Are Beta Blockers More Effective than Calcium Channel Blockers in Controlling Heart Rate in Patients with Atrial Fibrillation?A Meta-Analysis.
Mohammad Murtaza Zaman, Abdalazeem AIbrahem, AamirShamsi,Sonia Shad
Word Count:1629
Tables:1, 2, 3
BACKGROUND:
Atrial fibrillation(AF) is the most common sustained cardiac arrhythmia and results in significant mortality and morbidity predominantly due to ischemic stroke and heart failure.1 The prevalence is rising due to an increasing elderly population. Improved management strategies for ischemic heart disease and heart failure haveresulted in a longer life expectancy and therefore increases the likelihood of developing AF secondary to these cardiac conditions.2 The main aims of management include rate or rhythm control alongwith anticoagulation for prevention of thromboembolic events. Large Randomized Controlled Trials(RCTs) such as the Rate Control versus Electrical Cardioversion (RACE)have shown that rate control strategy is not inferior to rhythm control for preventing mortality and morbidity.3Rate control should be the first-line management strategy unless the patient has anew-onset AF secondary to a reversible cause such as sepsis, thyrotoxicosis or electrolyte imbalance. 4
The American College of Cardiology, European College Society of Cardiology and National Institute for Health and Care Excellence (NICE)recommend a beta-blocker or a rate limiting calcium-channel blocker as first line treatment for controlling heart rate in patients who are haemodynamically stable. 4-6In clinical practice there seems to be debate among clinicians as to the superiority of one agent over the other.
METHODOLOGY:
Searches were conducted in November 2015 on Embase (1974 to 2015 November), Ovid Medline (1946 to November Week 2, 2015) and the Cochrane Database.Four main facets were searched; ‘atrialfibrillation’, ‘beta-blockers’, ‘calcium-channel blockers’ and ‘rate control’. The ‘explode’ command was employed to get the maximum yield. All possible synonyms were individually searched (free text searches) and results were combined by using Boolean operator ‘OR’. Once the search results of the 3 facets i.e. population, intervention and comparison were available, they were combined using the Boolean operator ‘OR’. The results were filtered as to include only RCTs.
FINDINGS OF THE SEARCH:
All the search terms were used across all databases. In total one hundred and nine (n=109) papers were returned. The duplicates were removed leaving ninety three (n=93) papers. All titles were reviewed and seventy-four were removed as they were irrelevant with regards to the research question. Nineteen (n= 19) abstracts were pursued out of which fourteen were discarded for not meeting the eligibility criteria which were as follows:
1) RCTs that compare participants who received beta-blockers to those who received calcium-channel blockers
2) Studies that do not use other medication in combination with beta-blockers and calcium channel blockers
3) Patients with atrial flutter could be included in the trials as the main management principles were similar to that of atrial fibrillation
4) The clinical setting should be clearly mentioned for example, primary care or the emergency department
5) The primary end point or outcome of the study should be control of rapid ventricular rate
6) The studies should have clearly defined inclusion and exclusion criteria
Table 1: Overview of Selected Studies
Diltiazem vs. Metoprolol in the Management of Atrial Fibrillation or Flutter with Rapid Ventricular Rate in the Emergency Department Fromm et al.(2015)9 / Comparison of the effectiveness of intravenous Diltiazem and Metoprolol in the management of rapid ventricular rate in atrial fibrillation Demicranet al.(2005)8Design / Prospective, randomized, double-blind study / Prospective, randomized, double-blind study
Population size / 52 patients / 40 patients
Clinical setting / Emergency department (ED) / ED
Inclusion criteria / Patients aged 18 years or older with atrial fibrillation/flutter on 12 lead electrocardiogram (ECG), ventricular rate of >120bpm and a systolic blood pressure (SBP) >90 mm Hg / Patients aged >18 years with atrial fibrillation on 12 lead ECG, ventricular rate of >120bpm and a SBP >95 mm Hg
Exclusion criteria / SBP< 90 mm Hg, heart rate > 220bpm, QRS >0.100s, 2nd or 3rd degree atrio-ventricular block (AV), temperature >38 degree C, acute ST elevation myocardial infarction (MI), New York Association (NYHA) Class 4 heart failure, wheezing on a background of asthma/COPD, prehospital administration of AV nodal blocking medication, cocaine or methamphetamine use, prior allergic reaction to diltiazem or metoprolol, known sick sinus syndrome, anaemia with haemoglobin (Hb)<11 g/dl, breastfeeding or pregnancy / Prior allergic reaction to diltiazem or metoprolol, congestive cardiac failure with NYHA Class 4, SBP< 90 mm Hg, heart rate > 220bpm, sick sinus syndrome, 2nd or 3rd degree AV block, QRS >0.08s, asthma, COPD, unstable angina, acute MI, diabetes, peripheral vascular disease, Hb <11 g/dl, pregnancy and use of diltiazem, verapamil, digoxin, beta-blockers, theophylline or beta agonists in the last 5 days
