Marlene R. Miller, MD, MSc

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.

Study Inclusion

Articles had to report original data on pharmacologic management of nonpostoperative AF in adults in the context of a randomized clinical trial to be eligible for inclusion in our review. Pairs of independent investigators reviewed all identified abstracts according to these inclusion criteria. All discrepancies about inclusion were resolved by consensus.

Study Quality Assessment

The Evidence-Based Practice Center team developed a data form for extracting information on study quality based on a review of forms used in other meta-analytic studies by study investigators,^9-11 a literature review of the topic,^12,13 and with the assistance of the Cochrane Collaboration. The form contained 22 questions assessing study quality in 5 areas: clarity of description of the study population; potential for bias and confounding; description of therapy, outcomes and follow-up; and statistical quality and interpretation. Each question included a 4 to 5–level subjective ranking of study quality with the resultant score for each of the 5 areas comprising the total points accumulated out of the maximum possible points for all relevant questions in that area. The overall study quality score consisted of the mean score of these 5 areas.

Teams of independent reviewers assessed the quality of each study with differences resolved by consensus. Given the difficult nature of assessing study quality based on article review, the team decided to collectively review and discuss any articles receiving an overall score less than 50% to reach decisions regarding study inclusion.

Data Extraction

Because of the large volume of articles for review, quantitative data were extracted by one reviewer and then checked for accuracy by a second reviewer with consensus resolution of differences. The reviewers were not blinded to the author, institution, and journal, because recent work has indicated that such masking makes little difference in the results.¹⁴ In trials involving both AF and atrial flutter patients, data were only extracted for the AF patients whenever possible.

Data Synthesis and Analysis

Before doing the meta-analysis we first performed both qualitative and quantitative assessments of heterogeneity between the trials to ensure appropriateness of subsequent data combination. The reviewers subjectively assessed qualitative heterogeneity on the basis of similarity between studies on age of subjects, type and duration of AF, comorbidities, therapeutic regimens, and follow-up times. We performed quantitative analysis of heterogeneity using the statistical test of data heterogeneity included in Review Manager (RevMan) version 3.1 (Cochrane Collaboration, Oxford, England).

For data synthesis we defined control treatment to include placebo, verapamil, diltiazem, or digoxin. An analysis of identified trials evaluating verapamil, diltiazem, or digoxin compared with placebo supported this definition, since all of these agents were found to have no efficacy compared with placebo for either conversion or MSR.¹⁵ We also combined treatment arms within a given study that used the same antiarrhythmic agent at different dosages. Analysis of these arms individually supported their consideration as one arm.¹⁵ When life table analysis was used, we extracted the resultant cumulative percentages of successful outcomes and applied them to the initial overall subject number in each trial arm to derive a proportion for meta-analysis inclusion.

We constructed evidence tables to present the data separately for the 2 main outcomes of conversion of AF and MSR and created scatter plots of the absolute rates of conversion and MSR.

For meta-analysis the primary effect measure chosen was the odds ratio (OR) with studies weighted based on the precision of the estimate within each study. A fixed-effects model was used. In cases of significant quantitative data heterogeneity, we explored the etiology of the heterogeneity and used random-effects modeling when appropriate.

We chose the following categorization of strength of evidence by noting the placement of the point estimate of the OR and the width of the confidence interval (CI) surrounding it: (1) strong evidence of efficacy: OR >1.0, 99% CI does not include 1.0 (P <.01); (2) moderate evidence of efficacy: OR >1.0, 95% CI does not include 1.0, but 99% CI includes 1.0 (.01 P .05); (3) suggestive evidence of efficacy: 95% CI includes 1.0 in the lower tail (.05< P <.25), and the OR is in a clinically meaningful range; (4) inconclusive evidence of efficacy: 95% CI is widely distributed around 1.0; and (5) strong evidence of lack of efficacy: OR near 1.0, 95% CI is narrow and does not include a clinically meaningful difference from an OR of 1.0. When the point estimate was less than 1.0, we called this negative efficacy and used the same categorization of strong, moderate, and suggestive evidence on the basis of the point estimate OR and CI. For clarity our reported CIs are at the 95% level.

We also estimated the number needed to treat (NNT) from the resultant OR. The NNT provides an estimate of the number of subjects needed to treat with a therapy to have one more subject experience a desired outcome relative to the comparison group. To do these calculations for the conversion data we assumed a 30% spontaneous conversion rate for the control treatment group, which was consistent with the data. Similarly, to calculate the NNT for MSR we assumed a 30% recurrence rate of AF by 6 months in the control treatment group, which was also consistent with the data. The upper and lower 95% CI estimates for each OR were used to estimate the NNT.

All analyses were completed using RevMan.

Results

Search Strategy and Study Inclusion

Our review of 521 abstracts identified 130 articles for review.¹⁵ After article review, 36 studies^16-51 were eligible for inclusion in our meta-analysis,²⁵ relevant to the conversion of AF outcome and 15 to MSR outcome. All 36 studies used control treatment comparison groups. Our inquiry of experts did not identify any trials for inclusion that had been completed but not published.

In addition to these 36 trials our search identified 16 trials involving unique comparisons between antiarrhythmic agents that precluded meta-analysis. For completeness the results of these trials are discussed and the data presented in Tables 1E and 2E.* We also identified 15 trials using new or uncommon agents. Discussion of these results was published previously.¹⁵

Study Quality Assessment

Based on study quality scores we concluded that all 36 identified trials were of sufficient quality for inclusion. The overall quality scores ranged from 36% to 84% with only 2 studies^17,22 having an overall score less than 50%. Team review of these articles deemed them acceptable for inclusion. Details on the study quality scores was published previously.¹⁵

Study Characteristics and Qualitative Synthesis

Table 1 and Table 2 show important design elements and results of the trials (ie, subject characteristics, sample size, treatment regimens, follow-up times, and reported treatment effects).

The important subject characteristics reported involve age, type of AF, and duration of AF. These areas have an impact on the responsiveness to conversion and ability to avoid recurrent AF.

