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
Similarly, more research on the efficacy of amiodarone is warranted given the paucity of data, a general perception of relatively minor side effects, and a high prevalence of clinical use for AF.
Pharmacologic MSR for AF is a therapeutic option for patients with high recurrence rates and patients with symptomatic AF. Comparable with conversion of AF therapy, no consensus exists on the best pharmacologic agents to achieve MSR in AF. Our formal data synthesis was unable to show definitively the relative efficacy of the agents for MSR 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 strong and comparable efficacy evidence for quinidine, disopyramide, flecainide, propafenone, and sotalol. Notably, the data for amiodarone use for MSR are sparse with no trials comparing amiodarone with control treatment, and no trial evaluated procainamide either compared with control treatment or another agent.
The clinical implications of these data also need to be viewed in light of previous reports regarding adverse events, since our ability to synthesize the adverse event data was limited. The issues regarding flecainide have already been discussed. The Class Ia agents quinidine, disopyramide, and procainamide have classically been associated with torsade de pointes because of their prolongation of the QT interval, but cases of torsade de pointes have also been reported with propafenone, flecainide, amiodarone, and sotalol. The reported risk factors for proarrhythmic events with each of the agents vary from hypokalemia and bradycardia for quinidine to serum concentration for sotalol. A recent review concluded that all of the antiarrhythmic agents have potential for uncommon but serious proarrhythmic effects.56 Unfortunately, this does not help the clinician sort through all of the available agents.
More research involving direct comparisons between all these agents for MSR in AF would help to definitively rank the efficacy of the agents and to compare their adverse event profiles. Stratification of patients on the basis of the presence of coronary artery disease, structural heart disease, left ventricular hypertrophy, and long QT intervals would permit better assessment of adverse event risks. Both the ongoing AF Follow-up Investigation of Rhythm Management (AFFIRM)57 sponsored by the National Heart, Lung, and Blood Institute and the ongoing Prognosis in Afib (PAIF)58 study may help provide more information directly comparing agents for MSR.
Limitations
Overall with respect to our data synthesis for both conversion of AF and MSR, we cannot exclude a publication bias despite our best efforts to minimize this known limitation of evidence reviews.
In terms of the actual trials reviewed, we do not believe that subject-specific factors significantly influenced the accumulated evidence based on examination of the inclusion/exclusion criteria and baseline subject characteristics of all the reviewed trials. However, 4 points about this should be noted. First, the age range of the subjects in these trials was somewhat younger than might be seen in a population-based sample of AF. Since it is possible that response to pharmacologic therapy may differ with age, this needs to be kept in mind. Second, our target population consisted of nonpostoperative AF. The accumulated evidence, therefore, may not be applicable to subjects with postoperative AF. In addition, it is difficult to assure the generalizability of our results based on randomized clinical trials to everyday clinical practice. Third, given the relatively small number of trials for any given comparison, we were unable to perform sensitivity analysis on estimated treatment effects on the basis of our assessments of study quality. Finally, our results regarding quinidine may partially reflect time-dependent improvements in medical care. The majority of trials evaluating quinidine were older. However, for both conversion and MSR at least one trial of quinidine was contemporary, and in both conditions found quinidine less efficacious than the older trials.
It is important to note areas of missing evidence that limit more definitive statements for selection of antiarrhythmic agents for management of AF. First, there are few direct comparisons between antiarrhythmic agents for either conversion of AF or MSR. Since control treatment groups vary between trials, direct comparisons between antiarrhythmic agents are instrumental in assessing relative efficacy. Second, there are particularly sparse data for amiodarone and procainamide, especially with respect to MSR. Although several published reviews6,59 report efficacy of these agents for conversion of AF or MSR, our data from randomized clinical trials (particularly for MSR) do not support this. The AFFIRM and PIAF trials may help address this issue. Third, almost no data were found in this review for the effects of the various antiarrhythmic agents on quality of life. Since patient experiences may significantly influence treatment compliance, quality of life effects need to be better defined. Finally, the follow-up times for all trials on MSR were relatively short. Since the ability to remain free of recurrence has an impact on a patient’s preference for continuing therapy, it would be informative to test the antiarrhythmic agents over a longer period of time for efficacy. These last 2 points may also be addressed in the AFFIRM trial.
