Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation

Lucie Valembois; Etienne Audureau; Andrea Takeda; Witold Jarzebowski; Joël Belmin; Carmelo Lafuente‐Lafuente

doi:10.1002/14651858.CD005049.pub5

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Figure 1

Selection of studies for inclusion. AF: atrial fibrillation.

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Figure 2

Funnel plot of comparison: 9 Sotalol versus placebo/no treatment, outcome: 9.6 Withdrawals due to adverse effects – main analysis.

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Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 4

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 5

All‐cause mortality with sotalol compared with placebo/no treatment: main analysis.

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Analysis 1.1

Comparison 1 Quinidine versus placebo or no treatment, Outcome 1 All‐cause mortality – main analysis.

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Analysis 1.2

Comparison 1 Quinidine versus placebo or no treatment, Outcome 2 All‐cause mortality – sensitivity analysis intention to treat (ITT) worse case: missing participants counted as events.

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Analysis 1.3

Comparison 1 Quinidine versus placebo or no treatment, Outcome 3 All‐cause mortality – subgroup analysis: older and recent studies.

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Analysis 1.4

Comparison 1 Quinidine versus placebo or no treatment, Outcome 4 All‐cause mortality – sensitivity analysis: persistent atrial fibrillation.

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Analysis 1.5

Comparison 1 Quinidine versus placebo or no treatment, Outcome 5 All‐cause mortality – sensitivity analysis: low risk of bias studies.

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Analysis 1.6

Comparison 1 Quinidine versus placebo or no treatment, Outcome 6 All‐cause mortality – sensitivity analysis: studies > 200 participants.

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Analysis 1.7

Comparison 1 Quinidine versus placebo or no treatment, Outcome 7 Withdrawals due to adverse effects – main analysis.

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Analysis 1.8

Comparison 1 Quinidine versus placebo or no treatment, Outcome 8 Withdrawals due to adverse effects – subgroup analysis: older and recent studies.

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Analysis 1.9

Comparison 1 Quinidine versus placebo or no treatment, Outcome 9 Withdrawals due to adverse effects – sensitivity analysis: persistent atrial fibrillation.

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Analysis 1.10

Comparison 1 Quinidine versus placebo or no treatment, Outcome 10 Withdrawals due to adverse effects – sensitivity analysis: low risk of bias studies.

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Analysis 1.11

Comparison 1 Quinidine versus placebo or no treatment, Outcome 11 Withdrawals due to adverse effects – sensitivity analysis: studies > 200 participants.

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Analysis 1.12

Comparison 1 Quinidine versus placebo or no treatment, Outcome 12 Proarrhythmia – main analysis.

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Analysis 1.13

Comparison 1 Quinidine versus placebo or no treatment, Outcome 13 Proarrhythmia – subgroup analysis: older and recent studies.

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Analysis 1.14

Comparison 1 Quinidine versus placebo or no treatment, Outcome 14 Proarrhythmia – sensitivity analysis: persistent atrial fibrillation.

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Analysis 1.15

Comparison 1 Quinidine versus placebo or no treatment, Outcome 15 Proarrhythmia – sensitivity analysis: low risk of bias studies.

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Analysis 1.16

Comparison 1 Quinidine versus placebo or no treatment, Outcome 16 Proarrhythmia – sensitivity analysis: studies > 200 participants.

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Analysis 1.17

Comparison 1 Quinidine versus placebo or no treatment, Outcome 17 Stroke – main analysis.

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Analysis 1.18

Comparison 1 Quinidine versus placebo or no treatment, Outcome 18 Stroke – sensitivity analysis: persistent atrial fibrillation.

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Analysis 1.19

Comparison 1 Quinidine versus placebo or no treatment, Outcome 19 Stroke – sensitivity analysis: low risk of bias studies.

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Analysis 1.20

Comparison 1 Quinidine versus placebo or no treatment, Outcome 20 Stroke – sensitivity analysis: studies > 200 participants.

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Analysis 1.21

Comparison 1 Quinidine versus placebo or no treatment, Outcome 21 Atrial fibrillation recurrence – main analysis.

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Analysis 1.22

Comparison 1 Quinidine versus placebo or no treatment, Outcome 22 Atrial fibrillation recurrence – sensitivity analysis: persistent atrial fibrillation.

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Analysis 1.23

Comparison 1 Quinidine versus placebo or no treatment, Outcome 23 Atrial fibrillation recurrence – sensitivity analysis: low risk of bias studies.

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Analysis 1.24

Comparison 1 Quinidine versus placebo or no treatment, Outcome 24 Atrial fibrillation recurrence – sensitivity analysis: studies > 200 participants.

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Analysis 2.1

Comparison 2 Disopyramide versus placebo or no treatment, Outcome 1 All‐cause mortality – main analysis.

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Analysis 2.2

Comparison 2 Disopyramide versus placebo or no treatment, Outcome 2 All‐cause mortality – intention to treat (ITT) worse case: missing participants counted as events.

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Analysis 2.3

Comparison 2 Disopyramide versus placebo or no treatment, Outcome 3 Withdrawals due to adverse effects – main analysis.

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Analysis 2.4

Comparison 2 Disopyramide versus placebo or no treatment, Outcome 4 Withdrawals due to adverse effects – sensitivity analysis: persistent atrial fibrillation.

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Analysis 2.5

Comparison 2 Disopyramide versus placebo or no treatment, Outcome 5 Stroke – main analysis.

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Analysis 2.6

Comparison 2 Disopyramide versus placebo or no treatment, Outcome 6 Stroke – subgroup analysis: persistent atrial fibrillation.

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Analysis 2.7

Comparison 2 Disopyramide versus placebo or no treatment, Outcome 7 Atrial fibrillation recurrence – main analysis.

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Analysis 2.8

Comparison 2 Disopyramide versus placebo or no treatment, Outcome 8 Atrial fibrillation recurrence – sensitivity analysis: persistent atrial fibrillation.