The mean ages for the trials were generally comparable, ranging between 47 and 71 years with only 7 trials (19%) having mean ages greater than 65 years.

Overall, the studies provided sparse and varying terminology regarding the type and duration of AF; because of this we were unable to reliably segregate studies accordingly. Thus, we relied on the verbatim descriptive terminology used by each study with the understanding that this represented differing definitions between the studies. This difficulty in assessing the type of AF was primarily relevant to conversion studies involving propafenone, amiodarone, and quinidine.^{16,29,32,35,36} These 5 trials all reported control treatment conversion rates greater than 70%, suggesting that the enrolled subjects had predominantly paroxysmal AF. To examine the potential effect of this, we evaluated the quantitative change in the meta-analysis data when excluding these 5 articles with high outlier spontaneous conversion rates.

The therapeutic regimens were generally comparable for any given antiarrhythmic agent for both conversion of AF and MSR. Notably, of the 12 trials evaluating propafenone for conversion of AF, half used oral regimens, and half used intravenous regimens. Separate quantitative analysis comparing these routes showed no significant differences in treatment effects.¹⁵

Regarding follow-up times, the 25 trials of conversion of AF were all comparable and were typically less than 24 hours. There was variability in follow-up time among the 15 trials involving MSR, with a range of 1 to 15 months. For any given antiarrhythmic agent, there was at least one trial with a minimum of 6 months follow-up time.

Overall, our subjective qualitative synthesis of the 36 trials regarding trial inclusion/exclusion criteria, trial size, subject age, subject sex, comorbidities, therapeutic regimens, follow-up times, and reported treatment effects suggested that quantitative synthesis was reasonable because of relatively minor qualitative differences among the studies.

Quantitative Synthesis: Evidence on Pharmacologic Conversion of AF Figure 1 shows the scatter plot of absolute conversion rates for these 25 studies. Two trials involved 2 antiarrhythmic agent arms compared with a third placebo arm thus providing 27 data points.^6,20

All of the antiarrhythmic agents except sotalol had point estimates of conversion rates consistent with efficacy compared with control treatment, though many were not statistically significant. The evidence for sotalol was consistent with negative efficacy for conversion of AF.

The results of the mathematical pooling of these 25 trials are shown in Table 3. The strongest evidence of efficacy of conversion of AF compared with control treatment existed for ibutilide/dofetilide (OR=29.1; 95% CI, 9.8-86.1)^38-40 and flecainide (OR=24.7; 95% CI, 9.0-68.3).^20-23 The range of estimated NNT to have one more subject convert relative to control treatment is 1.5 to 2.0 for both ibutilide/dofetilide and flecainide.

With respect to propafenone there was some modest quantitative heterogeneity of the data for conversion of AF presumably related to issues regarding type and duration of AF. Since we were unable to definitively clarify these issues, we felt a more conservative random-effects model was appropriate for this meta-analysis since that type of modeling assumes variability in the estimated population treatment effects between the studies. Thus, although the magnitude of treatment effect compared with control treatment was less for propafenone (OR=4.6; 95% CI, 2.6-8.2)^16,20,24-33 than for ibutilide/dofetilide or flecainide, the results gave strong evidence of propafenone efficacy for conversion of AF. The estimated range of NNT to have one more subject convert relative to control treatment is 2.0 to 4.5.

We analyzed the impact of the 5 trials with exceptionally high spontaneous conversion rates for AF, 3 of which involved propafenone. Exclusion of these 3 trials^16,29,32 did not substantially alter the pooled treatment effect of the remaining 9 trials (OR=6.6; 95% CI, 3.6-12.0).

The data on quinidine (OR=2.9; 95% CI, 1.2-7.0)^16-18 were consistent with moderate evidence of efficacy for conversion of AF. The summary data for quinidine versus control treatment remained consistent with moderate evidence of efficacy for conversion of AF (OR=7.2; 955 CI, 1.7-30.4) when we performed outlier analysis by excluding the trial by Capucci and colleagues¹⁶ that had a high spontaneous conversion rate.

Comparable with the situation with propafenone, the data on amiodarone had modest quantitative heterogeneity, likely because of issues regarding type and duration of AF and prevalence of coronary artery disease. Given this, we again chose to perform more conservative random-effects modeling for this data synthesis. As such, the data on amiodarone (OR=5.7; 95% CI, 1.0-33.4)^34-36 were consistent with suggestive evidence of efficacy for conversion of AF compared with control treatment. Outlier analysis involving exclusion of 2 trials with high spontaneous conversion rates^35,36 left only one small trial³⁴ as evidence of amiodarone efficacy versus control treatment for conversion of AF. This trial had a sample size of only 24 subjects with resultant extremely wide CIs that made interpretation of this data difficult (OR=69.0; 95% CI, 3.2-1500.0).

The summary data for both disopyramide and sotalol each reflected only one relatively small trial. For disopyramide the data (OR=7.0; 95% CI, 0.3-153.0)¹⁹ were consistent with suggestive evidence of efficacy compared with control treatment. For sotalol the data (OR=0.4; CI, 0.0-3.0)³⁷ were consistent with suggestive evidence of negative efficacy compared with control treatment.

As part of the overall project evaluating management of atrial fibrillation by the Johns Hopkins Evidence-Based Practice Center, we also reviewed the data on 8 trials that had direct comparisons between the major antiarrhythmic agents for conversion of AF.¹⁵ Because of the overall paucity of data on these direct comparisons, mathematical data pooling was not feasible. The one trial evaluating procainamide compared with flecainide reported lower conversion rates for procainamide. In general, these results were consistent with our meta-analysis results.

Quantitative Synthesis: Evidence of Pharmacologic MSR

Figure 2 shows the scatter plot of absolute rates for MSR of the identified trials. Two trials reported their results in a manner not conducive for our data extraction.^17,48 The results of these 2 trials are included in Table 2. Two other trials involved 2 pharmacologic arms compared with one control treatment arm, resulting in 15 data points on Figure 2.^41,49 Notably, none of these trials examined the efficacy of amiodarone or procainamide compared with control treatment for MSR.

