Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation

Carmelo Lafuente‐Lafuente; Miguel Angel Longas‐Tejero; Jean‐François Bergmann; Joël Belmin

doi:10.1002/14651858.CD005049.pub3

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Figure 1

Figure 1. PRISMA chart

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Figure 2

Funnel plot of comparison: All‐cause mortality, by individual antiarrhythmics, compared vs control.

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Figure 3

Overall mortality

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Figure 4

Withdrawals due to adverse events and Pro‐arrhythmia

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Figure 5

Atrial fibrillation recurrence

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Analysis 1.1

Comparison 1 All‐cause mortality, Outcome 1 Individual antiarrhythmics.

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Analysis 1.2

Comparison 1 All‐cause mortality, Outcome 2 Individual antiarrhythmics ‐ ITT Worst case: missing patients counted as events.

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Analysis 1.3

Comparison 1 All‐cause mortality, Outcome 3 Quinidine: older and recent studies.

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Analysis 1.4

Comparison 1 All‐cause mortality, Outcome 4 Quinidine: older and recent studies ‐ ITT Worst case: missing patients counted as events.

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Analysis 1.5

Comparison 1 All‐cause mortality, Outcome 5 Class I antiarrhythmics.

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Analysis 1.6

Comparison 1 All‐cause mortality, Outcome 6 Class I antiarrhythmics ‐ ITT Worst case: missing patients counted as events.

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Analysis 1.7

Comparison 1 All‐cause mortality, Outcome 7 Class III antiarrhythmics.

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Analysis 1.8

Comparison 1 All‐cause mortality, Outcome 8 Class III antiarrhythmics ‐ ITT Worst case: missing patients counted as events.

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Analysis 1.9

Comparison 1 All‐cause mortality, Outcome 9 Comparing antiarrhythmic drugs.

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Analysis 1.10

Comparison 1 All‐cause mortality, Outcome 10 Subgroup analysis: Persistent atrial fibrillation.

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Analysis 1.11

Comparison 1 All‐cause mortality, Outcome 11 Sensitivity analysis: Best quality studies.

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Analysis 1.12

Comparison 1 All‐cause mortality, Outcome 12 Sensitivity analysis: Studies > 200 patients.

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Analysis 2.1

Comparison 2 Withdrawals due to adverse effects, Outcome 1 Individual antiarrhythmics.

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Analysis 2.2

Comparison 2 Withdrawals due to adverse effects, Outcome 2 Quinidine: older and recent studies.

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Analysis 2.3

Comparison 2 Withdrawals due to adverse effects, Outcome 3 Class I antiarrhythmics.

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Analysis 2.4

Comparison 2 Withdrawals due to adverse effects, Outcome 4 Sotalol: heterogeneity study.

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Analysis 2.5

Comparison 2 Withdrawals due to adverse effects, Outcome 5 Class III antiarrhythmics.

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Analysis 2.6

Comparison 2 Withdrawals due to adverse effects, Outcome 6 Comparing antiarrhythmic drugs.

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Analysis 2.7

Comparison 2 Withdrawals due to adverse effects, Outcome 7 Subgroup analysis: Persistent atrial fibrillation.

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Analysis 2.8

Comparison 2 Withdrawals due to adverse effects, Outcome 8 Sensitivity analysis: Best quality studies.

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Analysis 2.9

Comparison 2 Withdrawals due to adverse effects, Outcome 9 Sensitivity analysis: Studies > 200 patients.

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Analysis 3.1

Comparison 3 Pro‐arrhythmia, Outcome 1 Individual antiarrhythmics.

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Analysis 3.2

Comparison 3 Pro‐arrhythmia, Outcome 2 Quinidine: older and recent studies.

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Analysis 3.3

Comparison 3 Pro‐arrhythmia, Outcome 3 Class I antiarrhythmics.

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Analysis 3.4

Comparison 3 Pro‐arrhythmia, Outcome 4 Sotalol: heterogeneity study.

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Analysis 3.5

Comparison 3 Pro‐arrhythmia, Outcome 5 Class III antiarrhythmics.

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Analysis 3.6

Comparison 3 Pro‐arrhythmia, Outcome 6 Comparing antiarrhythmic drugs.

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Analysis 3.7

Comparison 3 Pro‐arrhythmia, Outcome 7 Subgroup analysis: Persistent atrial fibrillation.

