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

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.