All of the major antiarrhythmic agents had evidence of efficacy for MSR compared with control treatment, although some were not statistically significant.

The results of mathematical data pooling for MSR are shown in Table 4. All of the antiarrhythmic agents had strong and relatively comparable evidence of efficacy compared with control treatment, and the point estimates were all consistent with fairly large treatment effect sizes: quinidine (OR=4.1; 95% CI, 2.5-6.7)^18,41-43; disopyramide (OR=3.4; 95% CI, 1.6-7.1)^44-45; flecainide (OR=3.1; 95% CI, 1.5-6.2)^46-48; propafenone (OR=3.7; 95% CI, 2.4-5.7)^27,49-51; and sotalol (OR=7.1; 95% CI, 3.8-13.4).^37,49

The estimated range of NNT to have one less subject experience AF recurrence relative to control treatment is as follows: quinidine 2.3 to 4.6, disopyramide 2.2 to 9.4, flecainide 2.3 to 10.9, propafenone 2.4 to 4.8, and sotalol 1.8 to 3.1.

Although we identified no clinical trials comparing amiodarone with a control treatment, 2 trials did compare amiodarone to other antiarrhythmic agents (Table 2) and should at least be noted given the overall paucity of data on amiodarone for MSR. One small trial compared amiodarone with quinidine (OR=1.1; 95% CI, 0.1-20.0) and was inconclusive. However, a second trial⁶⁵ compared amiodarone with disopyramide (OR=3.2; 95% CI, 1.0-9.6) and was consistent with moderate evidence of amiodarone efficacy compared with disopyramide for MSR. This study reported only interim results, and our searches did not identify the final results of the trial. One could infer from this study that there is indirect strong evidence of amiodarone efficacy for MSR compared with control treatment, since disopyramide had strong evidence of efficacy compared with control treatment.

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.

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 reviews^6,59 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.

Conclusions

Our formal data synthesis of 36 randomized clinical trials of pharmacologic AF conversion and MSR found evidence consistent with superior efficacy relative to control treatment for AF conversion with ibutilide/dofetilide and flecainide. The strength of evidence for MSR relative to control treatment was strong and comparable for quinidine, disopyramide, flecainide, propafenone, and sotalol. Most important, despite the high prevalence of AF the data for the relative efficacy of the antiarrhythmic agents for both conversion and MSR are sparse and inconclusive. Defining these relative efficacies should be a research priority.

Recommendations for clinical practice

On the basis of data from randomized clinical trials, ibutilide, dofetilide, and flecainide have superior efficacy for conversion of AF. However, the data are sparse for ibutilide and dofetilide, and use of flecainide needs to be considered in the context of other comorbidities, such as ventricular ectopy and coronary artery disease. For maintenance of sinus rhythm, no one agent has been shown to have superior efficacy. Clinical practices need to focus on upcoming trial results that involve direct comparisons among agents to better understand relative efficacies of the antiarrhythmic agents for both aspects of AF management.

Acknowledgments

Our study was conducted by the Johns Hopkins Evidence-Based Practice Center through contract No. 290-97-0006 from the Agency for Health Care Policy and Research, Rockville, Maryland. We are responsible for its contents including any clinical or treatment recommendations. No statement in this article should be construed as an official position of the Agency for Healthcare Research and Quality or the United States Department of Health and Human Services. Dr Miller was supported by the Hayden Whitney Smith Research Scholarship. We thank Hanan S. Bell, PhD; Ronald D. Berger, MD; Gary Gerstenblith, MD; David E. Haines, MD; Michael L. Lefevre, MD, MSPH; Andrew Epstein, MD; John A. Kastor, MD; Chris Burton, MD; Jerome A. Osheroff, MD; Barbara J. Drew, RN, PhD; and Kathleen McCauley, RN, PhD, for their assistance as expert advisers for this study. We also thank David Yu, MD, and Paul Abboud for their assistance with this study.

We are especially grateful to Donna Lea for her secretarial support.

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.

Study Inclusion

Articles had to report original data on pharmacologic management of nonpostoperative AF in adults in the context of a randomized clinical trial to be eligible for inclusion in our review. Pairs of independent investigators reviewed all identified abstracts according to these inclusion criteria. All discrepancies about inclusion were resolved by consensus.

Study Quality Assessment

The Evidence-Based Practice Center team developed a data form for extracting information on study quality based on a review of forms used in other meta-analytic studies by study investigators,^9-11 a literature review of the topic,^12,13 and with the assistance of the Cochrane Collaboration. The form contained 22 questions assessing study quality in 5 areas: clarity of description of the study population; potential for bias and confounding; description of therapy, outcomes and follow-up; and statistical quality and interpretation. Each question included a 4 to 5–level subjective ranking of study quality with the resultant score for each of the 5 areas comprising the total points accumulated out of the maximum possible points for all relevant questions in that area. The overall study quality score consisted of the mean score of these 5 areas.

Teams of independent reviewers assessed the quality of each study with differences resolved by consensus. Given the difficult nature of assessing study quality based on article review, the team decided to collectively review and discuss any articles receiving an overall score less than 50% to reach decisions regarding study inclusion.

Data Extraction

Because of the large volume of articles for review, quantitative data were extracted by one reviewer and then checked for accuracy by a second reviewer with consensus resolution of differences. The reviewers were not blinded to the author, institution, and journal, because recent work has indicated that such masking makes little difference in the results.¹⁴ In trials involving both AF and atrial flutter patients, data were only extracted for the AF patients whenever possible.

Data Synthesis and Analysis

Before doing the meta-analysis we first performed both qualitative and quantitative assessments of heterogeneity between the trials to ensure appropriateness of subsequent data combination. The reviewers subjectively assessed qualitative heterogeneity on the basis of similarity between studies on age of subjects, type and duration of AF, comorbidities, therapeutic regimens, and follow-up times. We performed quantitative analysis of heterogeneity using the statistical test of data heterogeneity included in Review Manager (RevMan) version 3.1 (Cochrane Collaboration, Oxford, England).