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Analysis 3.8

Comparison 3 Pro‐arrhythmia, Outcome 8 Sensitivity analysis: Best quality studies.

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Analysis 3.9

Comparison 3 Pro‐arrhythmia, Outcome 9 Sensitivity analysis: Studies > 200 patients.

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Analysis 4.1

Comparison 4 Atrial fibrillation recurrence, Outcome 1 Individual antiarrhythmics.

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Analysis 4.2

Comparison 4 Atrial fibrillation recurrence, Outcome 2 Quinidine: old and recent studies.

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Analysis 4.3

Comparison 4 Atrial fibrillation recurrence, Outcome 3 Class I antiarrhythmics.

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Analysis 4.4

Comparison 4 Atrial fibrillation recurrence, Outcome 4 Class III antiarrhythmics.

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Analysis 4.5

Comparison 4 Atrial fibrillation recurrence, Outcome 5 Comparing antiarrhythmic drugs.

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Analysis 4.6

Comparison 4 Atrial fibrillation recurrence, Outcome 6 Subgroup analysis: Persistent atrial fibrillation.

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Analysis 4.7

Comparison 4 Atrial fibrillation recurrence, Outcome 7 Sensitivity analysis: Best quality studies.

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Analysis 4.8

Comparison 4 Atrial fibrillation recurrence, Outcome 8 Sensitivity analysis: Studies > 200 patients.

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Comparison 1. All‐cause mortality

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Individual antiarrhythmics Show forest plot	39	19057	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.09 [0.91, 1.30]

1.1 Class Ia: Quinidine	7	1676	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.26 [0.93, 5.45]
1.2 Class Ia: Disopyramide	2	146	Peto Odds Ratio (Peto, Fixed, 95% CI)	7.56 [0.47, 122.66]
1.3 Class Ic: Flecainide	3	149	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.4 Class Ic: Propafenone	5	1098	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.05 [0.00, 1.02]
1.5 Class I others: aprindine, bidisomide, pilsicainide	3	1383	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.94 [0.62, 6.02]
1.6 Class II: Beta‐blockers	2	562	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.75 [0.39, 19.56]
1.7 Class III: Amiodarone	4	673	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.96 [0.68, 5.67]
1.8 Class III: Azimilide	5	3114	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.18 [0.98, 4.89]
1.9 Class III: Dofetilide	3	1183	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.98 [0.68, 1.41]
1.10 Class III: Dronedarone	3	6071	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.85 [0.67, 1.09]
1.11 Class III: Sotalol	12	3002	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.47 [1.21, 5.05]
2 Individual antiarrhythmics ‐ ITT Worst case: missing patients counted as events Show forest plot	39	19226	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.16 [0.99, 1.36]

2.1 Class Ia: Quinidine	7	1676	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.29 [1.05, 5.01]
2.2 Class Ia: Disopyramide	2	146	Peto Odds Ratio (Peto, Fixed, 95% CI)	7.18 [1.21, 42.55]
2.3 Class Ic: Flecainide	4	318	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.4 Class Ic: Propafenone	5	1098	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.27 [0.48, 3.37]
2.5 Class I others: aprindine, bidisomide, pilsicainide	3	1383	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.94 [0.62, 6.02]
2.6 Class II: Beta‐blockers	2	562	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.75 [0.39, 1.47]
2.7 Class III: Amiodarone	4	673	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.49 [0.69, 3.20]
2.8 Class III: Azimilide	5	3114	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.74 [0.99, 3.06]
2.9 Class III: Dofetilide	3	1183	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.02 [0.72, 1.45]
2.10 Class III: Dronedarone	3	6071	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.84 [0.66, 1.08]
2.11 Class III: Sotalol	12	3002	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.14 [1.40, 3.25]
3 Quinidine: older and recent studies Show forest plot	7	1676	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.26 [0.93, 5.45]

3.1 Older studies, higher dose	5	442	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.17 [0.99, 10.14]
3.2 More recent studies, lower dose	2	1234	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.42 [0.37, 5.51]
4 Quinidine: older and recent studies ‐ ITT Worst case: missing patients counted as events Show forest plot	7	1676	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.29 [1.05, 5.01]

4.1 Older studies, higher dose	5	442	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.91 [1.12, 7.56]
4.2 More recent studies, lower dose	2	1234	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.42 [0.37, 5.51]
5 Class I antiarrhythmics Show forest plot	18	4427	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.84 [0.95, 3.57]

