a b s t r a c t

Objective: Compare heart Rate control between parenteral metoprolol and diltiazem and identify Safety outcomes in the acute management of Atrial fibrillation with rapid ventricular response (RVR) in patients with heart failure with reduced ejection fraction (HFrEF).

Methods: This retrospective, single-center, cohort study included adult patients with HFrEF who received intra- venous (IV) metoprolol or diltiazem for AFib RVR in the emergency department (ED). The primary outcome was rate control defined as HR <100 bpm or a HR reduction >=20% within 30 min of first dose administration. The secondary outcomes included rate control within 60 min and 120 min from first dose, need for repeat dosing, and disposition. Safety outcomes included hypotensive and bradycardic events.

Results: Out of 552 patients, 45 patients met the inclusion criteria with 15 in the metoprolol group and 30 in the diltiazem group. Using bootstrapping method, patients treated with metoprolol were equally able to reach the primary outcome as those treated with diltiazem (BCa 95% CI: 0.14, 4.31). Hypotensive and bradycardia events remained zero in both groups.

Conclusion: Our study provides further evidence that short term use of diltiazem is likely as safe and effective as metoprolol in the acute management of HFrEF patients with AFib RVR and provides support for the use of non- dihydropyridine calcium channel blockers (non-DHP CCBs) in this patient population.

(C) 2023

1. Introduction

Atrial fibrillation (AFib) and heart failure often coexist and po- tentiate one another due to shared and synergistic pathophysiological processes. [1] A sustained Rapid ventricular rate , defined by a heart rate (HR) of >=120 beats per minute (bpm) in the setting of AFib, can induce left ventricular dysfunction if left untreated. As one of the few Reversible causes of heart failure, the need for efficient yet rapid ventricular control is often the primary goal of therapy. Intravenous

(IV) Beta blockers (BBs) and non-dihydropyridine calcium channel blockers (non-DHP CCBs) are first line agents in the management of AFib RVR in Hemodynamically stable patients without heart failure. [2] However, there is no clear consensus on how best to treat AFib RVR pa- tients with concomitant HFrEF. The current 2022 AHA/ACC/HFSA heart failure guideline does not recommend CCBs as routine treatment in pa- tients with HFrEF and emphasizes the cardiac risks associated with the Long-term treatment of non-DHP CCBs. [3] The latest update to the

* Corresponding author at: Riverside University Health System, 26520 Cactus Ave, Moreno Valley, CA 92555, USA.

E-mail address: [email protected] (M. Choi).

2014 AHA/ACC/HRS AFib guideline recommends both BBs and non- DHP CCBs for the acute management of AFib in patients with heart fail- ure with preserved ejection fraction (HFpEF) but does not clearly pro- vide guidance for patients with HFrEF. [4] The current HF guideline recommendation stems from literature that reported increased inci- dence of cardiac mortality or recurrent infarction in HFrEF patients on chronic diltiazem therapy, while the chronic use of beta blockers pro- vided neurohormonal benefit, delayed HF progression, and reduced mortality. As a result, the current AFib and HF treatment guidelines do not directly translate to the clinical management of acute short-term treatment of AFib RVR in the HFrEF setting creating a lack of guidance on the use of non-DHP CCBs in this patient population.

Literature comparing the use of IV diltiazem compared to metopro- lol in the acute management of AFib RVR in HF patients is very limited. However, available literature slightly supports a more rapid achieve- ment of successful rate control with diltiazem in hemodynamically sta- ble patients without heart failure. [5] Hirschy et al. demonstrated IV diltiazem reached similar rate control to IV metoprolol with no differ- ence in adverse events when used for the short-term, acute manage- ment of AFib with RVR in HFrEF patients. [6] A study by Compagner et al. showed similar results of no difference in rate control at 30 min

https://doi.org/10.1016/j.ajem.2023.02.019

0735-6757/(C) 2023

or safety outcomes between the two medications in patients with heart failure. This outcome was the same for a subgroup of patients with HFrEF. [7] On the other hand, another study found a higher incidence of HF exacerbation among the diltiazem group when using diltiazem to manage AFib RVR. [8] Given recent findings, this study aims to com- pare HR control between parenteral metoprolol and diltiazem and fur- ther elucidate safety outcomes in the acute management of AFib RVR with HFrEF.

