Low-dose diltiazem in atrial fibrillation with rapid ventricular response
Original Contribution
Low-dose diltiazem in atrial fibrillation with rapid ventricular response
Jungyoup Lee MD a, Kyuseok Kim MD a,?, Christopher C. Lee MD b, Yeoun Woo Nam MD a, Jin Hee Lee MD a, Joong Eui Rhee MD a, Adam J. Singer MD b, Kyung Su Kim MD c, Youngsun Ro MD c
aDepartment of Emergency Medicine, Seoul National University, Bundang Hospital, Sungnam-si,
Gyeonggi-do 463-707, Republic of Korea
bDepartment of Emergency Medicine, Center for International Emergency Medicine, Stony Brook University Hospital,
Stony Brook, NY, USA
cDepartment of Emergency Medicine, Seoul National University College of Medicine, Republic of Korea
Received 12 March 2010; revised 16 March 2010; accepted 17 March 2010
Abstract
Objectives: Diltiazem is one of the most commonly used medications to control the rapid ventricular response in Atrial fibrillation . The recommended starting dose is an Intravenous bolus of 0.25 mg/ kg over 2 minutes. To avoid hypotension, we have empirically used a lower dose of diltiazem. We compared the efficacy and safety of different doses of diltiazem in rapid AF.
Methods: A retrospective chart review was undertaken in patients who presented to the emergency department with rapid AF. Patients were divided into 3 groups according to diltiazem dosage: low dose (<=0.2 mg/kg), standard dose (N0.2 and <=0.3 mg/kg), and high dose (N0.3 mg/kg). We compared the rates of therapeutic response (adequate Rate control) and complications (such as hypotension). multivariate regression analysis was used to determine the effect of diltiazem dose on the occurrence of complications.
Results: A total of 180 patients were included in the analysis. There were no significant differences in the rates of therapeutic response for the low-, standard-, and high-dose groups (70.5%, 77.1%, and 77.8%; P = .605). The rates of hypotension in the low-, standard-, and high-dose groups were 18%, 34.9%, and 41.7%, respectively. After adjusting confounding variables, the rate of hypotension was significantly lower in the low-dose group in comparison with the standard-dose group (adjusted odds ratio, 0.39; 95% confidence interval, 0.16-0.94).
Conclusions: Low-dose diltiazem might be as effective as the standard dose in controlling rapid AF and reduce the risk of hypotension.
(C) 2011
* Corresponding author. Tel.: +82 31 787 7571; fax: +82 31 787 4055.
E-mail address: [email protected] (K. Kim).
0735-6757/$ - see front matter (C) 2011 doi:10.1016/j.ajem.2010.03.021
Introduction
Background and significance
Acute Atrial fibrillation is the most common cardiac rhythm disturbance encountered in clinical practice and is commonly seen in the emergency department (ED) [1]. Symptomatic patients with rapid ventricular response during AF require prompt medical management; cardio- version should be considered if symptomatic hypotension, angina, or heart failure is present and related to the rapid ventricular response [2]. In the absence of preexcitation, intravenous administration of ?-blockers (esmolol, metoprolol, or propranolol) or nondihydropyr- idine calcium channel antagonists (verapamil, diltiazem) is recommended to slow the ventricular response to AF in the acute setting, exercising caution in patients with hypotension or HF [3].
Diltiazem is one of the most common agents used to slow the ventricular rate in patients with AF with rapid ventricular response. According to the 2006 guidelines developed by the American College of Cardiology/American Heart Associa- tion/European Society of Cardiology for the management of patients with AF, diltiazem is recommended to be admin- istered as a Bolus injection of 0.25 mg/kg over 2 minutes [3]. However, we have tried lower dose of diltiazem at our institution for several years to avoid hypotension and found that rapid AF could be controlled effectively by lower dose of diltiazem. However, we are unaware of any published evidence regarding whether lower dose of diltiazem could also control rapid AF effectively.
