-DRG all patient refined diagnosis-related group, DIF digoxin immune fab, ICU intensive care unit

aMore than one type of medication may have been administered

bPatients who died during the admission were excluded

Regressions

Several clinical parameters differentiated the DIF from the non-DIF group (p < 0.05): higher mean SDC (3.41 ± 1.63 vs 2.87 ± 1.17), higher mean potassium (5.33 ± 1.48 vs 4.55 ± 0.87), more patients who were severely toxic (85% vs 49%), and more likely to require pacing (Table 1). The DIF group was more likely to be appropriately managed (i.e., received DIF treatment only if DIF study indications were met) versus the non-DIF group (85% vs 61%, p < 0.001). In patients admitted to the ICU (n = 49), the DIF group (n = 33) had shorter ICU LOS compared with the non-DIF (n = 16) group (12.4 ± 20.3 vs 24.4 ± 28.7 days, p = 0.018). Electronic supplementary material (ESM) Table 1 compares additional clinical parameters for patients admitted to the ICU by DIF treatment group. Additionally, digoxin toxicity resolved sooner in the DIF group (0.6 ± 1.1 log days) compared with the non-DIF group (1.1 ± 0.4 log days) (coefficient − 0.702, 95% CI − 1.137 to − 0.267) (p < 0.01).

There were 12 deaths during hospital admission. Of the seven deaths in the non-DIF group, 86% (n = 6) were admitted to the ICU and had a mean ICU LOS of 37.6 days (range 4–121). In the DIF group, all five patients who died were admitted to the ICU and had a mean ICU LOS of 26 days (range 1–86). Groups did not differ in demographic factors, toxicity type (acute versus chronic), hospital LOS, digoxin-related diagnoses, mortality rates during admission, adjunctive medication administrations, APR-DRG severity or Charlson comorbidity estimated 10-year survival.

DIF was not indicated in 15% (n = 7) of the DIF group. DIF was underutilized in 39% (n = 19) of the untreated group. Of the 64 patients who met study criteria for severe toxicity, 24 (38%) did not receive DIF treatment.

Comparison of DIF Utilization

Table 2 compares demographic and clinical factors by DIF utilization. Symptoms of heart block/arrhythmia (55, 79%) and heart rate ≤ 50 (25, 53%) were more common in patients where DIF was utilized appropriately. Altered mental status was present in a higher proportion of patients where DIF treatment was underutilized (6, 32%) versus patients in which DIF was appropriately utilized (12, 17%). Digoxin toxicity was the primary diagnosis in only 26% (n = 5) of patients in which DIF was underutilized compared with 60% (n = 42) of patients where DIF was appropriately utilized. Severe digoxin toxicity was present in all patients who did not receive DIF (underutilized group), while none of the not-indicated group had severe digoxin toxicity. SDC were highest in the underutilized group (3.38 ± 1.69 ng/mL), while the not-indicated group had the lowest SDC (2.56 ± 1.36 ng/mL). The all-cause mortality rate in patients appropriately managed with DIF therapy versus those patients where DIF was underutilized was 11% and 21%, respectively.Table 2 Comparison of demographic and clinical factors by DIF utilization

