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Review article
β-Blockers versus calcium channel blockers for acute rate control of atrial fibrillation with rapid ventricular response: a systematic review Jennifer L. Martindale, Ian S. deSouza, Mark Silverberg, Joseph Freedman and Richard Sinert This is a systematic review of the literature to compare the efficacy of calcium channel blockers to β-blockers for acute rate control of atrial fibrillation with rapid ventricular response in the emergency department setting. PubMed, EMBASE, and the Cochrane Registry were searched. Relative risk (95% confidence interval) was calculated between drugs and methodological quality of included studies was evaluated. Of the 1003 studies yielded by our initial search, two met inclusion criteria and provided sufficient data. These were randomized double-blinded studies (n = 92) comparing intravenous diltiazem with intravenous metoprolol. The combined relative risk of acute rate control by diltiazem versus metoprolol was 1.8 (95% confidence interval 1.2–2.6). On the basis of the paucity of available evidence, diltiazem may be more effective than
Introduction Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in emergency medicine. Approximately 564 000 patients with atrial fibrillation are admitted annually to hospitals in the USA [1]. A subset of these patients are hemodynamically stable, but present to the emergency department (ED) with symptoms related to rapid ventricular rates. For many of these patients, the time of arrhythmia onset is unknown, equivocal, or greater than 48 h before presentation. The thromboembolic risk in this group precludes the option of cardioversion, making rate control the preferred management strategy. Placebo-controlled studies in the 1980s and 1990s have demonstrated safe and effective rate control with intravenous β-adrenergic antagonists [2] and nondihydropyridine calcium channel blockers [3,4]. These studies, in addition to a small, unblinded, randomized trial comparing esmolol with verapamil [5], are cited by current US guidelines. Both US and European guidelines impartially recommend intravenous β-blockers and nondihydropyridine calcium channel blockers as agents for acute rate control [6,7]. To rapidly alleviate symptoms and prevent hemodynamic deterioration, the emergency physician must choose an agent that will successfully control ventricular Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (www.euro-emergencymed.com). 0969-9546 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
metoprolol in achieving rapid rate control, but high-quality randomized studies are needed. European Journal of Emergency Medicine 22:150–154 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. European Journal of Emergency Medicine 2015, 22:150–154 Keywords: atrial fibrillation, β-blocker, calcium channel blocker, rate control Department of Emergency Medicine, SUNY Downstate/Kings County Hospital, New York, Brooklyn, USA Correspondence to Jennifer L. Martindale, MD, Department of Emergency Medicine, SUNY Downstate, 450 Clarkson Ave, Box 1228, Brooklyn, NY 11203, USA Tel: + 1 718 245 2973; fax: + 1 718 245 4799; e-mail: [email protected] Received 7 July 2014 Accepted 29 October 2014
rate without subsequent hypotension. Drug selection may be based on institutional preference as well as patient comorbidities and home medications. Nondihydropyridine calcium channel blockers, for example, are contraindicated in patients with acutely decompensated systolic heart failure [7]. The relative efficacy and safety of β-blockers and calcium channel blockers for tachycardic patients without specific drug contraindications is less explicit. To determine which drug class is more effective in rapidly controlling ventricular rates associated with AF, we performed a systematic review of the literature. We reviewed all trials comparing the efficacy of β-blockers and calcium channel blockers administered in the acute care setting to hemodynamically stable patients with atrial fibrillation and rapid ventricular response.
Materials and methods Study design
We conducted a systematic review of studies that examined the efficacy of rate-control agents in the management of atrial fibrillation with rapid ventricular response. We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [8]. Search strategy
Our medical librarian developed the Medical Subject Headings terms ‘calcium channel blockers’, ‘adrenergic DOI: 10.1097/MEJ.0000000000000227
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
Acute rate control of atrial fibrillation Martindale et al. 151
beta-antagonist’, ‘atrial fibrillation’, and ‘heart rate’ (see online appendix-web only file, Supplemental digital content 1, http://links.lww.com/EJEM/A85). Bibliographies of guidelines and review articles were reviewed to identify additional original research articles. To find unpublished studies, we reviewed abstracts from the following scientific meetings: American College of Emergency Physicians (1998–2013), Society for Academic Emergency Medicine (1995–2014), American Heart Association (2007–2013), and the European Society of Cardiology (2005–2013). Three independent reviewers (M.S., I.S.d., and J.L.M) screened the following databases from their inception to June 2014: EMBASE, MEDLINE, and the Cochrane Controlled Trials Registry. A fourth author (R.S.) adjudicated final choices for study inclusion.
associated with the use of rate control medications. Adverse events included hypotension, bradycardia, and death. The Mann-Whitney U-test was used to calculate baseline differences in heart rate and age between treatment groups.
Quality assessment
Included studies were evaluated for adequacy in randomization, concealment of allocation, intention-to-treat, baseline comparisons, cointerventions, blinding, and completeness of follow-up.