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Analysis 3.1

Comparison 3 Propafenone versus placebo or no treatment, Outcome 1 All‐cause mortality – main analysis.

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Analysis 3.2

Comparison 3 Propafenone versus placebo or no treatment, Outcome 2 All‐cause mortality – intention to treat (ITT) worse case: missing participants counted as events.

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Analysis 3.3

Comparison 3 Propafenone versus placebo or no treatment, Outcome 3 All‐cause mortality – sensitivity analysis: low risk of bias studies.

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Analysis 3.4

Comparison 3 Propafenone versus placebo or no treatment, Outcome 4 Withdrawals due to adverse effects – main analysis.

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Analysis 3.5

Comparison 3 Propafenone versus placebo or no treatment, Outcome 5 Withdrawals due to adverse effects – sensitivity analysis: studies > 200 participants.

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Analysis 3.6

Comparison 3 Propafenone versus placebo or no treatment, Outcome 6 Proarrhythmia – main analysis.

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Analysis 3.7

Comparison 3 Propafenone versus placebo or no treatment, Outcome 7 Proarrhythmia – sensitivity analysis: low risk of bias studies.

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Analysis 3.8

Comparison 3 Propafenone versus placebo or no treatment, Outcome 8 Atrial fibrillation recurrence – main analysis.

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Analysis 3.9

Comparison 3 Propafenone versus placebo or no treatment, Outcome 9 Atrial fibrillation recurrence – sensitivity analysis: low risk of bias studies.

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Analysis 3.10

Comparison 3 Propafenone versus placebo or no treatment, Outcome 10 Atrial fibrillation recurrence – sensitivity analysis: studies > 200 participants.

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Analysis 4.1

Comparison 4 Flecainide versus placebo or no treatment, Outcome 1 Withdrawals due to adverse effects – main analysis.

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Analysis 4.2

Comparison 4 Flecainide versus placebo or no treatment, Outcome 2 Proarrhythmia – main analysis.

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Analysis 4.3

Comparison 4 Flecainide versus placebo or no treatment, Outcome 3 Proarrhythmia – sensitivity analysis: persistent atrial fibrillation.

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Analysis 4.4

Comparison 4 Flecainide versus placebo or no treatment, Outcome 4 Proarrhythmia – sensitivity analysis: low risk of bias studies.

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Analysis 4.5

Comparison 4 Flecainide versus placebo or no treatment, Outcome 5 Proarrhythmia – sensitivity analysis: studies > 200 participants.

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Analysis 4.6

Comparison 4 Flecainide versus placebo or no treatment, Outcome 6 Stroke – main analysis.

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Analysis 4.7

Comparison 4 Flecainide versus placebo or no treatment, Outcome 7 Stroke – subgroup analysis: persistent atrial fibrillation.

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Analysis 4.8

Comparison 4 Flecainide versus placebo or no treatment, Outcome 8 Stroke – sensitivity analysis: low risk of bias studies.

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Analysis 4.9

Comparison 4 Flecainide versus placebo or no treatment, Outcome 9 Stroke – sensitivity analysis: studies > 200 participants.

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Analysis 4.10

Comparison 4 Flecainide versus placebo or no treatment, Outcome 10 Atrial fibrillation recurrence – main analysis.

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Analysis 4.11

Comparison 4 Flecainide versus placebo or no treatment, Outcome 11 Atrial fibrillation recurrence – sensitivity analysis: persistent atrial fibrillation.

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Analysis 4.12

Comparison 4 Flecainide versus placebo or no treatment, Outcome 12 Atrial fibrillation recurrence – sensitivity analysis: low risk of bias studies.

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Analysis 4.13

Comparison 4 Flecainide versus placebo or no treatment, Outcome 13 Atrial fibrillation recurrence – sensitivity analysis: studies > 200 participants.

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Analysis 5.1

Comparison 5 Metoprolol versus placebo or no treatment, Outcome 1 All‐cause mortality – main analysis.

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Analysis 5.2

Comparison 5 Metoprolol versus placebo or no treatment, Outcome 2 All‐cause mortality – intention to treat (ITT) worse case: missing participants counted as events.

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Analysis 5.3

Comparison 5 Metoprolol versus placebo or no treatment, Outcome 3 All‐cause mortality – sensitivity analysis: persistent atrial fibrillation.

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Analysis 5.4

Comparison 5 Metoprolol versus placebo or no treatment, Outcome 4 All‐cause mortality – sensitivity analysis: low risk of bias studies.

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Analysis 5.5

Comparison 5 Metoprolol versus placebo or no treatment, Outcome 5 All‐cause mortality – sensitivity analysis: studies > 200 participants.

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Analysis 5.6

Comparison 5 Metoprolol versus placebo or no treatment, Outcome 6 Withdrawals due to adverse effects – main analysis.

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Analysis 5.7

Comparison 5 Metoprolol versus placebo or no treatment, Outcome 7 Withdrawals due to adverse effects – sensitivity analysis: persistent atrial fibrillation.

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Analysis 5.8

Comparison 5 Metoprolol versus placebo or no treatment, Outcome 8 Withdrawals due to adverse effects – sensitivity analysis: low risk of bias studies.

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Analysis 5.9

Comparison 5 Metoprolol versus placebo or no treatment, Outcome 9 Withdrawals due to adverse effects – sensitivity analysis: studies > 200 participants.

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Analysis 5.10

Comparison 5 Metoprolol versus placebo or no treatment, Outcome 10 Proarrhythmia – main analysis.

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Analysis 5.11

Comparison 5 Metoprolol versus placebo or no treatment, Outcome 11 Proarrhythmia – sensitivity analysis: persistent atrial fibrillation.

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Analysis 5.12

Comparison 5 Metoprolol versus placebo or no treatment, Outcome 12 Proarrhythmia – sensitivity analysis: low risk of bias studies.

