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. 2020 Jun 3;56(5):519–524. doi: 10.1177/0018578720925388

The Safety and Efficacy of Verapamil Versus Diltiazem Continuous Infusion for Acute Rate Control of Atrial Fibrillation at an Academic Medical Center

Charlotte M Forshay 1, J Michael Boyd 1, Alan Rozycki 1, Jeffrey Pilz 1,
PMCID: PMC8554608  PMID: 34720155

Abstract

Purpose

Due to critical shortages of intravenous diltiazem in 2018, the Ohio State University Wexner Medical Center (OSUWMC) adopted intravenous verapamil as an alternative. However, there is a paucity of data supporting the use of intravenous verapamil infusions for rate control in the acute treatment of atrial arrhythmias. The purpose of this study was to determine the safety and efficacy of intravenous verapamil as compared with diltiazem for the acute treatment of atrial arrhythmias.

Methods

This retrospective, case-control study compared patients who received verapamil infusions between June 1 and September 30, 2018, with patients who received diltiazem infusions between June 1 and September 30, 2017, at OSUWMC. Patients were matched 1:1 based on age, sex, and the presence of comorbid heart failure with reduced ejection fraction (≤40%).

Results

A total of 73 patients who received at least 1 verapamil infusion and 73 patients who received at least 1 diltiazem infusion met inclusion criteria. The composite need for inotrope or vasopressor was similar for both groups (5% with verapamil versus 4% with diltiazem, P = .999). The rate of hypotension was similar between groups (37% versus 33% experiencing a systolic blood pressure <90 mm Hg, P = .603, and 27% versus 23% experiencing a mean arterial pressure <65 mm Hg, P = .704), as was the rate of bradycardia (19% versus 18%, P = .831). The efficacy outcomes of this study were similar for both groups, with 89% of patients in the verapamil group and 90% of patients in the diltiazem group achieving a heart rate less than 110 beats per minute (P = .785).

Conclusion

Intravenous verapamil and diltiazem infusions had similar safety and efficacy outcomes when used for acute treatment of atrial arrhythmias in the institutional setting.

Keywords: cardiac agents, cardiovascular, intravenous therapy

Introduction

Atrial fibrillation is a supraventricular tachyarrhythmia characterized by uncoordinated atrial activation and ineffective atrial contraction, leading to an increased ventricular rate. The American College of Cardiology/American Heart Association guidelines recommend the use of an intravenous beta-blocker or nondihydropyridine calcium channel blocker to slow the ventricular rate in the acute setting. The nondihydropyridine calcium channel blockers, including diltiazem and verapamil, block L-type calcium channels of cardiac muscle to decrease atrioventricular node conduction and slow the ventricular rate. Intravenous infusions of both diltiazem and verapamil can be used to achieve ventricular rate control in patients with atrial fibrillation or atrial flutter. 1

Diltiazem has been shown to be safe and effective for controlling ventricular response in acute atrial fibrillation. 2 6 Verapamil is also effective in achieving ventricular rate control in patients with atrial fibrillation and atrial flutter. 6 9 A retrospective review of 10 patients with atrial tachyarrhythmias found that intravenous verapamil infused at a mean rate of 9.4 mg/h led to a significant reduction in the ventricular rate. While the study found no significant reduction in mean arterial pressure (MAP), 1 patient reported dizziness with a decrease in MAP from 90 mm Hg to 70 mm Hg. 7 A second prospective, double-blind cross-over study included 17 patients with atrial arrhythmias and a ventricular rate greater than 120 beats per minute (bpm) randomized to receive an 8-hour continuous infusion of either verapamil or diltiazem, followed by a washout period and cross-over to the other agent. This study found that both calcium channel blockers resulted in similar reductions in ventricular rates (97 bpm with verapamil versus 96 bpm with diltiazem) and no significant change in blood pressure. However, 3 patients originally randomized to receive verapamil developed symptomatic hypotension, 1 of which was life-threatening. 6 Overall, limited data suggest that verapamil may increase the risk of symptomatic hypotension.6,7 Because diltiazem is thought to have less significant hypotensive and negative inotropic effects as compared with verapamil, intravenous diltiazem is the preferred calcium channel blocker for acute rate control in clinical practice.10,11 In addition, verapamil has more significant drug-drug interactions as compared with diltiazem, further supporting the preferential use of diltiazem for this indication. 11 13

In recent years, the increasing number, severity, and duration of sterile injectable drug shortages have significantly affected health care organizations and patient care. Hospitals manage drug shortages through both operational and therapeutic strategies. Therapeutic strategies for managing drug shortages include restricting the use of the medication and identifying potential therapeutic alternatives. 14 The Ohio State University Wexner Medical Center (OSUWMC) is cognizant of the need to maintain inventory of critical pharmaceutical agents even in times of shortage. The OSUWMC Drug Shortage Committee meets regularly to develop operational and therapeutic strategies for managing drug shortages.