Results
Inclusion and exclusion criteria
Search results
Studies comparing β-blockers and calcium channel blockers in adult patients presenting to the ED with atrial fibrillation with rapid ventricular response were included. Both reduction in ventricular response and conversion to sinus rhythm were targeted outcome measures. The literature search included studies published between 1965 and June 2014 and was not limited by language of the publication. Studies that evaluated long-term outcomes of rate control or compared rhythm control to rate control were excluded. An a-priori decision was made to exclude studies examining rate control of atrial fibrillation in the postoperative setting, as postoperative patients with this arrhythmia constitute a distinct patient population.
The flow diagram of our search is illustrated in Fig. 1. Our search of MEDLINE, EMBASE, and Cochrane registries yielded 1003 unique studies. Our search of abstracts published in the archives of scientific sessions and of the references of guidelines and review articles did not produce any additional studies. After review of titles and abstracts, 998 were rejected for relevance. The majority of studies were excluded because they evaluated long-term outcomes of rate control, compared rhythm control with rate control, or evaluated rate control in the postoperative patient. Of the five studies reviewed further, three studies, Platia et al. [5], Mieure et al. [9], and Hassan et al. [10], provided insufficient data. We attempted without success to obtain patient-level data from these studies. The study by Platia et al. [5] reported only summary statistics for ventricular rates in groups receiving esmolol and verapamil in the text. Patient-level data for ventricular rates at two points in time (the end of study drug titration period and the end of a 30-min observation period that followed) are represented in graphical form. The percentage of patients in each group achieving rate control could not be extracted from this graph. The study by Mieure et al. [9] reported only the number of patients who achieved rate control at the end of the 24-h study period. Hassan et al. [10] reported group-level data for mean ventricular rates achieved at 1, 6, 12, and 24 h after initiation of study drug, but did not provide the number of patients in each group who had achieved rate control by these time points. This left two prospective studies by Fromm et al. [11] and Demircan et al. [12] that provided sufficient information to compute the RRs of achieving acute rate control in atrial fibrillation with rapid ventricular response. The study by Fromm et al. [11] is published in the form of an abstract. While sufficient data were available to compute RR, details regarding this study’s design and primary results remained unavailable. Publication bias could not be assessed.
Data collection and processing
Data elements extracted directly from the included article(s) were (a) patient characteristics (age, sex), (b) trial inclusion and exclusion criteria, (c) study medication, dose, and route of administration, (d) efficacy of intervention at controlling rapid ventricular response or converting to sinus rhythm, (e) timing of rate/rhythm control after drug administration, and (f) adverse events including bradycardia, hypotension, and death. Authors of studies with insufficient data were contacted. Outcome measures and data analysis
Our primary outcome measure was a decrease in ventricular rate (< 100 beats/min) at a specific time point defined by the included study. Both decrease in ventricular response to atrial fibrillation and conversion to sinus rhythm were considered effective means of achieving rate control. A two-by-two table was constructed with primary data extracted from the included studies. Relative risk (RR) and number needed to treat with 95% confidence intervals (CIs) were used to estimate the treatment effect (RevMan5; The Cochrane Collaboration, Copenhagen, Denmark). Our secondary outcome measure was the rate of adverse events
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152 European Journal of Emergency Medicine 2015, Vol 22 No 3
Fig. 1
Titles and abstracts screened MEDLINE (191) and EMBASE (883) Afetr removal of duplicates: n=1003 1003
Cochrane library (0) Additional studies from references (0) Additional studies from archives of scientific sessions (0)
Excluded by abstract based on relevance 998
Full-text review 5
Insufficient data 3
Selected studies 2
Flow diagram of study selection process.
Study characteristics
The two studies that met our inclusion criteria were randomized, double-blinded, prospective trials of 40 [12] and 52 [11] patients. Patients presenting to the ED with atrial fibrillation and a ventricular rate of at least 120 beats/min were included in both studies. Fromm et al. [11] included patients with atrial flutter and a rapid ventricular rate; inclusion and exclusion criteria for this study were not stated in the published abstract. The following exclusion criteria were applied to the Demircan et al. [12] study: congestive heart failure (New York Heart Association Class IV), sick sinus syndrome, second or third degree atrioventricular (AV) block, pre-excitation syndromes, ventricular rate of more than 220 beats/min, QRS duration more than 0.08 s, unstable angina, acute myocardial infarction, hyperthyroidism, fever, anemia (hemoglobin < 11 g/dl), bronchial asthma, chronic obstructive pulmonary disease, diabetes mellitus, peripheral vascular disease, pregnancy, and history of having used diltiazem, verapamil, digoxin, β-blockers, theophylline or β-agonists within the previous 5 days. Doses of intravenous diltiazem and metoprolol used in this
study were 0.25 mg/kg, (maximum 25 mg) and 0.15 mg/ kg (maximum 20 mg) respectively. The doses used by Fromm et al. [11] were not published. Successful treatment was defined by Fromm et al. [11] as a reduction in heart rate to less than 100 beats/min 30 min after drug administration. Demircan et al. [12] defined treatment success as a decrease in a ventricular rate by 20% (< 120 beats/min at least) or conversion to sinus rhythm within 20 min of drug administration. Group comparison data for baseline characteristics including underlying coronary artery disease, structural heart disease, history of atrial fibrillation, or left ventricular fraction were not available for either study. The mean age and blood pressure were reported to be similar in both treatment groups by Fromm et al. [11]; Baseline mean heart rate for the metoprolol group was 142.2 and 136.8 beats/min for the diltiazem group (P = 0.231). Median initial heart rates in the metoprolol and diltiazem groups in the Demircan et al. [12] study were 150 and 154 beats/min, respectively (P = 0.45). Median ages for
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Acute rate control of atrial fibrillation Martindale et al. 153
the metoprolol and diltiazem group were 64.5 and 65.6 (P = 0.31).
