a b s t r a c t

Objectives: The aim of this study was to evaluate factors of digoxin use and its relation to mortality in ED patients with Atrial fibrillation .

Methods: The Chinese AF registry enrolled 2016 AF patients from 20 representative EDs, and the period of study

was one year. Predictors of digoxin use and its relation to mortality were assessed by logistic and Cox regression analyses.

Results: Digoxin was assigned in 609 patients (30.6%), and younger age, lower body mass index values, and exis- tence of permanent AF, heart failure , chronic obstructive pulmonary disease, and valvular heart disease were identified to be factors associated with digoxin use. During the follow-up, compared to patients without di- goxin therapy, digoxin-treated patients had significantly higher risk of All-cause death (17.2% vs. 13.0%, P = 0.012) and cardiovascular death (15.1% vs. 6.7%, P b 0.001), but similar risk of sudden cardiac death (1.1% vs. 0.7%, P = 0.341). However, after adjustment for related covariates, digoxin use was no longer notably associated with increased all-cause mortality (hazards ratio [HR] 0.973, 95% confidence interval [CI] 0.718-1.318) and car- diovascular death (HR 1.313, 95% CI 0.905-1.906). Besides, neutral associations of digoxin treatment to mortality were obtained in relevant subgroups, with no interactions observed between digoxin and gender, HF, valvular heart disease, or concomitant warfarin treatment in mortality risk.

Conclusions: In ED patients with AF, digoxin was more frequently assigned to vulnerable patients with concom- itant HF or valvular heart disease, and digoxin use was not related to a significantly increased risk of mortality.

(C) 2017

Introduction

Atrial fibrillation is the most prevalent sustained cardiac rhythm disturbance encountered in clinical practice, and affects N 30 million individuals worldwide [1]. AF significantly increases the risk of morbidity and mortality, causing great threat to public health and sub- stantial Medical expenses [2]. Apart from anticoagulant therapy for the prevention of thromboembolic complications in high-risk patients, maintaining sinus rhythm or controlling ventricular rate is another vital aspect in the management of AF [3]. Digoxin, due to its effects of slowing down the conduction in the AV node and increasing the

* Corresponding author.

E-mail address: yymfuwai@163.com (Y. Yang).

refractory period, has been widely applied in patients with AF to achieve Rate control, alone or in combination with ? blockers or non- dihydropyridine calcium channel antagonists.

Although digoxin has been endorsed as a class I recommendation in the current guidelines for rate control in AF patients concomitant heart failure and left ventricular dysfunction [3], the effect of digoxin use on mortality remains controversial. The Digitalis Investigation Group (DIG) study, as the landmark randomized controlled trial (RCT) de- signed to evaluate the effect of digoxin on mortality among patients with HF, indicated a neutral relation of digoxin use and all-cause mortal- ity [4]. However, a definite relation of digoxin use on mortality in the setting of AF has not been elucidated, as post-hoc analyses of observa- tional studies and RCTs with distinct research designs and purposes re- vealing contradictory associations between digoxin use and survival

http://dx.doi.org/10.1016/j.ajem.2017.04.070 0735-6757/(C) 2017

[5-22]. Besides, factors related to digoxin use and its relation to mortal- ity has been rarely examined in real-world AF patients attending emer- gency departments (EDs), thus we aimed to explore these issues in this study by conducting an analysis of a prospective multicenter AF registry in China.

Methods

Study design and participants

The Chinese AF registry was a multicenter prospective study and aimed to evaluate the clinical characteristics, treatments, and 1-year outcomes of ED patients presenting with a diagnosis of AF from Novem- ber 2008 to October 2011. A total of 20 centers representing different levels of medical care in China (i.e., academic and non-academic, urban and rural, general and specialized) were selected to participate in the AF registry, and all centers were encouraged to recruit patients consecutively. Patients of interest were identified by reviewing clinical records and electronic databases. The diagnosis of AF was verified by re- search staff by screening their electrocardiograms, records of Holter monitor and rhythm strip according to clinical guidelines of AF [3]. Treatment decisions were made at the discretion of the treating physi- cian. Study protocols were approved by the ethics committee of each center and complied with the principles outlined in the Declaration of Helsinki. All participants were provided with written informed consent.