In February of 2018, the United States Food and Drug Administration reported a national shortage of diltiazem injection. 15 To mitigate the lack of availability of diltiazem injection, the OSUWMC Drug Shortage Committee considered therapeutic alternatives including amiodarone, esmolol, metoprolol, and digoxin. 1 However, several of these alternatives, including amiodarone and esmolol injections, also became unavailable due to shortage, leading to the adoption of verapamil infusion as an alternate agent for rate control. Despite the shift in our clinical practice to use verapamil infusion for rate control during the shortage period, there is a paucity of data supporting its use in this role. The purpose of this study was to determine the safety and efficacy of intravenous verapamil as compared with diltiazem for the acute treatment of atrial arrhythmias.

Methods

This retrospective, matched case-control study was conducted at OSUWMC, a multihospital 1506-licensed bed academic medical center located in Columbus, Ohio. The verapamil dosing used at OSUWMC for acute rate control, determined based on previous published literature and institutional guidelines, included a bolus dose of 5 to 10 mg over 2 minutes, which may be repeated once within 30 minutes, an initial infusion rate of 5 mg/h, and a maximum infusion rate of 15 mg/h. All patients receiving verapamil infusions between June 1 and September 30, 2018, were identified and case-matched to patients who received diltiazem infusions between June 1 and September 30, 2017, based on age, sex, and the presence of comorbid heart failure with a reduced ejection fraction (HFrEF). The definition of HFrEF was left ventricular ejection fraction less than or equal to 40%. Patients were excluded from analysis if they did not receive the infusion of calcium channel blocker prior to order discontinuation. Patients in the diltiazem group were rematched if their most recent echocardiogram for their hospital admission indicated a different heart failure diagnosis than what was documented by the International Classification of Diseases (ICD)-10 codes. Data for each patient were collected from the electronic health record (EHR; Epic Systems Corporation®, Verona, WI).

Patient information was collected and analyzed using Microsoft Excel® and IBM® SPSS software for statistical analysis. The mean and standard deviation were calculated for normally distributed variables, and the median and interquartile range were calculated for nonparametric variables. Student's t test and the Mann-Whitney U test were used to compare parametric and nonparametric variables, respectively. The chi-square test and Fisher's exact test were used for nominal data. An a priori level of 0.05 was set for statistical significance.

Baseline patient demographics collected included age, sex, race, height, weight, admission date, discharge date, service, department, primary diagnosis term (as determined by the ICD-10 code), diagnostic comorbidities including heart failure, and the indication for verapamil or diltiazem infusion. In addition, baseline vital signs, defined as the last recorded value before the initiation of the infusion, were collected. Vital signs included the heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure, and calculated MAP. Infusion data collected for both groups included the number of bolus doses, if any, administered prior to the infusion, the dose of each bolus given, the initial infusion rate, the maximum infusion rate, and the infusion duration.

The primary safety outcome of this study was to assess the need for inotrope or vasopressor following the discontinuation of calcium channel blocker infusion in each group. The need for inotrope or vasopressor was defined as the initiation of dobutamine, dopamine, epinephrine, milrinone, norepinephrine, phenylephrine, or vasopressin during the diltiazem or verapamil infusion or within 12 hours after discontinuation of the diltiazem or verapamil infusion. The secondary safety outcome of this study was to determine the incidence of hypotension (SBP < 90 mm Hg and MAP< 65 mm Hg) and bradycardia (HR < 60 bpm). The minimum HR and MAP during calcium channel blocker infusion were recorded to determine incidence of hypotension (SBP < 90 mm Hg and MAP < 65 mm Hg) and bradycardia (HR < 60 bpm). The maximum change in MAP and HR was determined using the baseline vital signs and the minimum measured values during the infusion.

The efficacy outcomes of this study included the percentage of patients who achieved rate control (HR <110 bpm) and the percentage of patients requiring a second agent to achieve rate control. The minimum HR during the infusion was collected to determine the percentage of patients who achieved rate control. The requirement of a second agent to achieve rate control was defined as the initiation of amiodarone, digoxin, or esmolol continuous infusion in addition to the calcium channel blocker infusion. Outcomes that could be attributed to either safety or efficacy were defined as switching the calcium channel blocker to an alternate agent, including amiodarone, beta-blocker, digoxin, or diltiazem infusion.

