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Meta-analysis of randomised controlled trials of the effectiveness of antiarrhythmic agents at promoting sinus rhythm in patients with atrial fibrillation

G Nichol, F McAlister, B Pham, et al.

Heart 2002 87: 535-543 doi: 10.1136/heart.87.6.535

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535

CARDIOVASCULAR MEDICINE Meta-analysis of randomised controlled trials of the effectiveness of antiarrhythmic agents at promoting sinus rhythm in patients with atrial fibrillation G Nichol, F McAlister, B Pham, A Laupacis, B Shea, M Green, A Tang, G Wells ......

Heart 2002;87:535–543

Objective: To conduct a meta-analysis of randomised controlled trials to estimate the effectiveness of antiarrhythmic drugs at promoting sinus rhythm in patients with atrial fibrillation. Design: Articles were identified by using a comprehensive search of English language papers indexed in Medline from 1966 to August 2001. For the outcomes of sinus rhythm and death, a random effects model was used to model repeated assessments within a study at different time points. Setting: Emergency departments and ambulatory clinics. Patients: Patients with atrial fibrillation. Interventions: Antiarrhythmic agents grouped according to their Vaughan-Williams class. Main outcome measures: Sinus rhythm and mortality. Results: 91 articles met a priori criteria for inclusion in the analysis. Median duration of follow up was See end of article for one day (range 0.04–1096, mean (SD) 46 (136) days). The median proportion of patients in sinus authors’ affiliations rhythm at follow up was 55% (range 0–100%) and 32% (range 0–90%) receiving active treatment and ...... placebo, respectively. Median survival was 99% (range 55–100%) and 99% (range 55–100%). Com- Correspondence to: pared with placebo, the following drug classes were associated with increased sinus rhythm at follow Dr Graham Nichol, F6, up: IA (treatment difference 21.5%, 95% confidence interval (CI) 16.3% to 26.8%); IC (treatment dif- Ottawa Hospital, Civic ference 33.1%, 95% CI 23.3% to 42.9%); and III (treatment difference 17.4%, 95% CI 11.5% to Site, 1053 Carling Avenue, Ottawa, Ontario, 23.3%). Class IC drugs were associated with increased sinus rhythm at follow up compared with class Canada K1Y 4E9; IV drugs (treatment difference 43.2%, 95% CI 11.5% to 75.0%). There was no significant difference in [email protected] mortality between any drug classes. Accepted Conclusions: Class IA, IC, and III drugs are associated with increased sinus rhythm at follow up com- 27 February 2002 pared with placebo. It is unclear whether any antiarrhythmic drug class is associated with increased or ...... decreased mortality.

trial fibrillation is the most common cardiac arrhythmia1 unlikely to determine whether a specific antiarrhythmic drug and can be associated with disabling complications.12At has long term effectiveness in atrial fibrillation. Despite ongo- least 5% of admissions for cardiovascular disease are for ing and previous trials, there is major interphysician variabil- A 1 management of atrial fibrillation. ity in prescribing behaviours related to antiarrhythmic Patients in atrial fibrillation can receive treatment to treatment in patients with atrial fibrillation.9 decrease embolic complications, to promote sinus rhythm, or Meta-analysis is a method of pooling the results of to control ventricular rate. Each of these treatments is associ- individual trials statistically to provide an overall estimate of ated with particular risks and benefits. Although the the effectiveness of a treatment. The combination of several effectiveness of anticoagulant treatment in atrial fibrillation is studies can yield additional power to detect significant differ- well established, use of electrical cardioversion or antiarrhyth- ences between treatments. Therefore, the purpose of this mic drugs may offer additional benefits. Compared with meta-analysis was to estimate the effectiveness of various patients with atrial fibrillation, patients in whom sinus classes of antiarrhythmic drugs in patients with atrial fibrilla- 2 rhythm is restored have fewer strokes, greater cardiac tion. Using a protocol that was developed a priori, we 3 3–5 output, and reversal of cardiomyopathy. However, attempts conducted a meta-analysis based on conventional to maintain sinus rhythm may be associated with increased techniques.10 11 The protocol consisted of selection criteria for 6 mortality. Furthermore, as many as 75% of patients relapse the primary studies, definitions of the primary end points, and into chronic atrial fibrillation within 12 months of restoration an analysis plan. of sinus rhythm.7 Any reduction in the mortality or morbidity caused by stroke that is attained by use of antiarrhythmic drugs may be offset by adverse drug effects or relapse to atrial METHODS fibrillation. Identification of trials Antiarrhythmic treatment to restore and maintain sinus Our aim was to identify all randomised controlled trials for rhythm after atrial fibrillation has been evaluated in many which results were available by August 2001. A randomised small trials. These trials evaluated several drugs, each of which controlled trial was defined as a research study in which has unique mechanisms of action and side effects. A large trial patients were assigned prospectively to a treatment group by underway is evaluating the effectiveness of antiarrhythmic random allocation. Studies were identified by using a compre- drugs in patients with atrial fibrillation. In the AFFIRM study hensive search of English language articles indexed in (atrial fibrillation follow-up investigation of rhythm manage- Medline for the keywords “atrial fibrillation” and “an- ment), the choice of antiarrhythmic drug was at the discretion tiarrhythmic agents”. Potentially relevant randomised trials of the physician.8 Therefore, the results of this study are were identified by combining these keywords with the

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536 Nichol, McAlister, Pham, et al

Table 1 Effect of antiarrhythmic agents on sinus rhythm in placebo controlled trials

Proportion in sinus rhythm Proportion in sinus rhythm Treatment Number Follow up* (days), at follow up in treatment at follow up in control arm difference† (%), Comparators of trials median (range) arm (%), mean (95% CI) (%), mean (95% CI) mean (95% CI) p Value

IA v Placebo 7 93 (0.04–372) 54.7 (50.7 to 58.6) 33.1 (29.2 to 37.0) 21.5 (16.3 to 26.8) <0.0001 IC v placebo 17 0.29 (0.04–186) 60.2 (52.6 to 67.8) 27.1 (19.6 to 34.6) 33.1 (23.3 to 42.9) <0.0001 III v placebo 19 0.33 (0.04–1096) 46.5 (41.4 to 51.6) 29.1 (23.9 to 34.4) 17.4 (11.5 to 23.3) 0.001 Digoxin v placebo 4 0.58 (0.04–0.75) 48.4 (31.0 to 65.7) 35.3 (19.3 to 51.3) 13.1 (−7.2 to 33.3) 0.15 IA v III 6 1.0 (0.04–186) 44.3 (33.0 to 55.6) 40.1 (29.1 to 51.2) 4.1 (−8.0 to 16.2) 0.42 1C v III 10 0.91 (0.04–372) 56.7 (45.2 to 68.2) 60.1 (49.6 to 70.5) −3.4 (17.2 to 10.5) 0.6 1C v IV 4 0.04 (0.04–2.0) 77.8 (42.7 to 100) 34.5 (0 to 77.2) 43.2 (11.5 to 75.0) 0.03 III v digoxin 2 1 (1–2) 82.9 (46.8 to 100) 67.7 (17.6 to 100) 15.2 (−43.7 to 74.2) 0.19

*Estimates from the control groups; †Percentage difference between treatment and control groups. CI, confidence interval.