Data collection and processing

Patients’ demographic information, admission vital signs, medical histories, and treatments were collected at baseline by interviewing the participants, reviewing their medical records, and contacting their treating physicians. Body mass index (BMI) was calculated by dividing weight in kilograms by the square of height in meters. Patients were classified according to their type of AF: paroxysmal AF, persistent AF, and permanent AF based on recommendations of clinical guidelines [3]. Blood pressure was accurately measured at least twice and the average were recorded by treating physicians via mercury sphyg- momanometers according to the American Heart Association’s scientific statement on human BP determination by sphygmomanometer [23]. Heart rate was measured by 12-lead electrocardiography in the supine position after at least 3 min of rest. Medical histories, including myocar- dial infarction (MI), coronary artery disease (CAD), congenital heart dis- ease, valvular heart disease, heart failure , hypertension, diabetes mellitus , previous stroke or Transient ischemic attack , chronic obstructive pulmonary disease (COPD), dementia, hyperthy- roidism, previous major bleeding, and smoking, were also collected at baseline. The diagnosis of HF was made according to clinical guidelines of HF [24]. Left ventricular ejection fraction (LVEF) was measured using Simpson’s biplane method [25]. The CHADS₂ score was calculated by assigning 1 point each for the presence of congestive HF, hypertension, age >= 75 years, DM, and 2 points for previous stroke/TIA [3]. Besides, medical therapies, including aspirin, warfarin, clopidogrel, statin, ? blockers, Angiotensin converting enzyme inhibitor , angiotensin receptor blocker (ARB), diuretic, calcium channel blocker, and anti-ar- rhythmia agents were obtained from medical records and electronic databases.

Follow-up and outcome definition

Follow-up was completed in November 2012 by trained research personnel via clinic visit, telephone or delivery of medical records, with a mean follow-up period of 1 year. In the present study, primary outcome was all-cause mortality, and secondary outcomes were de- fined as cardiovascular death and sudden cardiac death, as assessed by an independent outcome adjudication committee through reviewing all the events in a blinded, preplanned fashion. Cardiovascular death

included sudden cardiac death, and death caused by heart failure, stroke, myocardial infarction, pulmonary embolus, peripheral embolus, aortic dissection, etc. Sudden cardiac death was defined as natural death from various types of cardiac causes, with an abrupt attack and rapid progress to death within 1 h of the onset of acute symptoms.

Statistical analysis

Continuous variables were expressed as means with standard devi- ations or medians with quartiles; categorical variables were expressed as frequencies and percentages. Differences in continuous variables be- tween patients grouped according to digoxin use were analyzed using unpaired t-test or the Mann-Whitney U test; comparison of categorical variables was performed using chi-?2 test or Fisher’s exact test.

Logistic regression analysis was utilized to identify factors related to

digoxin receipt. Kaplan-Meier curves and log-rank tests were conducted to illustrate survival discrepancies between digoxin-treated and un- treated patients. Cox proportional hazards models were performed to evaluate the effects of digoxin therapy on the incidence of all-cause mortality, cardiovascular death, and sudden cardiac death, with addi- tional covariates (including age, sex, BMI, admission vital signs, type of AF, medical histories, and concomitant treatments) included into multi- variable Cox models to assess the independent association of digoxin use to the defined outcomes. Besides, we performed subgroup analyses to evaluate whether discrepancies in the association of digoxin use and mortality existed among the following specific subsets of patients, in- cluding sex, presence of HF and valvular heart disease, and concomitant use of warfarin. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated in comparison with no digoxin use.

The software package SPSS version 22.0 (IBM Corporation, New York, NY, USA) was used for statistical analysis. All statistical tests were 2-tailed, and a P value b 0.05 were considered significant.

Results

Of the 2016 patients with AF, 25 patients were excluded due to in- complete data, and 1991 patients with a mean age of 68.5 years and 1093 females (54.9%) were included in the present study. Of the 1991 patients, 609 patients (30.6%) were treated with digoxin.

Baseline characteristics and treatments are shown in Table 1. Com- pared to patients without digoxin therapy, those treated with digoxin were significantly younger, more likely to be female, and had lower BMI and systolic blood pressure values; they tended to present with AF as a secondary diagnosis, and suffered from non-paroxysmal AF, con- genital heart disease, valvular heart disease, HF, COPD, and smoking more frequently, while less likely to coexist with CAD, hypertension, previous stroke or TIA, and hyperthyroidism. Besides, no remarkable difference existed in the prevalence of MI, DM, dementia, previous major bleeding and CHADS₂ scores between these two groups. For treatment, patients in digoxin group received warfarin, aspirin, ? blocker, ACEI, and diuretic more frequently, while less likely to take clopidogrel, statin, dihydropyridine and anti-arrhythmia agents. In ad- dition, significantly higher proportion of digoxin prescription was ob- served in patients recruited from rural areas (49.5%) compared to patients recruited in the urban setting (24.3%), and this practice was in accordance with much higher prevalence of HF and left ventricular systolic dysfunction in Rural patients than urban patients (Supplemen- tary table 1).

