Cardiology

Acute management of atrial fibrillation in congestive heart failure with reduced ejection fraction in the emergency department

a b s t r a c t

Introduction: Acute heart Rate control for Atrial fibrillation with rapid ventricular response (RVR) in the emergency department (ED) is often achieved utilizing intravenous (IV) non-dihydropyridine calcium channel blockers (CCB) or Beta blockers (BB). For patients with concomitant heart failure with a reduced ejection fraction (HFrEF), the American Heart Association and other clinical groups note that CCB should be avoided due to their potential negative inotropic effects. However, minimal evidence exists to guide this current recommendation. The primary objective of this study was to compare the incidence of adverse effects in the HFrEF patient popula- tion whose AF with RVR was treated with IV diltiazem or metoprolol in the ED. Methods: This single center, retrospective review included patients >=18 years old with HFrEF who presented in AF with RVR and received IV diltiazem or metoprolol in the ED. The primary outcome was adverse effects of therapy defined as: 1) hypotension (systolic blood pressure < 90 mmHg requiring fluid bolus or vasopressors) or brady- cardia (heart rate < 60 beats/min) within 60 min of medication administration 2) worsening heart failure symp- toms defined as increased oxygen requirements within four hours or inotropic support within 48 h. Secondary outcomes included the incidence of rate control failure, patient disposition, ED length of stay, hospital length of stay, and in-hospital mortality.

Results: One hundred and twenty-five patients met inclusion criteria, with 57 receiving diltiazem and 68 receiv- ing metoprolol. Overall adverse effects for diltiazem and metoprolol were similar (32% vs. 21%, P = 0.217). How- ever, there was a significantly higher incidence of worsening heart failure symptoms within the diltiazem group (33% vs 15%, P = 0.019). Rate control failure at 60 min did not differ significantly between diltiazem and meto- prolol (51% vs 62%, P = 0.277).

Conclusions: In HFrEF patients with AF, there was no difference in total adverse events in patients treated with IV diltiazem compared to metoprolol. However, the diltiazem group had a higher incidence of worsening CHF symptoms defined as increased oxygen requirement within four hours or initiation of inotropic support within 48 h.

(C) 2022

  1. Introduction

Atrial fibrillation and congestive heart failure (CHF) individu- ally affect between three and six million people in the United States [1-3]. When patients have both AF and CHF, their combined mortality risk increases by 14-57% [4]. Results from the AFFIRM trial by Wyse et al. suggest that management with rate control is just as effective as Rhythm control while minimizing medication adverse effects [5]. Acute rate control in the emergency department (ED) is often achieved utilizing intravenous (IV) non-dihydropyridine calcium channel blockers (CCB) or beta blockers (BB) [1,6]. For patients with

* Corresponding author.

E-mail address: [email protected] (T.T. Nguyen).

concomitant heart failure with a reduced ejection fraction (HFrEF), the American Heart Association and other clinical groups note that CCB should be avoided, due to their potential negative inotropic effects [1,6,7]. However, minimal evidence exists to guide these current recom- mendations. Patients who present to the ED in acute AF with rapid ven- tricular response (RVR) may not have their CHF history fully elucidated and be treated with a CCB. A recent study of 48 patients evaluated dilti- azem versus metoprolol for acute rate control in patients with HFrEF and found no differences in successful rate control at 30 min and re- ported no variation in adverse effects between the two groups, includ- ing hypotension, bradycardia, and worsening CHF [8]. The primary objective of this study was to compare the incidence of adverse effects in a larger HFrEF patient population whose AF with RVR was treated with IV diltiazem or metoprolol in the ED.

https://doi.org/10.1016/j.ajem.2022.03.058

0735-6757/(C) 2022

  1. Methods

Met inclusion criteria n = 125

Excluded Patients:

21 did not receive medication in the ED 13 did not have AF with RVR

5 prisoners

4 included in alternate encounter 1 did not receive within 12 hr

Patients reviewed N = 169

Metoprolol n = 68

Diltiazem n = 57

    1. Study design

This was a single-center, retrospective study of patients with HFrEF who received diltiazem or metoprolol for acute management of AF with RVR in the ED between January 1, 2018 and December 31, 2019. This health system is a level 1 trauma center that sees over 105,000 pa- tients per year. The local institutional review board approved the study. Patients were included if they were 18 years of age or older, pre- sented to the ED in AF with RVR, had an order for IV diltiazem or meto- prolol within 12 h of arrival, and a formal echocardiogram with a documented EF <= 40% during that same encounter. Patients were ex- cluded if they did not receive the rate control agent in the ED, were pregnant, or incarcerated at the time of presentation. If patients were treated for AF with RVR in the ED multiple times during the review, all repeat encounters were removed from the study and only the first

encounter was used.

    1. Study outcomes

The primary outcome of adverse effects was defined as hypotension, bradycardia, or worsening heart failure symptoms within a specific time period of diltiazem or metoprolol administration. Hypotension was de- fined as a systolic blood pressure (SBP) of less than 90 mmHg requiring a fluid bolus or vasopressors (norepinephrine, epinephrine, dopamine, or vasopressin) within 60 min of ED intervention. Bradycardia was a heart rate of less than 60 beats/min within 60 min of ED intervention. Worsening heart failure symptoms were defined as an increase in

Fig. 1. Patient flow diagram.

classified as NYHA heart failure class II or III. Patients who were on a ?-blocker at home were more likely to receive metoprolol IV for acute HR control compared to diltiazem (81% vs 58%, P = 0.006).

Table 1

Baseline characteristics.

their oxygen requirement by at least two liters within four hours or the initiation of an inotrope within 48 h of ED intervention.

Characteristic Diltiazem

(n = 57)

Metoprolol (n = 68)

P-value

Secondary outcomes included characterizing the incidence of rate con- trol failure, admission level of care, ED length of stay, hospital length of stay, and in-hospital mortality. Rate control failure was defined as a

Age in years, mean +- SD 59 +- 15 65 +- 13 0.027

Male sex, n (%) 44 (77) 51 (75) 0.835

Race

– Caucasian, n (%) 22 (39) 33 (49)

heart rate > 110 beats/min at 60 min, a change in rate control agent within

60 min, or administration of electrical cardioversion within 60 min.

    1. Statistical analysis

Descriptive statistics were used to evaluate the baseline data. For the two-group analysis of diltiazem and metoprolol, descriptive statistics and student’s t-tests were used to report normally distributed continu-

– African American, n (%) 33 (58) 33 (49)

– Hispanic, n (%) 1 (2) 1 (1)

– Asian, n (%) 1 (2) 1 (1)

Weight in kg, mean +- SD

98.6 +- 35.4

99.4 +- 31.9

0.903

Type of Heart Failure

19 (33)

35 (51)

0.131

– Systolic, n (%) 11 (19) 6 (8)

– Diastolic, n (%) 0 (0) 1 (1)

– Both systolic and diastolic HF, n (%) 27 (47) 26 (38)

– Unknown 24 (42) 33 (48.5)

0.743

ous data, while incidence (%) and Chi-square tests were performed for dichotomous outcomes. Univariate logistic regression was used to iden- tify the characteristics that were associated with adverse effects and therefore eligible for inclusion in a final, multivariable model. Per the modeling strategy presented by Hosmer et al., a liberal P-value of 0.15 was used to identify these potential confounders [9]. Multivariable lo-

Ejection fraction % in last 12 months, mean 15 (26) 17 (25) 0.542

NYHA Classification Reported, yes (%)

– Class I, n (%) 0 (0) 1 (1)

– Class II, n (%) 7 (12) 9 (13) 0.545

– Class III, n (%) 7 (12) 7 (10)

– Class IV, n (%) 1 (2) 0 (0)

Comorbidities

– Coronary artery disease (CAD), n (%) 12 (21) 17 (25) 0.673

gistic regression was used to control for these confounding characteris-

– Asthma/COPD, n (%)

15 (26)

11 (16)

0.189

tics while modeling the association between medication selection and

– History of atrial fibrillation/flutter, n (%)

36 (63)

52 (76)

0.119

adverse effect [10]. An a priori ? level of <=0.05 was used to determine statistical significance. Statistical Package for the Social Sciences (SPSS) version 26 was used for all the statistical analyses.