Cochrane Collaboration’s search strategy.12 Only references they were lost to follow up. Patients were considered to have published in the English language were considered. The bibli- withdrawn if they stopped taking the study drug. ographies of published studies were reviewed to identify addi- All studies were independently reviewed for eligibility, data tional references. The authors of the primary studies were not abstraction, and study quality (by MG, FM, GN, BS, and AT). contacted to identify additional studies. All published primary Differences were resolved by discussion until consensus was studies, but not unpublished studies or abstracts, were achieved. Data were abstracted twice and checked for accuracy considered for inclusion in the analysis. after data entry. Primary analyses Classification of antiarrhythmic agents 15 All antiarrhythmic agents were grouped according to their Data were analysed by using the SAS mixed procedure. mechanism of action by using the Vaughan-Williams classifi- Primary analyses compared the effect of each class of cation system. Accordingly, drugs that were studied were clas- antiarrhythmic agent on the two outcome measures: sified as class I, which block sodium channels; class II, which the proportion of patients in sinus rhythm at the time of block β receptors (for example, practolol); class III, which pro- study follow up, and mortality. long repolarisation (for example, amiodarone, dofetilide, ibu- For each outcome measure, a repeated measures random tilide, sotalol, and lidoflazine); class IV, which block calcium effects model was used to model the repeated assessments within a study at different time points.16 In the model, the channels (for example, clonidine, diltiazem, magnesium, and outcome measure at each time point was weighted by the verapamil); and other agents (for example, digoxin). Class I inverse variance of the outcome measure estimate. The model agents were subclassified as IA, which depress action potential included treatment, assessment time, and a trial factor to force upstroke, slow conduction, and prolong repolarisation (for treatment comparison within the trial. Standard residual example, cibenzoline, disopyramide, procainamide, and quini- diagnostics were used to check for model goodness of fit. Least dine); and class IC, which depress upstroke depolarisation, square means and their 95% confidence intervals (CI) for slow conduction, and have a slight effect on repolarisation (for treatment difference were derived from the fitted models at example, flecainide, pilsicainide, and propafenone.) the median follow up duration. Treatment difference was defined as the absolute difference in the proportion of patients Inclusion and exclusion criteria who had experienced the outcome of interest (that is, sinus A priori exclusion criteria were studies that did not use a ran- rhythm or mortality.) To avoid overfitting, effects were consid- domised study design; enrolled patients with induced atrial ered for classes of drugs rather than for individual drugs. fibrillation; evaluated treatments other than antiarrhythmic Indicator variables were used for each class of drug, regardless agents; evaluated use of antiarrhythmic agents for prophylaxis of whether they were used singly or in combination. Two tailed of atrial fibrillation alone; followed up patients for < 60 min- p = 0.05 was considered significant. utes after drug administration; or lacked data on the proportion of patients in sinus rhythm at study follow up. Sensitivity analyses For normal sinus rhythm at follow up, we performed the fol- Study quality lowing sensitivity analyses. Firstly, we conducted subgroup The quality of each primary study was evaluated by using a analyses to determine the effectiveness of antiarrhythmic validated assessment tool.13 This is a three item scale that agents in trials that reported follow up of less than one week measures the methodological quality of clinical studies. Indi- or at least one week. These analyses were conducted to iden- vidual items are randomisation, blinding, and withdrawal and tify whether any observed effectiveness was transient or sus- dropout. Allocation concealment was also included (with two tained. They were also conducted to differentiate use of additional bonus points).14 Therefore, the maximum number antiarrhythmic agents for conversion to sinus rhythm from of points per study was seven. Numbers were abstracted twice use for maintenance of sinus rhythm. These analyses were by two independent reviewers, and checked for accuracy after done only for comparators where at least three trials were data entry. available since the model would not run with one or two trials. Secondly, we included cohorts of patients who were taking Outcomes and data abstraction one of the medications under comparison in the main The following variables were extracted from each study, if model.16 These cohorts were extracted from other controlled available: type and dose of intervention and control drugs; trials that were included in the meta-analysis but that did not type and dose of concomitant drugs; number, age, and sex of directly compare the medications under comparison. For patients randomly allocated; duration of follow up; number of example, if the main model compared class IA drugs with pla- patients who dropped out; number of patients who withdrew; cebo, we checked the results of this model by including all the number of patients in sinus rhythm at each follow up; and cohorts of patients who were taking either class IA drugs or number of patients deceased. For the purpose of this analysis, placebo even though these additional cohorts were not part of patients were considered to have dropped out of the study if a trial that directly compared class IA drugs with placebo.

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Meta-analysis of antiarrhythmia trials 537

Active drug, Follow up Figure 1 Absolute treatment year (reference) n (days) difference in proportion of patients with normal sinus rhythm (%) at end Disopyramide, 1988 (32) 50 31 of study between class IA drugs and placebo. Disopyramide, 1974 (21) 52 93

Procainamide, 1998 (83) 114 0.04

Quinidine, 1981 (25) 212 93

Quinidine, 1975 (22) 176 372

Quinidine,1970 (19) 92 93

Quinidine, 1984 (27) 53 136

Overall 789 93

–20 –10 100 20 30 40 50 60 Treatment better (absolute difference in %)