The factors related to digoxin use are shown in Table 2. In the multi- variable logistic regression models, younger age, lower BMI values, and existence of non-paroxysmal AF, HF, LVEF b 45%, COPD, and valvular heart disease were identified to be predictors associated with digoxin treatment, and existence of permanent AF, HF, and valvular heart dis- ease were indicated to be strong predictors of digoxin use in patients re- cruited both from rural areas and urban areas (Supplementary table 2). Outcomes and associations between digoxin use and risk of mortality

Table 1

Baseline characteristics of patients with atrial fibrillation divided by digoxin use.

regression analyses, digoxin use was related to significantly increased risk of all-cause mortality (HR 1.353, 95% CI 1.063-1.721; P = 0.014;

Variables

Overall

(n = 1991)

Digoxin (n = 609)

No Digoxin

(n = 1382) P value

Fig. 1A) and cardiovascular death (HR 2.349, 95% CI 1.761-3.133; P b

0.001), while was not related to notably higher risk of sudden cardiac

Age (years, mean +- SD) 68.5 +- 13.3 66.4 +- 13.0 69.4 +- 13.3 b0.001

Female (n, %) 1093 (54.9) 356 (58.5) 737 (53.3) 0.034

BMI (kg/m², mean +- SD) 23.5 +- 3.6 22.9 +- 3.8 23.8 +- 3.5 b0.001

death (HR 1.590, 95% CI 0.605-4.177; P = 0.347). After adjustment for additional covariates, digoxin use was no longer a risk factor for remark- ably increased all-cause mortality (HR 0.973, 95% CI 0.718-1.318; P =

SBP (mmHg, mean +- SD) 131.8 +-

23.5

129.0 +-

23.8

133.0 +-

23.3

b0.001

0.858; Fig. 1B) and cardiovascular death (HR, 1.313, 95% CI 0.905-

1.906; P = 0.152) as noted in univariate analyses, and the neutral effect

DBP (mmHg, mean +- SD) 79.8 +- 14.9 79.5 +- 15.4 80.0 +- 14.6 0.455

Heart rate (bpm, mean +- SD)	101.7 +-	100.5 +-	102.3 +-	0.218 of digoxin on sudden cardiac death still existed (HR 1.398, 95% CI 0.394-
	29.3	28.4	29.7	4.958; P = 0.604).

Associations between digoxin use and all-cause mortality in sub- group patients with AF are shown in Table 4, and results of clinically rel-

AF as a main diagnosis (n, %) Type of AF (n, %)	819 (41.1)	173 (28.4)	646 (46.7)	b0.001 b0.001
Paroxysmal	608 (30.5)	86 (14.1)	522 (37.8)

Persistent	449 (22.6)	111 (18.2)	338 (24.5)	evant subgroup analyses were consistent with estimates for the overall
Permanent	934 (46.9)	412 (67.7)	522 (37.8)	patients. A neutral effect of digoxin use on all-cause mortality was indi-

Comorbidities (n, %)

Myocardial infarction	147 (7.4)	47 (7.7)	100 (7.2)	0.705
Coronary artery disease	835 (41.9)	234 (38.4)	601 (43.5)	0.035
congenital heart disease	43 (2.2)	23 (3.8)	20 (1.4)	0.001
Valvular heart disease	333 (16.7)	228 (37.4)	105 (7.6)	b0.001
Heart failure	744 (37.4)	424 (69.6)	320 (23.2)	b0.001
LVEF b45%	382 (19.2)	224 (36.8)	158 (11.4)	b0.001
Hypertension	1110 (55.8)	278 (45.6)	832 (60.2)	b0.001
Diabetes mellitus	309 (15.5)	88 (14.4)	221 (16.0)	0.381
Previous stroke or TIA	374 (18.8)	96 (15.8)	278 (20.1)	0.022
COPD	228 (11.5)	524 (14.0)	143 (10.3)	0.020
Dementia	44 (2.2)	11 (1.8)	33 (2.4)	0.416
Hyperthyroidism	66 (3.3)	11 (1.8)	55 (4.0)	0.013
Previous major bleeding	48 (2.4)	16 (2.6)	32 (2.3)	0.676
Smoking	425 (21.3)	149 (24.5)	276 (20.0)	0.024
CHADS2 score (IQR)a Medications (n, %)	1 (1-3)	2 (1-3)	1 (1-3)	0.144
Warfarin	335 (16.8)	162 (26.6)	173 (12.5)	b0.001
Aspirin	1092 (54.8)	359 (58.9)	733 (53.0)	0.015
Clopidogrel	138 (6.9)	31 (5.1)	107 (7.7)	0.032
Statin	475 (23.9)	112 (18.4)	363 (26.3)	b0.001
Beta-blocker	874 (43.9)	285 (46.8)	589 (42.6)	0.083
ACEI	458 (23.0)	224 (36.8)	234 (16.9)	b0.001
ARB	318 (16.0)	93 (15.3)	225 (16.3)	0.571
Diuretic	768 (38.6)	466 (76.5)	302 (21.9)	b0.001
Verapamil or diltiazem	130 (6.5)	40 (6.6)	90 (6.5)	0.963
Dihydropyridine	432 (21.7)	74 (12.2)	358 (25.9)	b0.001
Amiodarone	191 (9.6)	33 (5.4)	158 (11.4)	b0.001
Propafenone	53 (2.7)	9 (1.5)	44 (3.2)	0.029