5.1 Class Ia	8	1797	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.39 [1.03, 5.59]
5.2 Class Ib	2	1321	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.89 [0.59, 6.03]
5.3 Class Ic	9	1309	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.14 [0.01, 1.88]
6 Class I antiarrhythmics ‐ ITT Worst case: missing patients counted as events Show forest plot	18	4427	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.94 [1.15, 3.25]

6.1 Class Ia	8	1797	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.45 [1.18, 5.08]
6.2 Class Ib	2	1321	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.89 [0.59, 6.03]
6.3 Class Ic	9	1309	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.31 [0.50, 3.42]
7 Class III antiarrhythmics Show forest plot	24	14043	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.03 [0.85, 1.24]

7.1 Amiodarone	4	673	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.96 [0.68, 5.67]
7.2 Azimilide	5	3114	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.18 [0.98, 4.89]
7.3 Dofetilide	3	1183	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.98 [0.68, 1.41]
7.4 Dronedarone	3	6071	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.85 [0.67, 1.09]
7.5 Sotalol	12	3002	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.47 [1.21, 5.05]
8 Class III antiarrhythmics ‐ ITT Worst case: missing patients counted as events Show forest plot	24	14043	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.13 [0.95, 1.33]

8.1 Amiodarone	4	673	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.49 [0.69, 3.20]
8.2 Azimilide	5	3114	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.74 [0.99, 3.06]
8.3 Dofetilide	3	1183	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.02 [0.72, 1.45]
8.4 Dronedarone	3	6071	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.86 [0.67, 1.09]
8.5 Sotalol	12	3002	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.27 [1.45, 3.56]
9 Comparing antiarrhythmic drugs Show forest plot	28		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

9.1 Disopyramide vs other Class I drugs	2	113	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.46 [0.05, 4.52]
9.2 Quinidine vs Flecainide	2	269	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.3 Quinidine vs other Class I drugs	4	526	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.04 [0.14, 7.46]
9.4 Quinidine vs Sotalol	6	1978	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.71 [0.34, 1.46]
9.5 Flecainide vs Propafenone	2	297	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.14 [0.00, 6.96]
9.6 Amiodarone vs Class I drugs	5	643	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.59 [0.31, 1.11]
9.7 Amiodarone vs Dronedarone	1	504	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.32 [0.52, 10.32]
9.8 Amiodarone vs Sotalol	5	1113	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.77 [0.47, 1.25]
9.9 Sotalol vs Class I drugs other than quinidine	4	494	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.94 [0.44, 1.99]
9.10 Sotalol vs Dofetilide	1	429	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.26 [0.00, 24.03]
9.11 Sotalol vs Other Beta‐blockers	2	263	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.12 Class III vs Class I drugs	13	2875	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.79 [0.49, 1.26]
10 Subgroup analysis: Persistent atrial fibrillation Show forest plot	20		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

10.1 Class Ia: Quinidine	5	877	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.11 [0.84, 5.32]
10.2 All class Ia antiarrhythmics	6	998	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.27 [0.94, 5.49]
10.3 All class I antiarrhythmics	8	1133	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.29 [0.96, 5.48]
10.4 Class II antiarrhythmics	2	562	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.75 [0.39, 19.56]
10.5 Class III: Sotalol	6	1687	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.30 [1.10, 4.80]
10.6 All class III antiarrhythmics	11	3485	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.17 [0.84, 1.61]
11 Sensitivity analysis: Best quality studies Show forest plot	12		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

11.1 Class Ia: Quinidine	2	1234	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.42 [0.37, 5.51]
11.2 All class I antiarrhythmics	5	1503	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.99 [0.27, 3.63]
11.3 Class II antiarrhythmics	2	562	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.75 [0.39, 19.56]
11.4 Class III: Sotalol	4	1686	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.78 [1.00, 7.69]
11.5 Class III: Azimilide	1	447	Peto Odds Ratio (Peto, Fixed, 95% CI)	7.52 [1.05, 53.77]
11.6 All class III antiarrhythmics	7	6919	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.92 [0.75, 1.13]
12 Sensitivity analysis: Studies > 200 patients Show forest plot	17		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