90 mmHg, or bradycardia. Hypotension and bradycardia were not reported in the abstract by Fromm et al. [11].
Trial quality
Discussion
Neither study was registered in clinicaltrials.gov. In the Demircan et al. [12] study, subjects were randomized and methods of allocation concealment and blinding were described. A predetermined sample size estimate and baseline comparisons were not reported in this study. Follow-up was complete. The authors of this study do not explicitly state whether or not an intention-to-treat analysis was used to estimate treatment effect. The study by Fromm et al. [11] was a double-blinded trial. Sequence allocation, allocation concealment, intention-to-treat analysis, and follow-up completion are not described in the published abstract. Primary outcomes analysis
The primary outcome, defined by Demircan et al. [12] as a ventricular rate of less than 100 beats/min or a 20% decrease in ventricular rate, was achieved in 90% of the patients who received diltiazem and 80% who received metoprolol at the end of the 20-min study period. None of the patients converted to sinus rhythm. We redefined the treatment outcome in the Demircan et al. [12] study as achievement of ventricular rates less than 100 beats/min by 20 min after drug administration to combine these data with the data provided by the Fromm et al. [11] study. At the end of the 20-min period, 65% of patients receiving diltiazem and 50% of patients receiving metoprolol had ventricular rates less than 100 beats/min (Table 1). At the end of 20 min after drug administration in the study by Fromm et al. [11], 83% of the patients who received diltiazem and 36% of those who received metoprolol had a ventricular rate of less than 100 beats/min. The combined RR (95% CI) for achieving a heart rate of less than 100 beats/min with diltiazem compared with metoprolol was 1.80 (1.23–2.62). On the basis of the data from the studies combined, the calculated number needed to achieve rate control by diltiazem compared with metoprolol was 3 (95% CI 1.9–6.9). Secondary outcomes analysis
None of the patients in either treatment arm of the study by Demircan et al. [12] experienced hypotension, as defined by a systolic blood pressure of less than Table 1
In the outpatient setting, where rate control may be more important for avoiding tachycardia-related cardiomyopathy, β-blockers are more effective than calcium channel blockers in achieving rate control in atrial fibrillation [13]. In the postoperative setting, diltiazem has been shown to be more effective than metoprolol in achieving rate control after nonthoracic surgery [14]. Our systematic review suggests that in the ED, diltiazem may be more effective than metoprolol in rapidly controlling ventricular rates. Diltiazem both slows conduction through the AV node and prolongs the refractory period of AV nodal tissue by blocking L-type calcium channels; metoprolol works more indirectly, by blocking sympathetic input to the AV node. The current literature suggesting diltiazem’s superior efficacy in the acute care setting, however, is limited to two small-sample sized studies that lack a priori sample size determination and have limited generalizability. The external validity of the study by Demircan et al. [12] is undermined by its exclusion of patients who have taken oral AV-nodal blocking agents within 5 days before randomization. While these patients were presumably excluded to eliminate possible confounding effects of residual oral agents, atrial fibrillation is not a new diagnosis for most patients in the acute care setting, and a variable, but significant percentage of these patients take β-blockers or calcium channel blockers at home. Including such patients in a larger study would yield conclusions more relevant to an emergency physician. Exclusion of patients with common comorbid conditions such as diabetes mellitus, which are not contraindications to either type of AV nodal blocker, also makes this study less generalizable to an ED population. While no adverse events were found by this systematic review, hypotension is a legitimate concern while using these drugs. The dose used in the Demircan et al. [12] study (up to a maximum of 25 mg) is the same dose recommended by current guidelines [0.25 mg/kg (actual body weight) intravenous bolus over 2 min] [7]. In clinical practice, the dose of diltiazem administered to patients with AF and rapid ventricular response is variable. In one retrospective observational study, doses of 0.2 mg/kg or less of diltiazem were administered to one-
Rates of successful decrease in ventricular rate to less than 100 bpm at 20 min
Demircan et al. [12] Fromm et al. [11] Combined
Sample size
Diltiazem
Metoprolol
Relative risk (95% CI)
NNT (95% CI)
40 52 92
13/20 20/24 33/44
10/20 10/28 20/48
1.3 (0.75–2.24) 2.33 (1.38–3.96) 1.80 (1.23–2.62)
7 (− 15.3 to 45.3)a 2 (1.4–4.1) 3 (1.9–6.9)
The confidence interval (CI) for number needed to treat (NNT) includes negative numbers and zero. An alternative way to express the CI here is (NNH = 15.3 to ∞ to NNT = 45.4 to ∞).