ACEI, angiotensin converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin re- ceptor blocker; BMI, body mass index; COPD, chronic obstructive pulmonary disease; DBP, diastolic blood pressure; LVEF, left ventricular ejection fraction; SBP, systolic blood pres- sure; TIA, transient ischemic attack.

^a Confined to patients with non-valvular atrial fibrillation.

are shown in Table 3. During a mean follow-up of 1 year, a total of 284 deaths (14.3%) occurred; 185 patients (9.3%) suffered from cardiovascu- lar deaths and 17 patients (0.9%) underwent sudden cardiac death. Compared to patients without digoxin therapy, digoxin-treated patients had notably higher all-cause mortality (17.2% vs. 13.0%, P = 0.012) and cardiovascular mortality (15.1% vs. 6.7%, P b 0.001), but equivalent risk of sudden cardiac death (1.1% vs. 0.7%, P = 0.341). In univariate Cox

cated in all subgroups, and no significant interactions existed between digoxin use and gender (P = 0.304), existence of HF (P = 0.614), valvu- lar heart disease (P = 0.148), or concomitant treatment of warfarin (P

= 0.249) in the risk of all-cause mortality.

Discussions

In the present study, we explored factors of digoxin use and its effect on mortality in ED patients with AF, and revealed that younger age, lower BMI values, and existence of permanent AF, HF, LVEF b 45%, COPD, and valvular heart disease were predictors of digoxin treatment. Besides, digoxin therapy was not related to significantly increased risk of all-cause mortality, cardiovascular death, and sudden cardiac death after adjustment for known risk factors and relevant confounding co- variates of mortality, although significantly increased risk of all-cause mortality and cardiovascular death was exhibited in the primary uni- variate analyses, indicating that additional risk factors might distort the real relation of digoxin use to mortality. Notably, a neutral relation was also observed in clinically relevant subgroups.

In the present study, 30.6% of ED patients with a diagnosis of AF were assigned to digoxin therapy at baseline. Notably, considerable discrep- ancies in the ratios reported in previous studies existed, with a ratio ranging from 17.3% to 37% in general AF populations [5-13] and a ratio ranging from 47% to 69.4% in post hoc analyses of RCTs evaluating the efficacy and safety of rate control and Rhythm control strategies [15-18]. It should be noted that ratios of digoxin therapy extremely depended on the study circumstances, and distinct selection criteria, study purposes and designs might largely affect the ratio of digoxin use. Among digoxin-treated patients, 69.6% suffered from HF, and com- pared with digoxin-untreated group, patients with digoxin therapy were frailer, more likely to be female and suffer from left ventricular systolic dysfunction, valvular heart disease, permanent AF, and COPD, besides, they received ACEI, diuretics and anticoagulants more fre- quently, and less likely to receive statins and antiarrhythmic agents. Consistent with our observations, an analysis of SCAF (Stockholm Co- hort study of Atrial Fibrillation) study including 2824 patients with AF identified female sex, permanent AF, no pacemaker, internal medicine

Table 2

Factors related to digoxin use in atrial fibrillation.