12.1 Class Ia: Quinidine	2	1234	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.42 [0.37, 5.51]
12.2 All class I antiarrhythmics	4	2984	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.68 [0.69, 4.05]
12.3 Class II antiarrhythmics	1	394	Peto Odds Ratio (Peto, Fixed, 95% CI)	7.47 [0.77, 72.18]
12.4 Class III: Sotalol	7	2543	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.97 [1.03, 3.75]
12.5 Class III: Azimilide	4	2704	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.06 [0.85, 4.99]
12.6 All class III antiarrhythmics	14	12294	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.99 [0.82, 1.20]

Comparison 1. All‐cause mortality

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Comparison 2. Withdrawals due to adverse effects

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Individual antiarrhythmics Show forest plot	36	16532	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.69 [1.51, 1.88]

1.1 Class Ia: Quinidine	7	1676	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.13 [0.86, 1.49]
1.2 Class Ia: Disopyramide	2	146	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.85 [1.13, 13.18]
1.3 Class Ic: Flecainide	3	149	Peto Odds Ratio (Peto, Fixed, 95% CI)	9.14 [1.94, 42.94]
1.4 Class Ic: Propafenone	5	1098	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.69 [1.09, 2.62]
1.5 Class I others: aprindine, pilsicainide	2	156	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.89 [0.18, 4.48]
1.6 Class II: Beta‐blockers	2	562	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.38 [1.57, 7.25]
1.7 Class III: Amiodarone	3	274	Peto Odds Ratio (Peto, Fixed, 95% CI)	5.55 [2.24, 13.72]
1.8 Class III: Azimilide	5	3114	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.35 [1.72, 3.20]
1.9 Class III: Dofetilide	2	677	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.68 [0.79, 3.59]
1.10 Class III: Dronedarone	3	6071	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.64 [1.38, 1.94]
1.11 Class III: Sotalol	11	2609	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.61 [1.25, 2.06]
2 Quinidine: older and recent studies Show forest plot	7	1676	Odds Ratio (M‐H, Random, 95% CI)	1.90 [0.90, 4.02]

2.1 Older studies, higher dose	5	442	Odds Ratio (M‐H, Random, 95% CI)	3.62 [1.71, 7.65]
2.2 More recent studies, lower dose	2	1234	Odds Ratio (M‐H, Random, 95% CI)	0.84 [0.52, 1.36]
3 Class I antiarrhythmics Show forest plot	17	3200	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.34 [1.07, 1.68]

3.1 Class Ia	8	1797	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.18 [0.90, 1.54]
3.2 Class Ib	1	94	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.66 [0.11, 3.95]
3.3 Class Ic	9	1309	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.93 [1.27, 2.93]
4 Sotalol: heterogeneity study Show forest plot	11	2609	Odds Ratio (M‐H, Random, 95% CI)	2.25 [1.28, 3.94]

4.1 PAFAC and SOPAT trials	2	986	Odds Ratio (M‐H, Random, 95% CI)	0.95 [0.68, 1.33]
4.2 Rest of studies	9	1623	Odds Ratio (M‐H, Random, 95% CI)	3.31 [2.08, 5.25]
5 Class III antiarrhythmics Show forest plot	22	12745	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.77 [1.56, 2.00]

5.1 Amiodarone	3	274	Peto Odds Ratio (Peto, Fixed, 95% CI)	5.55 [2.24, 13.72]
5.2 Azimilide	5	3114	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.35 [1.72, 3.20]
5.3 Dofetilide	2	677	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.68 [0.79, 3.59]
5.4 Dronedarone	3	6071	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.64 [1.38, 1.94]
5.5 Sotalol	11	2609	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.61 [1.25, 2.06]
6 Comparing antiarrhythmic drugs Show forest plot	27		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

6.1 Disopyramide vs other Class I drugs	2	113	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.37 [0.14, 1.03]
6.2 Quinidine vs Flecainide	2	269	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.04 [1.14, 3.64]
6.3 Quinidine vs other Class I drugs	4	526	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.25 [1.45, 3.51]
6.4 Quinidine vs Sotalol	6	1978	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.12 [0.89, 1.40]
6.5 Flecainide vs Propafenone	2	297	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.68 [0.32, 1.43]
6.6 Amiodarone vs Class I drugs	5	652	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.55 [0.36, 0.84]
6.7 Amiodarone vs Dronedarone	1	504	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.45 [0.89, 2.35]
6.8 Amiodarone vs Sotalol	4	618	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.19 [0.73, 1.95]
6.9 Sotalol vs Class I drugs other than quinidine	4	567	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.45 [0.28, 0.72]
6.10 Sotalol vs Dofetilide	1	429	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.67 [1.24, 5.76]
6.11 Sotalol vs Other Beta‐blockers	2	263	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.86 [1.15, 7.11]
6.12 Class III vs Class I drugs	13	2975	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.79 [0.65, 0.96]
7 Subgroup analysis: Persistent atrial fibrillation Show forest plot	18		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