Results

There were 73 patients identified as meeting the inclusion criteria in the verapamil group. Of the 334 patients receiving diltiazem during the aforementioned time period, 73 patients were manually case-matched to the verapamil patients. Baseline characteristics were comparable for both groups (Table 1). The mean age of patients included was 64.5 years, and 50% of patients were men. There were 4 patients identified in each group who had comorbid heart failure. Administration of bolus doses varied between groups (Table 2). A single bolus dose prior to the infusion was more frequent in the diltiazem group than the verapamil group (60% versus 36%, P = .005). The bolus doses of verapamil were significantly lower than diltiazem, which is consistent with our institution's dosing recommendations. The average initial and maximum infusion rates and the infusion durations were similar for both groups.

Table 1.

Patient Demographics and Baseline Characteristics.

Patient demographics Verapamil (N = 73) Diltiazem (N = 73) P value
Age, mean ± SD 64.6 ± 12.9 64.4 ± 12.3 .813
Sex, men, n (%) 50 (68) 50 (68) .999
Weight (kg) 84.8 [74–99] 85.3 [73–105] .968
Height (cm) 174 [167–185] 175 [168–183] .682
Race, n (%)
 Caucasian 61 (84) 62 (85) .874
 African American 10 (14) 8 (11)
 Other 2 (2.7) 3 (4)
Heart failure with reduced ejection fraction, n (%) 4 (5) 4 (5) .999
The Ohio State University Wexner Medical Center department, n (%) .0001
  Nonintensive care unit 47 (64.4) 45 (61.6)
  Intensive care unit 20 (27.4) 6 (8.2)
  Emergency department 6 (8.2) 22 (30.1)
Initial vital signs, median [IQR]
 Heart rate (bpm) 138.5 [124–153] 140 [124–153] .849
 Systolic blood pressure (mm Hg) 125 [112–137] 122 [110–143] .681
 Mean arterial pressure (mm Hg) 91.1 [82–103] 92.7 [82–102] .585

Note. IQR = interquartile range; bpm = beats per minute.

Table 2.

Infusion Data for Both Verapamil and Diltiazem Groups.

Verapamil group (N = 73) Diltiazem group (N = 73) P value
Bolus dose received, n (%)
 First bolus dose received 26 (36) 44 (60) .005
 Second bolus dose received 8 (11) 8 (11) .999
Bolus dose given, median [IQR]
 First bolus dose (mg) 5.0 [5.0–5.0] 12.5 [10.0–20.0] .0001
 Second bolus dose (mg) 5.0 [5.0–6.0] 10.0 [10.0–20.0] .001
Infusion rate, median [IQR]
 Initial rate (mg/h) 5.0 [5.0–5.0] 5.0 [5.0–5.0] .120
 Maximum rate (mg/h) 10.0 [7.5–15.0] 10.0 [5.0–15.0] .751
 Infusion duration (h) 18.0 [5.9–44.5] 18.4 [6.8–31.2] .545

Note. IQR = interquartile range.

Safety and efficacy outcomes are displayed in Table 3. The primary safety outcome of need for inotrope or vasopressor was similar for both groups (5% with verapamil versus 4% with diltiazem, P = .999). Additional safety outcomes were statistically similar between groups, with 37% in the verapamil group versus 33% in the diltiazem group experiencing an SBP < 90 mm Hg (P = .603), 27% in the verapamil group versus 23% in the diltiazem group experiencing a MAP < 65 mm Hg (P = .704), and 19% in the verapamil group versus 18% in the diltiazem group experiencing an HR < 60 bpm (P = .831). The total number of patients who experienced SBP < 90 mm Hg, MAP < 65 mm Hg, or both was 27 patients (37%) in the verapamil group and 26 patients (35%) in the diltiazem group. The minimum average vital signs recorded during the infusion were also similar for both agents.

Table 3.

Outcome Data for Both Verapamil and Diltiazem Groups.

Verapamil group(N = 73) Diltiazem group (N = 73) P value
Safety outcomes, n (%)
 Inotrope or vasopressor 4 (5) 3 (4) .999
 SBP < 90 (mm Hg) 27 (37) 24 (33) .603
 MAP < 65 (mm Hg) 20 (27) 17 (23) .704
 HR < 60 (bpm) 14 (19) 13 (18) .831
Efficacy outcomes, n (%)
 HR < 110 (bpm) 65 (89) 66 (90) .785
 Addition of amiodarone 1 (1.4) 3 (4) .620
 Switch to amiodarone 7 (10) 6 (8) .771
 Switch to alternate calcium channel blocker 0 (0) 0 (0) .999
 Switch to digoxin 0 (0) 1 (1) .999
Minimum vitals during infusion, median [IQR]
 HR (bpm) 73 [62–82] 77 [62–85] .227
 SBP (mm Hg) 96 [85–107] 98 [88–111] .361
 MAP (mm Hg) 69 [64–78] 73 [65–82] .439
Length of stay in days, median [IQR] 8.1 [5.3–17.4] 6.2 [3.5–10.7] .035

Note. SBP = systolic blood pressure; MAP = mean arterial pressure; HR = heart rate; IQR = interquartile range; bpm = beats per minute.