Variables	Hazard ratio represents	Hazard ratio (95% CI)a	P value
Age	Per 1 year increase	0.987 (0.978-0.997)	0.008
Body mass index	Per 1 kg/m2 increase	0.958 (0.929-0.989)	0.008
Permanent atrial fibrillation	Paroxysmal atrial fibrillation as reference	2.493 (1.852-3.355)	b 0.001
Heart failure	Without heart failure as reference	4.276 (3.310-5.525)	b 0.001
LVEF b45%	LVEF >= 45% as reference	1.628 (1.216-2.180)	0.001
COPD	Without COPD as reference	1.490 (1.062-2.091)	0.021
Valvular heart disease	Without valvular heart disease as reference	3.667 (2.696-4.987)	b 0.001

CI, confidence interval; COPD, chronic obstructive pulmonary disease; LVEF, left ventricular ejection fraction.

^a Factors of digoxin use were identified by performing logistic regression analyses, and the following variables were included in the models: age, sex, body mass index, blood pressure, heart rate, atrial fibrillation as a main diagnosis, Type of ATrial fibrillation, myocardial infarction, coronary artery disease, congenital heart disease, valvular heart disease, heart failure, LVEF b45%, hypertension, diabetes mellitus, previous stroke or transient ischemic attack, COPD, dementia, hyperthyroidism, previous major bleeding, smoking.

Table 3

Association between digoxin use and risk of mortality in atrial fibrillation.

Events during follow-up^a, n (%)

Outcome	All patients	Patients treated with digoxin	Patients not treated with digoxin	P value	Hazard ratio (95% CI)	P value	Adjusted hazard ratio (95% CI)b	P value
All-cause mortality	284 (14.3)	105 (17.2)	179 (13.0)	0.012	1.353 (1.063-1.721)	0.014	0.973 (0.718-1.318)	0.858
Cardiovascular mortality	185 (9.3)	92 (15.1)	93 (6.7)	b 0.001	2.349 (1.761-3.133)	b0.001	1.313 (0.905-1.906)	0.152
Sudden cardiac death	17 (0.9)	7 (1.1)	10 (0.7)	0.341	1.590 (0.605-4.177)	0.347	1.398 (0.394-4.958)	0.604

CI, confidence interval.

^a The mean follow-up duration was 1 year.

^b Adjusted for age, sex, body mass index, systolic blood pressure, diastolic blood pressure, heart rate, atrial fibrillation as main diagnosis, type of atrial fibrillation, myocardial infarction, coronary artery disease, congenital heart disease, valvular heart disease, heart failure, left ventricular ejection fraction b45%, hypertension, diabetes mellitus, previous stroke or transient ischemic attack, chronic obstructive pulmonary disease, dementia, hyperthyroidism, previous major bleeding, smoking, warfarin, aspirin, clopidogrel, statin, beta-blocker, Angiotensin converting enzyme inhibitors, angiotensin receptor blocker, calcium channel blocker.

ward, warfarin treatment, COPD, and absence of hypertension as predic- tors related to digoxin treatment [12].

Among patients with HF and AF, the prognostic value of digoxin therapy has been evaluated in plenty of studies, but came into conflict- ing results. Although no impact of digoxin on all-cause or cardiovascular death among patients with HF in sinus rhythm were revealed in the ran- domized DIG trial [4], studies focused on patients with LVEF <= 35% and symptomatic HF resulted in disturbing trends with digoxin use [26, 27]. Rathore et al. explored sex-based discrepancies in the relation of di- goxin to prognosis among HF patients, and stated that digoxin signifi- cantly increased all-cause death among women, but not men [28]. Besides, post hoc analyses from the DIG study revealed the effect of di- goxin on death was affected by serum concentrations, with serum di- goxin levels >= 1.2 ng/ml identified to be associated with 11.8% higher absolute mortality than placebo [29].

In the setting of AF, this issue is still further complicated. In an early analysis of data from the AFFIRM (the AF Follow-Up Investigation of Rhythm Management) study aimed to compare strategies of rate con- trol and rhythm control in AF patients, on-treatment use of digoxin, when treated as a time-dependent covariate in multivariable Cox models, was related to 41%, 35%, and 61% increased risk of all-cause, car- diovascular, and arrhythmic death, respectively [16]. However, ina sub- sequent post hoc analysis of the same population by propensity score matching method, digoxin was no longer related to higher risk of death, hospitalization, or non-fatal cardiac arrhythmias [17], and the conclusions were confirmed by findings from other analyses of the RACE (Rate Control Efficacy in Permanent AF: A Comparison between