For data synthesis we defined control treatment to include placebo, verapamil, diltiazem, or digoxin. An analysis of identified trials evaluating verapamil, diltiazem, or digoxin compared with placebo supported this definition, since all of these agents were found to have no efficacy compared with placebo for either conversion or MSR.¹⁵ We also combined treatment arms within a given study that used the same antiarrhythmic agent at different dosages. Analysis of these arms individually supported their consideration as one arm.¹⁵ When life table analysis was used, we extracted the resultant cumulative percentages of successful outcomes and applied them to the initial overall subject number in each trial arm to derive a proportion for meta-analysis inclusion.

We constructed evidence tables to present the data separately for the 2 main outcomes of conversion of AF and MSR and created scatter plots of the absolute rates of conversion and MSR.

For meta-analysis the primary effect measure chosen was the odds ratio (OR) with studies weighted based on the precision of the estimate within each study. A fixed-effects model was used. In cases of significant quantitative data heterogeneity, we explored the etiology of the heterogeneity and used random-effects modeling when appropriate.

We chose the following categorization of strength of evidence by noting the placement of the point estimate of the OR and the width of the confidence interval (CI) surrounding it: (1) strong evidence of efficacy: OR >1.0, 99% CI does not include 1.0 (P <.01); (2) moderate evidence of efficacy: OR >1.0, 95% CI does not include 1.0, but 99% CI includes 1.0 (.01 P .05); (3) suggestive evidence of efficacy: 95% CI includes 1.0 in the lower tail (.05< P <.25), and the OR is in a clinically meaningful range; (4) inconclusive evidence of efficacy: 95% CI is widely distributed around 1.0; and (5) strong evidence of lack of efficacy: OR near 1.0, 95% CI is narrow and does not include a clinically meaningful difference from an OR of 1.0. When the point estimate was less than 1.0, we called this negative efficacy and used the same categorization of strong, moderate, and suggestive evidence on the basis of the point estimate OR and CI. For clarity our reported CIs are at the 95% level.

We also estimated the number needed to treat (NNT) from the resultant OR. The NNT provides an estimate of the number of subjects needed to treat with a therapy to have one more subject experience a desired outcome relative to the comparison group. To do these calculations for the conversion data we assumed a 30% spontaneous conversion rate for the control treatment group, which was consistent with the data. Similarly, to calculate the NNT for MSR we assumed a 30% recurrence rate of AF by 6 months in the control treatment group, which was also consistent with the data. The upper and lower 95% CI estimates for each OR were used to estimate the NNT.

All analyses were completed using RevMan.

Results

Search Strategy and Study Inclusion

Our review of 521 abstracts identified 130 articles for review.¹⁵ After article review, 36 studies^16-51 were eligible for inclusion in our meta-analysis,²⁵ relevant to the conversion of AF outcome and 15 to MSR outcome. All 36 studies used control treatment comparison groups. Our inquiry of experts did not identify any trials for inclusion that had been completed but not published.

In addition to these 36 trials our search identified 16 trials involving unique comparisons between antiarrhythmic agents that precluded meta-analysis. For completeness the results of these trials are discussed and the data presented in Tables 1E and 2E.* We also identified 15 trials using new or uncommon agents. Discussion of these results was published previously.¹⁵

Study Quality Assessment

Based on study quality scores we concluded that all 36 identified trials were of sufficient quality for inclusion. The overall quality scores ranged from 36% to 84% with only 2 studies^17,22 having an overall score less than 50%. Team review of these articles deemed them acceptable for inclusion. Details on the study quality scores was published previously.¹⁵

Study Characteristics and Qualitative Synthesis

Table 1 and Table 2 show important design elements and results of the trials (ie, subject characteristics, sample size, treatment regimens, follow-up times, and reported treatment effects).

The important subject characteristics reported involve age, type of AF, and duration of AF. These areas have an impact on the responsiveness to conversion and ability to avoid recurrent AF.

The mean ages for the trials were generally comparable, ranging between 47 and 71 years with only 7 trials (19%) having mean ages greater than 65 years.

Overall, the studies provided sparse and varying terminology regarding the type and duration of AF; because of this we were unable to reliably segregate studies accordingly. Thus, we relied on the verbatim descriptive terminology used by each study with the understanding that this represented differing definitions between the studies. This difficulty in assessing the type of AF was primarily relevant to conversion studies involving propafenone, amiodarone, and quinidine.^{16,29,32,35,36} These 5 trials all reported control treatment conversion rates greater than 70%, suggesting that the enrolled subjects had predominantly paroxysmal AF. To examine the potential effect of this, we evaluated the quantitative change in the meta-analysis data when excluding these 5 articles with high outlier spontaneous conversion rates.

The therapeutic regimens were generally comparable for any given antiarrhythmic agent for both conversion of AF and MSR. Notably, of the 12 trials evaluating propafenone for conversion of AF, half used oral regimens, and half used intravenous regimens. Separate quantitative analysis comparing these routes showed no significant differences in treatment effects.¹⁵

Regarding follow-up times, the 25 trials of conversion of AF were all comparable and were typically less than 24 hours. There was variability in follow-up time among the 15 trials involving MSR, with a range of 1 to 15 months. For any given antiarrhythmic agent, there was at least one trial with a minimum of 6 months follow-up time.

Overall, our subjective qualitative synthesis of the 36 trials regarding trial inclusion/exclusion criteria, trial size, subject age, subject sex, comorbidities, therapeutic regimens, follow-up times, and reported treatment effects suggested that quantitative synthesis was reasonable because of relatively minor qualitative differences among the studies.

Quantitative Synthesis: Evidence on Pharmacologic Conversion of AF Figure 1 shows the scatter plot of absolute conversion rates for these 25 studies. Two trials involved 2 antiarrhythmic agent arms compared with a third placebo arm thus providing 27 data points.^6,20

All of the antiarrhythmic agents except sotalol had point estimates of conversion rates consistent with efficacy compared with control treatment, though many were not statistically significant. The evidence for sotalol was consistent with negative efficacy for conversion of AF.

