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.
References
As another part of the project evaluating management of atrial fibrillation by the Johns Hopkins Evidence-Based Practice Center, we reviewed the data on 10 trials that had direct comparisons between the major antiarrhythmic agents regarding MSR in AF.15 Because of the overall paucity of data on these direct comparisons, mathematical data pooling was not feasible and definitive ranking of the agents for MSR efficacy was not possible. Overall, these results were consistent with our meta-analysis showing no one agent as clearly superior over other agents.
Evidence on Adverse Events
During our data extraction we only noted where trials specifically mentioned various events such as ventricular arrhythmias or other nontransient arrhythmias (Table 5). We did not perform formal data synthesis regarding adverse events because the data were too sporadically reported.
In addition, caution must be used in interpreting rates of adverse events that resulted in study withdrawal or dosage decreases, since there was no uniformity regarding the indications for withdrawals of dosage decreases among the studies. Also with respect to conversion trials, many studies involved one-time study drug administration that limited the applicability of this adverse event definition.
Discussion
Pharmacologic conversion of AF is frequently the therapy of choice compared with electrical cardioversion, especially in cases of short-duration AF, significant anesthesia risk, or recent postprandial status of a patient. Little guidance based on scientific evidence has existed regarding the best pharmacologic agents to achieve conversion of AF. On the basis of this formal data review, we are unable to state definitively the relative efficacy of the agents compared with each other because of the inability to ensure comparable subjects within the control treatment groups for the evaluated trials. However, this data synthesis did find that the strongest evidence of efficacy compared with control treatment for conversion of AF existed for ibutilide/dofetilide and flecainide. Less strong but still conclusive evidence existed for propafenone. Quinidine had moderate evidence of efficacy, while only suggestive evidence of efficacy existed for disopyramide and amiodarone. Finally, sotalol had suggestive evidence of negative efficacy compared with control treatment for conversion of AF. Notably, there was no randomized trial on the use of procainamide compared with control treatment for conversion of AF.
The clinical implications of these findings need to be viewed in the light of previous reports regarding adverse events, since our ability to synthesize the adverse event data from these trials was limited.
Ibutilide and dofetilide are new class III antiarrhythmic agents currently undergoing extensive clinical trials. Although limited primarily to clinical trial data, our data and other reports conclude that these drugs have a rate of ventricular arrhythmias (particularly torsade de pointes) of 3% to 9%.52 However, there were no reported deaths or prolonged resuscitations among the trials examined.38-40 Data from long-term use in everyday clinical practice evaluating these agents in less controlled circumstances are not available.
There have been reports of increased mortality with flecainide, although this occurred for prevention of ventricular ectopic activity in subjects with coronary artery disease in the Cardiac Arrhythmia Suppression Trial.53 However, patients with atrial fibrillation may frequently also have ventricular ectopic activity and coronary artery disease. A recent review of flecainide safety for treatment of supraventricular arrhythmias using both randomized clinical trials and uncontrolled trials concluded that the risk of clinically significant adverse cardiac effects was small but not negligible.54 From 1794 reviewed treatment courses 2% had atrial proarrhythmic events with some requiring urgent electrical cardioversion because of hemodynamic compromise, and 2% had pre-excitation worsening or new ventricular arrhythmias including 9 cases of sustained ventricular tachycardia or fibrillation and 4 cases of sudden cardiac death. Another report retrospectively compared the mortality rates of patients with atrial arrhythmias in completed pharmaceutical company–sponsored trials treated with flecainide with a population seen at the research arrhythmia clinic.55 The researchers concluded that there appeared to be no excess mortality in patients treated with flecainide for supraventricular arrhythmias. If the main concern among patients with atrial fibrillation is coronary artery disease and resultant ventricular dysfunction, our data synthesis was unable to address this because of poor documentation of definitions regarding presence of coronary artery disease, presence of abnormal left ventricular function, and lack of result stratification by these conditions.
Since these 2 agents (ibutilide/dofetilide and flecainide) had the largest treatment effect sizes for conversion of AF, additional research directly comparing them, comparing them with electrical cardioversion, and better quantifying adverse event rates stratified by the presence of coronary artery disease, structural heart disease, left ventricular hypertrophy, and long QT intervals would help solidify their efficacy and safety for conversion of AF.