Thirdly, we accounted for variation in trial quality by design (n = 128); induced atrial fibrillation (n = 3); treat- weighting an outcome on both its precision and its quality.17 ments other than antiarrhythmic agents (n = 34); use of For mortality data, we also performed three sensitivity antiarrhythmic agents for prophylaxis alone (n = 56); follow analyses. Firstly, we included cohorts of patients as described up for < 60 minutes after drug administration (n = 8); lack of above. Secondly, we assumed that no death was observed for data on the proportion of patients in sinus rhythm at study trials that did not report mortality. Thirdly, we accounted for follow up (n = 92); and duplicate publication (n = 16). variation in trial quality. Ninety one trials met the criteria for inclusion in the Since amiodarone has several mechanisms of action, we analysis.19–109 considered the effect of amiodarone versus any other The appendix (on Heart website only) shows the data antiarrhythmic agent on sinus rhythm or mortality. abstracted from these articles. There were 43, 29, 47, 1, 51, 21, Lastly, we considered a large randomised controlled trial and 12 trials for placebo, class IA, IC, II, III or IV drugs, and that included patients who had recently had atrial fibrillation digoxin, respectively. Some trials evaluated more than two but did not necessarily have it at the time of enrolment.18 drugs or evaluated combinations of drugs. These articles Although this study considered a slightly different population from the other studies included in this analysis, it was consid- described trials that were conducted in 24 countries and pub- ered because of its large sample size and relatively long dura- lished between 1970 and 2001. The total number of enrolled tion of follow up. patients was 8563 (range 18–506). The median duration of follow up was one day (range 0.04–1096, mean (SD) 46 (136) RESULTS days.) The median proportion of patients in sinus rhythm at Literature review follow up was 55% (range 0–100%) and 32% (range 0–90%) Four hundred twenty eight potentially relevant articles were for patients receiving active treatment and placebo, respec- identified. Reasons for exclusion were non-randomised study tively. The median survival was 99% (range 55–100%) and 99%

Active drug, Follow up Figure 2 Absolute treatment year (reference) n (days) difference in proportion of patients with normal sinus rhythm (%) at end Propafenone, 1998 (82) 95 1 of study between class IC agents and placebo. Propafenone, 1998 (81) 156 0.08 Propafenone, 1998 (80) 83 0.04 Propafenone, 1997 (79) 136 0.08 Propafenone, 1997 (75) 240 0.33 Propafenone, 1997 (74) 55 1 Propafenone, 1996 (69) 75 0.13 Propafenone, 1996 (66) 105 1 Propafenone, 1996 (65) 100 2 Propafenone, 1995 (57) 87 0.33 Propafenone, 1995 (56) 182 1 Propafenone, 1994 (53) 58 2 Pilsicainide, 1996 (64) 75 0.06 Flecainide, 1989 (34) 34 186 Flecainide, 1995 (60) 66 0.33 Flecainide, 1992 (44) 43 0.33 Flecainide, 1991 (41) 102 0.25 Overall 1692 0.33

–40 –30 –10–20 02010 30 40 50 60 8070 Treatment better (absolute difference in %)

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538 Nichol, McAlister, Pham, et al

Active drug, Follow up Figure 3 Absolute treatment difference in proportion of patients year (reference) n (days) with normal sinus rhythm (%) at end Amiodarone, 2000 (98) 208 30 of study between class III agents and placebo. Amiodarone, 2000 (97) 62 0.33 Amiodarone, 1999 (93) 67 30 Amiodarone, 1999 (90) 100 0.33 Amiodarone, 1998 (82) 97 1 Amiodarone, 1996 (70) 64 15 Amiodarone, 1995 (60) 64 0.33 Amiodarone, 1994 (54) 30 1 Amiodarone, 1992 (44) 40 0.33 Dofetilide, 2001 (108) 506 1096 Dofetilide, 2000 (107) 325 0 Dofetilide, 2000 (104) 69 0.04 Dofetilide, 2000 (100) 22 0.12 Dofetilide, 1999 (94) 79 0.12 Dofetilide, 1997 (76) 98 0.12 Ibutilide, 1999 (95) 201 0.06 Ibutilide, 1996 (72) 167 0.06 Ibutilide, 1996 (68) 99 0.04 Sotalol, 1991 (43) 30 186 Overall 2328 0.33

–60 –40 0–20 20 40 60 80 100 120 Treatment better (absolute difference in %)

(range 55–100%) for patients receiving active treatment and Adverse effects of antiarrhythmic agents placebo, respectively. The median quality score was 4 (range Although we attempted to abstract data describing any 0–7). adverse effects that were observed in each trial, these were not reported frequently or consistently. Therefore, we were unable Effect of antiarrhythmic agents on promoting sinus to analyse the association between individual classes of drugs rhythm at follow up and adverse effects. Compared with placebo, use of the following classes of drugs Sensitivity analyses was associated with significant increases in the proportion of Among trials that followed up patients for less than seven patients who were in sinus rhythm, adjusted for variation in days, class IC and class III antiarrhythmic drugs were associ- follow up duration (table 1): IA (treatment difference 21.5%, ated with increased sinus rhythm compared with placebo 95% CI 16.3% to 26.8%, p < 0.0001; fig 1; IC (treatment differ- (table 3). Among the same group of trials, no class ence 33.1%, 95% CI 23.3% to 42.9%, p < 0.0001; fig 2; III antiarrhythmic drugs were associated with a significant (treatment difference 17.4%, 95% CI 11.5% to 23.3%, decrease in mortality. p = 0.001; fig 3). Class IC was associated with significant Among trials that followed up patients for at least seven increases in the proportion of patients who were in sinus days, class IA and class III antiarrhythmic drugs were associ- rhythm at the end of study follow up compared with class IV ated with increased sinus rhythm compared with placebo (treatment difference 43.2%, 95% CI 11.5% to 75.0%, (table 3). Among the same group of trials, there were no sig- p = 0.03). For each figure, the combined treatment effect was nificant differences in mortality between the classes of drugs estimated at the median follow up time. compared. Among trials that compared amiodarone with other Effect of antiarrhythmic agents on mortality antiarrhythmic drugs, there was no significant difference in There was no significant difference in mortality between sinus rhythm at follow up or in mortality (table 4). When a active treatment and placebo for any of the classes of recent large randomised trial was included in the secondary antiarrhythmic drugs considered (table 2). analysis,18 the p value was closer to the critical value but was

Table 2 Effect of antiarrhythmic agents on mortality in placebo controlled trials

Proportion dead at follow Proportion dead at follow Number up in treatment arm (%), up in control arm (%), Treatment difference (%), Comparators of trials mean (95% CI) mean (95% CI) mean (95% CI) p Value

IA v placebo 5 2.53 (1.41 to 3.64) 1.57 (0.58 to 2.56) 0.96 (–0.45 to 2.36) 0.14 IC v placebo 14 1.20 (1.10 to 1.30) 1.28 (1.17 to 1.39) −0.08 (−0.20 to 0.04) 0.16 III v placebo 17 4.28 (4.06 to 4.50) 4.39 (4.16 to 4.62) −0.11 (−0.32 to 0.09) 0.25 Digoxin v placebo 4 1.76 (1.71 to 1.80) 1.73 (1.69 to 1.78) 0.02 (−0.01 to 0.06) 0.12 IA v III 5 7.29 (6.12 to 8.45) 7.12 (6.01 to 8.23) 0.17 (−0.58 to 0.92) 0.53 IC v III 8 1.76 (1.07 to 2.45) 2.01 (1.28 to 2.74) −0.26 (−1.10 to 0.59) 0.50 IC v IV 3 1.85 (0.53 to 3.17) 1.91 (0.23 to 3.59) −0.06 (−2.26 to 2.13) 0.91 III v digoxin 2 3.29 (0 to 14.37) 2.82 (0 to 13.26) 0.48 (−13.71 to 14.67) 0.74