The results of the mathematical pooling of these 25 trials are shown in Table 3. The strongest evidence of efficacy of conversion of AF compared with control treatment existed for ibutilide/dofetilide (OR=29.1; 95% CI, 9.8-86.1)^38-40 and flecainide (OR=24.7; 95% CI, 9.0-68.3).^20-23 The range of estimated NNT to have one more subject convert relative to control treatment is 1.5 to 2.0 for both ibutilide/dofetilide and flecainide.

With respect to propafenone there was some modest quantitative heterogeneity of the data for conversion of AF presumably related to issues regarding type and duration of AF. Since we were unable to definitively clarify these issues, we felt a more conservative random-effects model was appropriate for this meta-analysis since that type of modeling assumes variability in the estimated population treatment effects between the studies. Thus, although the magnitude of treatment effect compared with control treatment was less for propafenone (OR=4.6; 95% CI, 2.6-8.2)^16,20,24-33 than for ibutilide/dofetilide or flecainide, the results gave strong evidence of propafenone efficacy for conversion of AF. The estimated range of NNT to have one more subject convert relative to control treatment is 2.0 to 4.5.

We analyzed the impact of the 5 trials with exceptionally high spontaneous conversion rates for AF, 3 of which involved propafenone. Exclusion of these 3 trials^16,29,32 did not substantially alter the pooled treatment effect of the remaining 9 trials (OR=6.6; 95% CI, 3.6-12.0).

The data on quinidine (OR=2.9; 95% CI, 1.2-7.0)^16-18 were consistent with moderate evidence of efficacy for conversion of AF. The summary data for quinidine versus control treatment remained consistent with moderate evidence of efficacy for conversion of AF (OR=7.2; 955 CI, 1.7-30.4) when we performed outlier analysis by excluding the trial by Capucci and colleagues¹⁶ that had a high spontaneous conversion rate.

Comparable with the situation with propafenone, the data on amiodarone had modest quantitative heterogeneity, likely because of issues regarding type and duration of AF and prevalence of coronary artery disease. Given this, we again chose to perform more conservative random-effects modeling for this data synthesis. As such, the data on amiodarone (OR=5.7; 95% CI, 1.0-33.4)^34-36 were consistent with suggestive evidence of efficacy for conversion of AF compared with control treatment. Outlier analysis involving exclusion of 2 trials with high spontaneous conversion rates^35,36 left only one small trial³⁴ as evidence of amiodarone efficacy versus control treatment for conversion of AF. This trial had a sample size of only 24 subjects with resultant extremely wide CIs that made interpretation of this data difficult (OR=69.0; 95% CI, 3.2-1500.0).

The summary data for both disopyramide and sotalol each reflected only one relatively small trial. For disopyramide the data (OR=7.0; 95% CI, 0.3-153.0)¹⁹ were consistent with suggestive evidence of efficacy compared with control treatment. For sotalol the data (OR=0.4; CI, 0.0-3.0)³⁷ were consistent with suggestive evidence of negative efficacy compared with control treatment.

As part of the overall project evaluating management of atrial fibrillation by the Johns Hopkins Evidence-Based Practice Center, we also reviewed the data on 8 trials that had direct comparisons between the major antiarrhythmic agents for conversion of AF.¹⁵ Because of the overall paucity of data on these direct comparisons, mathematical data pooling was not feasible. The one trial evaluating procainamide compared with flecainide reported lower conversion rates for procainamide. In general, these results were consistent with our meta-analysis results.

Quantitative Synthesis: Evidence of Pharmacologic MSR

Figure 2 shows the scatter plot of absolute rates for MSR of the identified trials. Two trials reported their results in a manner not conducive for our data extraction.^17,48 The results of these 2 trials are included in Table 2. Two other trials involved 2 pharmacologic arms compared with one control treatment arm, resulting in 15 data points on Figure 2.^41,49 Notably, none of these trials examined the efficacy of amiodarone or procainamide compared with control treatment for MSR.

All of the major antiarrhythmic agents had evidence of efficacy for MSR compared with control treatment, although some were not statistically significant.

The results of mathematical data pooling for MSR are shown in Table 4. All of the antiarrhythmic agents had strong and relatively comparable evidence of efficacy compared with control treatment, and the point estimates were all consistent with fairly large treatment effect sizes: quinidine (OR=4.1; 95% CI, 2.5-6.7)^18,41-43; disopyramide (OR=3.4; 95% CI, 1.6-7.1)^44-45; flecainide (OR=3.1; 95% CI, 1.5-6.2)^46-48; propafenone (OR=3.7; 95% CI, 2.4-5.7)^27,49-51; and sotalol (OR=7.1; 95% CI, 3.8-13.4).^37,49

The estimated range of NNT to have one less subject experience AF recurrence relative to control treatment is as follows: quinidine 2.3 to 4.6, disopyramide 2.2 to 9.4, flecainide 2.3 to 10.9, propafenone 2.4 to 4.8, and sotalol 1.8 to 3.1.

Although we identified no clinical trials comparing amiodarone with a control treatment, 2 trials did compare amiodarone to other antiarrhythmic agents (Table 2) and should at least be noted given the overall paucity of data on amiodarone for MSR. One small trial compared amiodarone with quinidine (OR=1.1; 95% CI, 0.1-20.0) and was inconclusive. However, a second trial⁶⁵ compared amiodarone with disopyramide (OR=3.2; 95% CI, 1.0-9.6) and was consistent with moderate evidence of amiodarone efficacy compared with disopyramide for MSR. This study reported only interim results, and our searches did not identify the final results of the trial. One could infer from this study that there is indirect strong evidence of amiodarone efficacy for MSR compared with control treatment, since disopyramide had strong evidence of efficacy compared with control treatment.

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.

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 reviews^6,59 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.