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Analysis 5.13

Comparison 5 Metoprolol versus placebo or no treatment, Outcome 13 Proarrhythmia – sensitivity analysis: studies > 200 participants.

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Analysis 5.14

Comparison 5 Metoprolol versus placebo or no treatment, Outcome 14 Atrial fibrillation recurrence – main analysis.

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Analysis 5.15

Comparison 5 Metoprolol versus placebo or no treatment, Outcome 15 Atrial fibrillation recurrence – sensitivity analysis: persistent atrial fibrillation.

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Analysis 5.16

Comparison 5 Metoprolol versus placebo or no treatment, Outcome 16 Atrial fibrillation recurrence – sensitivity analysis: low risk of bias studies.

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Analysis 5.17

Comparison 5 Metoprolol versus placebo or no treatment, Outcome 17 Atrial fibrillation recurrence – sensitivity analysis: studies > 200 participants.

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Analysis 6.1

Comparison 6 Amiodarone versus placebo or no treatment, Outcome 1 All‐cause mortality – main analysis.

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Analysis 6.2

Comparison 6 Amiodarone versus placebo or no treatment, Outcome 2 All‐cause mortality – intention to treat (ITT) worse case: missing participants counted as events.

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Analysis 6.3

Comparison 6 Amiodarone versus placebo or no treatment, Outcome 3 All‐cause mortality – sensitivity analysis: persistent atrial fibrillation.

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Analysis 6.4

Comparison 6 Amiodarone versus placebo or no treatment, Outcome 4 Withdrawals due to adverse effects – main analysis.

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Analysis 6.5

Comparison 6 Amiodarone versus placebo or no treatment, Outcome 5 Withdrawals due to adverse effects – sensitivity analysis: low risk of bias studies.

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Analysis 6.6

Comparison 6 Amiodarone versus placebo or no treatment, Outcome 6 Proarrhythmia – main analysis.

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Analysis 6.7

Comparison 6 Amiodarone versus placebo or no treatment, Outcome 7 Proarrhythmia – sensitivity analysis: persistent atrial fibrillation.

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Analysis 6.8

Comparison 6 Amiodarone versus placebo or no treatment, Outcome 8 Proarrhythmia – sensitivity analysis: low risk of bias studies.

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Analysis 6.9

Comparison 6 Amiodarone versus placebo or no treatment, Outcome 9 Proarrhythmia – sensitivity analysis: studies > 200 participants.

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Analysis 6.10

Comparison 6 Amiodarone versus placebo or no treatment, Outcome 10 Stroke – main analysis.

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Analysis 6.11

Comparison 6 Amiodarone versus placebo or no treatment, Outcome 11 Stroke – sensitivity analysis: persistent atrial fibrillation.

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Analysis 6.12

Comparison 6 Amiodarone versus placebo or no treatment, Outcome 12 Stroke – sensitivity analysis: studies > 200 participants.

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Analysis 6.13

Comparison 6 Amiodarone versus placebo or no treatment, Outcome 13 Atrial fibrillation recurrence – main analysis.

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Analysis 6.14

Comparison 6 Amiodarone versus placebo or no treatment, Outcome 14 Atrial fibrillation recurrence – sensitivity analysis: persistent atrial fibrillation.

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Analysis 6.15

Comparison 6 Amiodarone versus placebo or no treatment, Outcome 15 Atrial fibrillation recurrence – sensitivity analysis: low risk of bias studies.

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Analysis 6.16

Comparison 6 Amiodarone versus placebo or no treatment, Outcome 16 Atrial fibrillation recurrence – sensitivity analysis: studies > 200 participants.

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Analysis 7.1

Comparison 7 Dofetilide versus placebo or no treatment, Outcome 1 All‐cause mortality – main analysis.

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Analysis 7.2

Comparison 7 Dofetilide versus placebo or no treatment, Outcome 2 All‐cause mortality – intention to treat (ITT) worse case: missing participants counted as events.

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Analysis 7.3

Comparison 7 Dofetilide versus placebo or no treatment, Outcome 3 All‐cause mortality – sensitivity analysis: persistent atrial fibrillation.

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Analysis 7.4

Comparison 7 Dofetilide versus placebo or no treatment, Outcome 4 All‐cause mortality – sensitivity analysis: low risk of bias studies.

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Analysis 7.5

Comparison 7 Dofetilide versus placebo or no treatment, Outcome 5 All‐cause mortality – sensitivity analysis: studies > 200 participants.

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Analysis 7.6

Comparison 7 Dofetilide versus placebo or no treatment, Outcome 6 Withdrawals due to adverse effects – main analysis.

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Analysis 7.7

Comparison 7 Dofetilide versus placebo or no treatment, Outcome 7 Withdrawals due to adverse effects – sensitivity analysis: persistent atrial fibrillation.

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Analysis 7.8

Comparison 7 Dofetilide versus placebo or no treatment, Outcome 8 Withdrawals due to adverse effects – sensitivity analysis: studies > 200 participants.

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Analysis 7.9

Comparison 7 Dofetilide versus placebo or no treatment, Outcome 9 Proarrhythmia – main analysis.

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Analysis 7.10

Comparison 7 Dofetilide versus placebo or no treatment, Outcome 10 Proarrhythmia – sensitivity analysis: persistent atrial fibrillation.

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Analysis 7.11

Comparison 7 Dofetilide versus placebo or no treatment, Outcome 11 Proarrhythmia – sensitivity analysis: low risk of bias studies.

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Analysis 7.12

Comparison 7 Dofetilide versus placebo or no treatment, Outcome 12 Proarrhythmia – sensitivity analysis: studies > 200 participants.

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Analysis 7.13

Comparison 7 Dofetilide versus placebo or no treatment, Outcome 13 Atrial fibrillation recurrence – main analysis.

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Analysis 7.14

Comparison 7 Dofetilide versus placebo or no treatment, Outcome 14 Atrial fibrillation recurrence – sensitivity analysis: persistent atrial fibrillation.