7.1 Class Ia: Quinidine	5	877	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.87 [1.26, 2.79]
7.2 All class I antiarrhythmics	8	1133	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.13 [1.48, 3.08]
7.3 Class II antiarrhythmics	2	562	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.38 [1.57, 7.25]
7.4 Class III: Sotalol	5	1294	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.86 [1.30, 2.66]
7.5 All class III antiarrhythmics	9	2319	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.03 [1.50, 2.75]
8 Sensitivity analysis: Best quality studies Show forest plot	11		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

8.1 Class Ia: Quinidine	2	1234	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.81 [0.59, 1.10]
8.2 All class I antiarrhythmics	5	1503	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.94 [0.70, 1.26]
8.3 Class II antiarrhythmics	2	562	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.38 [1.57, 7.25]
8.4 Class III: Sotalol	4	1686	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.33 [1.00, 1.75]
8.5 All class III antiarrhythmics	6	6413	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.55 [1.33, 1.81]
9 Sensitivity analysis: Studies > 200 patients Show forest plot	14		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

9.1 Class Ia: Quinidine	2	1234	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.81 [0.59, 1.10]
9.2 All class I antiarrhythmics	3	1757	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.91 [0.70, 1.20]
9.3 Class II antiarrhythmics	1	394	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.16 [1.43, 6.99]
9.4 Class III: Sotalol	5	1900	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.44 [1.11, 1.89]
9.5 All class III antiarrhythmics	12	11128	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.64 [1.44, 1.87]

Comparison 2. Withdrawals due to adverse effects

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Comparison 3. Pro‐arrhythmia

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Individual antiarrhythmics Show forest plot	37	17695	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.23 [2.68, 3.90]

1.1 Class Ia: Quinidine	7	1676	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.10 [1.02, 4.33]
1.2 Class Ia: Disopyramide	2	146	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.3 Class Ic: Flecainide	3	149	Peto Odds Ratio (Peto, Fixed, 95% CI)	5.97 [1.67, 21.34]
1.4 Class Ic: Propafenone	5	1098	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.52 [0.33, 7.02]
1.5 Class I others: aprindine, pilsicainide	2	156	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.6 Class II: Beta‐blockers	2	562	Peto Odds Ratio (Peto, Fixed, 95% CI)	7.92 [3.01, 20.82]
1.7 Class III: Amiodarone	4	673	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.65 [0.88, 8.00]
1.8 Class III: Azimilide	5	3114	Peto Odds Ratio (Peto, Fixed, 95% CI)	5.82 [3.69, 9.19]
1.9 Class III: Dofetilide	3	1183	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.79 [1.54, 9.33]
1.10 Class III: Dronedarone	3	6071	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.48 [1.85, 3.32]
1.11 Class III: Sotalol	11	2867	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.26 [2.13, 4.98]
2 Quinidine: older and recent studies Show forest plot	7	1676	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.10 [1.02, 4.33]

2.1 Older studies, higher dose	5	442	Peto Odds Ratio (Peto, Fixed, 95% CI)	4.56 [1.20, 17.33]
2.2 More recent studies, lower dose	2	1234	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.52 [0.64, 3.60]
3 Class I antiarrhythmics Show forest plot	17	3200	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.46 [1.38, 4.41]

3.1 Class Ia	8	1797	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.06 [1.00, 4.26]
3.2 Class Ib	1	94	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.3 Class Ic	9	1309	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.41 [1.28, 9.09]
4 Sotalol: heterogeneity study Show forest plot	11	2867	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.26 [2.13, 4.98]

4.1 PAFAC and SOPAT trials	2	986	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.42 [0.56, 3.60]
4.2 Rest of studies	9	1881	Peto Odds Ratio (Peto, Fixed, 95% CI)	4.05 [2.52, 6.51]
5 Class III antiarrhythmics Show forest plot	23	13908	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.21 [2.62, 3.93]

