Marlene R. Miller, MD, MSc Robert L. McNamara, MD, MHS Jodi B. Segal, MD, MPH Nina Kim, MA Karen A. Robinson, MSc Steven N. Goodman, MD, PhD Neil R. Powe, MD, MPH, MBA Eric B. Bass, MD, MPH Baltimore, Maryland From the Division of Pediatric Cardiology (M.R.M.), Division of Cardiology (R.L.N.), Division of General Internal Medicine (J.B.S., N.R.P., E.B.B.), Oncology Center (S.N.G.), Division of Biostatistics at Johns Hopkins University School of Medicine; Graduate Training Program in Clinical Investigation (M.R.M.), Department of Epidemiology at Johns Hopkins University School of Hygiene and Public Health (R.L.M., N.R.P.); and the Baltimore Cochrane Center at University of Maryland (N.K., K.A.R.). This material was previously presented orally at the American College of Cardiology 48th Annual Scientific Session, March 1999. Dr Miller completed this study while she was a clinical fellow at Johns Hopkins University School of Medicine and a graduate student at Johns Hopkins University School of Hygiene and Public Health.
Reprint requests should be addressed to Marlene R. Miller, MD, MSc, Center for Quality, Measurement and Improvement, Agency for Healthcare Research and Quality, 2101 East Jefferson Street, Suite 502, Rockville, MD 20852. Email: mmiller@ahrq.gov.
A Meta-Analysis of Clinical Trials
References
CONTEXT: Physicians have little evidentiary guidance for pharmacologic agent selection for atrial fibrillation (AF).
OBJECTIVE: To assess antiarrhythmic agent efficacy for AF conversion and subsequent maintenance of sinus rhythm (MSR).
DATA SOURCE: We searched the clinical trial database of the Cochrane Collaboration and MEDLINE encompassing literature from 1948 to May 1998.
STUDY SELECTION: We selected 36 (28%) articles eligible as randomized trials of nonpostoperative AF conversion or MSR in adults.
DATA EXTRACTION: Study quality; rates of conversion, MSR, and adverse events were extracted.
DATA SYNTHESIS: Compared with control treatment (placebo, verapamil, diltiazem, or digoxin), the odds ratio (OR) for conversion was greatest for ibutilide/dofetilide (OR=29.1; 95% confidence interval [CI], 9.8-86.1) and flecainide (OR=24.7; 95% CI, 9.0-68.3). Less strong but conclusive evidence existed for propafenone (OR=4.6; 95% CI, 2.6-8.2). Quinidine (OR=2.9; 95% CI, 1.2-7.0) had moderate evidence of efficacy for conversion. Disopyramide (OR=7.0; 95% CI, 0.3-153.0) and amiodarone (OR=5.7; 95% CI, 1.0-33.4) had suggestive evidence of efficacy. Sotalol (OR=0.4; 95% CI, 0.0-3.0) had suggestive evidence of negative efficacy. For MSR, strong evidence of efficacy existed for quinidine (OR=4.1; 95% CI, 2.5-6.7), disopyramide (OR=3.4; CI, 1.6-7.1), flecainide (OR=3.1; 95 % CI, 1.5-6.2), propafenone (OR=3.7; 95% CI, 2.4-5.7), and sotalol (OR=7.1; 95% CI, 3.8-13.4). The only amiodarone data, from comparison with disopyramide, provided moderate evidence of efficacy for MSR. No trial evaluated procainamide. Direct agent comparisons and adverse event data were limited.
CONCLUSIONS: Although multiple antiarrhythmic agents had strong evidence of efficacy compared with control treatment for MSR, ibutilide/dofetilide and flecainide had particularly strong evidence of efficacy compared with control treatment for AF conversion. There is sparse and inconclusive evidence on direct agent comparisons and adverse event rates. Obtaining information regarding these relative efficacies should be a research priority.
Clinical question
Which antiarrhythmic agents are efficacious for conversion of nonpostoperative atrial fibrillation and for subsequent maintenance of sinus rhythm?
Atrial fibrillation (AF) is the most common sustained tachyarrhythmia faced by all physicians. The prevalence of AF, estimated at 0.4% in the general population,1 increases with age to almost 10% among those aged 80 to 89 years.2,3 The age-adjusted incidence of AF has increased over the last 30 years.4 AF accounts for more days of hospitalization for either acute hemodynamic compromise or treatment of the arrhythmia than all ventricular arrhythmias combined.5 All admissions for the complications of stroke and chronic heart failure are not reflected in these data. Overall, patients with AF have twice the mortality of a control population without AF and an attributable risk of stroke of 24% in those aged 80 to 89 years.2
One of the most important issues for management of AF is the need for conversion to sinus rhythm and subsequent maintenance of sinus rhythm (MSR), particularly for symptomatic patients. Although conversion can be accomplished by electrical cardioversion, it is frequently accomplished with pharmacologic agents because of patient or physician preference and anesthesia risks. These agents may also be used for subsequent MSR. In addition to the numerous relatively new or investigational agents such as ibutilide and dofetilide there are at least 7 agents commonly used for either conversion or MSR: quinidine, disopyramide, procainamide, flecainide, propafenone, amiodarone, and sotalol.6 This plethora of antiarrhythmic agents for either conversion of AF or MSR makes it difficult for physicians to know which are best for their patients. We reviewed the evidence on pharmacologic management of AF as part of the Johns Hopkins Evidence-Based Practice Center sponsored by the Agency for Health Care Policy and Research (now the Agency for Healthcare Research and Quality).
Methods
Search Strategy
We used the Medical Subject Heading terms “atrial fibrillation,” “atrial flutter,” “random allocation,” “double-blind method,” and “single-blind method.” Publication types of “randomized controlled trial” and “controlled clinical trial” were included. Although the search was not restricted to citations in the English-language literature, subsequent article review involved only English-language publications because of budgetary constraints.
The primary literature source was the CENTRAL database, The Cochrane Library 1998 issues 1 and 2, produced by the Cochrane Collaboration from EMBASE and MEDLINE and encompassing 1948 through the present.7,8 Second, MEDLINE was searched using both OVID and PubMed from 1966 to May 1998. Third, we used the PubMed feature of “related articles” for primary articles identified in the CENTRAL database. Fourth, a review of recent hand search results submitted to the Baltimore Cochrane Center from the Cardiovascular Randomized Controlled Trial Registry was used. Finally, to capture newly published studies the core study team scanned the contents of the journals most frequently cited in the search results database.
To address the issue of publication bias we asked investigators in the field and search coordinators of relevant Cochrane Collaborative Review Groups to identify any trials they were aware of that had been completed but not published. We decided that construction of funnel plots was practical because of the relatively small number of trials for any specific pharmacologic agent.