	Underutilized (19, 20%)	Appropriate utilization (70, 73%)	Not indicated (7, 7%)	Overall (96, 100%)	
Demographics	
 Age, years (mean ± SD)	69.6 ± 12.6	71 ± 17.5	73 ± 13.5	70.7 ± 16.4	
 Gender					
  Males	6 (32)	24 (34)	2 (29)	32 (33)	
  Females	13 (68)	45 (64)	5 (71)	63 (66)	
 Race					
  White	11 (58)	51 (73)	5 (71)	67 (70)	
  Black/African American	6 (32)	15 (21)	2 (29)	23 (24)	
  Other/unknown	2 (11)	4 (6)	0 (0)	5 (5)	
 Ethnicity					
  Hispanic	1 (5)	4 (6)	0 (0)	5(5)	
  Non-Hispanic	17 (89)	64 (91)	7 (100)	88 (92)	
 Charlson comorbidity estimated 10-year survival (mean ± SD)	28.7 ± 35.7	32.3 ± 33.3	33.0 ± 31.2	33.0 ± 34.3	
Toxicity characteristics	
 Acute digoxin toxicity					
  Yes	6 (32)	34 (49)	5 (71)	45 (47)	
  No	13 (68)	36 (52)	2 (29)	51 (53)	
 Severe digoxin toxicity					
  Yes	19 (100)	45 (64)	0 (0)	64 (67)	
  No	0 (0)	25 (36)	7 (100)	32 (33)	
 Serum digoxin concentrations, ng/mL (mean ± SD)	3.38 ± 1.69	3.12 ± 1.36	2.56 ± 1.36	3.13 ± 1.43	
 Serum potassium mEq/mL (mean ± SD)	4.89 ± 0.886	4.97 ± 1.34	4.64 ± 1.52	4.93 ± 1.27	
 Heart rate, beats/min					
  ≤ 50	4 (21)	33 (47)	3 (43)	40 (42)	
  > 50	15 (79)	36 (51)	4 (57)	55 (57)	
Diagnostic codes					
 Primary diagnosis of digoxin toxicity					
  Yes	5 (26)	42 (60)	7 (100)	54 (56)	
  No	14 (74)	28 (40)	0 (0)	42 (44)	
 Kidney injury or failure					
  Yes	6 (32)	23 (33)	2 (29)	31 (32)	
  No	13 (68)	47 (67)	5 (71)	65 (68)	
 Altered level of consciousness					
  Yes	6 (32)	12 (17)	4 (57)	22 (23)	
  No	13 (68)	58 (83)	3 (43)	74 (77)	
 Dehydration					
  Yes	2 (10)	2 (3)	0 (0)	4 (4)	
  No	17 (90)	68 (97)	7 (100)	92 (96)	
 Fatigue/generalized weakness					
  Yes	1 (5)	3 (4)	0 (0)	4 (4)	
  No	18 (95)	67 (96)	7 (100)	92 (96)	
 Heart block or arrhythmia					
  Yes	13 (68)	55 (79)	4 (57)	72 (75)	
  No	6 (32)	15 (21)	3 (43)	24 (25)	
 Visual changes					
  Yes	0 (0)	2 (3)	0 (0)	2 (2)	
  No	19 (100)	68 (97)	7 (100)	94 (98)	
 Nausea/vomiting					
  Yes	2 (10)	6 (9)	2 (29)	10 (10)	
  No	17 (90)	64 (91)	5 (71)	86 (90)	
 Hyperkalemia					
  Yes	5 (26)	14 (20)	1 (14)	20 (21)	
  No	14 (74)	56 (80)	6 (86)	76 (80)	
Medications and procedures					
 Medicationsa					
  Yes	10 (53)	44 (73)	2 (29)	56 (58)	
  No	9 (47)	26 (37)	5 (71)	40 (42)	
   Magnesium	4 (21)	25 (36)	0 (0)	29 (30)	
   Lidocaine	0	6 (9)	0 (0)	6 (6)	
   Amiodarone	5 (26)	14 (20)	0 (0)	19 (20)	
   Atropine	2 (11)	15 (21)	2 (29)	19 (20)	
   Kayexalate	4 (21)	15 (21)	0 (0)	19 (20)	
   Catecholamines	4 (21)	20 (29)	1 (14)	25 (26)	
 Temporary pacing	0	13 (19)	1 (14)	14 (15)	
Health care utilization and other outcomes	
 APR-DRG severity (mean ± SD)	273 ± 261.70	335 ± 268.67	240 ± 272.60	315 (269)	
 Admitted from emergency department					
  Yes	14 (74)	61 (87)	7 (100)	82 (85)	
  No/unknown	5 (26)	9 (13)	0 (0)	14 (15)	
 Hospital length of stay (mean ± SD days)	12.6 ± 20.24	15.9 ± 26.16	18.71 ± 14.33	15.2 ± 23.7	
 ICU admission					
  Yes	7 (37)	40 (57)	2 (29)	49 (51)	
  No	12 (63)	30 (43)	5 (71)	47 (49)	
 ICU length of stay (mean ± SD days)	14.16 ± 13.38	15.82 ± 27.98	37.5 ± 23.01	17.2 ± 24.5	
 Mechanical ventilation (%)					
  Yes	4 (21)	14 (20)	1 (14)	19 (20)	
  No	15 (79)	55 (80)	6 (86)	76 (79)	
 Time to toxicity resolution (mean days ± SD)b	3.75 ± 2.49	3.05 ± 1.59	4.4 ± 3.90	3.73 ± 2.66	
 Death during admission					
  Yes	4 (21)	8 (11)	0 (0)	12 (12)	
  No	15 (79)	62 (89)	7 (100)	84 (88)	
 60-day readmission					
  Yes	0 (0)	16 (23)	0 (0)	16 (17)	
  No	19 (100)	54 (77)	7 (100)	80 (83)	
Means and standard deviation values are reported as means ± standard deviation