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Analysis 7.15

Comparison 7 Dofetilide versus placebo or no treatment, Outcome 15 Atrial fibrillation recurrence – sensitivity analysis: low risk of bias studies.

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Analysis 7.16

Comparison 7 Dofetilide versus placebo or no treatment, Outcome 16 Atrial fibrillation recurrence – sensitivity analysis: studies > 200 participants.

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Analysis 8.1

Comparison 8 Dronedarone versus placebo or no treatment, Outcome 1 All‐cause mortality – main analysis.

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Analysis 8.2

Comparison 8 Dronedarone versus placebo or no treatment, Outcome 2 All‐cause mortality – intention to treat (ITT) worse case: missing participants counted as events.

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Analysis 8.3

Comparison 8 Dronedarone versus placebo or no treatment, Outcome 3 All‐cause mortality – sensitivity analysis: persistent atrial fibrillation.

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Analysis 8.4

Comparison 8 Dronedarone versus placebo or no treatment, Outcome 4 All‐cause mortality – sensitivity analysis: low risk of bias studies.

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Analysis 8.5

Comparison 8 Dronedarone versus placebo or no treatment, Outcome 5 All‐cause mortality – sensitivity analysis: studies > 200 participants.

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Analysis 8.6

Comparison 8 Dronedarone versus placebo or no treatment, Outcome 6 Withdrawals due to adverse effects – main analysis.

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Analysis 8.7

Comparison 8 Dronedarone versus placebo or no treatment, Outcome 7 Withdrawals due to adverse effects – sensitivity analysis: persistent atrial fibrillation.

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Analysis 8.8

Comparison 8 Dronedarone versus placebo or no treatment, Outcome 8 Withdrawals due to adverse effects – sensitivity analysis: low risk of bias studies.

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Analysis 8.9

Comparison 8 Dronedarone versus placebo or no treatment, Outcome 9 Withdrawals due to adverse effects – sensitivity analysis: studies > 200 participants.

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Analysis 8.10

Comparison 8 Dronedarone versus placebo or no treatment, Outcome 10 Proarrhythmia – main analysis.

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Analysis 8.11

Comparison 8 Dronedarone versus placebo or no treatment, Outcome 11 Proarrhythmia – sensitivity analysis: low risk of bias studies.

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Analysis 8.12

Comparison 8 Dronedarone versus placebo or no treatment, Outcome 12 Proarrhythmia – sensitivity analysis: studies > 200 participants.

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Analysis 8.13

Comparison 8 Dronedarone versus placebo or no treatment, Outcome 13 Stroke – main analysis.

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Analysis 8.14

Comparison 8 Dronedarone versus placebo or no treatment, Outcome 14 Stroke – sensitivity analysis: studies > 200 participants.

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Analysis 8.15

Comparison 8 Dronedarone versus placebo or no treatment, Outcome 15 Atrial fibrillation recurrence – main analysis.

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Analysis 8.16

Comparison 8 Dronedarone versus placebo or no treatment, Outcome 16 Atrial fibrillation recurrence – sensitivity analysis: persistent atrial fibrillation.

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Analysis 8.17

Comparison 8 Dronedarone versus placebo or no treatment, Outcome 17 Atrial fibrillation recurrence – sensitivity analysis: studies > 200 participants.

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Analysis 9.1

Comparison 9 Sotalol versus placebo or no treatment, Outcome 1 All‐cause mortality – main analysis.

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Analysis 9.2

Comparison 9 Sotalol versus placebo or no treatment, Outcome 2 All‐cause mortality – intention to treat (ITT) worse case: missing participants counted as events.

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Analysis 9.3

Comparison 9 Sotalol versus placebo or no treatment, Outcome 3 All‐cause mortality – sensitivity analysis: persistent atrial fibrillation.

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Analysis 9.4

Comparison 9 Sotalol versus placebo or no treatment, Outcome 4 All‐cause mortality – sensitivity analysis: low risk of bias studies.

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Analysis 9.5

Comparison 9 Sotalol versus placebo or no treatment, Outcome 5 All‐cause mortality – sensitivity analysis: studies > 200 participants.

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Analysis 9.6

Comparison 9 Sotalol versus placebo or no treatment, Outcome 6 Withdrawals due to adverse effects – main analysis.

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Analysis 9.7

Comparison 9 Sotalol versus placebo or no treatment, Outcome 7 Withdrawals due to adverse effects – sotalol: heterogeneity study.

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Analysis 9.8

Comparison 9 Sotalol versus placebo or no treatment, Outcome 8 Withdrawals due to adverse effects – sensitivity analysis: persistent atrial fibrillation.

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Analysis 9.9

Comparison 9 Sotalol versus placebo or no treatment, Outcome 9 Withdrawals due to adverse effects – sensitivity analysis: low risk of bias studies.

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Analysis 9.10

Comparison 9 Sotalol versus placebo or no treatment, Outcome 10 Withdrawals due to adverse effects – sensitivity analysis: studies > 200 participants.

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Analysis 9.11

Comparison 9 Sotalol versus placebo or no treatment, Outcome 11 Proarrhythmia – main analysis.

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Analysis 9.12

Comparison 9 Sotalol versus placebo or no treatment, Outcome 12 Proarrhythmia – sotalol: heterogeneity study.

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Analysis 9.13

Comparison 9 Sotalol versus placebo or no treatment, Outcome 13 Proarrhythmia – sensitivity analysis: persistent atrial fibrillation.

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Analysis 9.14

Comparison 9 Sotalol versus placebo or no treatment, Outcome 14 Proarrhythmia – sensitivity analysis: low risk of bias studies.

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Analysis 9.15

Comparison 9 Sotalol versus placebo or no treatment, Outcome 15 Proarrhythmia – sensitivity analysis: studies > 200 participants.

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Analysis 9.16

Comparison 9 Sotalol versus placebo or no treatment, Outcome 16 Stroke – main analysis.