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Meta-analysis of antiarrhythmia trials 539

Table 3 Short term and long term effect of antiarrhythmic agents on sinus rhythm in placebo controlled trials

Follow up duration Number of Treatment difference (%), Comparators (days) trials mean (95% CI), p Value

1A v placebo >7 (all studies) 6 21.1 (15.0 to 27.2) 0.0003 1C v placebo <7 17 31.9 (22.6 to 41.1) <0.0001 III v placebo <7 12 17.3 (9.6 to 25.0) 0.0002 III v placebo >7 3 17.6 (3.3 to 31.9) 0.03 Digoxin v placebo <7 (all studies) 4 13.1 (−7.2, 33.3) 0.15 IA v III <7 4 12.5 (−29.7 to 33.3) 0.11 IA v III >72−6.6 (−36.7 to 23.5) 0.22 IC v III <7 9 2.5 (−12.2 to 17.2) 0.71

Table 4 Effect of amiodarone versus other antiarrhythmic agents in placebo controlled trials

Number of Amiodarone estimate (%), Other active drugs* estimate Treatment difference (%), Outcome trials mean (95% CI) (%), mean (95% CI) mean (95% CI) p Value

Sinus rhythm 20 50.0 (6.7 to 93.3) 47.2 (1.84 to 92.6) 2.7 (−51.2 to 56.7) 0.64 Mortality 20 2.12 (0.68 to 3.56) 2.29 (0.88 to 3.69) −0.17 (−1.66 to 1.32) 0.38

*Other active drugs are digoxin, verapamil, propafenone, quinidine, procainamide, and flecainide. still not significant (details available from authors). Similar proarrhythmia in patients with ventricular dysfunction who results to those of the primary analysis were obtained when received dofetilide.111 Therefore, caution is required when the analysis adjusted for differences in study quality or using class III agents other than amiodarone to promote sinus included study cohorts (details available from authors). rhythm in patients with pre-existing heart disease. The use of class IA or IC drugs may be associated with increased mortality.7 112 113 Therefore, these drugs are now not DISCUSSION usually used in patients known to have coronary artery Compared with placebo, use of several of the classes of drugs disease. The use of class IV drugs is restricted to situations considered in this analysis was associated with a significant where the primary goal is control of ventricular rate rather increase in the proportion of patients who were in sinus than restoration of sinus rhythm. rhythm at the time of follow up. However, there were limited A previous meta-analysis of placebo controlled trials in data to show whether one class of drug was better than patients with atrial fibrillation showed that quinidine another. Compared with placebo, use of any of the classes of treatment was more effective than no antiarrhythmic drugs considered in this analysis was not associated with a treatment but was associated with increased mortality.7 These significant increase or decrease in mortality at the time of fol- findings are consistent with our finding that use of class IA low up. Compared with any other active antiarrhythmic agent, antiarrhythmics is associated with increased sinus rhythm. It amiodarone was not associated with a significant difference in is also consistent with our finding of no difference in sinus rhythm at follow up or mortality. mortality, since the confidence intervals for the effect The primary reason to use antiarrhythmic agents in estimate from the quinidine analysis and that of the present patients with atrial fibrillation is to improve survival, quality analysis both overlapped zero. However, the previous analysis of life, or both. Improvement in quality of life may be caused considered only the effect of quinidine rather than all class IA by decreased symptomatic arrhythmia or to decreased drugs. disabling complications such as stroke. No randomised trials Controlled trials of class III agents such as amiodarone for have had sufficient power to address these issues. Whether ventricular arrhythmias showed small but significant reduc- sinus rhythm is present several months after antiarrhythmic tions in all cause mortality or arrhythmic death in patients treatment is initiated is at best a surrogate marker for either who received treatment rather than the control treatment,114–117 in contrast to controlled trials of class IC survival or quality of life. Meta-analysis of previous ran- 112–113 domised controlled trials provides the best available infor- agents. However, it would be premature to generalise the mation to address this issue but does not provide sufficient results of these trials to all patients with atrial fibrillation. Others have considered the cost effectiveness of treatments information on which to base clinical recommendations con- for patients with atrial fibrillation.118 119 A decision analytical fidently. However, it appears that there is little difference model was used to show that cardioversion followed by aspi- between classes of antiarrhythmic agents in terms of achieve- rin with or without amiodarone was effective and ment and maintenance of sinus rhythm. Furthermore, there is inexpensive.118 Cardioversion followed by treatment with war- no evidence that any class of antiarrhythmic agents is associ- farin and amiodarone was effective but more expensive. The ated with increased or decreased mortality. This lack of effect present analysis supports the findings that amiodarone is is important since previous trials of antiarrhythmic agents for effective and appropriate in patients with atrial fibrillation. other arrhythmias have shown that these agents are Another decision analysis had slightly different findings.119 associated with increased mortality. Of the treatment strategies that were considered, cardiover- Based on this analysis, if a patient or physician chooses to sion followed by repeat cardioversion plus amiodarone on use an antiarrhythmic agent as a treatment for atrial fibrilla- relapse was most cost effective. Our findings support the use tion, use of class III drugs as first line agents for treatment of of initial treatment with amiodarone rather than delayed atrial fibrillation is reasonable since they are both effective and treatment, since class III agents are associated with increased safe. The present analysis did not find a significant difference sinus rhythm and may be associated with decreased mortality. in effectiveness between amiodarone and other class III drugs. However, we have not incorporated our results into a decision However, previous trials showed increased mortality after model since we were unable to show a significant difference in myocardial infarction in patients who received D-sotalol110 or mortality between any class of antiarrhythmic drugs.