Lenient versus Strict Rate Control) II study, the SCAF study, and the AFBAR (Atrial Fibrillation in the BARrbanza area) registry [10,12,15]. Conversely, post hoc analysis of the SPORTIF (Stroke prevention using an ORal Thrombin Inhibitor in atrial Fibrillation) III and V studies com- prising of 7329 AF patients all receiving anticoagulant therapy found that digoxin added all-cause mortality by 53% [19]. Besides, another re- cent analysis of a large-scale RCT evaluating the efficacy and safety of rivaroxaban with 14,171 AF patients indicated that digoxin indepen- dently increased risk of all-cause death, vascular death, and sudden death by 17%, 19%, and 36%, respectively [13]. Moreover, two analyses of AF cohort studies with large sample size, i.e., the TREAT-AF (The Ret- rospective Evaluation and Assessment of Therapies in AF) study and the ATRIA-CVRN (Atrial fibrillation Cardiovascular Research Network) study, revealed that digoxin use was related to 71% and 29% higher death risk than those without digoxin therapy, respectively [5,7].

Our present study extends previous observations and assessed the effect of digoxin on mortality among patients presenting to EDs with a diagnosis of AF, revealing that this disturbing association ultimately lost statistical significance after adjustment for additional prognostic factors, although notably increased risk of all-cause death and cardio- vascular death related to digoxin use was indicated in univariate analy- ses. It should be noted that participants in our study had remarkably worse prognosis than subjects in other AF cohorts with various designs, which might be due to the coexistence of more critical conditions and heavier comorbidities in patients presenting to EDs [9-12]. Moreover, only a total of 1.2% (n = 25) of the patients were lost to follow-up dur- ing a mean follow-up of 1 year in our present study, which therefore

Fig. 1. Unadjusted and adjusted Kaplan-Meier survival curves in patients with atrial fibrillation divided by digoxin use: A) Unadjusted Survival Curve; B) Adjusted Survival Curve.

Table 4

Associations between digoxin use and all-cause mortality in subgroup patients with atrial fibrillation.^a

Model	Unadjusted hazard ratio	95% CI	P value for interaction	Adjusted hazard ratiob	95% CI	P value for interaction
Male	1.609	1.131-2.289	0.201	1.060	0.698-1.609	0.304
Female	1.176	0.845-1.636		0.896	0.604-1.328
Heart failure	0.965	0.696-1.337	0.543	1.406	0.728-1.503	0.614
Without heart failure	1.143	0.731-1.789		0.918	0.571-1.474
LVEF b45%	1.189	0.748-1.889	0.896	1.061	0.612-1.841	0.458
LVEF >= 45%	1.230	0.908-1.665		0.922	0.650-1.308
Valvular heart disease	1.872	0.934-3.749	0.369	1.851	0.813-4.214	0.148
Without valvular heart disease	1.326	0.998-1.763		0.914	0.667-1.251
Warfarin use	2.098	1.044-4.217	0.249	1.405	0.585-3.374	0.249
No warfarin use	1.354	1.040-1.764		0.906	0.667-1.229

CI, confidential interval; HR, hazards ratio; LVEF, left ventricular ejection fraction.

^a The mean follow-up duration was 1 year.

^b Adjusted for age, sex, body mass index, systolic blood pressure, diastolic blood pressure, heart rate, atrial fibrillation as main diagnosis, type of atrial fibrillation, myocardial infarction, coronary artery disease, congenital heart disease, valvular heart disease, heart failure, left ventricular ejection fraction b45%, hypertension, diabetes mellitus, previous stroke or transient ischemic attack, chronic obstructive pulmonary disease, dementia, hyperthyroidism, previous major bleeding, smoking, warfarin, aspirin, clopidogrel, statin, beta-blocker, angiotensin converting enzyme inhibitors, angiotensin receptor blocker, calcium channel blocker.

should not result in a substantial negative effects on our results. In line with prior studies, our digoxin-treated patients were weaker and had worse cardiac function than those without digoxin therapy, and the ab- sence of statistical significance in the adverse impact of digoxin use on death after adjustment for additional covariates indicated the unadjust- ed increased death risk may be more strongly reflect a greater propen- sity to use digoxin in critically ill patients rather than a real increased mortality risk caused by digoxin use. We considered our observation was firm, as independent risk factors of adverse outcomes and predic- tors of digoxin receipt, i.e., BMI, blood pressure, heart rate, comorbidi- ties, and concomitant medications, were all adjusted in the multivariable models as fully as possible. Besides, in contrast to the speculation that increased all-cause mortality related to digoxin use might be partially mediated by its cardiovascular toxicity [16], neither the risk of cardiovascular death or sudden cardiac death with digoxin therapy was remarkably increased in our current study. Moreover, al- though previous studies demonstrated that the relation of digoxin use to mortality might differ when participants were stratified by gender and HF [22,26], our subgroup analyses indicated neutral effect of digox- in use on all-cause death existed in all subgroup patients, and no inter- actions existed between digoxin use and gender, existence of HF, valvular heart disease, or concomitant treatment of warfarin in the risk of all-cause mortality.