Goals of this investigation
The purpose of the current study was to compare the efficacy and safety of low-dose, standard-dose, and high-dose diltiazem in patients presenting to the ED with rapid AF.
Methods
Study design
A retrospective chart review was undertaken to determine the efficacy and safety of various doses of diltiazem in patients who presented to our ED with rapid AF. This study was approved by institutional review board committee of our hospital (B-0906/077-101).
Setting
The study was conducted at a 950-bed urban academic tertiary hospital, with an annual ED census of 67 000. The ED was staffed by emergency medicine residents or rotating
residents with other specialties supervised by board-certified emergency physicians. The study hospital was a paperless institution where all medical records were fully electronic or computerized.
Subjects
The subjects of this study were adult patients older than 18 years with AF with a rapid ventricular response (heart rate N100/min) who presented to the ED and were administered intravenous boluses of diltiazem. Patients who were administered any other medications within 30 minutes of the diltiazem bolus were excluded because we wanted to evaluate the diltiazem loading effect exclusively. If body weight was not measured in the hospital, patients were excluded form the data analysis.
Measurements and outcomes
Demographic and clinical data were abstracted from the electronic medical records according to the methods described by Gilbert et al [4]. Clinical information included a prior history of hypertension, diabetes mellitus, and congestive heart failure (CHF); recent medications; and ventricular function (ejection fraction). Congestive heart failure was defined as acute, decompensated or chronic, significant, but currently compensated HF. Abstracted physical findings were all vital signs before and up to 30 minutes after the diltiazem bolus injection. Patients who were admitted to the hospital generally underwent echocar- diography. For patients that were not admitted, we also recorded any measured ejection fraction within 3 months of the ED visit. heart function of patients who did not undergo echocardiography within 3 months was classified into a missing value. We also abstracted body weights measured in the ED from the nursing records. If the body weight of the patient was not measured in the ED, values measured on the inpatient ward were abstracted and regarded as the patient’s body weight.
Patients were divided into 3 groups according to diltiazem dosage: low dose (<=0.2 mg/kg), standard dose (N0.2 and
<=0.3 mg/kg), or high dose (N0.3 mg/kg).
A positive therapeutic response to diltiazem was defined as the occurrence of any one of the following events within 30 minutes after diltiazem injection: (1) reduction of the lowest ventricular response rate (VRR) to 100 beats per minute or less or (2) reduction of VRR by 20% or greater from baseline.
A complication was defined as the occurrence of any one of following events within 30 minutes after diltiazem injection: (1) lowest systolic blood pressure (SBP) less than 90 mm Hg, (2) reduction of SBP by 20% or greater from baseline, (3) respiratory failure requiring intubation,
(4) cardiac arrest, or (5) the onset of unstable dysrhythmias requiring emergency interventions such as cardioversion or defibrillation.
Continuous variables were dichotomized as follows: lowest SBP not exceeding 90 mm Hg or greater than 90 mm Hg; lowest VRR not exceeding 100/min or greater than 100/min; (baseline SBP - lowest SBP)/baseline SBP at least
0.2 or less than 0.2; (baseline VRR - lowest VRR)/baseline VRR at least 0.2 or less than 0.2; and age not exceeding 65 years or greater than 65 years.
The outcomes of this investigation were the rate of a successful therapeutic response and the rate of any complications.
Data analysis
Data were analyzed using SPPS for Windows 15.0 (SPSS Inc, Chicago, IL). Continuous data are presented as means and standard deviations and compared with 1-way analysis of variance. Binomial data are presented as the percentage frequency of occurrence and compared with ?2 test or Fisher exact test.
Unadjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for each risk factor to assess the magnitude and direction of the effect on the complication rate. We included all significant variables (P value b .05) in the univariate analysis or clinically important covariates in the subsequent multivariate logistic regression analysis.