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Analysis 9.17

Comparison 9 Sotalol versus placebo or no treatment, Outcome 17 Stroke – sensitivity analysis: persistent atrial fibrillation.

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Analysis 9.18

Comparison 9 Sotalol versus placebo or no treatment, Outcome 18 Stroke – sensitivity analysis: low risk of bias studies.

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Analysis 9.19

Comparison 9 Sotalol versus placebo or no treatment, Outcome 19 Stroke – sensitivity analysis: studies > 200 participants.

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Analysis 9.20

Comparison 9 Sotalol versus placebo or no treatment, Outcome 20 Atrial fibrillation recurrence – main analysis.

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Analysis 9.21

Comparison 9 Sotalol versus placebo or no treatment, Outcome 21 Atrial fibrillation recurrence – sensitivity analysis: persistent atrial fibrillation.

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Analysis 9.22

Comparison 9 Sotalol versus placebo or no treatment, Outcome 22 Atrial fibrillation recurrence – sensitivity analysis: low risk of bias studies.

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Analysis 9.23

Comparison 9 Sotalol versus placebo or no treatment, Outcome 23 Atrial fibrillation recurrence – sensitivity analysis: studies > 200 participants.

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Summary of findings for the main comparison. Quinidine compared to placebo or no treatment for maintaining sinus rhythm after cardioversion of atrial fibrillation

Quinidine compared to placebo or no treatment for maintaining sinus rhythm after cardioversion of atrial fibrillation
Patient or population: adults in sinus rhythm after cardioversion of atrial fibrillation Setting: hospital/community Intervention: quinidine Comparison: placebo or no treatment
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo or no treatment	Risk with quinidine
All‐cause mortality follow‐up: median 12 months	Study population		RR 2.01 (0.84 to 4.77)	1646 (6 RCTs)	⊕⊕⊝⊝ Low^a,b	—
	8 per 1000	15 per 1000 (6 to 36)
Withdrawals due to adverse effects follow‐up: median 12 months	Study population		RR 1.56 (0.87 to 2.78)	1669 (7 RCTs)	⊕⊕⊕⊝ Moderate^c,d,e	Heterogeneity was high for the main analysis (I² = 67%), but the test for subgroup differences indicated that the RR was higher in older studies which used a higher dose.
	163 per 1000	254 per 1000 (142 to 452)
Proarrhythmia follow‐up: median 12 months	Study population		RR 2.05 (0.95 to 4.41)	1676 (7 RCTs)	⊕⊕⊕⊕ High^c,f	—
	11 per 1000	22 per 1000 (10 to 48)
Stroke follow‐up: median 12 months	Study population		RR 0.97 (0.25 to 3.83)	1107 (4 RCTs)	⊕⊕⊝⊝ Low^a,g	—
	5 per 1000	5 per 1000 (1 to 19)
Recurrence of atrial fibrillation follow‐up: median 12 months	Study population		RR 0.83 (0.78 to 0.88)	1624 (7 RCTs)	⊕⊕⊕⊕ High^c	—
	80.5 per 100	66.8 per 100 (62.8 to 70.8)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded one level for study limitations: majority of studies were at low or unclear risk of bias for at least one of the key domains (allocation concealment, blinding, incomplete outcome data). ^bDowngraded one level for imprecision: confidence interval included no effect, the possibility of a beneficial effect and a strong harmful effect. ^cNot downgraded for study limitations, as the two studies contributing majority of weight were at low risk for key domains (allocation concealment, blinding, incomplete outcome data). ^dNot downgraded for inconsistency: although heterogeneity was high for the main analysis, this was partially explained by subgroup analysis. ^eDowngraded one level for imprecision: confidence interval included possibility of no effect or small beneficial effect as well as harmful effect. ^fNot downgraded for imprecision, although CI just included null. ^gDowngraded one level for imprecision: confidence interval included both important benefits and harms, and event rate was very low.

Summary of findings for the main comparison. Quinidine compared to placebo or no treatment for maintaining sinus rhythm after cardioversion of atrial fibrillation

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Summary of findings 2. Disopyramide compared to placebo or no treatment for maintaining sinus rhythm after cardioversion of atrial fibrillation

Disopyramide compared to placebo or no treatment for maintaining sinus rhythm after cardioversion of atrial fibrillation
Patient or population: adults in sinus rhythm after cardioversion of atrial fibrillation Setting: hospital/community Intervention: disopyramide Comparison: placebo or no treatment
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo or no treatment	Risk with disopyramide
All‐cause mortality follow‐up: mean 12 months	Study population		RR 5.00 (0.25 to 101.37)	92 (1 RCT)	⊕⊝⊝⊝ Very low^a,b	Anticipated absolute effects per 1000 could not be calculated because there were no deaths in the control group. Risks were the data from the RCT.
	0/71	5/75
Withdrawals due to adverse effects follow‐up: range 6–12 months	Study population		RR 3.68 (0.95 to 14.24)	146 (2 RCTs)	⊕⊕⊝⊝ Low^a,c	—
	28 per 1000	104 per 1000 (27 to 401)
Proarrhythmia	—	—	—	—	—	Not reported
Stroke follow‐up: range 6–12 months	Study population		RR 0.31 (0.03 to 2.91)	146 (2 RCTs)	⊕⊝⊝⊝ Very low^a,b	—
	28 per 1000	9 per 1000 (1 to 82)
Recurrence of atrial fibrillation follow‐up: range 6–12 months	Study population		RR 0.77 (0.59 to 1.01)	146 (2 RCTs)	⊕⊕⊝⊝ Low^a,c	—
	69.0 per 100	53.1 per 100 (40.7 to 69.7)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded one level for study limitations: both studies had unclear risk of bias for one of the key domains. ^bDowngraded two levels for imprecision: very small sample size and wide confidence intervals including both important benefits and harms. ^cDowngraded one level for imprecision: very small sample size.