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540 Nichol, McAlister, Pham, et al

A large randomised controlled trial underway is evaluating including use of electrical cardioversion before or after initia- the use of antiarrhythmic agents by patients with atrial tion of antiarrhythmic agents, use of transoesophageal fibrillation.8 The results of the AFFIRM trial will be reported in echocardiography to identify clot before cardioversion, or 2002. It evaluated the effectiveness of either ventricular rate clinical characteristics of the patients. Although we attempted control or rhythm control with antiarrhythmic agents for total to extract such data, the vast majority of the studies analysed mortality and stroke. All patients received concurrent did not report them. Therefore, we were unable to evaluate the anticoagulation treatment. Since selection of the type or class influence of these variables on sinus rhythm, survival, or other of drug was not randomised in this trial, any observed differ- clinical outcomes. ence between types of antiarrhythmic agents may be Despite the limitations of the data described above, we confounded by differences in other factors. believe that this analysis is the most comprehensive assess- Since the present analysis is complex, we will now review ment to date of the effectiveness of different antiarrhythmic the rationale for the inclusion criteria we used and discuss agents in patients with atrial fibrillation. It offers estimates of their implications. Firstly, we excluded studies not published the effectiveness of different classes of drugs. No other studies in English. Compared with meta-analyses that considered have pooled the results of different studies using statistical only English articles, those that considered English and non- analysis and adjusted for differences in follow up time. Given English articles did not differ with respect to the estimate of the large number of antiarrhythmic agents and large benefit of the effectiveness of an intervention.120 Also, use of uncertainty about which agent is effective, this meta-analysis such articles would require translation, which was outside of is an important advance. Future studies should directly com- the scope of this study because of the anticipated difficulty in pare specific class III agents and be of sufficient size to deter- abstracting information about duration of follow up, and rates mine effectiveness and safety. of dropout and withdrawal. Thus, we relied on citations that In summary, evaluation of the effectiveness of different were identified by review of English language papers indexed classes of antiarrhythmic agents continues to be difficult in Medline and of the bibliographies of these articles. because of inadequate data. The effectiveness estimates Studies that considered patients with induced atrial derived in this analysis must be interpreted with caution fibrillation were excluded since the efficacy of antiarrhythmic because of the wide variety of classes of drugs considered and agents in patients in an electrophysiology laboratory may not of differences in the duration of follow up. be generalisable to their effectiveness in a less selected popu- lation. Treatments other than antiarrhythmic agents, such as ablation, are not widely available. Therefore, the results of Conclusion studies of these interventions are not generalisable to the On the basis of a meta-analysis of data from 91 randomised population as a whole. trials of antiarrhythmic agents promoting sinus rhythm in Studies that considered the use of antiarrhythmic agents patients with atrial fibrillation, we confirm that class IA, IC, for prophylaxis alone were also excluded. Since the frequency and III drugs are associated with increased sinus rhythm of the arrhythmia in these patients is unclear, it is difficult to compared with placebo. Class IC drugs are associated with interpret the presence of sinus rhythm at the time of follow increased sinus rhythm compared with class IV drugs. We are up. unable to confirm whether any antiarrhythmic class of drug is Finally, studies that followed up patients for < 60 minutes associated with increased or decreased mortality in this popu- after drug administration were excluded, since transient con- lation. Patients, physicians, and policy makers should consider version may be unsustained. Such transient benefits are the impact of each class of drug on sinus rhythm, mortality, unlikely to affect patient morbidity or quality of life. quality of life, and patient compliance. The effectiveness of each class of drug was expressed as the percentage difference in this analysis. A common alternative approach is to express the effectiveness of each class as an ACKNOWLEDGEMENTS odds ratio. However, odds ratios may be misleading when Funding for this project was provided in part by the Bickell Founda- events are common or when they are observed in a tion of Canada. Dr Nichol is supported by an Ontario Ministry of 121–123 randomised trial rather than a case–control study. Both Health Career Scientist Award. Dr McAlister is supported by a Popula- conditions apply to this analysis. Also, odds ratios do not con- tion Health Investigatorship from the Alberta Heritage Foundation for vey the absolute magnitude of the benefit of treatment. Medical Research. Dr Laupacis is a Senior Scientist of the Canadian Institute of Health Research .

Limitations of analysis This analysis has several limitations because of the constraints of the existing literature. Firstly, there are several ways of clas- Summary of studies examined in the meta-analysis sifying the underlying pattern of atrial fibrillation.124 In our appear on the Heart website—www.heartjnl.com analysis, it was sometimes difficult to determine whether patients who were enrolled in a particular clinical trial had isolated, paroxysmal, persistent, or chronic atrial fibrillation. Despite this, we found consistent results when the data were pooled and analysed in different ways. Thus, we believe that it ...... is unlikely that considering alternative ways of classifying Authors’ affiliations atrial fibrillation would yield different results. G Nichol, Clinical Epidemiology Program, Ottawa Health Research Secondly, the analysis lacked statistical power to detect dif- Institute, Ottawa Hospital, Ottawa, Ontario, Canada ferences between individual antiarrhythmic agents or to F McAlister, Division of General Internal Medicine, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada detect small differences between classes of antiarrhythmic B Pham, Glaxo Wellcome Inc, Mississauga, Ontario, Canada agents. Nevertheless, this is the first meta-analysis to A Laupacis, Institute of Clinical Evaluative Sciences in Ontario, Toronto, discriminate between each class of antiarrhythmic agent and Ontario, Canada is the largest analysis performed to date of the use of these B Shea, Institute of Population Health, Ottawa, Ontario, Canada agents in patients with atrial fibrillation. M Green, A Tang, University of Ottawa Heart Institute, Ottawa, Ontario, Canada Thirdly, the analysis adjusted for variation in follow up G Wells, Department of Epidemiology and Community Medicine, duration but not for other parameters of potential interest University of Ottawa, Ottawa, Ontario, Canada

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Meta-analysis of antiarrhythmia trials 541

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IMAGES IN CARDIOLOGY...... Intermittent Brugada syndrome misdiagnosed as acute myocardial infarction and unmasked with propafenone

40 year old man was admitted to the emergency department with While magnetic resonance imaging (MRI) of the heart was normal, chest and left shoulder pain for an hour. His admission ECG MRI of the neck delineated cervical herniation, which might explain Arevealed 3–5 mm ST segment elevation on leads V1–3 and right the patient’s symptoms. bundle branch block (RBBB). His previous ECGs were normal. Acute Brugada syndrome can present with a typical ECG but in some myocardial infarction was diagnosed and thrombolytic treatment ini- cases the patient can present with concealed or intermittent forms. In tiated. Six hours later, there was no ST segment elevation on leads the presented case propafenone unmasked ST segment elevation in V1–3 or RBBB on the ECG, and all cardiac enzymes were within nor- leads V1–3 and RBBB. The blocking of the sodium channels and β mal limits. Echocardiography was normal. Coronary angiography adrenoreceptors contribute to the unmasking effect of propafenone. revealed normal coronary arteries. All ECGs were reviewed and it was This case indicates that Brugada syndrome may be confused with decided that the diagnosis of acute myocardial infarction was AMI, and that propafenone is useful for unmasking the Brugada syn- incorrect. Because of typical ECG findings, an intermittent form of drome ECG pattern. Brugada syndrome was suspected. To confirm the diagnosis (and because of the absence of ajmaline, flecainide, and procainamide) a I Akdemir provocation test with propafenone was performed. The test proved V Davutoglu strongly positive for the Brugada syndrome. ECGs of his four family M Aksoy members revealed similar electrocardiographic abnormalities. [email protected]

Admission ECG revealed ST elevation and RBBB.