Results
A total of 214 patients received Intravenous diltiazem to control rapid VRR with AF from March 2004 to October 2008. Of these patients, 29 patients were excluded because they had received diltiazem continuously or any other drug
within 30 minutes after initial bolus injection. Five patients were excluded because body weight was not measured in the ED or the ward (Fig. 1).
There were 61, 83, and 36 patients in the low-, standard-, and high-dose groups, respectively. Their baseline demo- graphics and clinical characteristics were summarized in Table 1. Baseline demographic characteristics were similar among groups. Their baseline vital signs were not signifi- cantly different. However, the body weights of the high-dose group were significantly lower than those of the other 2 groups (Table 1).
The average dose of diltiazem administrated to the low-dose group was 0.14 +- 0.04 mg/kg. In the standard- dose group, the mean dose was 0.24 +- 0.02 mg/kg. A mean of 0.34 +- 0.02 mg/kg diltiazem was administrated in the high-dose group.
Therapeutic responses and complications are summarized in Table 2. Changes in VRR and SBP are summarized in Table 2. The mean percentage reduction of VRR in the low-, standard-, and high-dose group was 26.3%, 27.9%, and 29.9%, respectively. These differences were not statistically significant (P = .588). The mean percentage reduction of SBP in the low-, standard-, and high-dose diltiazem group was 9.7%, 12.6%, and 13.4%, respectively. Although the percentage reduction of SBP in the low-dose group was the lowest, the differences between the groups were not significant (P = .369).
In the low-dose group, 43 (70.5%) of 61 patients experienced an appropriate therapeutic response. In the standard- and high-dose groups, 64 (77.1%) of 83 and 28 (77.8%) of 36 experienced appropriate therapeutic responses, respectively. There were no significant differences in overall therapeutic response between the groups (P = .605).
Fig. 1 Inclusion and exclusion criteria.
Table 1 Baseline characteristics
Low-dose group Standard-dose group High-dose group P value n = 61 n = 83 n = 36
|
Age (y) |
66.8 +- 13.5 |
66.7 +- 13.5 |
72.1 +- 10.7 |
.129 |
|
Male sex, n (%) |
27 (44.3%) |
40 (48.2%) |
15 (41.7%) |
.781 |
|
Dosage (mg/kg) |
0.14 +- 0.04 |
0.24 +- 0.02 |
0.34 +- 0.02 |
|
|
Weight (kg) |
63.8 +- 17.1 |
61.3 +- 11.2 |
54.6 +- 9.5 |
.005 |
|
PMHx |
||||
|
HTN, n (%) |
36 (59.0%) |
35 (42.2%) |
18 (50.0%) |
.135 |
|
DM, n (%) |
12 (19.7%) |
16 (19.3%) |
7 (19.4%) |
.956 |
|
CHF, n (%) |
7 (11.5%) |
3 (3.6%) |
2 (5.6%) |
.167 |
|
Hyperlipidemia, n (%) |
3 (4.7%) |
3 (3.6%) |
2 (5.6%) |
.873 |
|
Medications |
||||
|
Aspirin, n (%) |
13 (21.3%) |
14 (16.9%) |
8 (22.2%) |
.717 |
|
Warfarin, n (%) |
4 (6.6%) |
5 (6.0%) |
3 (8.3%) |
.897 |
|
CCB, n (%) |
20 (32.8%) |
18 (21.7%) |
7 (19.4%) |
.217 |
|
BB, n (%) |
9 (14.8%) |
11 (13.3%) |
5 (13.9%) |
.967 |
|
DGX, n (%) |
1 (1.6%) |
2 (2.4%) |
3 (8.3%) |
.169 |
|
Baseline V/S |
||||
|
SBP (mm Hg) |
132 +- 26 |
135 +- 29 |
138 +- 32 |
.629 |
|
DBP (mm Hg) |
79 +- 18 |
78 +- 17 |
76 +- 22 |
.779 |
|
HR (/min) |
139 +- 19 |
138 +- 21 |
142 +- 25 |
.707 |
|
RR (/min) |
23 +- 5 |
23 +- 6 |
23 +- 6 |
.949 |
|
BT (?C) |
36.3 +- 0.7 |
36.4 +- 0.8 |
36.3 +- 0.6 |
.934 |
|
EF (%) |
56 +- 9 |
56 +- 9 |
58 +- 11 |
.774 |
|