1. Methods
   1. Study design

This was a retrospective, single center, cohort study at an academic medical center. Reports were electronically generated for adult patients with HF and AFib (International Classification of Diseases 9th /10th revi- sion (ICD-9/10)) who received at least 1 dose of IV metoprolol or IV dil- tiazem in the emergency department (ED) from 07/01/2017-07/01/ 2021. This study was approved by the RUHSMC Institutional Review Board Committee.

• 1. Patients

Inclusion criteria consisted of patients of at least 18 years of age with an ejection fraction (EF) of <=40% prior to first dose administration, a di- agnosis of AFib, HR of >=120 bpm prior to first dose administration, and receipt of IV metoprolol or IV diltiazem in the ED for AFib RVR. Ex- clusion criteria included a HR >= 220 bpm, systolic blood pressure (SBP) < 90 mmHg prior to first dose administration, receipt of amioda- rone or digoxin prior to first dose administration, crossover receipt of treatment medications within 120 min of first dose administration, pregnant patients, prisoners, and discharge within 24 h due to expira- tion, transfer or leaving against medical advice.

• 1. Methodology

After receiving approval from RUHSMC Institutional Review Board, medical records were reviewed for specified inclusion and exclusion criteria. Data were collected and recorded in the Research Electronic Data Capture (REDCap) database at RUHSMC. Data extracted included age, sex, weight, EF, diastolic blood pressure , SBP, mean arterial pressure (MAP), Home medications (metoprolol, diltiazem, none), HR (baseline, within 30, 60, 120 min), dose timing and frequency of study medications, hypotensive events, bradycardic events, and disposition. Time of first dose administration was defined as time zero. Blood pres- sure readings were obtained from an Arterial line whenever possible. Assuming 80% power with an a priori alpha level of 0.05 and treatment effect of 12%, the initial sample size was calculated to be 415.

• 1. Outcomes

The primary outcome was rate control defined as HR <100 bpm or a HR reduction >=20% within 30 min of first dose administration. The sec- ondary outcomes included a HR <100 bpm or HR reduction >=20% within 60 min and 120 min from first dose, mean first dose in milligram, need for repeat dosing, and disposition. Safety outcomes included hypoten- sive events (defined as SBP <90 mmHg or initiation of vasopressors within 60 min) and bradycardia (defined as HR <60 bpm or initiation of inotropic agents within 60 min). Vasopressor agents included norepi- nephrine, epinephrine, vasopressin, dopamine, phenylephrine, and an- giotensin II. Inotropic agents included dobutamine and milrinone.

• 1. Analysis

Statistical analysis was performed and completed on Statistical Pack- age for the Social Sciences (SPSS) software. Unadjusted odds ratios were

used for categorical data and independent t-tests for continuous data. Categorical data were reported as frequencies and percentages, and continuous data as mean +- standard deviation. To optimize the current sample size, the statistical technique of bootstrapping was used to per- form approximately 1000 simulated resamplings of patients who met inclusion criteria.

1. Results

Out of 552 patients, 45 patients met the inclusion criteria with 15 and 30 in the metoprolol and diltiazem group, respectively. The most common reason for exclusion was a baseline EF >40% followed by a lack of previously documented EF (Table 1). The mean age was

59.4 years and 71.1% were male, with an average EF of 25.8% and base- line HR of 136.3 beats per minute. Baseline characteristics were similar with no statistically significant difference in age, sex, weight, EF, SBP, MAP, home medications, and baseline HR. According to Table 2, after employing the method of bootstrapping, patients treated with IV meto- prolol and IV diltiazem were equally likely to impact each of the out- comes spelled out in this table. This is indicated by the value of 1.00 contained between the lower and upper BCa (bias corrected and accel- erated) 95% confidence interval.