Unmasking effect of propafenone following the provacation test (20 minutes after). ECG findings normalised six hours later.

www.heartjnl.com Appendix 1 Data abstracted from the literature

Author (reference) Drug, daily dose (mg) Number of Mean Number Minimum Maximum Number of Number of Number in Number dead

patients age of male follow up follow up patients patients who sinus rhythm at follow up

(years) patients duration duration who withdrew (%) at follow up (%)

(%) (days) (days) dropped (%)

out (%)

Byrne-Quinn (19) Quinidine 1200 45 54 26 (58) 93 – 0 15 (33) 19 (42) 1 (2)

Placebo 47 54 23 (49) 0 0 13 (28) 0

Levi (20) Practolol 400 26 – 13 (50) 7 – 0 1 (4) 11 (42) 0

Placebo 28 – 9 (32) 0 1 (4) 13 (46) 0

Hartel (21) Disopyramide 26 54 13 (50) 93 – 2 (8) – 13 (50) –

Placebo 26 57 16 (62) 2 (8) – 6 (23) –

Sodermark (22) Quinidine 1200 101 58 78 (77) 372 – 9 (9) 12 (12) 52 (52) 5 (5)

Placebo 75 56 47 (63) 3 (4) 0 21 (28) 2 (3)

Normand (23)* Quinidine 660 20 61 15 (83) 31 548 – 2 (11) 5 (25) 0

Quinidine 660 20 60 13 (65) – 0 11 (55) 0

Kennelly (24) Quinidine 1172 25 38 – 31 – – 8 (32) 13 (51) 0

Lidoflazine 300 15 44 – – 1 (7) 8 (53) 4 (27)

Boissel (25) Quinidine 660 105 – – 93 – 0 9 (9) 77 (73) 2 (2)

Placebo 107 – – 2 (2) 0 58 (54) 1 (1)

Rasmussen (26) Quinidine 500 31 – – 31 – 3 (10) 11 (35) 8 (26) 0

Verapamil 240 25 – – 0 0 2 (8) 0 Lloyd (27) Quinidine 1440 28 48 – 183 – 2 (7) 4 (14) 12 (43) 2 (7)

Disopyramide 450 29 45 – 3 (10) 2 (7) 13 (45) 0

Placebo 25 44 – 0 0 8 (32) 0

Campbell (28) Sotalol 84 22 61 19 (86) 0.5 – 2 (9) 2 (9) 17 (77) 0

Digoxin and 20 64 15 (75) 0 0 15 (75) 0

disopyramide

Ochs (29) Diltiazem 180 15 52 8 (53) 6 – 1 (7) 1 (7) 1 (7) 0

Verapamil 240 15 51 4 (27) 4 (27) 4 (27) 1 (7) 0

Cowan (30) Amiodarone 1500 18 69 – 1 2 – 1 (6) 12 (67) 1 (6)

Digoxin 1 16 67 – – 0 9 (58) 0

Falk (31) Digoxin 1.4 18 – – 0.67 – 0 0 9 (50) 0

Placebo 18 – – 0 0 8 (44) 0

Karlson (32) Disopyramide 500 44 60 32 (73) 31 – – – 31 (70) 0

Placebo 46 61 32 (70) – – 18 (39) 0

Suttorp (33) Flecainide 150 20 60 19 (95) 0.04 – 0 0 14 (70) –

Verapamil 10 20 58 13 (65) 0 0 1 (5) –

Van Gelder (34)† Flecainide 300 36 60 20 (56) 31 365 – 3 (8) (49) –

Placebo 37 57 22 (59) – 0 (36) –

Juul-Moller (36) Sotalol 320 98 59 81 (83) 186 – 6 (6) 11 (11) 49 (50) 1 (1)

Quinidine 1200 85 59 68 (80) 8 (9) 22 (26) 36 (42) 1 (1)

Noc (39) Amiodarone 350 13 – – 0.13 – – – 10 (77) –

Verapamil 10.5 11 – – – – 0 – Suttorp (40) Propafenone 140 25 61 19 (76) 0.04 – 5 (20) 0 11 (44) 0

Flecainide 140 25 58 12 (48) 5 (20) 0 18 (72) 0

Bertini (35) Amiodarone 2350 12 68 9 (75) 0.08 5 0 0 12 (100) 0

Propafenone 140 16 63 7 (44) 0 0 16 (100) 0

Kondili (37) Verapamil 10 29 57 16 (55) 0.04 – 0 0 4 (14) 0

Flecainide 140 20 53 11 (55) 0 0 10 (50) 0

Propafenone 150 20 58 12 (60) 0 0 5 (25) 0

McAlister (38) Amiodarone 350 41 59 25 (61) 0.33 – 0 0 17 (41) 0

Quinidine 800 39 59 23 (59) 0 2 (5) 25 (64) 0

Donovan (41) Flecainide 150 51 61 – 0.04 0.25 – – 34 (67) –

Placebo 51 59 – – – 17 (35) –

Singh (43) Sotalol 320 24 60 17 (71) 7 183 – 3 (13) 5 (21) 0

Placebo 10 61 7 (70) – 0 0 0

Kuhlkamp (42) Cibenzoline 320 19 – – 5 – – – 7 (37) 0

Flecainide 300 12 – – – – 3 (25) 0

Cappuci (44) Flecainide 150 22 58 14 (64) 0.13 1 0 0 8 (37) 0

Amiodarone 350 19 59 10 (53) 0 0 17 (91) 0

Placebo 21 57 11 (52) 0 0 11 (48) 0

Zehender (48)‡ Quinidine 1500 20 57 11 (55) 3 93 – – 11 (91) 0

Verapamil 20 59 12 (60) – – 10 (92) 0

Amiodarone 1200 Kingma (46) Flecainide 150 45 59 35 (78) 0.04 – – – 32 (71) 0

Verapamil 10 20 57 13 (65) – – 1 (5) 0

Propafenone 150 25 61 19 (76) – – 11 (44) 0

Hjelms (45) Procainamide 1050 15 – 13 (87) 0.5 – 0 0 14 (93) 0

Digoxin 1 15 – 11 (73) 0 0 9 (60) 0

Roth (47) Clonidine 0.15 9 65 5 (56) 0.17 – 0 0 6 (67) 0

Placebo 9 69 5 (56) 0 0 1 (11) 0

Reimold (52)† Propafenone 750 50 61 33 (66) 93 365 0 4 (8) (30) 0

Sotalol 960 50 62 31 (62) 0 6 (12) (37) 2 (4)