Intervention / Parenteral metoprolol 0.15mg/kg / Parenteral metoprolol 0.15mg/kg
Comparison / Parentraldiltiazem 0.25mg/kg / Parentraldiltiazem 0.25mg/kg
Mode of administration / IV / IV
Primary outcome / Ventricular rate <100/min / Ventricular rate <100/min, decrease in rate of 20%(<120/min at least) or conversion to sinus rhythm
Assessment of heart rate (HR) post intervention / 2, 5, 10, 15 and 20 minutes / 5, 10, 15, 20, 25 and 30 minutes
Source of funding / Not declared / Not declared
CRITICAL APPRAISAL:
The first paper selected was ‘Comparison of the effectiveness of intravenous diltiazem and metoprolol in the management of rapid ventricular rate in atrial fibrillation’ by Demicran et al.8The second paper selected was ‘Diltiazem vs. Metoprolol in the Management of Atrial Fibrillation or Flutter with Rapid Ventricular Rate in the Emergency Department’ by Fromm et al.9 (Table 1).
Both studies were double blind RCTs. The authors obtained written consent from participants and followed ethical guidelines. The Demicran paper did not specify whether a power calculation was undertaken while the Fromm investigators performed a power calculation based on standard deviations from the Demicran paper. They estimated that a sample size of 200 patients would achieve 80% power to detect non inferiority using a two sample t-test,however enrollment was stopped as the safety monitoring team noticed that significantly more patients from one group were achieving the desired endpoint, in total 54 patients were enrolled and so the study was ‘under powered’.
Though the clinical setting (Emergency Department) was adequately described in both studies, the Demicran paper did not describe the population adequately. Fromm et al. described the hospital as an urban center but used convenience sampling and included patients with atrial flutter in the trial.Also in both trials patients with other co-morbidities such as diabetes and COPD were excluded which affected ‘generalizability’.
The Fromm and Demicran investigators used computer generated randomization and cards in sealed opaque envelopes respectively hence there was adequate allocation concealment in both studies.Both studies used valid and reliable methods (heart rate, blood pressure and electrocardiogram monitoring) to determine precisely defined outcomes and patients were followed up appropriately at fixed time intervals.
SYNTHESIS:
Demicran et al. reported the mean percentage decrease in ventricular rate and the rate of success at 2, 5, 10, 15 and 20 minutes. They concluded that both interventions were effective in decreasing HR (p<0.01) but the rate control effect of diltiazem began sooner and the percentage decrease was higher as compared to metoprolol at different time intervals.8
Fromm et al. presented data on the decrease in HR (in terms of actual HR and not percentile) and rate of success in the form of a Kaplan-Meier curve at 0, 5, 10, 15, 20, 25 and 30 minutes.The authors concluded that the diltiazem group were 4.66 times more likely to reach target HR at 30 minutes (CI 2.09 to 10.36, p = 0.0001). 9
For data analysis, the mean HR at 20 minutes was used.Statistical analysis was carried out using the Review Manager software (RevMan version 5.3). The P value is shown and was considered statistically significant if less than 0.05. A Forest plot is used to represent the meta-analysis graphically. The results showed that calcium-channel blockers were more effective than beta-blockers in controlling the heart rate at 20 minutes with a trend towards significance (p = 0.07). (Table 2)
Table 2:Meta-analysis favouring Diltiazem at 20minutes
DISCUSSION:
According to the Vaughan-Williams classification of antiarrhythmic drugs(Table3),16metoprolol is a beta-blocker which is a Class II agent while diltiazem, a non-dihydropyridine calcium-channel blocker, is a Class IV drug.18Both drugs slow conduction through the AV node and prolong AV node refractoriness albeit via different mechanisms. In heart failure patients calcium-channel blockers are contra-indicated due to their negative ionotropic effects.15Beta-blockers on the other hand offer prognostic benefit in patients with left ventricular failure and ischemic heart disease both of which are important drivers of atrial fibrillation.14 There exists a gap in literature with regards to which is a better rate control agent. This is evidenced by the fact that most clinical guidelines still advise either of the two drug classes as first line agents. To settle this debate, better-designed and sufficiently powered RCTs are needed in future. Also, research should focus on newer agentslike Digoxin and combination therapy which could be superior to both agents in question. Failure to do so would continue to fuel the ongoing indecisiveness in clinical practice.