Summary of findings 2. Disopyramide compared to placebo or no treatment for maintaining sinus rhythm after cardioversion of atrial fibrillation

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Summary of findings 3. Propafenone compared to placebo or no treatment for maintaining sinus rhythm after cardioversion of atrial fibrillation

Propafenone compared to placebo or no treatment for maintaining sinus rhythm after cardioversion of atrial fibrillation
Patient or population: adults in sinus rhythm after cardioversion of atrial fibrillation Setting: hospital/community Intervention: propafenone Comparison: placebo or no treatment
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo or no treatment	Risk with propafenone
All‐cause mortality follow‐up: range 6–15 months	Study population		RR 0.19 (0.02 to 1.68)	212 (2 RCTs)	⊕⊝⊝⊝ Very low^a,b	Very few data available for this outcome: only 2 deaths reported in 5 included RCTs.
	26 per 1000	5 per 1000 (1 to 44)
Withdrawals due to adverse effects follow‐up: range 6–15 months	Study population		RR 1.62 (1.07 to 2.46)	1098 (5 RCTs)	⊕⊕⊕⊝ Moderate^a	—
	61 per 1000	99 per 1000 (65 to 150)
Proarrhythmia follow‐up: range 6–15 months	Study population		RR 1.32 (0.39 to 4.47)	381 (3 RCTs)	⊕⊝⊝⊝ Very low^a,b	—
	13 per 1000	17 per 1000 (5 to 56)
Stroke	—	—	—	—	—	Not reported
Recurrence of atrial fibrillation follow‐up: range 6–15 months	Study population		RR 0.67 (0.61 to 0.74)	1098 (5 RCTs)	⊕⊕⊕⊝ Moderate^a	—
	73.0 per 100	48.9 per 100 (44.5 to 54.0)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded one level for study limitations. All studies had unclear or high risk of bias in at least one of the three key domains (allocation concealment, blinding, incomplete outcome data). ^bDowngraded two levels for imprecision due to small sample size and confidence interval wide enough to include both important benefit and harm.

Summary of findings 3. Propafenone compared to placebo or no treatment for maintaining sinus rhythm after cardioversion of atrial fibrillation

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Summary of findings 4. Flecainide compared to placebo or no treatment for maintaining sinus rhythm after cardioversion of atrial fibrillation

Flecainide compared to placebo or no treatment for maintaining sinus rhythm after cardioversion of atrial fibrillation
Patient or population: adults in sinus rhythm after cardioversion of atrial fibrillation Setting: hospital/community Intervention: flecainide Comparison: placebo or no treatment
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo or no treatment	Risk with flecainide
All‐cause mortality	—	—	—	—	—	Not reported
Withdrawals due to adverse effects follow‐up: mean 6 months	Study population		RR 15.41 (0.91 to 260)	73 (1 RCT)	⊕⊕⊝⊝ Low^a,b	Anticipated absolute effects per 1000 could not be calculated because there were no withdrawals in the control group. Risks were the data from the RCT.
	0/37	7/36
Proarrhythmia follow‐up: range 6–12 months	Study population		RR 4.80 (1.30 to 17.7)	511 (4 RCTs)	⊕⊕⊕⊝ Moderate^c	—
	6 per 1000	30 per 1000 (8 to 112)
Stroke follow‐up: mean 6 months	Study population		RR 2.04 (0.11 to 39)	362 (1 RCT)	⊕⊕⊝⊝ Low^a,b	Anticipated absolute effects per 1000 could not be calculated because there were no strokes in the control group. Risks were the data from the RCT.
	0/81	3/281
Recurrence of atrial fibrillation follow‐up: range 6–12 months	Study population		RR 0.65 (0.55 to 0.77)	511 (4 RCTs)	⊕⊕⊕⊕ High^d	—
	69.8 per 100	45.4 per 100 (38.4 to 53.8)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aNot downgraded for study limitations. the only included study was at high risk of bias for blinding (less relevant for this outcome) but low risk for other key domains. ^bDowngraded two levels for imprecision due to small sample size and wide confidence interval that included both possible harm and no effect. ^cDowngraded one level for study limitations; all studies were at high or unclear risk of bias in at least one of the key domains. ^dNot downgraded for study limitations. Majority of weight came from 2 largest studies which were at high risk of bias for blinding (less relevant for this outcome) but low risk for other key domains.

Summary of findings 4. Flecainide compared to placebo or no treatment for maintaining sinus rhythm after cardioversion of atrial fibrillation

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Summary of findings 5. Metoprolol compared to placebo or no treatment for maintaining sinus rhythm after cardioversion of atrial fibrillation

Metoprolol compared to placebo or no treatment for maintaining sinus rhythm after cardioversion of atrial fibrillation
Patient or population: adults in sinus rhythm after cardioversion of atrial fibrillation Setting: hospital/community Intervention: metoprolol Comparison: placebo or no treatment
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo or no treatment	Risk with Metoprolol
All‐cause mortality follow‐up: mean 6 months	Study population		RR 2.02 (0.37 to 11.1)	562 (2 RCTs)	⊕⊕⊕⊝ Moderate^a	—
	4 per 1000	7 per 1000 (1 to 39)
Withdrawals due to adverse effects follow‐up: mean 6 months	Study population		RR 3.47 (1.48 to 8.1)	562 (2 RCTs)	⊕⊕⊕⊕ High	—
	21 per 1000	74 per 1000 (31 to 173)
Proarrhythmia follow‐up: mean 6 months	Study population		RR 18.14 (2.42 to 135.6)	562 (2 RCTs)	⊕⊕⊕⊕ High	Anticipated absolute effects per 1000 could not be calculated because there were no events in the control group. Risks are the data from the RCTs.
	0 / 282	17 / 280
Stroke	—	—	—	—	—	Not reported
Recurrence of atrial fibrillation follow‐up: mean 6 months	Study population		RR 0.83 (0.68 to 1.02)	562 (2 RCTs)	⊕⊕⊕⊝ Moderate^b	—
	72.0 per 100	59.7 per 100 (49.0 to 73.4)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded one level for imprecision. Confidence intervals included both possible harm and possible benefit. ^bDowngraded one level for inconsistency: high I² statistic (59%) indicated heterogeneity and this could not be explored in subgroup analysis due to only two studies being included.

