Efficacy of Agents for Pharmacologic Conversion of Atrial Fibrillation and Subsequent Maintenance of Sinus Rhythm

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.