Table 3: Vaughan-Williams classification of antiarrhythmic drugs
Class Basic Mechanism CommentsI sodium-channel blockade Reduce phase 0 slope and peak of action potential.
IA - moderate Moderate reduction in phase 0 slope; increase APD; increase ERP.
IB - weak Small reduction in phase 0 slope; reduce APD; decrease ERP.
IC - strong Pronounced reduction in phase 0; no effect on APD or ERP.
II beta-blockade Block sympathetic activity; reduce rate and conduction.
III potassium-channel Delay repolarization (phase 3) and thereby increase action potential duration and
blockade effective refractory period.
IV calcium-channel Block L-type calcium channels; most effective at SA and AV nodes;
blockade reduce rate and conduction.
Ref: cvpharmacology.com
(APD, action potential duration; ERP, effective refractory period; SA, sinoatrial node; AV, atrioventricular node)
REFERENCES:
1.Lip GY, TseH-F. Management of atrial fibrillation.Lancet.2007 Aug 18; 370(9587):60418.
2.Atrial fibrillation: management | introduction | Guidance and guidelines | NICE. (accessed on 20 January, 2016).
3. Van Gelder IC, Hagens VE, Bosker HA, Kingma JHet al.A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation.N Engl J Med. 2002; 347(23):1834–40.
4. Atrial fibrillation: management | 1-recommendations | Guidance and guidelines | NICE. (accessed on 20 January, 2016).
5. Camm AJ, Kirchhof P, Lip GYH, Schotten U et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010 Oct; 31(19):2369–429.
6. January CT, Wann LS, Alpert JS, Calkins H et al. AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am CollCardiol. 2014; 64(21):e1–76.
7. Kendall JM. Designing a research project: randomised controlled trials and their principles.Emerg Med J. 2003; 20(2):164–8.
8. Demircan C, Cikriklar HI, Engindeniz Z, Cebicci H 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(6):411–4.
9. Fromm C, Suau SJ, Cohen V, Likourezos Aet al. Diltiazem vs. Metoprolol in the Management of Atrial Fibrillation or Flutter with Rapid Ventricular Rate in the Emergency Department. J Emerg Med. 2015; 49(2):175–82.
10. Farshi R, Kistner D, Sarma JS, Longmate JA et al. Ventricular rate control in chronic atrial fibrillation during daily activity and programmed exercise: a crossover open-label study of five drug regimens. J Am CollCardiol. 1999; 33(2):304–10.
11. Siu C-W, Lau C-P, Lee W-L, Lam K-F et al. Intravenous diltiazem is superior to intravenous amiodarone or digoxin for achieving ventricular rate control in patients with acute uncomplicated atrial fibrillation. Crit Care Med. 2009; 37(7):2174–9.
12. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ et al. A comparison of rate control and rhythm control in patients with atrial fibrillation.N Engl J Med. 2002; 347(23):1825–33.
13.Martindale JL, deSouza IS, Silverberg M, Freedman J et al. β-Blockers versus calcium channel blockers for acute rate control of atrial fibrillation with rapid ventricular response: a systematic review. Eur J Emerg Med. 2015; 22(3):150–4.
14.Vantrimpont P, Rouleau JL, WunCC, Ciampi A et al. Additive beneficial effects of beta-blockers to angiotensin-converting enzyme inhibitors in the Survival and Ventricular Enlargement (SAVE) Study. SAVE Investigators. J Am CollCardiol. 1997; 29(2):229–36.
15. Vaughan Williams EM. "Classifying antiarrhythmic actions: by facts or speculation".J ClinPharmacol.32 (11): 964–77. doi:10.1002/j.1552-4604.1992.tb03797.x. PMID1474169.
16. KlabundeRichard E."Vaughan-Williams Classification of Antiarrhythmic Drugs". Cardiovascular Pharmacology Concept.
1