Conclusions

Our formal data synthesis of 36 randomized clinical trials of pharmacologic AF conversion and MSR found evidence consistent with superior efficacy relative to control treatment for AF conversion with ibutilide/dofetilide and flecainide. The strength of evidence for MSR relative to control treatment was strong and comparable for quinidine, disopyramide, flecainide, propafenone, and sotalol. Most important, despite the high prevalence of AF the data for the relative efficacy of the antiarrhythmic agents for both conversion and MSR are sparse and inconclusive. Defining these relative efficacies should be a research priority.

Recommendations for clinical practice

On the basis of data from randomized clinical trials, ibutilide, dofetilide, and flecainide have superior efficacy for conversion of AF. However, the data are sparse for ibutilide and dofetilide, and use of flecainide needs to be considered in the context of other comorbidities, such as ventricular ectopy and coronary artery disease. For maintenance of sinus rhythm, no one agent has been shown to have superior efficacy. Clinical practices need to focus on upcoming trial results that involve direct comparisons among agents to better understand relative efficacies of the antiarrhythmic agents for both aspects of AF management.

Acknowledgments

Our study was conducted by the Johns Hopkins Evidence-Based Practice Center through contract No. 290-97-0006 from the Agency for Health Care Policy and Research, Rockville, Maryland. We are responsible for its contents including any clinical or treatment recommendations. No statement in this article should be construed as an official position of the Agency for Healthcare Research and Quality or the United States Department of Health and Human Services. Dr Miller was supported by the Hayden Whitney Smith Research Scholarship. We thank Hanan S. Bell, PhD; Ronald D. Berger, MD; Gary Gerstenblith, MD; David E. Haines, MD; Michael L. Lefevre, MD, MSPH; Andrew Epstein, MD; John A. Kastor, MD; Chris Burton, MD; Jerome A. Osheroff, MD; Barbara J. Drew, RN, PhD; and Kathleen McCauley, RN, PhD, for their assistance as expert advisers for this study. We also thank David Yu, MD, and Paul Abboud for their assistance with this study.

We are especially grateful to Donna Lea for her secretarial support.

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.

Study Inclusion

Articles had to report original data on pharmacologic management of nonpostoperative AF in adults in the context of a randomized clinical trial to be eligible for inclusion in our review. Pairs of independent investigators reviewed all identified abstracts according to these inclusion criteria. All discrepancies about inclusion were resolved by consensus.

Study Quality Assessment

The Evidence-Based Practice Center team developed a data form for extracting information on study quality based on a review of forms used in other meta-analytic studies by study investigators,^9-11 a literature review of the topic,^12,13 and with the assistance of the Cochrane Collaboration. The form contained 22 questions assessing study quality in 5 areas: clarity of description of the study population; potential for bias and confounding; description of therapy, outcomes and follow-up; and statistical quality and interpretation. Each question included a 4 to 5–level subjective ranking of study quality with the resultant score for each of the 5 areas comprising the total points accumulated out of the maximum possible points for all relevant questions in that area. The overall study quality score consisted of the mean score of these 5 areas.

Teams of independent reviewers assessed the quality of each study with differences resolved by consensus. Given the difficult nature of assessing study quality based on article review, the team decided to collectively review and discuss any articles receiving an overall score less than 50% to reach decisions regarding study inclusion.

Data Extraction

Because of the large volume of articles for review, quantitative data were extracted by one reviewer and then checked for accuracy by a second reviewer with consensus resolution of differences. The reviewers were not blinded to the author, institution, and journal, because recent work has indicated that such masking makes little difference in the results.¹⁴ In trials involving both AF and atrial flutter patients, data were only extracted for the AF patients whenever possible.

Data Synthesis and Analysis

Before doing the meta-analysis we first performed both qualitative and quantitative assessments of heterogeneity between the trials to ensure appropriateness of subsequent data combination. The reviewers subjectively assessed qualitative heterogeneity on the basis of similarity between studies on age of subjects, type and duration of AF, comorbidities, therapeutic regimens, and follow-up times. We performed quantitative analysis of heterogeneity using the statistical test of data heterogeneity included in Review Manager (RevMan) version 3.1 (Cochrane Collaboration, Oxford, England).

For data synthesis we defined control treatment to include placebo, verapamil, diltiazem, or digoxin. An analysis of identified trials evaluating verapamil, diltiazem, or digoxin compared with placebo supported this definition, since all of these agents were found to have no efficacy compared with placebo for either conversion or MSR.¹⁵ We also combined treatment arms within a given study that used the same antiarrhythmic agent at different dosages. Analysis of these arms individually supported their consideration as one arm.¹⁵ When life table analysis was used, we extracted the resultant cumulative percentages of successful outcomes and applied them to the initial overall subject number in each trial arm to derive a proportion for meta-analysis inclusion.

We constructed evidence tables to present the data separately for the 2 main outcomes of conversion of AF and MSR and created scatter plots of the absolute rates of conversion and MSR.

For meta-analysis the primary effect measure chosen was the odds ratio (OR) with studies weighted based on the precision of the estimate within each study. A fixed-effects model was used. In cases of significant quantitative data heterogeneity, we explored the etiology of the heterogeneity and used random-effects modeling when appropriate.

We chose the following categorization of strength of evidence by noting the placement of the point estimate of the OR and the width of the confidence interval (CI) surrounding it: (1) strong evidence of efficacy: OR >1.0, 99% CI does not include 1.0 (P <.01); (2) moderate evidence of efficacy: OR >1.0, 95% CI does not include 1.0, but 99% CI includes 1.0 (.01 P .05); (3) suggestive evidence of efficacy: 95% CI includes 1.0 in the lower tail (.05< P <.25), and the OR is in a clinically meaningful range; (4) inconclusive evidence of efficacy: 95% CI is widely distributed around 1.0; and (5) strong evidence of lack of efficacy: OR near 1.0, 95% CI is narrow and does not include a clinically meaningful difference from an OR of 1.0. When the point estimate was less than 1.0, we called this negative efficacy and used the same categorization of strong, moderate, and suggestive evidence on the basis of the point estimate OR and CI. For clarity our reported CIs are at the 95% level.