Home medications

  • Beta blocker, n (%)
  • Calcium channel blocker, n (%)
  • ACEi/ARB, n (%)

33 (58)

7 (12)

26 (46)

55 (81)

6 (9)

29 (43)

0.006

0.568

0.857

– Digoxin, n (%)

1 (2)

3 (4)

0.625

3. Results

– Amiodarone, n (%)

6 (11)

7 (10)

1.000

Loop diuretic, n (%)

20 (35)

35 (51)

0.073

3.1. Baseline characteristics

– Anticoagulation, n (%)

– Warfarin, n (%)

3 (5)

9 (13)

0.222

One hundred and sixty-nine patients were screened for eligibility.

One hundred and twenty-five patients met inclusion criteria, with 57 receiving diltiazem and 68 receiving metoprolol (See Fig. 1). The mean

age was 62 years, 76% were male, and the average weight was 99.3 kg

– <48 h, n (%)

– >48 h, n (%)

– Unknown, n (%)

Initial heart rate in bpm, mean +- SD

7 (12)

5 (9)

45 (79)

144 +- 21

9 (13)

7 (10)

52 (76)

140 +- 17

0.941

0.184

(See Table 1). For the analysis of diltiazem compared to metoprolol,

the groups were well balanced in terms of demographics, except for

initial systolic blood pressure in mmHg, mean +- SD

138 +- 22

130 +- 22

0.055

– DOAC, n (%)

24 (42)

29 (43)

1.000

Duration of atrial fibrillation

baseline age (59 years vs. 65 years, P = 0.027). The average ejection fraction of patients included in the study was 16% with most patients

Initial diastolic blood pressure in mmHg, mean +- SD

100 +- 23 90 +- 21 0.008

Table 2

Primary outcome – adverse effects of therapy.

Table 4

medication dosing.

Adverse effects of therapy

Diltiazem

Metoprolol

P-value

Dosing variable

Diltiazem

Metoprolol

P-value

(n = 57)

(n = 68)

(n = 57)

(n = 68)

Composite of all adverse events, n (%)

18 (32)

14 (21)

0.217

Initial dose

N/A

Incidence of hypotension within 60 min,

– Actual dose in mg, mean +- SD

16 +- 6.9

4.9 +- 0.5

n (%)

– Weight-based dose in mg/kg,

0.18 +- 0.07

– Systolic BP < 90 mmHg, n (%)

4 (7)

9 (13)

0.379

mean +- SD

– Requiring a fluid bolus, n (%)

0 (0)

6 (9)

0.070

Received subsequent doses, n (%)

15 (26)

10 (15)

0.121

– Requiring vasopressors, n (%)

0 (0)

1 (1)

1.000

– Total actual dose in mg, mean +- SD

30 +- 12

11 +- 2

N/A

HR < 60 bpm within 60 min, n (%)

0 (0)

0 (0)

N/A

– Total weight-based dose (mg/kg),

0.31 +- 0.12

0.11 +- 0.03

N/A

Worsening CHF symptoms, n (%)

19 (33)

10 (15)

0.019

mean +- SD

– Increased oxygen requirement within 4 h,

15 (26)

9 (13)

0.072

Continuous infusion within 4 h, n (%)

23 (40)

10 (15)

0.002

n (%)

Oral therapy administered within 4 h, n (%)

21 (37)

22 (32)

0.706

– Inotrope administration within 48 h, n (%)

5 (9)

1 (1)

0.092

3.2. Primary outcome

For the composite adverse event outcome there was no difference between patients treated with diltiazem or metoprolol (32% vs 21%, P

= 0.217) (Table 2). However, there was a statistically significantly higher incidence of worsening CHF symptoms in the diltiazem treat- ment group compared to metoprolol (33% vs. 15%, P = 0.019) as de- scribed by an increased oxygen requirement within four hours of the intervention (26% vs 13%) and requirement of an inotrope within 48 h of ED intervention (9% vs 1%).