APR-DRG all patient refined diagnosis-related group, DIF digoxin immune fab, ICU intensive care unit

aMore than one type of medication may have been administered

bPatients who died during the admission were excluded

Comparison of Demographic and Clinical Factors with Study Outcomes

ESM Tables 2–6 characterize the association between demographic and certain clinical factors with time to toxicity resolution, ICU admission, ICU LOS, all-cause 60-day readmissions and all-cause fatalities during admission for digoxin toxicity. APR-DRG severity scores were inversely associated with ICU LOS (p = 0.012) (ESM Table 4). The likelihood of 60-day all-cause re-admissions differed by race and age; with non-White patients having a 4.8-fold increased likelihood compared with White patients (p = 0.035) and each additional year of age associated with a decrease in the likelihood of re-admission (p = 0.038) (ESM Table 5). All-cause fatalities during admission were associated with increased age (p = 0.027) (ESM Table 6).

Costs Analysis

In the US, the average cost for one day of ICU level care is around US$2000 [13]. Per communication with the manufacturer, the average wholesale price of DigFab in the US is reported to be US$4599 [14]. The cost of DigiFab administration in our DIF cohort was US$17,016.30 per patient (US$4599 × 3.7 vials, average number of vials per patient). The cost for the average ICU stay in the DIF group was US$24,800 (12.4 days × US$2000); whereas the average ICU cost was US$48,800 in the non-DIF group (24.4 days × US$2000).

Discussion

Despite the DIF group exhibiting greater toxicity (higher SDC, higher potassium levels, and higher proportions of patients requiring cardiac pacing and meeting study definition of severe toxicity), digoxin toxicity resolved sooner in this group and they experienced shorter ICU stays compared with the non-DIF group (nearly 50% reduction in both mean time to toxicity resolution and ICU LOS). These outcomes were not associated with any other measured demographic or clinical factor, including Charlson Comorbidity and APR-DRG severity score, suggesting DIF treatment alone may be responsible for these findings. Previous studies have shown mixed results in the association of DIF with reduction in mean hospital LOS [8–10, 15]. Study population differences (demographics, proportion of patients with acute, subacute, or chronic toxicity, comorbidity status) may potentially explain these discrepant findings. Our findings were derived from a cohort of all digoxin toxic patients and suggests DIF, when clinically indicated, may improve patient morbidity (shorten toxicity) and reduce ICU healthcare costs, but not overall hospital LOS.

Although DigiFab can be an expensive therapy, within our cohort, it was associated with a substantial reduction in ICU LOS (12.4 vs 24.4 days) and, subsequently, may actually reduce overall healthcare costs. However, this cost savings may not translate to other cohorts composed of a different mix of chronic and acute digoxin toxic patients, patients within a different hospital system (particularly within other geographic regions of the US), or those managed in different countries where DigiFab pricing and healthcare costs may differ [16]. Future studies employing a formal cost-effectiveness analysis are needed to fully address the potential for healthcare savings.

A recent report compared clinical features of patients with elevated digoxin serum concentrations treated with DIF therapy with those who were not administered DIF [11]. Patients receiving DIF were more likely to have a heart rate < 51 beats per minute, evidence of abnormal renal function, serum potassium > 5.1 mmol/L and require multiple medical therapies for the treatment of their atrial fibrillation and/or CHF. In our cohort of digoxin toxic patients, we also found patients receiving DIF to have higher potassium levels, but also higher SDC, more severe digoxin toxicity, and a primary diagnosis of digoxin toxicity. DIF-treated patients also had heart rates that were lower (≤ 50 beats/min), but this was not statistically significant. It is not surprising that hyperkalemia is a common factor in patients receiving DIF therapy, as it is a well-known indication of serious, acute digoxin toxicity and is a clinical finding that is easy to diagnose [17].

Proper utilization of DIF is unknown. This real-world evidence study indicates that DIF was appropriately utilized (i.e., DIF treatment was given only if DIF study indications were met) in the majority of patients within our cohort (73%). However, there was a substantial proportion of patients in which DIF was underutilized in our cohort (20%). We found the all-cause mortality during hospital admission was lower when DIF was appropriately utilized compared with when it was underutilized. A similar trend in nonsignificant, numerically lower in-hospital mortality rates has also previously been noted [10].