Efficacy outcomes were also similar for both groups. Overall, 65 patients (89%) in the verapamil group and 66 patients (90%) in the diltiazem group achieved an HR <110 bpm during the infusion (P = .785), and 1 patient (1.4%) in the verapamil group and 3 patients (4%) in the diltiazem group required amiodarone in addition to the calcium channel blocker (P = .620). Outcomes that could be attributed to safety or efficacy, including switching therapy to a different agent, were similar in both groups. Seven patients in the verapamil group and 6 patients in the diltiazem group were switched to amiodarone (P = .771). One patient in the diltiazem group was switched to digoxin, and no patients in this study population received esmolol.

Four patients in each group had HFrEF, and the ejection fractions of heart failure patients ranged from 20% to 40%. Rates of safety outcomes appeared similar among patients with comorbid heart failure. Of patients with HFrEF, 1 patient in the verapamil group and no patients in the diltiazem group required an inotrope or vasopressor. Two HFrEF patients in each group experienced hypotension (SBP < 90 mm Hg and MAP < 65 mm Hg). Bradycardia was noted in 1 patient with heart failure in the verapamil group and 2 patients in the diltiazem group. Finally, 2 of the 4 patients with HFrEF in the verapamil group and no patients in the diltiazem group failed to achieve an HR < 110 bpm.

Discussion

This study provides safety and efficacy information for the use of intravenous verapamil and diltiazem in current clinical practice. This study is the first addition to the available literature regarding intravenous verapamil infusion in over 2 decades and is the largest sample size to have been assessed. Overall, baseline characteristics in both groups were similar, allowing for meaningful comparison. Of note, the median length of stay was longer in the verapamil group as compared with the diltiazem group. While this could be indicative of an overall difference in severity of illness between the 2 groups, it could also indicate a delay in treatment efficacy in the verapamil group. Due to the retrospective nature of the study, a cause-effect relationship is unable to be determined.

The verapamil and diltiazem infusion rates were comparable between both groups. However, an initial bolus dose was more common in the diltiazem group as compared with the verapamil group. This difference is likely due to a conservative dosing approach with the verapamil infusion, possibly due to provider unfamiliarity. Despite the possibility of conservative dosing of verapamil, safety and efficacy outcomes were similar across both treatment groups for both patients with and without heart failure. There was low representation of HFrEF patients in this study. This may be due to utilization of agents with less inotropic effects in these patients in clinical practice.

This study has several limitations. First, the overall sample size was relatively small. In addition, the retrospective study design did not control for variations in dosing and treatment strategies. Patients included had a variety of clinical diagnoses and comorbidities or other medications administered during the treatment course could affect the outcomes measured. Dosing was individualized by patient, and additional research is warranted to determine the benefits or risks of more aggressive verapamil dosing. In addition, the OSUWMC admitting department varies between groups, with more emergency department admissions in the diltiazem group as compared with the verapamil group. This difference is due to the availability of a supply of diltiazem in the emergency department during the time of the diltiazem shortage that was unavailable in other care locations. This diltiazem supply limited the need to use verapamil initially in those cases presenting through the emergency department.

Data were manually collected based on documentation in the EHR, which offers challenges due to variations in documentation. To minimize impact, this study used objective criteria that could be recorded from the EHR upon chart review. Rates of bradycardia and hypotension were recorded based on objective cutoff values, which may not reflect symptomatic bradycardia and hypotension. Further prospective evaluation may be useful to determine the rates of symptomatic hypotension as a direct result of the calcium channel blocker infusion. The addition of the amiodarone drip was considered to be an indicator of a lack of efficacy of the calcium channel blocker for the purposes of this study. The need to switch from a calcium channel blocker to amiodarone was considered an additional outcome because this outcome could have resulted from either treatment failure of the calcium channel blocker or side effects from the calcium channel blocker. In addition, further evaluation may be useful to determine the overall efficacy of the verapamil infusion, including time to rate control and percent of time at rate control while on the infusion.

Conclusion

Little evidence currently exists supporting the use of intravenous verapamil infusion for the acute treatment of atrial arrhythmias. This retrospective study provides safety and efficacy information regarding the use of intravenous verapamil as compared with diltiazem in clinical practice. The use of intravenous verapamil for the acute treatment of atrial arrhythmias had similar rates for both safety and efficacy outcomes as compared with intravenous diltiazem. The results of this study support the use of intravenous verapamil for acute atrial arrhythmias when treatment with a calcium channel blocker is warranted.

Acknowledgment

The authors thank Ellen Keating, PharmD, MS, BCPS, for assistance with data collection and Bruce Doepker, PharmD, BCPS, for statistical analysis.

Footnotes

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD: Charlotte M. Forshay https://orcid.org/0000-0003-2204-113X

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