5.1 Amiodarone	4	673	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.65 [0.88, 8.00]
5.2 Azimilide	5	3114	Peto Odds Ratio (Peto, Fixed, 95% CI)	5.82 [3.69, 9.19]
5.3 Dofetilide	3	1183	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.79 [1.54, 9.33]
5.4 Dronedarone	3	6071	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.48 [1.85, 3.32]
5.5 Sotalol	11	2867	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.26 [2.13, 4.98]
6 Comparing antiarrhythmic drugs Show forest plot	24		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

6.1 Disopyramide vs other Class I drugs	2	113	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.43 [0.04, 4.25]
6.2 Quinidine vs Flecainide	2	269	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.60 [0.64, 3.96]
6.3 Quinidine vs other Class I drugs	4	526	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.59 [0.71, 3.56]
6.4 Quinidine vs Sotalol	6	1978	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.00 [0.60, 1.68]
6.5 Flecainide vs Propafenone	2	297	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.43 [0.10, 1.93]
6.6 Amiodarone vs Class I drugs	3	475	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.28 [0.13, 0.59]
6.7 Amiodarone vs Dronedarone	1	504	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.91 [0.38, 9.56]
6.8 Amiodarone vs Sotalol	3	943	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.60 [0.30, 1.20]
6.9 Sotalol vs Class I drugs other than quinidine	4	567	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.77 [0.44, 1.34]
6.10 Sotalol vs Dofetilide	1	429	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.85 [0.19, 3.90]
6.11 Sotalol vs Other Beta‐blockers	1	128	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.35 [0.30, 6.16]
6.12 Class III vs Class I drugs	12	2899	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.78 [0.54, 1.13]
7 Subgroup analysis: Persistent atrial fibrillation Show forest plot	20		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

7.1 Class Ia: Quinidine	5	877	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.79 [1.08, 7.21]
7.2 All class I antiarrhythmics	8	1133	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.48 [1.50, 8.08]
7.3 Class II antiarrhythmics	2	562	Peto Odds Ratio (Peto, Fixed, 95% CI)	7.92 [3.01, 20.82]
7.4 Class III: Sotalol	6	1687	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.61 [2.17, 6.02]
7.5 All class III antiarrhythmics	11	3485	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.59 [2.33, 5.53]
8 Sensitivity analysis: Best quality studies Show forest plot	12		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

8.1 Class Ia: Quinidine	2	1234	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.52 [0.64, 3.60]
8.2 All class I antiarrhythmics	5	1503	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.08 [1.07, 4.02]
8.3 Class II antiarrhythmics	2	562	Peto Odds Ratio (Peto, Fixed, 95% CI)	7.92 [3.01, 20.82]
8.4 Class III: Sotalol	4	1686	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.78 [1.71, 4.53]
8.5 All class III antiarrhythmics	7	6919	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.85 [2.20, 3.70]
9 Sensitivity analysis: Studies > 200 patients Show forest plot	16		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

9.1 Class Ia: Quinidine	2	1234	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.52 [0.64, 3.60]
9.2 All class I antiarrhythmics	3	1757	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.52 [0.64, 3.60]
9.3 Class II antiarrhythmics	1	394	Peto Odds Ratio (Peto, Fixed, 95% CI)	7.96 [2.84, 22.30]
9.4 Class III: Sotalol	6	2293	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.74 [1.75, 4.30]
9.5 All class III antiarrhythmics	14	12294	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.85 [2.30, 3.55]

Comparison 3. Pro‐arrhythmia

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Comparison 4. Atrial fibrillation recurrence

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Individual antiarrhythmics Show forest plot	37	12865	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.48 [0.45, 0.53]

1.1 Class Ia: Quinidine	7	1624	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.51 [0.40, 0.65]
1.2 Class Ia: Disopyramide	2	146	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.52 [0.27, 1.01]
1.3 Class Ic: Flecainide	3	149	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.31 [0.16, 0.60]
1.4 Class Ic: Propafenone	5	1098	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.37 [0.28, 0.48]
1.5 Class I others: aprindine, bidisomide, pilsicainide	3	1383	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.80 [0.60, 1.07]
1.6 Class II: Beta‐blockers	2	562	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.62 [0.44, 0.88]
1.7 Class III: Amiodarone	4	673	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.19 [0.14, 0.27]
1.8 Class III: Azimilide	4	1602	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.70 [0.55, 0.90]
1.9 Class III: Dofetilide	3	1183	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.30 [0.23, 0.39]
1.10 Class III: Dronedarone	2	1443	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.59 [0.46, 0.75]
1.11 Class III: Sotalol	12	3002	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.51 [0.43, 0.60]
2 Quinidine: old and recent studies Show forest plot	7	1624	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.51 [0.40, 0.65]