We also estimated the number needed to treat (NNT) from the resultant OR. The NNT provides an estimate of the number of subjects needed to treat with a therapy to have one more subject experience a desired outcome relative to the comparison group. To do these calculations for the conversion data we assumed a 30% spontaneous conversion rate for the control treatment group, which was consistent with the data. Similarly, to calculate the NNT for MSR we assumed a 30% recurrence rate of AF by 6 months in the control treatment group, which was also consistent with the data. The upper and lower 95% CI estimates for each OR were used to estimate the NNT.

All analyses were completed using RevMan.

Results

Search Strategy and Study Inclusion

Our review of 521 abstracts identified 130 articles for review.¹⁵ After article review, 36 studies^16-51 were eligible for inclusion in our meta-analysis,²⁵ relevant to the conversion of AF outcome and 15 to MSR outcome. All 36 studies used control treatment comparison groups. Our inquiry of experts did not identify any trials for inclusion that had been completed but not published.

In addition to these 36 trials our search identified 16 trials involving unique comparisons between antiarrhythmic agents that precluded meta-analysis. For completeness the results of these trials are discussed and the data presented in Tables 1E and 2E.* We also identified 15 trials using new or uncommon agents. Discussion of these results was published previously.¹⁵

Study Quality Assessment

Based on study quality scores we concluded that all 36 identified trials were of sufficient quality for inclusion. The overall quality scores ranged from 36% to 84% with only 2 studies^17,22 having an overall score less than 50%. Team review of these articles deemed them acceptable for inclusion. Details on the study quality scores was published previously.¹⁵

Study Characteristics and Qualitative Synthesis

Table 1 and Table 2 show important design elements and results of the trials (ie, subject characteristics, sample size, treatment regimens, follow-up times, and reported treatment effects).

The important subject characteristics reported involve age, type of AF, and duration of AF. These areas have an impact on the responsiveness to conversion and ability to avoid recurrent AF.

The mean ages for the trials were generally comparable, ranging between 47 and 71 years with only 7 trials (19%) having mean ages greater than 65 years.

Overall, the studies provided sparse and varying terminology regarding the type and duration of AF; because of this we were unable to reliably segregate studies accordingly. Thus, we relied on the verbatim descriptive terminology used by each study with the understanding that this represented differing definitions between the studies. This difficulty in assessing the type of AF was primarily relevant to conversion studies involving propafenone, amiodarone, and quinidine.^{16,29,32,35,36} These 5 trials all reported control treatment conversion rates greater than 70%, suggesting that the enrolled subjects had predominantly paroxysmal AF. To examine the potential effect of this, we evaluated the quantitative change in the meta-analysis data when excluding these 5 articles with high outlier spontaneous conversion rates.

The therapeutic regimens were generally comparable for any given antiarrhythmic agent for both conversion of AF and MSR. Notably, of the 12 trials evaluating propafenone for conversion of AF, half used oral regimens, and half used intravenous regimens. Separate quantitative analysis comparing these routes showed no significant differences in treatment effects.¹⁵

Regarding follow-up times, the 25 trials of conversion of AF were all comparable and were typically less than 24 hours. There was variability in follow-up time among the 15 trials involving MSR, with a range of 1 to 15 months. For any given antiarrhythmic agent, there was at least one trial with a minimum of 6 months follow-up time.

Overall, our subjective qualitative synthesis of the 36 trials regarding trial inclusion/exclusion criteria, trial size, subject age, subject sex, comorbidities, therapeutic regimens, follow-up times, and reported treatment effects suggested that quantitative synthesis was reasonable because of relatively minor qualitative differences among the studies.

Quantitative Synthesis: Evidence on Pharmacologic Conversion of AF Figure 1 shows the scatter plot of absolute conversion rates for these 25 studies. Two trials involved 2 antiarrhythmic agent arms compared with a third placebo arm thus providing 27 data points.^6,20

All of the antiarrhythmic agents except sotalol had point estimates of conversion rates consistent with efficacy compared with control treatment, though many were not statistically significant. The evidence for sotalol was consistent with negative efficacy for conversion of AF.

The results of the mathematical pooling of these 25 trials are shown in Table 3. The strongest evidence of efficacy of conversion of AF compared with control treatment existed for ibutilide/dofetilide (OR=29.1; 95% CI, 9.8-86.1)^38-40 and flecainide (OR=24.7; 95% CI, 9.0-68.3).^20-23 The range of estimated NNT to have one more subject convert relative to control treatment is 1.5 to 2.0 for both ibutilide/dofetilide and flecainide.

With respect to propafenone there was some modest quantitative heterogeneity of the data for conversion of AF presumably related to issues regarding type and duration of AF. Since we were unable to definitively clarify these issues, we felt a more conservative random-effects model was appropriate for this meta-analysis since that type of modeling assumes variability in the estimated population treatment effects between the studies. Thus, although the magnitude of treatment effect compared with control treatment was less for propafenone (OR=4.6; 95% CI, 2.6-8.2)^16,20,24-33 than for ibutilide/dofetilide or flecainide, the results gave strong evidence of propafenone efficacy for conversion of AF. The estimated range of NNT to have one more subject convert relative to control treatment is 2.0 to 4.5.

We analyzed the impact of the 5 trials with exceptionally high spontaneous conversion rates for AF, 3 of which involved propafenone. Exclusion of these 3 trials^16,29,32 did not substantially alter the pooled treatment effect of the remaining 9 trials (OR=6.6; 95% CI, 3.6-12.0).

The data on quinidine (OR=2.9; 95% CI, 1.2-7.0)^16-18 were consistent with moderate evidence of efficacy for conversion of AF. The summary data for quinidine versus control treatment remained consistent with moderate evidence of efficacy for conversion of AF (OR=7.2; 955 CI, 1.7-30.4) when we performed outlier analysis by excluding the trial by Capucci and colleagues¹⁶ that had a high spontaneous conversion rate.