Limitations

Several limitations should be mentioned in this study. First, as an ob- servational study with its inherent defects, our results should be viewed with caution and as hypothesis generating. Second, we can not exclude the influence of various serum concentrations of digoxin on the progno- sis due to a lack of collection of relevant data. Another important limita- tion of our present study was that we did not dynamically collect information of digoxin treatment, therefore, we can not confirm wheth- er patients continued digoxin or changed to other medications during the follow-up period, and failed to assess digoxin as a time-dependent covariate to take the impact of digoxin Treatment changes on patients’ survival into account, which might affect the accuracy of our results to a certain extent. Last, although a neutral relation of digoxin therapy and worse prognosis was indicated in multivariate analysis, our results might still be affected by unknown potential confounders, therefore, prospective randomized study is certainly required to confirm our findings.

Conclusions

In our present study, digoxin therapy was not related to significantly increased risk of all-cause mortality, cardiovascular death, and sudden

cardiac death in AF patients presenting to EDs during a mean follow- up of 1 year. Our results indicate that digoxin can be safely used and continued for rate control in AF patients presenting to EDs.

Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ajem.2017.04.070.

Conflict of interest

The authors declare no conflict of interest with respect to this manuscript.

Acknowledgements

This work was supported by J. Zhu and Y. Yang, Fuwai Hospital, Bei- jing; C. Li, Chaoyang Hospital, Beijing; X. Bai, the First Hospital of China Medical University, Shenyang, Liaoning; F. Zhang, Qingdao Municipal Hospital, Shandong; J. Li, Bethune International Peace Hospital, Shijia- zhuang, Hebei; Y. Lu, Rujin Hospital, Shanghai; H. Tang, the Central Hos- pital of Wuhan, Hubei; J. Han, Wuhan Unin Hospital, Hubei; Q. He, West China Hospital, Chengdu, Sichuan; H. Zeng, Guangdong General Hospi- tal, Guangzhou; J. Lu, Guangzhou First Hospital, Guangdong; S. Wang, the First Hospital of Qiqihaer, Heilongjiang; L. Zhao, Fuxing Hospital, Beijing; P. Yu, Pingdu People’s Hospital, Shandong; X. Hui, Pudong Gongli Hospital, Shanghai; S. Liu, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan; X. Zhang, the First People’s Hospi- tal of Yichang, Hubei; X. Gu, the Sixth People’s Hospital of Chengdu, Si- chuan; Z. Zan, the Fourth Hospital of Langfang, Hebei; and H. Zhang, Qingdao Municipal Hospital (East), Shandong, China.

References

1. Chugh SS, Havmoeller R. Narayanan K, at al: worldwide epidemiology of atrial fibril- lation: a global burden of disease 2010 study. Circulation 2014;129:837-47.
2. Kim MH, Johnston SS, Chu BC, et al. Estimation of total incremental health care costs in patients with atrial fibrillation in the United States. Circ Cardiovasc Qual Out- comes 2011;4:313-20.
3. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the manage- ment of patients with atrial fibrillation: a report of the American College of Cardiol- ogy/American Heart Association task force on practice guidelines and the Heart Rhythm Society. Circulation 2014;130:2071-104.
4. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity. N Engl J Med 1997;336:525-33.
5. Turakhia MP, Santangeli P, Winkelmayer WC, et al. Increased mortality associated with digoxin in contemporary patients with atrial fibrillation: findings from the TREAT-AF study. J Am Coll Cardiol 2014;64:660-8.
6. Pastori D, Farcomeni A, Bucci T, et al. Digoxin treatment is associated with increased total and cardiovascular mortality in Anticoagulated patients with atrial fibrillation. Int J Cardiol 2015;180:1-5.
7. Freeman JV, Reynolds K, Fang M, et al. Digoxin and risk of death in adults with atrial

   fibrillation: the ATRIA-CVRN study. Circ Arrhythm Electrophysiol 2015;8:49-58.

   Hallberg P, Lindback J, Lindahl B, et al. Digoxin and mortality in atrial fibrillation: a prospective cohort study. Eur J Clin Pharmacol 2007;63:959-71.