Continuous data are presented as means and standard deviations and compared with 1-way analysis of variance. Binomial data are presented as the percentage frequency of occurrence and compared with ?2 test or Fisher exact test. PMHx indicates past medical history; HTN, hypertension; DM, diabetes mellitus; CCB, calcium channel blocker; BB, ?-blocker; DGX, digoxin; V/S, vital signs; DBP, diastolic blood pressure; HR, heart rate; RR, respiration rate; BT, body temperature; EF, ejection fraction (percentage). |
||||
The number of patients who developed hypotension or a 20% or greater reduction in baseline SBP was 11 (18%) of 61 in the low-dose group, 29 (34.9%) of 83 in the standard-dose group, and 15 (41.7%) of 36 in the high-dose group. Thus, as the diltiazem dose increased, the frequency of hypotensive episodes also significantly increased (P = .025) (Table 2). No patient receiving any dose of diltiazem had experienced endotracheal intuba- tion, cardioversion, cardiac arrest, or unstable dysrhyth- mias. From the univariate analysis, we found that complications occurred less frequently among the low-
dose group (OR, 0.41; 95% CI. 0.18-0.90) and among patients with an initial SBP between 90 and 140 mm Hg (reference). As a result, we included these variables and CHF in the subsequent multivariate logistic regression analysis (Table 3). Although CHF was not associated with complications in our study (OR, 0.74; 95% CI, 0.19-2.86), it is considered a relative contraindication to diltiazem due to its negative inotropic effect. After adjusting for the effects of the initial SBP and CHF, it was found that patients in the low-dose group showed a significantly lower complication rate in comparison with
|
Unadjusted OR |
95% CI |
P value |
|
|
Age (y) <=65 |
Reference |
||
|
N65 |
1.41 |
0.72-2.75 |
.306 |
|
Sex Male |
Reference |
||
|
Female |
1.11 |
0.59-2.11 |
.732 |
|
CHF No |
Reference |
||
|
Yes |
0.744 |
0.19-2.86 |
.666 |
|
CCB No |
Reference |
||
|
Yes Baseline 90 b SBP <= 140 |
0.48 Reference |
0.21-1.09 |
.08 |
|
SBP SBP N140 |
6 |
3.00-11.97 |
b.001 |
|
Diltiazem Low |
0.41 |
0.18-0.90 |
.028 |
|
dose Standard |
Reference |
||
|
High |
1.33 |
0.59-2.96 |
.486 |
the standard-dose group (adjusted OR, 0.39; 95% CI, 0.16-0.94) (Table 4).
Discussion
We initiated this study to determine which loading dose of diltiazem is most appropriate in patients presenting to the ED with AF with rapid ventricular response. If low- dose diltiazem has the same beneficial effect of standard or higher dose of diltiazem, using a lower dose would be desirable in accordance with the medical dictum “First, do no harm.”
In the American College of Cardiology/American Heart Association/European Society of Cardiology 2006 guide- lines for the management of patients with rapid AF, diltiazem is recommended to be administered as a bolus injection of
0.25 mg/kg over 2 minutes [3]. A prior study has demonstrated the efficacy of diltiazem in rapid AF with the use of the currently recommended dosage (0.25 mg/kg) [5,6]. However, we could not find any published research concerning the safety and efficacy of diltiazem according to dosage. Our study suggests that lower dosages of diltiazem may be safer than standard dose without interrupt- ing therapeutic efficacy. Obviously, to confirm the safety and efficacy of low-dose diltiazem, randomized controlled studies are necessary.