2.1 Older studies, higher dose	5	390	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.42 [0.27, 0.65]
2.2 More recent studies, lower dose	2	1234	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.55 [0.41, 0.73]
3 Class I antiarrhythmics Show forest plot	18	4375	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.51 [0.44, 0.58]

3.1 Class Ia	8	1745	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.51 [0.40, 0.64]
3.2 Class Ib	2	1321	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.84 [0.63, 1.13]
3.3 Class Ic	9	1309	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.36 [0.28, 0.45]
4 Class III antiarrhythmics Show forest plot	22	7903	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.46 [0.42, 0.51]

4.1 Amiodarone	4	673	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.19 [0.14, 0.27]
4.2 Azimilide	4	1602	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.70 [0.55, 0.90]
4.3 Dofetilide	3	1183	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.30 [0.23, 0.39]
4.4 Dronedarone	2	1443	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.59 [0.46, 0.75]
4.5 Sotalol	12	3002	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.51 [0.43, 0.60]
5 Comparing antiarrhythmic drugs Show forest plot	28		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

5.1 Disopyramide vs other Class I drugs	2	113	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.76 [0.36, 1.60]
5.2 Quinidine vs Flecainide	2	269	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.38 [0.79, 2.41]
5.3 Quinidine vs other Class I drugs	4	526	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.30 [0.90, 1.87]
5.4 Quinidine vs Sotalol	6	1978	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.92 [0.76, 1.11]
5.5 Flecainide vs Propafenone	2	297	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.87 [0.54, 1.40]
5.6 Amiodarone vs Class I drugs	5	643	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.36 [0.26, 0.50]
5.7 Amiodarone vs Dronedarone	1	504	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.45 [0.31, 0.63]
5.8 Amiodarone vs Sotalol	5	1113	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.43 [0.34, 0.54]
5.9 Sotalol vs Class I drugs other than quinidine	4	494	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.98 [0.67, 1.45]
5.10 Sotalol vs Dofetilide	1	429	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.38 [0.88, 2.16]
5.11 Sotalol vs Other Beta‐blockers	2	263	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.10 [0.64, 1.90]
5.12 Class III vs Class I drugs	13	2875	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.89 [0.76, 1.04]
6 Subgroup analysis: Persistent atrial fibrillation Show forest plot	20		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

6.1 Class Ia: Quinidine	5	825	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.43 [0.31, 0.60]
6.2 All class I antiarrhythmics	8	1081	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.44 [0.33, 0.59]
6.3 Class II antiarrhythmics	2	562	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.62 [0.44, 0.88]
6.4 Class III: Sotalol	6	1687	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.46 [0.37, 0.58]
6.5 All class III antiarrhythmics	11	3485	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.35 [0.30, 0.41]
7 Sensitivity analysis: Best quality studies Show forest plot	11		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

7.1 Class Ia: Quinidine	2	1234	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.55 [0.41, 0.73]
7.2 All class I antiarrhythmics	5	1503	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.56 [0.44, 0.72]
7.3 Class II antiarrhythmics	2	562	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.62 [0.44, 0.88]
7.4 Class III: Sotalol	4	1686	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.55 [0.43, 0.70]
7.5 All class III antiarrhythmics	6	2291	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.39 [0.32, 0.48]
8 Sensitivity analysis: Studies > 200 patients Show forest plot	15		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

8.1 Class Ia: Quinidine	2	1234	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.55 [0.41, 0.73]
8.2 All class I antiarrhythmics	4	2984	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.59 [0.49, 0.72]
8.3 Class II antiarrhythmics	1	394	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.74 [0.49, 1.13]
8.4 Class III: Sotalol	6	2293	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.51 [0.42, 0.62]
8.5 All class III antiarrhythmics	12	6154	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.49 [0.43, 0.55]

Comparison 4. Atrial fibrillation recurrence

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