a
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154 European Journal of Emergency Medicine 2015, Vol 22 No 3
third of patients presenting to the ED with AF and rapid ventricular response [15]. Hypotension, defined as systolic blood pressure less than 90, was observed in 1/61 patients who received 0.2 mg/kg or less, 6/83 patients who received more than 0.2 mg/kg, and 0.3 mg/kg or less, and 1/36 patients who received more than 0.3 mg/kg. Some clinicians choose to administer calcium before diltiazem to limit subsequent hypotension, although this failed in one prospective study to blunt a decrease in systolic blood pressure [16]. In that study, 4/8 patients receiving diltiazem (0.25 mg/kg, maximum 20 mg) became hypotensive, but three of these patients had borderline initial blood pressures (systolic blood pressures of < 100 mmHg). These results suggest that hypotension due to calcium channel blockers may not be dose-dependent and may be due to other factors such as initial baseline blood pressures. Variability in the management of controlling rapid ventricular rates associated with AF largely stems from a lack of evidence to guide emergency physicians in choosing the most effective and safest AV nodal blocker. Less clear is how home use of these agents should factor in to the ED physician’s choice of AV nodal blocker to achieve acute rate control. Preference for one drug class is variably based on perceived risk of symptomatic bradycardia and hypotension in patients taking a medication from another drug class. Evidence pertaining to the adverse effects of combining β-blockers and calcium channel blockers (when one is used orally at home, the other intravenously in the acute care setting) is lacking. In the study by Demircan et al. [12], the four patients in the metoprolol group who failed to achieve rate control by 20 min received intravenous diltiazem; subsequent hypotension did not occur. The safety of administering both types of AV-nodal blockers serially in the ED (when one agent has been deemed ineffective in achieving rapid rate control) has not been studied. Limitations
The available evidence comparing β-blockers and calcium channel blockers for rate control in AF is extremely limited. A quality assessment of one of the two included studies in this review could not be performed, as it was published as an abstract and more detailed methodological data could not be obtained. Future studies should be prospective, randomized, and methodologically sound trials that examine larger, predetermined sample sizes. A study that included patients already taking AV nodal blocking agents would be more generalizable to the ED population.
Conflicts of interest
There are no conflicts of interest.
References 1
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Acknowledgements The authors would like to thank Christopher Stewart, senior assistant librarian at SUNY Downstate Medical Center for his assistance in our literature search.
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McDonald AJ, Pelletier AJ, Ellinor PT, Camargo CA Jr. Increasing US emergency department visit rates and subsequent hospital admissions for atrial fibrillation from 1993 to 2004. Ann Emerg Med 2008; 51:58–65. Abrams J, Allen J, Allin D, Anderson J, Anderson S, Blanski L, et al. Efficacy and safety of esmolol vs propranolol in the treatment of supraventricular tachyarrhythmias: a multicenter double-blind clinical trial. Am Heart J 1985; 110:913–922. Ellenbogen KA, Dias VC, Plumb VJ, Heywood JT, Mirvis DM. A placebocontrolled trial of continuous intravenous diltiazem infusion for 24-hour heart rate control during atrial fibrillation and atrial flutter: a multicenter study. J Am Coll Cardiol 1991; 18:891–897. Ellenbogen KA, Dias VC, Cardello FP, Strauss WE, Simonton CA, Pollak SJ, et al. Safety and efficacy of intravenous diltiazem in atrial fibrillation or atrial flutter. Am J Cardiol 1995; 75:45–49. Platia EV, Michelson EL, Porterfield JK, Das G. Esmolol versus verapamil in the acute treatment of atrial fibrillation or atrial flutter. Am J Cardiol 1989; 63:925–929. Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, et al. Task Force on Practice Guidelines, American College of Cardiology/ American Heart Association; Committee for Practice Guidelines, European Society of Cardiology; European Heart Rhythm Association; Heart Rhythm Society. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation-executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients with Atrial Fibrillation). Eur Heart J 2006; 27:1979–2030. January CT, Wann LS, Alpert JS, Calkins H, Cleveland JC Jr, Cigarroa JE, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation 2014; 130:2071–2104. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 2009; 62:e1–e34. Mieure KD, Moranville MP, Park JJ, Lat I, Jennings HR, Lazar S, Beshai JF. A comparison of intravenous rate control agents for new onset atrial fibrillation with rapid ventricular rate. Heart Rhythm 2011; 8:S216–S217. Hassan S, Slim AM, Kamalakannan D, Khoury R, Kakish E, Maria V, et al. Conversion of atrial fibrillation to sinus rhythm during treatment with intravenous esmolol or diltiazem: a prospective, randomized comparison. J Cardiovasc Pharmacol Ther 2007; 12:227–231. Fromm C, Suau S, Cohen V, Jellinek S, Likourezos A, Rose J, Marshall J. Comparison of diltiazem and metoprolol in the management of atrial fibrillation or flutter with rapid ventricular rate in the emergency department: a prospective, randomized double-blind trial [abstract]. Emerg Med J 2011; 18 (Suppl 1):235. Demircan C, Cikriklar HI, Engindeniz Z, Cebicci H, Atar N, Guler V, et al. Comparison of the effectiveness of intravenous diltiazem and metoprolol in the management of rapid ventricular rate in atrial fibrillation. Emerg Med J 2005; 22:411–414. Olshansky B, Rosenfeld LE, Warner AL, Solomon AJ, O'Neill G, Sharma A, et al. AFFIRM Investigators. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study: approaches to control rate in atrial fibrillation. J Am Coll Cardiol 2004; 43:1201–1208. Personett HA, Smoot DL, Stollings JL, Sawyer M, Oyen LJ. Intravenous metoprolol versus diltiazem for rate control in noncardiac, nonthoracic postoperative atrial fibrillation. Ann Pharmacother 2014; 48:314–319. Lee J, Kim K, Lee CC, Nam YW, Lee JH, Rhee JE, et al. Low-dose diltiazem in atrial fibrillation with rapid ventricular response. Am J Emerg Med 2011; 29:849–854. Kolkebeck T, Abbrescia K, Pfaff J, Glynn T, Ward JA. Calcium chloride before i.v. diltiazem in the management of atrial fibrillation. J Emerg Med 2004; 26:395–400.
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Review article
β-Blockers versus calcium channel blockers for acute rate control of atrial fibrillation with rapid ventricular response: a systematic review Jennifer L. Martindale, Ian S. deSouza, Mark Silverberg, Joseph Freedman and Richard Sinert This is a systematic review of the literature to compare the efficacy of calcium channel blockers to β-blockers for acute rate control of atrial fibrillation with rapid ventricular response in the emergency department setting. PubMed, EMBASE, and the Cochrane Registry were searched. Relative risk (95% confidence interval) was calculated between drugs and methodological quality of included studies was evaluated. Of the 1003 studies yielded by our initial search, two met inclusion criteria and provided sufficient data. These were randomized double-blinded studies (n = 92) comparing intravenous diltiazem with intravenous metoprolol. The combined relative risk of acute rate control by diltiazem versus metoprolol was 1.8 (95% confidence interval 1.2–2.6). On the basis of the paucity of available evidence, diltiazem may be more effective than
Introduction Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in emergency medicine. Approximately 564 000 patients with atrial fibrillation are admitted annually to hospitals in the USA [1]. A subset of these patients are hemodynamically stable, but present to the emergency department (ED) with symptoms related to rapid ventricular rates. For many of these patients, the time of arrhythmia onset is unknown, equivocal, or greater than 48 h before presentation. The thromboembolic risk in this group precludes the option of cardioversion, making rate control the preferred management strategy. Placebo-controlled studies in the 1980s and 1990s have demonstrated safe and effective rate control with intravenous β-adrenergic antagonists [2] and nondihydropyridine calcium channel blockers [3,4]. These studies, in addition to a small, unblinded, randomized trial comparing esmolol with verapamil [5], are cited by current US guidelines. Both US and European guidelines impartially recommend intravenous β-blockers and nondihydropyridine calcium channel blockers as agents for acute rate control [6,7]. To rapidly alleviate symptoms and prevent hemodynamic deterioration, the emergency physician must choose an agent that will successfully control ventricular Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (www.euro-emergencymed.com). 0969-9546 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
metoprolol in achieving rapid rate control, but high-quality randomized studies are needed. European Journal of Emergency Medicine 22:150–154 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. European Journal of Emergency Medicine 2015, 22:150–154 Keywords: atrial fibrillation, β-blocker, calcium channel blocker, rate control Department of Emergency Medicine, SUNY Downstate/Kings County Hospital, New York, Brooklyn, USA Correspondence to Jennifer L. Martindale, MD, Department of Emergency Medicine, SUNY Downstate, 450 Clarkson Ave, Box 1228, Brooklyn, NY 11203, USA Tel: + 1 718 245 2973; fax: + 1 718 245 4799; e-mail: [email protected] Received 7 July 2014 Accepted 29 October 2014
rate without subsequent hypotension. Drug selection may be based on institutional preference as well as patient comorbidities and home medications. Nondihydropyridine calcium channel blockers, for example, are contraindicated in patients with acutely decompensated systolic heart failure [7]. The relative efficacy and safety of β-blockers and calcium channel blockers for tachycardic patients without specific drug contraindications is less explicit. To determine which drug class is more effective in rapidly controlling ventricular rates associated with AF, we performed a systematic review of the literature. We reviewed all trials comparing the efficacy of β-blockers and calcium channel blockers administered in the acute care setting to hemodynamically stable patients with atrial fibrillation and rapid ventricular response.