Comparable with the situation with propafenone, the data on amiodarone had modest quantitative heterogeneity, likely because of issues regarding type and duration of AF and prevalence of coronary artery disease. Given this, we again chose to perform more conservative random-effects modeling for this data synthesis. As such, the data on amiodarone (OR=5.7; 95% CI, 1.0-33.4)^34-36 were consistent with suggestive evidence of efficacy for conversion of AF compared with control treatment. Outlier analysis involving exclusion of 2 trials with high spontaneous conversion rates^35,36 left only one small trial³⁴ as evidence of amiodarone efficacy versus control treatment for conversion of AF. This trial had a sample size of only 24 subjects with resultant extremely wide CIs that made interpretation of this data difficult (OR=69.0; 95% CI, 3.2-1500.0).

The summary data for both disopyramide and sotalol each reflected only one relatively small trial. For disopyramide the data (OR=7.0; 95% CI, 0.3-153.0)¹⁹ were consistent with suggestive evidence of efficacy compared with control treatment. For sotalol the data (OR=0.4; CI, 0.0-3.0)³⁷ were consistent with suggestive evidence of negative efficacy compared with control treatment.

As part of the overall project evaluating management of atrial fibrillation by the Johns Hopkins Evidence-Based Practice Center, we also reviewed the data on 8 trials that had direct comparisons between the major antiarrhythmic agents for conversion of AF.¹⁵ Because of the overall paucity of data on these direct comparisons, mathematical data pooling was not feasible. The one trial evaluating procainamide compared with flecainide reported lower conversion rates for procainamide. In general, these results were consistent with our meta-analysis results.

Quantitative Synthesis: Evidence of Pharmacologic MSR

Figure 2 shows the scatter plot of absolute rates for MSR of the identified trials. Two trials reported their results in a manner not conducive for our data extraction.^17,48 The results of these 2 trials are included in Table 2. Two other trials involved 2 pharmacologic arms compared with one control treatment arm, resulting in 15 data points on Figure 2.^41,49 Notably, none of these trials examined the efficacy of amiodarone or procainamide compared with control treatment for MSR.

All of the major antiarrhythmic agents had evidence of efficacy for MSR compared with control treatment, although some were not statistically significant.

The results of mathematical data pooling for MSR are shown in Table 4. All of the antiarrhythmic agents had strong and relatively comparable evidence of efficacy compared with control treatment, and the point estimates were all consistent with fairly large treatment effect sizes: quinidine (OR=4.1; 95% CI, 2.5-6.7)^18,41-43; disopyramide (OR=3.4; 95% CI, 1.6-7.1)^44-45; flecainide (OR=3.1; 95% CI, 1.5-6.2)^46-48; propafenone (OR=3.7; 95% CI, 2.4-5.7)^27,49-51; and sotalol (OR=7.1; 95% CI, 3.8-13.4).^37,49

The estimated range of NNT to have one less subject experience AF recurrence relative to control treatment is as follows: quinidine 2.3 to 4.6, disopyramide 2.2 to 9.4, flecainide 2.3 to 10.9, propafenone 2.4 to 4.8, and sotalol 1.8 to 3.1.

Although we identified no clinical trials comparing amiodarone with a control treatment, 2 trials did compare amiodarone to other antiarrhythmic agents (Table 2) and should at least be noted given the overall paucity of data on amiodarone for MSR. One small trial compared amiodarone with quinidine (OR=1.1; 95% CI, 0.1-20.0) and was inconclusive. However, a second trial⁶⁵ compared amiodarone with disopyramide (OR=3.2; 95% CI, 1.0-9.6) and was consistent with moderate evidence of amiodarone efficacy compared with disopyramide for MSR. This study reported only interim results, and our searches did not identify the final results of the trial. One could infer from this study that there is indirect strong evidence of amiodarone efficacy for MSR compared with control treatment, since disopyramide had strong evidence of efficacy compared with control treatment.

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.

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 reviews^6,59 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.

Conclusions

Our formal data synthesis of 36 randomized clinical trials of pharmacologic AF conversion and MSR found evidence consistent with superior efficacy relative to control treatment for AF conversion with ibutilide/dofetilide and flecainide. The strength of evidence for MSR relative to control treatment was strong and comparable for quinidine, disopyramide, flecainide, propafenone, and sotalol. Most important, despite the high prevalence of AF the data for the relative efficacy of the antiarrhythmic agents for both conversion and MSR are sparse and inconclusive. Defining these relative efficacies should be a research priority.

Recommendations for clinical practice

On the basis of data from randomized clinical trials, ibutilide, dofetilide, and flecainide have superior efficacy for conversion of AF. However, the data are sparse for ibutilide and dofetilide, and use of flecainide needs to be considered in the context of other comorbidities, such as ventricular ectopy and coronary artery disease. For maintenance of sinus rhythm, no one agent has been shown to have superior efficacy. Clinical practices need to focus on upcoming trial results that involve direct comparisons among agents to better understand relative efficacies of the antiarrhythmic agents for both aspects of AF management.

Acknowledgments

Our study was conducted by the Johns Hopkins Evidence-Based Practice Center through contract No. 290-97-0006 from the Agency for Health Care Policy and Research, Rockville, Maryland. We are responsible for its contents including any clinical or treatment recommendations. No statement in this article should be construed as an official position of the Agency for Healthcare Research and Quality or the United States Department of Health and Human Services. Dr Miller was supported by the Hayden Whitney Smith Research Scholarship. We thank Hanan S. Bell, PhD; Ronald D. Berger, MD; Gary Gerstenblith, MD; David E. Haines, MD; Michael L. Lefevre, MD, MSPH; Andrew Epstein, MD; John A. Kastor, MD; Chris Burton, MD; Jerome A. Osheroff, MD; Barbara J. Drew, RN, PhD; and Kathleen McCauley, RN, PhD, for their assistance as expert advisers for this study. We also thank David Yu, MD, and Paul Abboud for their assistance with this study.

We are especially grateful to Donna Lea for her secretarial support.