3.3. Secondary outcomes

There was no difference in rate control failure between diltiazem and metoprolol (51% vs. 62%, P = 0.277) (Table 3). Although overall treatment failure was similar, patients who received diltiazem had lower average heart rate 60 min after the ED intervention (109 beats/ min vs. 117 beats/min, P = 0.028). No differences were observed in admission level of care, ED length of stay, hospital length of stay, or in-hospital mortality.

When looking at the dose of medication in the ED, most patients re- ceived an initial dose of 0.2 mg/kg of diltiazem (0.18 +- 0.07) and 5 mg of metoprolol (4.9 +- 0.5) (Table 4). Twenty-six percent of diltiazem pa- tients and 15% of metoprolol patients required a subsequent dose within 60 min (P = 0.121).

Using a multiple regression, it was identified that no indepen- dent predictors of adverse events were present between rate control agents when the following variables were accounted for: age, sex, race, type of heart failure, NYHA Classification, coronary artery disease, asthma/COPD, history of AF, and duration of active AF (P = 0.996).

Table 3

Secondary outcomes.

  1. Discussion

Atrial fibrillation with RVR in the HFrEF population is a frequent ED presentation, accounting for more than 450,000 ED visits annually [3]. While guidelines recommend against the use of diltiazem in this patient population, there is minimal evidence and the effect of diltiazem on clinical outcomes is not clear [1,6,8]. Roy et al. compared chronic rate control with rhythm control and found no differences in rates of cardio- vascular death or worsening CHF, but increased rates of hospitalizations with rhythm control; supporting the use of rate control in this popula- tion [9]. More specifically to CCB use, Jandali et al. evaluated patients who were treated for AF with a continuous infusion of diltiazem, strat- ified by whether they had preserved or reduced ejection fractions. No differences in hypotension were observed, although those with HFrEF did experience acute kidney injury more frequently [7]. Most recently, Hirschy et al. retrospectively reviewed the ability of metoprolol and diltiazem to achieve successful rate control in the HFrEF population in 48 patients [8]. They found no difference in this primary outcome. The study also reported no significant differences in hypotension, bradycardia, conversion to sinus rhythm, or signs of worsening heart failure as secondary endpoints. Our current study contradicts the conclusion by Hirschy et al. by finding that patients in the diltiazem group had a higher incidence of worsening heart failure symptoms in comparison to metoprolol.

Biases in initial treatment selection were evident in the baseline characteristics (Table 1). Patients who received diltiazem were younger (59 years vs. 65 years, P = 0.027) and possessed higher baseline blood pressures. Conversely, metoprolol was preferred in patients who were on ?-blockers at home (P = 0.006). There was no difference in the inci- dence of total adverse effects between diltiazem and metoprolol (32% vs. 21%, P = 0.217). However, the diltiazem treatment group had an in- creased incidence of worsening CHF symptoms defined as increasing oxygen requirement within four hours and inotrope administration within 48 h (33% vs. 15%, P = 0.019). Future Prospective trials are needed to validate the causality of these findings.