Altered mental status was present in a higher proportion of patients where DIF treatment was underutilized compared with patients in which DIF was appropriately utilized. Additionally, digoxin toxicity was the primary diagnosis in only 26% of patients in whom DIF was underutilized versus 60% of patients where DIF was appropriately utilized. Although there could be other possible reasons for this discrepancy, namely incomplete diagnostic coding by the clinical team despite their recognition of patients’ toxicity, these findings suggest recognizing mental status changes as a potential sign of digoxin toxicity and the need for DIF treatment may be difficult to recognize by clinical care teams. Deciphering the cause of a patient’s altered mental status can be challenging depending on the patient’s comorbid conditions and other concomitant acute medical conditions. This may be particularly difficult in the older adult patient population, some of whom may have pre-existing dementia, and when it is early in the clinical course and collateral information may be limited, it may not be apparent if a patient’s mental status is altered from their baseline, altered from digoxin toxicity, or altered from a co-existing acute medical condition (such as a urinary tract infection).

We also examined the relationship between demographic and clinical factors with the study outcomes. We identified that non-White patients had a 4.8-fold increased likelihood compared with White patients of having an all-cause 60-day readmission. Although we did not measure social determinants of health and other health disparity factors known to influence healthcare utilization, it is unlikely that DIF treatment would be related to racial differences in re-admission rates, particularly since we did not find the DIF and non-DIF treatment groups differed by race or ethnicity (i.e., one racial/ethnic group was not more likely to receive DIF treatment than another).

We found patients in our cohort had a decrease in the likelihood of all-cause 60-day re-admission with each additional year of age; a finding potentially explained by the life expectancy of our cohort given their older age and comorbidity status (estimated 10-year survival of only 33%). Additionally, APR-DRG severity scores were inversely associated with ICU LOS, which may seem counterintuitive, but perhaps suggests that these patients may have died early in the course of their ICU admission. We also found that all-cause fatalities during admission were associated with increasing age.

There are several limitations to note. First, all patients and patient data were identified and collected retrospectively via review of the electronic health record. Thus, data is limited by the inherent flaws associated with chart reviews and in that it was not collected prospectively, such as incomplete or missing data (although our dataset had very few encounters with missing data—APR-DRG scores were missing in 13 patients), bias in electronic health record documentation by clinical teams and potentially by data collectors as they were not blinded to treatment groups, and difficulty assessing temporal relationships. Second, due the study design, there likely was bias in the selection of patients for DIF treatment by clinical care teams which may have impacted study findings. However, our findings reflect real-world clinical practice for the management of digoxin toxicity and utilization of DIF therapy. Third, our cohort is composed of a relatively small number of patients presenting to only two clinical sites within the same geographic region, thus our findings may not be generalizable to other clinical settings and populations, particularly those residing outside the United States. Fourth, it is possible that our inclusion and exclusion criteria did not sufficiently include/exclude relevant cases potentially biasing the study sample and results. However, as we performed manual chart reviews of each included case, we are certain that we only included cases fitting the study criteria.

Conclusions

Based on our study population, DIF therapy appears to be beneficial in limiting duration of digoxin toxicity and ICU LOS in patients with digoxin toxicity. Although DIF was appropriately utilized in most cases of digoxin toxicity, there was a relatively high proportion of cases in which DIF treatment was either underutilized or not indicated. Patient selection/treatment bias on the part of the clinical care teams may have impacted study outcomes, particularly ICU LOS. Additionally, digoxin toxicity-related altered mental status, whether stemming from or exacerbated by digoxin toxicity, may be challenging to diagnose, particularly during the ED clinical course when details regarding a patient’s illness, history, and other collateral information may be limited. Education to improve and/or reinforce clinician knowledge on appropriate patient selection for DIF therapy and recognition of digoxin toxicity-related mental status changes may help address these issues.

Supplementary Information

Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 19 KB)

Declarations

Funding

Funding for this project was provided to the University of Florida by BTG International as a researcher-initiated study. We acknowledge the University of Florida Integrated Data Repository (IDR) and the UF Health Office of the Chief Data Officer for providing the analytic data set for this project. Additionally, the research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under University of Florida Clinical and Translational Science Awards UL1 TR000064 and UL1TR001427. The content of this publication, presentation and/or proposal is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Conflict of Interest

Dr Sophia Sheikh has no conflicts to report. Ms Munson has no conflicts to report. Mr Garvan has no conflicts to report. Ms Layton has no conflicts to report. Dr Sollee has no conflicts to report. Dr Cowdery has no conflicts to report. Dr Peterson has no conflicts to report. Dr Schaack Rothstein has no conflicts to report. Ms Henson has no conflicts to report. Dr Gartner has no conflicts to report. Dr Michael Ujhelyi is a paid consultant of BTG International.