8. Chao TF, Liu CJ, Chen SJ, et al. Does digoxin increase the risk of ischemic stroke and mortality in atrial fibrillation? A nationwide population-based cohort study. Can J Cardiol 2014;30:1190-5.
9. Rodriguez-Manero M, Otero-Ravina F, Garcia-Seara J, et al. Outcomes of a contempo- rary sample of patients with atrial fibrillation taking digoxin: results from the AFBAR study. (English Edition) Rev Esp Cardiol 2014;67:890-7.
10. Allen LA, Fonarow GC, Simon DN, et al. Digoxin use and subsequent outcomes among patients in a contemporary atrial fibrillation cohort. J Am Coll Cardiol 2015;65:2691-8.
11. Friberg L, Hammar N, Rosenqvist M. Digoxin in atrial fibrillation: report from the Stockholm cohort study of atrial fibrillation (SCAF). Heart 2010;9:275-80.
12. Washam JB, Stevens SR, Lokhnygina Y, et al. Digoxin use in patients with atria fibril- lation and adverse cardiovascular outcomes: a retrospective analysis of the rivaroxaban once daily oral direct factor Xa inhibition compared with vitamin K an- tagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF). Lancet 2015;385:2363-70.
13. Shah M, Avgil Tsadok M, Jackevicius CA, et al. Relation of digoxin use in atrial fibril- lation and the risk of all-cause mortality in patients >=65 years of age with versus without heart failure. Am J Cardiol 2014;114:401-6.
14. Mulder BA, Van Veldhuisen DJ, Crijns HJ, et al. Digoxin in patients with permanent atrial fibrillation: data from the RACE II study. Heart Rhythm 2014;11:1543-50.
15. Whitbeck MG, Charnigo RJ, Khairy P, et al. Increased mortality among patients tak-

    ing digoxin-analysis from the AFFIRM study. Eur Heart J 2013;34:1481-8.

    Gheorghiade M, Fonarow GC, van Veldhuisen DJ, et al. Lack of evidence of increased mortality among patients with atrial fibrillation taking digoxin: findings from post hoc propensity-matched analysis of the AFFIRM trial. Eur Heart J 2013;34:1489-97.

16. Fauchier L, Grimard C, Pierre B, et al. Comparison of beta blocker and digoxin alone and in combination for management of patients with atrial fibrillation and heart fail- ure. Am J Cardiol 2009;103:248-54.
17. Gjesdal K, Feyzi J, Olsson SB. Digitalis: a dangerous drug in atrial fibrillation? An analysis of the SPORTIF III and V data. Heart 2008;94:191-6.
18. Okin PM, Hille DA, Wachtell K, et al. Digoxin use and risk of mortality in hyperten- sive patients with atrial fibrillation. J Hypertens 2015;33:1480-6.
19. Chang SS, Chang KC, Wang YC, et al. Digoxin use is associated with increased risk of

    stroke in patients with non-valvular atrial fibrillation-a nationwide population- based cohort study. Int J Cardiol 2013;169:e26-7.

    Matzeu A, Kerr TM, Weiss F, et al. Impact of digoxin on mortality in patients with atrial fibrillation stratified by heart failure: findings from gulf survey of atrial fibril- lation events in the Middle East. J Cardiovasc Pharmacol Ther 2016;21:273-9.

20. Perloff D, Grim C, Flack J, et al. Human blood pressure determination by sphygmo- manometry. Circulation 1993;88:2460-70.
21. Swedberg K, Cleland J, Dargie H, et al. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): the task force for the diag- nosis and treatment of chronic heart failure of the European Society of Cardiology. Eur Heart J 2005;26:1115-40.
22. Otterstad JE, Froeland G, St John Sutton M, et al. Accuracy and reproducibility of bi- plane two-dimensional echocardiographic measurements of left ventricular dimen- sions and function. Eur Heart J 1997;18:507-13.
23. Domanski M, Fleg J, Bristow M, et al. The effect of gender on outcome in digitalis- treated heart failure patients. J Card Fail 2005;11:83-6.
24. Butler J, Anand IS, Kuskowski MA, et al. Digoxin use and heart failure outcomes: re- sults from the valsartan heart failure trial (Val-HeFT). Congest Heart Fail 2010;16: 191-5.
25. Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxin for the treatment of heart failure. N Engl J Med 2002;347:1403-11.
26. Rathore SS, Curtis JP, Wang Y, et al. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA 2003;289:871-8.