Summary of findings 5. Metoprolol compared to placebo or no treatment for maintaining sinus rhythm after cardioversion of atrial fibrillation

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Summary of findings 6. Amiodarone compared to placebo or no treatment for maintaining sinus rhythm after cardioversion of atrial fibrillation

Amiodarone compared to placebo or no treatment for maintaining sinus rhythm after cardioversion of atrial fibrillation
Patient or population: adults in sinus rhythm after cardioversion of atrial fibrillation Setting: hospital/community Intervention: amiodarone Comparison: placebo or no treatment
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo or no treatment	Risk with amiodarone
All‐cause mortality follow‐up: range 6–12 months	Study population		RR 1.66 (0.55 to 4.99)	444 (2 RCTs)	⊕⊕⊕⊝ Moderate^a	—
	26 per 1000	43 per 1000 (14 to 129)
Withdrawals due to adverse effects follow‐up: range 6–16 months	Study population		RR 6.70 (1.91 to 23.45)	319 (4 RCTs)	⊕⊕⊝⊝ Low^b,c	—
	7 per 1000	49 per 1000 (14 to 172)
Proarrhythmia follow‐up: range 6–16 months	Study population		RR 2.22 (0.71 to 6.96)	673 (4 RCTs)	⊕⊕⊕⊝ Moderate^a,d	—
	8 per 1000	18 per 1000 (6 to 57)
Stroke follow‐up: mean 12 months	Study population		RR 1.15 (0.30 to 4.39)	399 (1 RCT)	⊕⊕⊝⊝ Low^e	—
	23 per 1000	26 per 1000 (7 to 100)
Recurrence of atrial fibrillation follow‐up: median 12 months	Study population		RR 0.52 (0.46 to 0.58)	812 (6 RCTs)	⊕⊕⊕⊕ High^d	—
	81.2 per 100	42.2 per 100 (37.3 to 47.1)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded one level for imprecision: confidence interval included both possible benefit and harm. ^bDowngraded one level for study limitations: majority of weight was from studies with unclear or high risk of bias in key domains. ^cDowngraded one level for imprecision: small sample size. ^dNot downgraded for study limitations, as the majority weight was from studies at low risk of bias in all key domains. ^eDowngraded two levels for imprecision: small sample size and wide confidence interval which included both possible benefit and harm.

Summary of findings 6. Amiodarone compared to placebo or no treatment for maintaining sinus rhythm after cardioversion of atrial fibrillation

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Summary of findings 7. Dofetilide compared to placebo or no treatment for maintaining sinus rhythm after cardioversion of atrial fibrillation

Dofetilide compared to placebo or no treatment for maintaining sinus rhythm after cardioversion of atrial fibrillation
Patient or population: adults in sinus rhythm after cardioversion of atrial fibrillation Setting: hospital/community Intervention: dofetilide Comparison: placebo or no treatment
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo or no treatment	Risk with dofetilide
All‐cause mortality follow‐up: mean 12 months	Study population		RR 0.98 (0.76 to 1.27)	1183 (3 RCTs)	⊕⊕⊕⊝ Moderate^a	—
	193 per 1000	189 per 1000 (146 to 245)
Withdrawals due to adverse effects follow‐up: mean 12 months	Study population		RR 1.77 (0.75 to 4.2)	677 (2 RCTs)	⊕⊕⊝⊝ Low^a,b	—
	34 per 1000	61 per 1000 (26 to 144)
Proarrhythmia follow‐up: mean 12 months	Study population		RR 5.50 (1.33 to 22.8)	1183 (3 RCTs)	⊕⊕⊕⊝ Moderate^a	—
	2 per 1000	13 per 1000 (3 to 53)
Stroke	—	—	—	—	—	Not reported
Recurrence of atrial fibrillation follow‐up: mean 12 months	Study population		RR 0.72 (0.61 to 0.85)	1183 (3 RCTs)	⊕⊕⊕⊝ Moderate^c,d	—
	84.2 per 100	60.6 per 100 (51.4 to 71.6)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded one level for study limitations: majority of studies had unclear risk of selection bias. ^bDowngraded one level for imprecision: confidence interval included both possible benefit and harm. ^cNot downgraded for study limitations as 51% of weight came from a study with low risk of bias across all domains (but other two studies had unclear risk of selection bias). ^dDowngraded one level for heterogeneity due to very high I² value (79%).

Summary of findings 7. Dofetilide compared to placebo or no treatment for maintaining sinus rhythm after cardioversion of atrial fibrillation

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Summary of findings 8. Dronedarone compared to placebo or no treatment for maintaining sinus rhythm after cardioversion of atrial fibrillation

Dronedarone compared to placebo or no treatment for maintaining sinus rhythm after cardioversion of atrial fibrillation
Patient or population: adults in sinus rhythm after cardioversion of atrial fibrillation Setting: hospital/community Intervention: dronedarone Comparison: placebo or no treatment
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo or no treatment	Risk with dronedarone
All‐cause mortality follow‐up: range 6–12 months	Study population		RR 0.86 (0.68 to 1.09)	6071 (3 RCTs)	⊕⊕⊕⊕ High	—
	51 per 1000	44 per 1000 (35 to 56)
Withdrawals due to adverse effects follow‐up: range 6–12 months	Study population		RR 1.58 (1.34 to 1.85)	6071 (3 RCTs)	⊕⊕⊕⊝ Moderate^a	—
	77 per 1000	122 per 1000 (104 to 143)
Proarrhythmia follow‐up: mean 12 months	Study population		RR 1.95 (0.77 to 4.98)	5872 (2 RCTs)	⊕⊕⊕⊝ Moderate^b	—
	18 per 1000	36 per 1000 (14 to 91)
Stroke follow‐up: mean 12 months	Study population		RR 0.66 (0.47 to 0.95)	5872 (2 RCTs)	⊕⊕⊕⊕ High	—
	27 per 1000	18 per 1000 (13 to 25)
Recurrence of atrial fibrillation follow‐up: range 6–12 months	Study population		RR 0.85 (0.80 to 0.91)	1443 (2 RCTs)	⊕⊕⊕⊝ Moderate^c	—
	76.6 per 100	65.1 per 100 (61.3 to 69.7)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded one level for study limitations: 83% of weight came from a study with unclear blinding, which could be relevant to this outcome. ^bDowngraded one level for inconsistency due to very high I² statistic of 78%. ^cDowngraded one level for study limitations: most weight came from a study with unclear allocation concealment.