Ethics Approval

This study was approved by the University of Florida’s Institutional Review Board as an exempt study (IRB202201650).

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Data Availability

Data archiving is not mandated but anonymized data may be available via reasonable request to the corresponding author.

Code Availability

Not applicable.

Author Contributions

MU and SS conceived and designed the study and obtained research funding. TM, GG, and CL contributed to the design of the study. SS, TM, and MH supervised the conduct of the trial and data collection. DS, CC, AP, and LSR managed the data, including quality control. GG provided statistical advice on study design and analyzed the data. SS and HG drafted the manuscript, and all authors contributed substantially to its revision. SS takes responsibility for the paper as a whole. All authors read and approved the final version.
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References

1. Lavonas EJ Akpunonu PD Arens AM 2023 American Heart Association Focused Update on the Management of Patients With Cardiac Arrest or Life-Threatening Toxicity Due to Poisoning: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Circulation 2023 10.1161/CIR.0000000000001161 37942682
Lavonas EJ, Akpunonu PD, Arens AM, et al. 2023 American Heart Association Focused Update on the Management of Patients With Cardiac Arrest or Life-Threatening Toxicity Due to Poisoning: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2023. 10.1161/CIR.0000000000001161.37942682 10.1161/CIR.0000000000001161
2. Eisen A Ruff CT Braunwald E Digoxin use and subsequent clinical outcomes in patients with atrial fibrillation with or without heart failure in the ENGAGE AF-TIMI 48 Trial J Am Heart Assoc 2017 6 7 e006035 10.1161/JAHA.117.006035 28666993
Eisen A, Ruff CT, Braunwald E, et al. Digoxin use and subsequent clinical outcomes in patients with atrial fibrillation with or without heart failure in the ENGAGE AF-TIMI 48 Trial. J Am Heart Assoc. 2017;6(7): e006035. 10.1161/JAHA.117.006035.28666993 10.1161/JAHA.117.006035
3. Rich MW McSherry F Williford WO Yusuf S Digitalis Investigation Group Effect of age on mortality, hospitalizations and response to digoxin in patients with heart failure: the DIG study J Am Coll Cardiol 2001 38 3 806 813 10.1016/s0735-1097(01)01442-5 11527638
Rich MW, McSherry F, Williford WO, Yusuf S, Digitalis Investigation Group. Effect of age on mortality, hospitalizations and response to digoxin in patients with heart failure: the DIG study. J Am Coll Cardiol. 2001;38(3):806–13. 10.1016/s0735-1097(01)01442-5.11527638 10.1016/s0735-1097(01)01442-5
4. See I Shehab N Kegler SR Laskar SR Budnitz DS Emergency department visits and hospitalizations for digoxin toxicity Circ Heart Fail 2014 7 1 28 34 10.1161/CIRCHEARTFAILURE.113.000784 24300242
See I, Shehab N, Kegler SR, Laskar SR, Budnitz DS. Emergency department visits and hospitalizations for digoxin toxicity. Circ Heart Fail. 2014;7(1):28–34. 10.1161/CIRCHEARTFAILURE.113.000784.24300242 10.1161/CIRCHEARTFAILURE.113.000784
5. Charfi R Ben Sassi M Gaies E Jebabli N Daghfous R Trabelsi S Digoxin therapeutic drug monitoring: age influence and adverse events Tunis Med 2020 98 1 35 40 32395775
Charfi R, Ben Sassi M, Gaies E, Jebabli N, Daghfous R, Trabelsi S. Digoxin therapeutic drug monitoring: age influence and adverse events. Tunis Med. 2020;98(1):35–40.32395775
6. Ujhelyi M Management of digitalis intoxicated patients following the administration of digoxin FAB antibodies (Digibind) Conn Med 1990 54 2 63 64 2306942
Ujhelyi M. Management of digitalis intoxicated patients following the administration of digoxin FAB antibodies (Digibind). Conn Med. 1990;54(2):63–4.2306942