Materials and methods Study design
We conducted a systematic review of studies that examined the efficacy of rate-control agents in the management of atrial fibrillation with rapid ventricular response. We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [8]. Search strategy
Our medical librarian developed the Medical Subject Headings terms ‘calcium channel blockers’, ‘adrenergic DOI: 10.1097/MEJ.0000000000000227
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
Acute rate control of atrial fibrillation Martindale et al. 151
beta-antagonist’, ‘atrial fibrillation’, and ‘heart rate’ (see online appendix-web only file, Supplemental digital content 1, http://links.lww.com/EJEM/A85). Bibliographies of guidelines and review articles were reviewed to identify additional original research articles. To find unpublished studies, we reviewed abstracts from the following scientific meetings: American College of Emergency Physicians (1998–2013), Society for Academic Emergency Medicine (1995–2014), American Heart Association (2007–2013), and the European Society of Cardiology (2005–2013). Three independent reviewers (M.S., I.S.d., and J.L.M) screened the following databases from their inception to June 2014: EMBASE, MEDLINE, and the Cochrane Controlled Trials Registry. A fourth author (R.S.) adjudicated final choices for study inclusion.
associated with the use of rate control medications. Adverse events included hypotension, bradycardia, and death. The Mann-Whitney U-test was used to calculate baseline differences in heart rate and age between treatment groups.
Quality assessment
Included studies were evaluated for adequacy in randomization, concealment of allocation, intention-to-treat, baseline comparisons, cointerventions, blinding, and completeness of follow-up.
Results
Inclusion and exclusion criteria
Search results
Studies comparing β-blockers and calcium channel blockers in adult patients presenting to the ED with atrial fibrillation with rapid ventricular response were included. Both reduction in ventricular response and conversion to sinus rhythm were targeted outcome measures. The literature search included studies published between 1965 and June 2014 and was not limited by language of the publication. Studies that evaluated long-term outcomes of rate control or compared rhythm control to rate control were excluded. An a-priori decision was made to exclude studies examining rate control of atrial fibrillation in the postoperative setting, as postoperative patients with this arrhythmia constitute a distinct patient population.
The flow diagram of our search is illustrated in Fig. 1. Our search of MEDLINE, EMBASE, and Cochrane registries yielded 1003 unique studies. Our search of abstracts published in the archives of scientific sessions and of the references of guidelines and review articles did not produce any additional studies. After review of titles and abstracts, 998 were rejected for relevance. The majority of studies were excluded because they evaluated long-term outcomes of rate control, compared rhythm control with rate control, or evaluated rate control in the postoperative patient. Of the five studies reviewed further, three studies, Platia et al. [5], Mieure et al. [9], and Hassan et al. [10], provided insufficient data. We attempted without success to obtain patient-level data from these studies. The study by Platia et al. [5] reported only summary statistics for ventricular rates in groups receiving esmolol and verapamil in the text. Patient-level data for ventricular rates at two points in time (the end of study drug titration period and the end of a 30-min observation period that followed) are represented in graphical form. The percentage of patients in each group achieving rate control could not be extracted from this graph. The study by Mieure et al. [9] reported only the number of patients who achieved rate control at the end of the 24-h study period. Hassan et al. [10] reported group-level data for mean ventricular rates achieved at 1, 6, 12, and 24 h after initiation of study drug, but did not provide the number of patients in each group who had achieved rate control by these time points. This left two prospective studies by Fromm et al. [11] and Demircan et al. [12] that provided sufficient information to compute the RRs of achieving acute rate control in atrial fibrillation with rapid ventricular response. The study by Fromm et al. [11] is published in the form of an abstract. While sufficient data were available to compute RR, details regarding this study’s design and primary results remained unavailable. Publication bias could not be assessed.
Data collection and processing
Data elements extracted directly from the included article(s) were (a) patient characteristics (age, sex), (b) trial inclusion and exclusion criteria, (c) study medication, dose, and route of administration, (d) efficacy of intervention at controlling rapid ventricular response or converting to sinus rhythm, (e) timing of rate/rhythm control after drug administration, and (f) adverse events including bradycardia, hypotension, and death. Authors of studies with insufficient data were contacted. Outcome measures and data analysis
Our primary outcome measure was a decrease in ventricular rate (< 100 beats/min) at a specific time point defined by the included study. Both decrease in ventricular response to atrial fibrillation and conversion to sinus rhythm were considered effective means of achieving rate control. A two-by-two table was constructed with primary data extracted from the included studies. Relative risk (RR) and number needed to treat with 95% confidence intervals (CIs) were used to estimate the treatment effect (RevMan5; The Cochrane Collaboration, Copenhagen, Denmark). Our secondary outcome measure was the rate of adverse events
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
152 European Journal of Emergency Medicine 2015, Vol 22 No 3
Fig. 1
Titles and abstracts screened MEDLINE (191) and EMBASE (883) Afetr removal of duplicates: n=1003 1003
Cochrane library (0) Additional studies from references (0) Additional studies from archives of scientific sessions (0)
Excluded by abstract based on relevance 998
Full-text review 5
Insufficient data 3
Selected studies 2
Flow diagram of study selection process.