The primary outcome was reached by 40% of the metoprolol group and 46.7% of the diltiazem group (BCa 95%CI: 0.14, 4.31) (Fig. 1). There was no statistically significant difference in any secondary out- comes including Heart rate control at 60 min (40% metoprolol vs 56.7% diltiazem, BCa 95% CI 0.05, 3.33) and 120 min (40% metoprolol vs 66.7% diltiazem, BCa 95% CI 0.09, 1.15), need for repeat dosing, and dis- position after ED (Table 3). The mean first dose for IV metoprolol was 7 mg +- 5.3 mg and 11.4 mg +- 4.7 mg in the diltiazem group. The most common reason for ICU level of care was due to uncontrolled tachycardia or decompensated chronic heart failure. There was no sta- tistically significant difference in any safety outcomes (Table 4). There was no incidence of hypotension or bradycardia within 60 min of first dose administration.

1. Discussion

BBs and non-DHP CCBs continue to be first line agents in the man- agement of AFib RVR in hemodynamically stable patients without heart failure. Although there is no clear guidance on the use of non- DHP CCBs in HFrEF patients in the acute management of AFib RVR, there is literature that demonstrates the safety and efficacy of IV diltia- zem in the acute setting of heart failure. With similar baseline EF to our study (> 20%), Hirschy et al. found no significant differences regarding successful rate control within 30 min and associated adverse events.

[6] Compagner et al. also found no significant differences between dilti- azem and metoprolol in heart rate control at 30 min and safety

Table 1

Exclusion criteria.

Exclusion Criteria Amount

Transferred to another facility 1

Another medication was used for AFib 1

Administered during a code 2

Deceased 3

Left AMA <24 h 3

Crossover receipt of medications within 120 min of first dose 6

Receipt of amiodarone or digoxin prior to receipt of metoprolol or 7

diltiazem

Vitals not recorded 13

Prisoner 14

HR <120 prior to administration 14

Not given for AFib RVR 23

Not given in ED 63

EF unknown 169

EF >40% 188

Table 2

Baseline characteristics.
Outcome - M (SD)	Metoprolol	Diltiazem	Mean difference	BCa95%CI
	n = 15	n = 30
Age (years)	59.8 (10.6)	59.2 (9.3)	0.6	-5.5, 6.6
Male?	11 (73.3)	21 (70.0)	1.18?	0.27, 5.80
Weight (kg)	98.3 (27.2)	85.3 (28)	13.0	-4.9, 28.9
Ejection fraction (%)	28.9 (7.8)	24.3 (9.2)	4.6	-0.6, 9.1
SBP (mmHg)	136.9 (21.0)	131.6 (16.9)	5.3	-6.8, 17.5
MAP (mmHg)	111.9 (22.6)	106.8 (16)	5.1	-5.2, 15.8
Baseline HR (bpm)	137.2 (15.4)	135.9 (15)	1.3	-7.8, 10.1
Home Medication?	n = 7	n = 11
Metoprolol	6 (85.7)	10 (90.9)	0.60?	0.11, 3.43
Diltiazem	1 (14.3)	1 (9.1)

Definitions: CI: Confidence interval, SBP: Systolic blood pressure, MAP: Mean arterial pressure, HR: heart rate, SD: standard deviation, bpm: beats per minute.

* Data for categorial variables are presented as no. (%) and odds ratio.

Table 4

Safety outcomes.