Madrid (51) Flecainide 210 40 54 27 (68) 0.04 – 0 0 37 (93) 0

Procainamide 1120 40 55 23 (58) 0 0 25 (63) 0

Gullestad (50) Magnesium 9723 15 61 10 (67) 0.17 1 0 0 8 (53) 0

Verapamil 34 20 64 13 (65) 0 2 (10) 8 (40) 0

Chapman (49) Procainamide 3940 14 65 10 (71) 0.04 0.5 0 – 10 (71) –

Amiodarone 910 12 17 8 (67) 2 (17) – 7 (58) –

Capucci (53) Propafenone 1500 29 – 20 (69) 0.25 2 – 0 25 (86) 0

Digoxin and quinidine 29 – 20 (69) – 1 (3) 23 (79) 0

Placebo 29 – 16 (55) – 0 22 (76) 0

Cochrane (54) Amiodarone 1230 15 60 11 (73) 1 – 0 0 14 (93) 0

Placebo 15 66 10 (67) 0 0 13 (87) 0

Weiner (55) Propafenone 900 24 – – 0.5 2 1 (4) 0 21 (87) 0

Verapamil 480 25 – – 1 (4) 2 (8) 9 (41) 0 Hohnloser (62) Quinidine and verapamil 25 65 10 (40) 7 183 3 (12) 10 (40) 18 (86) 0

Sotalol 320 25 60 8 (72) 3 (12) 0 14 (77) 0

Halinen (61) Sotalol 320 33 55 21 (64) 0.13 0.33 0 0 8 (24) 0

Digoxin and quinidine 28 53 19 (68) 0 0 20 (71) 0

Boriani (57) Propafenone 926 29 55 17 (59) 0.04 0.33 0 1 (3) 12 (41) 0

Propafenone 600 29 57 18 (62) 0 0 16 (55) 0

Placebo 29 57 17 (59) 0 0 3 (10) 0

Donovan (60) Flecainide 150 34 59 – 0.04 0.33 – – 23 (68) 0

Amiodarone 490 32 56 – – – 19 (59) 0

Placebo 32 59 – – – 18 (56) 0

Bellandi (56) Propafenone 840 98 65 – 1 – 0 0 89 (91) 0

Placebo 84 66 – 0 0 27 (32) 0

Boudonas (58) Diltiazem 2.25 10 – – 0.04 – – – 0 (0) 0

Disopyramide 50 13 – – – – 5 (38) 0

Hou (63) Amiodarone 1620 26 70 22 (85) 1 – – 0 24 (92) 0

Digoxin 0.91 24 70 21 (88) – 0 2 (7) 0

Di Biasi (59) Amiodarone 1400 46 66 36 (78) 0.04 1 0 0 38 (83) 0

Propafenone 840 38 63 32 (84) 0 0 26 (68) 0

Galve (70) Amiodarone 1550 50 60 27 (54) 1 14 0 0 44 (88) 0

Placebo 50 61 28 (56) 0 0 45 (90) 0

Stambler (72) Ibutilide 1.5 81 66 66 (81) 0.06 – – – 25 (31) 0

Placebo 86 66 72 (84) – – 2 (2) 1 (1) Ellenbogen (68) Ibutilide 0.35 79 64 71 (90) 0.04 – – – 23 (29) 0

Placebo 20 65 20 (100) – – 1 (5) 0

Atarashi (64) Pilsicainide 150 40 – 26 (65) 0.06 – 0 0 18 (45) 0

Placebo 35 – 25 (71) 0 0 3 (9) 0

Bianconi (65) Propafenone 750 49 67 28 (57) 1 2 – – 36 (74) –

Placebo 51 64 26 (51) – – 27 (53) –

Larbuisson (71) Propafenone 560 18 66 17 (94) 0.04 1 – – (67) 0

Amiodarone 1250 22 67 20 (91) – – (77) 0

Crijns (67) Propafenone 900 25 59 21 (84) 31 183 – – 9 (36) –

Disopyramide 750 31 60 18 (58) – – 13 (42) –

Fresco (69) Propafenone 210 41 56 22 (54) 0.13 – – 2 (5) 24 (59) –

Placebo 34 51 28 (82) – 1 (3) 10 (29) –

Botto (66) Propafenone 450 35 63 18 (51) 0.08 1 – – 25 (71) 0

Propafenone 600 35 59 19 (54) – – 28 (80) 0

Placebo 35 60 15 (43) – – 24 (69) 0

Innes (77) Verapamil 20 19 62 11 (58) 0.25 1 0 – 17 (89) 0

Digoxin 1 25 58 14 (56) 3 (12) – 14 (64) 0

Azpitarte (74) Propafenone 750 29 60 14 (48) 0.08 1 0 – 23 (79) 0

Placebo 26 57 7 (27) 0 – 19 (73) 0

Stroobandt (79) Propafenone 490 101 61 77 (76) 0.08 – – – 29 (29) 0

Placebo 35 64 13 (37) – – 6 (17) 0 Frost (76) Dofetilide 0.28 33 – 27 (82) 0.13 – – – 12 (36) –

Dofetilide 0.56 32 – 26 (81) – – 14 (44) –

Placebo 33 – 26 (79) – – 8 (24) –

Jordaens (78) Digoxin 1.25 19 61 10 (53) 0.5 – – – 9 (47) 0

Dofetilide 0.28 20 67 13 (65) – – 8 (40) 0

Boriani (75) Propafenone 600 119 59 70 (59) 0.13 0.33 – – 91 (76) 0

Placebo 121 58 67 (55) – – 45 (37) 0

Ganau (81) Propafenone 140 81 59 36 (44) 0.08 – 0 0 57 (70) 0

Placebo 75 57 33 (44) 0 0 13 (17) 0

Volgman (87) Ibutilide 2 43 64 32 (75) 0.06 – – – 22 (51) 0

Procainamide 1200 38 68 27 (70) – – 8 (21) 0

Tisdale (86) Diltiazem 400 20 65 16 (80) 0.06 1 5 (25) – 11 (55) –

Digoxin 1 20 68 16 (80) 1(5) – 13 (65) –

Digitalis in Acute Digoxin 1.5 117 67 62 (53) 0.67 – – – 60 (51) 0 Atrial Fibrillation (DAAF) Trial Group Placebo 122 65 67 (55) – – 56 (46) 0 (73) Reisinger (85) Flecainide 150 54 65 30 (56) 0.08 – 0 0 28 (52) –