Study characteristics
The two studies that met our inclusion criteria were randomized, double-blinded, prospective trials of 40 [12] and 52 [11] patients. Patients presenting to the ED with atrial fibrillation and a ventricular rate of at least 120 beats/min were included in both studies. Fromm et al. [11] included patients with atrial flutter and a rapid ventricular rate; inclusion and exclusion criteria for this study were not stated in the published abstract. The following exclusion criteria were applied to the Demircan et al. [12] study: congestive heart failure (New York Heart Association Class IV), sick sinus syndrome, second or third degree atrioventricular (AV) block, pre-excitation syndromes, ventricular rate of more than 220 beats/min, QRS duration more than 0.08 s, unstable angina, acute myocardial infarction, hyperthyroidism, fever, anemia (hemoglobin < 11 g/dl), bronchial asthma, chronic obstructive pulmonary disease, diabetes mellitus, peripheral vascular disease, pregnancy, and history of having used diltiazem, verapamil, digoxin, β-blockers, theophylline or β-agonists within the previous 5 days. Doses of intravenous diltiazem and metoprolol used in this
study were 0.25 mg/kg, (maximum 25 mg) and 0.15 mg/ kg (maximum 20 mg) respectively. The doses used by Fromm et al. [11] were not published. Successful treatment was defined by Fromm et al. [11] as a reduction in heart rate to less than 100 beats/min 30 min after drug administration. Demircan et al. [12] defined treatment success as a decrease in a ventricular rate by 20% (< 120 beats/min at least) or conversion to sinus rhythm within 20 min of drug administration. Group comparison data for baseline characteristics including underlying coronary artery disease, structural heart disease, history of atrial fibrillation, or left ventricular fraction were not available for either study. The mean age and blood pressure were reported to be similar in both treatment groups by Fromm et al. [11]; Baseline mean heart rate for the metoprolol group was 142.2 and 136.8 beats/min for the diltiazem group (P = 0.231). Median initial heart rates in the metoprolol and diltiazem groups in the Demircan et al. [12] study were 150 and 154 beats/min, respectively (P = 0.45). Median ages for
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Acute rate control of atrial fibrillation Martindale et al. 153
the metoprolol and diltiazem group were 64.5 and 65.6 (P = 0.31).
90 mmHg, or bradycardia. Hypotension and bradycardia were not reported in the abstract by Fromm et al. [11].
Trial quality
Discussion
Neither study was registered in clinicaltrials.gov. In the Demircan et al. [12] study, subjects were randomized and methods of allocation concealment and blinding were described. A predetermined sample size estimate and baseline comparisons were not reported in this study. Follow-up was complete. The authors of this study do not explicitly state whether or not an intention-to-treat analysis was used to estimate treatment effect. The study by Fromm et al. [11] was a double-blinded trial. Sequence allocation, allocation concealment, intention-to-treat analysis, and follow-up completion are not described in the published abstract. Primary outcomes analysis
The primary outcome, defined by Demircan et al. [12] as a ventricular rate of less than 100 beats/min or a 20% decrease in ventricular rate, was achieved in 90% of the patients who received diltiazem and 80% who received metoprolol at the end of the 20-min study period. None of the patients converted to sinus rhythm. We redefined the treatment outcome in the Demircan et al. [12] study as achievement of ventricular rates less than 100 beats/min by 20 min after drug administration to combine these data with the data provided by the Fromm et al. [11] study. At the end of the 20-min period, 65% of patients receiving diltiazem and 50% of patients receiving metoprolol had ventricular rates less than 100 beats/min (Table 1). At the end of 20 min after drug administration in the study by Fromm et al. [11], 83% of the patients who received diltiazem and 36% of those who received metoprolol had a ventricular rate of less than 100 beats/min. The combined RR (95% CI) for achieving a heart rate of less than 100 beats/min with diltiazem compared with metoprolol was 1.80 (1.23–2.62). On the basis of the data from the studies combined, the calculated number needed to achieve rate control by diltiazem compared with metoprolol was 3 (95% CI 1.9–6.9). Secondary outcomes analysis
None of the patients in either treatment arm of the study by Demircan et al. [12] experienced hypotension, as defined by a systolic blood pressure of less than Table 1