Prior studies have compared the safety and efficacy of various doses of diltiazem in patients with Paroxysmal supraventricular tachycardia . In one study, patients with PSVT were randomized to receive 1 of 4 doses of diltiazem (0.05, 0.15, 0.25, or 0.45 mg/kg); and conversion to normal sinus rhythm was considered as successful therapeutic response. Conversion to sinus rhythm occurred in 4 (29%) of 14 patients with 0.05 mg/kg of diltiazem, 16 (64%) of 19 with 0.15 mg/kg, 13 (100%) of 13 with 0.25 mg/ kg, and 14 (62%) of 17 with 0.45 mg/kg. The most frequent
adverse event was hypotension (SBP b90 mm Hg), occurring in 10 (16%) of 63 patients receiving diltiazem. Although adverse effects occurred more frequently in the higher-dose groups, the difference between groups was not statistically significant. Based on these results, the authors suggested that the optimum dose of diltiazem for PSVT be 0.25 mg/kg in terms of the efficacy and Adverse effect profile [7].
In our study, we found that low-dose diltiazem could effectively control rapid AF and was less likely to cause hypotension than the standard dose. We believe that the differences between the study results found with AF and PSVT could be the result of a higher frequency of underlying ventricular dysfunction in patients with AF, making them more susceptible to hypotension after administration of diltiazem. Another possible explanation for the differing results could be the small sample size in the previous PSVT study, which was underpowered to detect differences in the complication rates.
We excluded 29 patients who received another drug for controlling rapid AF within 30 minutes of starting intrave- nous bolus diltiazem, but it did not make selection bias because there was nearly the same percentage of each dose group in excluded cases (data not shown).
Limitation
Our study has several limitations that merit further discussion. Firstly, because of the retrospective nature of this study, there could be multiple potential limitations, including selection bias and ascertainment bias, incomplete data documentation and extraction, and the nonstandardized Treatment regimens. Selection bias was minimized by the use of an electronic medical record system. Secondly, echocar- diography was not available in all patients. Of a total of 180 patients, 160 patients were examined with echocardiography within 3 months of the index visit. Thus, there is a possibility that we may have failed to identify differences in ventricular function among the groups. Thirdly, we defined a hypoten- sive episode as a SBP less than 90 mm Hg or a reduction from baseline SBP of 20% or greater. However, the clinical
.366
0.61-3.66
Reference 1.5
.037
0.16-0.94
Diltiazem Low dose
Standard High
3.17-13.42 b.001
6.52
0.39
SBP N140
90 b SBP <= 140 Reference
Baseline SBP
.636
0.15-3.18
95% CI P value
Adjusted OR
Reference 0.69
No Yes
CHF
Table 4 Multivariate logistic regression for complications
significance of such a decline in SBP in patients with rapid AF is unclear.
Conclusion
We conclude that administration of a low dose of diltiazem (b0.20 mg/kg) might be as effective as standard dose in patients with rapid AF and reduces the rate of hypotension. Although additional research is necessary to determine the optimal loading dosage, our results suggest that the initial loading dose of diltiazem might be less than 0.20 mg/kg.
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- Gilbert EH, Lowenstein SR, Koziol-McLain J, et al. Chart reviews in emergency medicine research: where are the methods? Ann Emerg Med 1996;27:305-8.
- Goldenberg IF, Lewis WR, Dias VC, et al. Intravenous diltiazem for the treatment of patients with atrial fibrillation or flutter and moderate to severe congestive heart failure. Am J Cardiol 1994;74:884-9.
- Demircan C, Cikriklar HI, Engindeniz Z, et al. Comparison of the effectiveness of intravenous diltiazem and metoprolol in the manage- ment of rapid ventricular rate in atrial fibrillation. Emerg Med J 2005;22:411-4.
- Dougherty AH, Jackman WM, Naccarelli GV, et al. Acute conversion of paroxysmal supraventricular tachycardia with intravenous diltiazem. Am J Cardiol 1992;70:567-92.