Overall, this study has several limitations. Its retrospective nature

limits sample size and abstraction. The sample size is relatively small,

Endpoint Diltiazem

(n = 57)

Rate control failure, n (%)

29 (51)

42 (62)

0.277

– HR > 110 bpm at 60 min, n (%)

27 (47)

39 (57)

0.285

– Change in therapeutic agent within 60 min,

2 (4)

6 (9)

0.289

n (%)

– Electrical cardioversion within 60 min,

0 (0)

0 (0)

n (%)

Heart rate at 60 min, mean +- SD

109

117

0.028

Admission level of care

0.538

– General, n (%)

19 (33)

22 (32)

– Step-down, n (%)

29 (51)

30 (44)

– Intensive Care Unit, n (%)

9 (16)

16 (24)

ED LOS in hours, mean +- SD

7.3

7.3

0.964

Hospital LOS in days, mean +- SD

7.9

8.7

0.441

In-hospital mortality, n (%)

2 (4)

6 (9)

0.289

Metoprolol (n = 68)

P-value

though larger than previous studies [8]. Due to the acuity of the ED there may have been inconsistent documentation of fluid boluses that could have affected the number of adverse effects. The statistically sig- nificant differences in the baseline characteristics also suggest a poten- tial selection treatment bias. Lastly, the rate control outcome was defined absolutely as a heart rate of less than 110 beats/min. Other rate control studies have also utilized an absolute 20% reduction in heart rate [8,13,14].

  1. Conclusion

There was no difference in total adverse effects between HFrEF patients treated with diltiazem or metoprolol for the management of acute AF. However, patients treated with diltiazem had a higher

incidence of worsening CHF symptoms defined as increased oxygen requirement within four hours or initiation of inotropic support within 48 h.

Credit authorship contribution statement

Michael Hasbrouck: Data curation, Formal analysis, Investigation, Methodology, Writing – original draft. Tammy Nguyen: Conceptualiza- tion, Formal analysis, Investigation, Methodology, Project administra- tion, Supervision, Validation, Writing – review & editing.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influ- ence the work reported in this paper.

References

  1. 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. J Am Coll Cardiol. 2014;64:e1-76.
  2. Chamberlain AM, Redfield MM, Alonso A, Weston SA, Roger VL. Atrial fibrillation and mortality in heart failure: a community study. Circ Heart Fail. 2011;4(6):740-6.
  3. Virani SS, Alonso A, Benjamin EJ, et al. Heart disease and stroke Statistics-2020 up- date: a report from the American Heart Association. Circulation. 2020;141: e139-596.
  4. Kotecha D, Piccini JP. Atrial fibrillation in heart failure: what should we do? Eur Heart J. 2015;36(46):3250-7.
  5. Wyse DG, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. New Eng J Med. 2002;347(23):1825-33.
  6. Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, et al. 2016 ESC guide- lines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 2016;37(38):2893-962.
  7. Jandali MB. Safety of Intravenous diltiazem in reduced ejection fraction heart failure with rapid atrial fibrillation. Clin Drug Investig. 2018;38(6):503-8.
  8. Hirschy R, Ackerbauer KA, Peksa GD, O’Donnell EP, DeMott JM. Metoprolol vs. dilti- azem in the acute management of atrial fibrillation in patients with heart failure with reduced ejection fraction. Am J Emerg Med. 2019;37(1):80-4.
  9. Roy D, Talajic M, Nattel S, et al. Rhythm control versus rate control for atrial fibrilla- tion and heart failure. N Engl J Med. 2008;358:2667-77.
  10. Hosmer DW, Lemeshow S, Sturdivant RX. Applied logistic regression. Hoboken, NJ: John Wiley & Sons, Inc; 2013..
  11. Demircan C, Cikriklar HI, Engindeniz Z, et al. Comparison of the effectiveness of in- travenous diltiazem and metoprolol in the management of rapid ventricular rate in atrial fibrillation. Emerg Med J. 2005;22(6):411-4.
  12. Wang HE, O’Connor RE, Megargel RE. The use of diltiazem for treating atrial fibrilla- tion in the out-of-hospital setting. Ann Emerg Med. 2001;37:38-45.

Interviews made during field work in 2012

  1. Page RL, O’Bryant CL, Cheng D, et al. Drugs that may cause or exacerbate heart fail- ure: a scientific statement from the American Heart Association. Circulation. 2016; 134(6):e32-9.
  2. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. J Am Coll Cardiol. 2013;62(16): e147-239.

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