7. Chan BSH Buckley NA Digoxin-specific antibody fragments in the treatment of digoxin toxicity Clin Toxicol 2014 52 8 824 836 10.3109/15563650.2014.943907
Chan BSH, Buckley NA. Digoxin-specific antibody fragments in the treatment of digoxin toxicity. Clin Toxicol. 2014;52(8):824–36. 10.3109/15563650.2014.943907.10.3109/15563650.2014.943907
8. Chan BS Isbister GK Page CB Clinical outcomes from early use of digoxin-specific antibodies versus observation in chronic digoxin poisoning (ATOM-4) Clin Toxicol 2019 57 7 638 643 10.1080/15563650.2018.1546010
Chan BS, Isbister GK, Page CB, et al. Clinical outcomes from early use of digoxin-specific antibodies versus observation in chronic digoxin poisoning (ATOM-4). Clin Toxicol. 2019;57(7):638–43. 10.1080/15563650.2018.1546010.10.1080/15563650.2018.1546010
9. Hauptman PJ Blume SW Lewis EF Ward S Digoxin toxicity and use of digoxin immune fab: insights from a National Hospital Database JACC Heart Fail. 2016 4 5 357 364 10.1016/j.jchf.2016.01.011 27039127
Hauptman PJ, Blume SW, Lewis EF, Ward S. Digoxin toxicity and use of digoxin immune fab: insights from a National Hospital Database. JACC Heart Fail. 2016;4(5):357–64. 10.1016/j.jchf.2016.01.011.27039127 10.1016/j.jchf.2016.01.011
10. Peters AE Chiswell K Hofmann P Ambrosy A Fudim M Characteristics and outcomes of suspected digoxin toxicity and immune fab treatment over the past two decades-2000–2020 Am J Cardiol 2022 183 129 136 10.1016/j.amjcard.2022.08.004 36089419
Peters AE, Chiswell K, Hofmann P, Ambrosy A, Fudim M. Characteristics and outcomes of suspected digoxin toxicity and immune fab treatment over the past two decades-2000–2020. Am J Cardiol. 2022;183:129–36. 10.1016/j.amjcard.2022.08.004.36089419 10.1016/j.amjcard.2022.08.004
11. Arbabian H Lee HM Graudins A Elderly patients with suspected chronic digoxin toxicity: a comparison of clinical characteristics of patients receiving and not receiving digoxin-Fab Emerg Med Australas EMA. 2018 30 2 242 248 10.1111/1742-6723.12873 29316267
Arbabian H, Lee HM, Graudins A. Elderly patients with suspected chronic digoxin toxicity: a comparison of clinical characteristics of patients receiving and not receiving digoxin-Fab. Emerg Med Australas EMA. 2018;30(2):242–8. 10.1111/1742-6723.12873.29316267 10.1111/1742-6723.12873
12. Champely S. pwr: basic functions for power analysis. 2020.
13. Gershengorn HB Garland A Gong MN Patterns of daily costs differ for medical and surgical intensive care unit patients Ann Am Thorac Soc 2015 12 12 1831 1836 10.1513/AnnalsATS.201506-366BC 26393984
Gershengorn HB, Garland A, Gong MN. Patterns of daily costs differ for medical and surgical intensive care unit patients. Ann Am Thorac Soc. 2015;12(12):1831–6. 10.1513/AnnalsATS.201506-366BC.26393984 10.1513/AnnalsATS.201506-366BC
14. Ward S. Average wholesale price of DigFab in the US. 2023.
15. 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 2 77 85 10.1053/XV.2000.5590 11150387
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(2):77–85. 10.1053/XV.2000.5590.11150387 10.1053/XV.2000.5590
16. Chan BS Isbister GK Chiew A Isoardi K Buckley NA Clinical experience with titrating doses of digoxin antibodies in acute digoxin poisoning (ATOM-6) Clin Toxicol 2022 60 4 433 439 10.1080/15563650.2021.1968422
Chan BS, Isbister GK, Chiew A, Isoardi K, Buckley NA. Clinical experience with titrating doses of digoxin antibodies in acute digoxin poisoning (ATOM-6). Clin Toxicol. 2022;60(4):433–9. 10.1080/15563650.2021.1968422.10.1080/15563650.2021.1968422
17. BTG International Inc. DIGIFAB DIGOXIN IMMUNE FAB (OVINE). https://www.fda.gov/media/74693/download. Accessed 4 Dec 2023.