Outcome - no (%)	Metoprolol	Diltiazem
Hypotensive events within 60 min	0	0
Bradycardia within 60 min	0	0

Fig. 1. Primary outcome.

outcomes in patients with AFib and HF. Diltiazem had a greater heart rate reduction at both 30 min and 60 min after medication adminis- tration. These results were preserved in the subgroup analysis of HFrEF patients. [7] In a study by Hasbrouck et al., patients treated by diltiazem were more likely to have increased oxygen requirement within 4 h and initiation of an inotrope within 48 h. [8] It is worth noting that these safety outcomes only reached statistical signifi- cance as a composite endpoint. Furthermore, their study included patients with lower mean EF (15-17%) and up to 40% of the diltia- zem group received a continuous infusion within 4 h for the manage- ment of AFib. Given these noteworthy differences, we believe our study findings still hold true and further corroborate the conclusions of Hirschy et al. and Compagner et al. However, it remains a great clinical interest to investigate the safety outcomes of diltiazem in HFrEF patients with EF < 20%.

Although digoxin and amiodarone are also used in the management of AFib RVR, they are not utilized as first line agents at our institution. Digoxin’s slower onset of action, increased risk of mortality and amiodarone’s side effect profile deem them less favorable. Conse- quently, we excluded patients who received amiodarone or digoxin prior to study medications, as our purpose was to solely evaluate the safety and efficacy of diltiazem in this patient population.

Our study was not without limitations. Due to the nature of a retro-

spective study, there was inconsistency in the recording of vitals, and a lack of a standardized protocol for selection of medication, dose, and timing of administration. Such decisions were all based on provider preference. Moreover, although four years of data were gathered, the study was severely underpowered due to the specificity of the inclusion criteria. To address this limitation, bootstrapping was employed as de- scribed above. In addition, it is possible that the most optimal dose of study medications was not utilized. Our providers use flat based dosing at our institution, and as a result, the mean first dose of both medica- tions was different than guideline recommended dosing in both groups. Although our study did not utilize weight-based dosing, it reflects real- world practice.

1. Conclusion

Our study provides further evidence that short term use of diltiazem is likely as safe and effective as metoprolol in the acute management of HFrEF patients with AFib RVR and provides support for the use of non-

Table 3

Secondary outcomes.

Outcome - no. (%) Metoprolol Diltiazem Odds Ratio BCa 95% CI Heart rate control within 60 min 6 (40) 17 (56.7) 0.51 0.05, 3.33

Heart rate control within 120 min 6 (40) 20 (66.7) 0.33 0.09, 1.15 Mean 1st dose, mg - mean +- SD 7 +- 5.3 11.4 +- 4.7 N/A N/A Need for repeat dosing: second dose 6 (40) 12 (40) 1.00 0.26, 4.35

Need for repeat dosing: third dose 1 (6.67) 3 (10) 0.64 0.26, 5.64 Disposition

• ICU
• Non-ICU
• Discharged

6 (40)

9 (53.33)

0 (0)

5 (16.7)

20 (66.7)

5 (16.7)

2.67 0.44, 27.66

Definitions: CI: Confidence interval, SD: standard deviation, bpm: beats per minute, ICU: intensive care unit.

dihydropyridine calcium channel blockers (non-DHP CCBs) in this patient population.

1. Future directions

Further support of these outcomes could be discerned through a prospective, multicenter study design with a 1:1 randomized cohort, weight-based dosing, and strict monitoring of vitals and congestive heart failure (CHF) symptoms adjusting for covariates. Further investi- gation into different tiers of EF may be beneficial in deciphering the best candidate for diltiazem.

Funding

This research did not receive any specific grant from funding agen- cies in the public, commercial, or not-for-profit sectors.

CRediT authorship contribution statement Karolina Kapustova: Writing - review & editing, Writing - original

draft, Project administration, Investigation, Data curation. Brian Phan: Writing - review & editing, Project administration, Methodology, Formal analysis, Conceptualization. Timothy-Allison Aipa: Writing - review & editing, Software, Formal analysis. Mia Choi: Writing - review & editing, Writing - original draft, Supervision, Project administration, Methodology, Data curation, Conceptualization.

Declaration of Competing Interest

None.

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