Sotalol 150 52 59 31 (60) 0 0 12 (23) –

Bianconi (80) Propafenone 140 41 59 26 (63) 0.04 – 0 0 20 (49) 0

Digoxin 0.49 40 59 19 (48) 0 0 13 (33) 0

Placebo 42 61 19 (45) 0 0 6 (14) 0

Vos (88) Ibutilide 1 83 62 71 (70) 0.04 – 0 0 17 (20) 0

Ibutilide 2 86 60 71 (65) 0 0 17 (20) 0

Sotalol 105 82 59 81 (75) 0 0 9 (11) 0 Mattioli (84) Propafenone 140 38 64 26 (68) 2 – 0 0 27 (70) 0

Procainamide 1000 38 64 29 (76) 0 0 19 (49) 0

Kochiadakis (82) Amiodarone 1700 48 63 27 (56) 1 – 0 0 40 (83) 0

Propafenone 840 46 63 25 (54) 0 0 36 (78) 0

Placebo 49 65 24 (49) 0 0 27 (55) 0

Kochiadakis (83) Procainamide 1000 57 64 29 (51) 0.04 – 0 0 29 (51) 0

Placebo 57 64 30 (53) 0 0 16 (28) 0

Cotter (90) Amiodarone 3000 50 65 24 (48) 0.33 1 0 0 46 (92) 0

Placebo 50 68 19 (38) 0 0 32 (64) 0

Geelen (91) Propafenone 140 29 67 8 (28) 0.04 – 0 0 22 (76) 0

Procainamide 1000 33 66 12 (36) 0 0 20 (61) 0

Kochiadakis (92) Amiodarone 1700 34 64 16 (47) 14 31 0 0 16 (47) 0

Propafenone 840 32 64 16 (50) 0 0 13 (41) 0

Kochiadakis (93) Amiodarone 1700 33 64 16 (48) 30 – 0 0 16 (48) 0

Placebo 34 63 15 (44) 0 0 0 0

Blanc (89) Propafenone 600 43 61 8 (19) 0.33 1 0 0 19 (14) 0

Amiodarone 2100 43 64 8 (19) 0 0 23 (44) 0

Norgaard (94) Dofetilide 0.56 55 69 – 0.13 – 0 0 13 (4) 0

Placebo 24 70 – 0 0 1 (4) 0

VanderLugt (95) Ibutilide 0.25 43 – – 0.06 – 0 0 12 (28) 0

Ibutilide 0.5 55 – – 0 0 23 (42) 0

Placebo 60 – – 0 0 12 (20) 0 Capucci (96) Amiodarone 400 31 59 16 (52) 30 – 0 0 8 (25) 0

Diltiazem 180 31 58 14 (45) 1 (3) 1 (3) 1 (3) 0

Diltiazem 180 and 30 60 16 (53) 0 0 2 (7) 0

glucose-insulin-KCl

infusion

Peuhkurinen (97) Amiodarone 2100 31 56 25 (81) 0.33 1 0 0 27 (87) 0

Placebo 31 62 20 (65) 0 0 11 (37) 0

Alp (99) Flecainide 140 40 65 24 (60) 0.08 0.33 0 0 30 (75) 0

Flecainide 280 39 64 22 (56) 0.08 0 0 28 (72) 0

Bianconi (100) Dofetilide 0.6 12 64 28 (56) 0.13 0 0 8 (75) 0

Amiodarone 350 9 63 31 (57) 0.13 0 0 0 0

Placebo 10 66 29 (54) 0.13 0 0 0 0

Hohnloser (101) Diltiazem 270 125 61 92 (74) 1 365 1/125 0 13 (10) 2/125

Amiodarone 600 127 60 92 (72) 1 365 5/127 0 71 (56) 2/125

Joseph (102) Sotalol 265 40 65 20 (50) 0.17 2 0 0 38 (95) 0

Amiodarone1150 39 61 25 (64) 0.17 2 0 0 37(94) 0

Digoxin 1.5 36 65 20 (56) 0.17 2 0 0 28 (78) 0

Kumagai (103) Pilsicainide 150 40 57 30 (75) 0.08 0 0 (29) 0

Disopyramide 140 32 59 21 (66) 0.08 0 0 (56) 0

Lindeboom (104) Dofetilide 0.14 16 62 11 (69) 0.04 0 0 4 (25) 0

Dofetilide 0.28 17 60 12 (71) 0.04 0 0 5 (29) 0

Dofetilide 0.56 18 63 12 (67) 0.04 0 0 7 (39) 0

Placebo 18 59 11 (61) 0.04 0 0 1 (6) 0 Madonia (105) Propafenone 510 49 56 28 (57) 0.04 0.5 0 0 48 (98) 0

Propafenone 1500 48 56 28 (58) 0 0 48 (100) 0

Martinez-Marcos Flecainide 210 50 57 26 (52) 0.04 0.5 – – 45 (90) – (106) Propafenone 210 50 62 20 (40) 0.5 – – 36 (72) –

Amiodarone 1500 50 62 24 (48) 0.5 – – 32 (64) –

Vardas (98) Amiodarone 1700 108 64 53 (49) 0.04 30 – – 87 (81) 0

Placebo 100 65 49 (49) – – 40 (40) 0

Singh (107) Dofetilide 0.25 82 66 68 (83) 0.04 3 – – 5 (6) –

Dofetilide 0.5 82 68 69 (84) 3 – – 8 (10) –

Dofetilide 1.0 77 67 63 (82) 3 – – 23 (30) –

Placebo 84 67 73 (87) 3 – – 1 (1) –

Pedersen (108) Dofetilide 0.25 249 72 188 (76) 31 1096 4 (2) 111 (45) 31 (44.98) –

Placebo 257 72 201 (78) 31 1096 0 116 (45) (13.618) –

Wattunasuwan (109) Diltiazem 124.2 26 64 15 (58) 0.5 – – 14 (53.84) –

Diltiazem 124.2 and 26 61 14 (54) 0.5 – – (46) –

digoxin 0.5

*Trial evaluated short acting and long acting preparations of same drug; †Reported as proportion in sinus rhythm at follow up; not all patients evaluable at 12 months; ‡Not all patients evaluable at three months.