In the outpatient setting, where rate control may be more important for avoiding tachycardia-related cardiomyopathy, β-blockers are more effective than calcium channel blockers in achieving rate control in atrial fibrillation [13]. In the postoperative setting, diltiazem has been shown to be more effective than metoprolol in achieving rate control after nonthoracic surgery [14]. Our systematic review suggests that in the ED, diltiazem may be more effective than metoprolol in rapidly controlling ventricular rates. Diltiazem both slows conduction through the AV node and prolongs the refractory period of AV nodal tissue by blocking L-type calcium channels; metoprolol works more indirectly, by blocking sympathetic input to the AV node. The current literature suggesting diltiazem’s superior efficacy in the acute care setting, however, is limited to two small-sample sized studies that lack a priori sample size determination and have limited generalizability. The external validity of the study by Demircan et al. [12] is undermined by its exclusion of patients who have taken oral AV-nodal blocking agents within 5 days before randomization. While these patients were presumably excluded to eliminate possible confounding effects of residual oral agents, atrial fibrillation is not a new diagnosis for most patients in the acute care setting, and a variable, but significant percentage of these patients take β-blockers or calcium channel blockers at home. Including such patients in a larger study would yield conclusions more relevant to an emergency physician. Exclusion of patients with common comorbid conditions such as diabetes mellitus, which are not contraindications to either type of AV nodal blocker, also makes this study less generalizable to an ED population. While no adverse events were found by this systematic review, hypotension is a legitimate concern while using these drugs. The dose used in the Demircan et al. [12] study (up to a maximum of 25 mg) is the same dose recommended by current guidelines [0.25 mg/kg (actual body weight) intravenous bolus over 2 min] [7]. In clinical practice, the dose of diltiazem administered to patients with AF and rapid ventricular response is variable. In one retrospective observational study, doses of 0.2 mg/kg or less of diltiazem were administered to one-
Rates of successful decrease in ventricular rate to less than 100 bpm at 20 min
Demircan et al. [12] Fromm et al. [11] Combined
Sample size
Diltiazem
Metoprolol
Relative risk (95% CI)
NNT (95% CI)
40 52 92
13/20 20/24 33/44
10/20 10/28 20/48
1.3 (0.75–2.24) 2.33 (1.38–3.96) 1.80 (1.23–2.62)
7 (− 15.3 to 45.3)a 2 (1.4–4.1) 3 (1.9–6.9)
The confidence interval (CI) for number needed to treat (NNT) includes negative numbers and zero. An alternative way to express the CI here is (NNH = 15.3 to ∞ to NNT = 45.4 to ∞).
a
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154 European Journal of Emergency Medicine 2015, Vol 22 No 3
third of patients presenting to the ED with AF and rapid ventricular response [15]. Hypotension, defined as systolic blood pressure less than 90, was observed in 1/61 patients who received 0.2 mg/kg or less, 6/83 patients who received more than 0.2 mg/kg, and 0.3 mg/kg or less, and 1/36 patients who received more than 0.3 mg/kg. Some clinicians choose to administer calcium before diltiazem to limit subsequent hypotension, although this failed in one prospective study to blunt a decrease in systolic blood pressure [16]. In that study, 4/8 patients receiving diltiazem (0.25 mg/kg, maximum 20 mg) became hypotensive, but three of these patients had borderline initial blood pressures (systolic blood pressures of < 100 mmHg). These results suggest that hypotension due to calcium channel blockers may not be dose-dependent and may be due to other factors such as initial baseline blood pressures. Variability in the management of controlling rapid ventricular rates associated with AF largely stems from a lack of evidence to guide emergency physicians in choosing the most effective and safest AV nodal blocker. Less clear is how home use of these agents should factor in to the ED physician’s choice of AV nodal blocker to achieve acute rate control. Preference for one drug class is variably based on perceived risk of symptomatic bradycardia and hypotension in patients taking a medication from another drug class. Evidence pertaining to the adverse effects of combining β-blockers and calcium channel blockers (when one is used orally at home, the other intravenously in the acute care setting) is lacking. In the study by Demircan et al. [12], the four patients in the metoprolol group who failed to achieve rate control by 20 min received intravenous diltiazem; subsequent hypotension did not occur. The safety of administering both types of AV-nodal blockers serially in the ED (when one agent has been deemed ineffective in achieving rapid rate control) has not been studied. Limitations
The available evidence comparing β-blockers and calcium channel blockers for rate control in AF is extremely limited. A quality assessment of one of the two included studies in this review could not be performed, as it was published as an abstract and more detailed methodological data could not be obtained. Future studies should be prospective, randomized, and methodologically sound trials that examine larger, predetermined sample sizes. A study that included patients already taking AV nodal blocking agents would be more generalizable to the ED population.
Conflicts of interest
There are no conflicts of interest.
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Acknowledgements The authors would like to thank Christopher Stewart, senior assistant librarian at SUNY Downstate Medical Center for his assistance in our literature search.
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