Summary of findings 8. Dronedarone compared to placebo or no treatment for maintaining sinus rhythm after cardioversion of atrial fibrillation

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Summary of findings 9. Sotalol compared to placebo or no treatment for maintaining sinus rhythm after cardioversion of atrial fibrillation

Sotalol compared to placebo or no treatment for maintaining sinus rhythm after cardioversion of atrial fibrillation
Patient or population: adults in sinus rhythm after cardioversion of atrial fibrillation Setting: hospital/community Intervention: sotalol Comparison: placebo or no treatment
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo or no treatment	Risk with sotalol
All‐cause mortality follow‐up: range 6–12 months	Study population		RR 2.23 (1.03 to 4.81)	1882 (5 RCTs)	⊕⊕⊕⊕ High	—
	8 per 1000	19 per 1000 (9 to 40)
Withdrawals due to adverse effects follow‐up: range 6–19 months; median 12 months	Study population		RR 1.95 (1.23 to 3.11)	2688 (12 RCTs)	⊕⊕⊕⊝ Moderate^a,b,c	Heterogeneity was high for the main analysis (I² = 56%), but the test for subgroup differences indicated that the RR was higher in older studies with sotalol.
	94 per 1000	183 per 1000 (116 to 293)
Proarrhythmia follow‐up: median 12 months	Study population		RR 3.55 (2.16 to 5.83)	2989 (12 RCTs)	⊕⊕⊕⊝ Moderate^a,c	—
	12 per 1000	41 per 1000 (25 to 68)
Stroke follow‐up: range 6–12 months	Study population		RR 1.47 (0.48 to 4.51)	1161 (3 RCTs)	⊕⊕⊕⊝ Moderate^d	—
	7 per 1000	10 per 1000 (3 to 30)
Recurrence of atrial fibrillation follow‐up: range 6–19 months; median 12 months	Study population		RR 0.83 (0.80 to 0.87)	3179 (14 RCTs)	⊕⊕⊕⊕ High^a,e,f	—
	78.8 per 100	65.4 per 100 (63.1 to 68.6)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aNot downgraded for study limitations. Although the majority of studies had unclear or high risk of bias in at least one of the key domains, the majority of the weight was from studies at low risk of bias in key domains. ^bNot downgraded for inconsistency. I² statistic was 56% for the main analysis, but this was partially explained by subgroup analysis. ^cDowngraded one level for publication bias: forest plot appeared to be asymmetrical. ^dDowngraded one level for imprecision: confidence interval included both possible benefit and harm. ^eNot downgraded for publication bias: funnel plot appears to be broadly symmetrical. ^fNot downgraded for inconsistency. I² statistic was 54% but the forest plot had good overlap in confidence intervals, so a fixed‐effect model was used to maintain the weight of the few larger studies.

Summary of findings 9. Sotalol compared to placebo or no treatment for maintaining sinus rhythm after cardioversion of atrial fibrillation

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Table 1. Number of studies assessing each primary outcome

Primary outcomes	n trials reporting (n participants)	n trials NOT reporting (n participants)
All‐cause mortality	39 (17,586)	3^a (393)
Cardiovascular mortality	Same as total mortality	Same as total mortality
Stroke	11 (9139)	30 (8840)
Adverse effects (proarrhythmia and withdrawals due to adverse effects)	39 (16,558)	3^b (1421)
Out of 41 studies comparing an active drug with a control group receiving no antiarrhythmic (total 17,979 participants). ^aChun 2014; DAPHNE 2008; Santas 2012. ^bAFIB 1997; Chun 2014; Santas 2012. Others studies did not reported proarrhythmia but reported withdrawals (DAPHNE 2008; Niu 2006; Villani 1992).

Table 1. Number of studies assessing each primary outcome

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Table 2. Head‐to‐head trials: all‐cause mortality

Drug 1 vs drug 2	Drug 1		Drug 2		RR (95% CI)
Drug 1 vs drug 2	Events	Total	Events	Total	RR (95% CI)
Disopyramide vs other class I drugs
Lloyd 1984	0	29	2	28	0.19 (0.01 to 3.86)
PRODIS 1996	1	31	0	25	2.44 (0.10 to 57.37)
Quinidine vs other class I drugs
Lloyd 1984	2	28	0	29	5.17 (0.26 to 103.18)
Richiardi 1992	0	98	2	102	0.21 (0.01 to 4.28)
Quinidine vs sotalol
Juul‐Moller 1990	1	85	1	98	1.15 (0.07 to 18.15)
Kalusche 1994	1	41	0	41	3.00 (0.13 to 71.56)
PAFAC 2004	9	377	13	383	0.70 (0.30 to 1.63)
SOCESP 1999	0	63	1	58	0.31 (0.01 to 7.40)
SOPAT 2004	2	518	2	264	0.51 (0.07 to 3.60)
Flecainide vs propafenone
Aliot 1996	0	48	1	49	0.34 (0.01 to 8.15)
Amiodarone vs class I drugs
AFFIRM Substudy 2003	10	106	26	116	0.42 (0.21 to 0.83)
PITAGORA 2008	6	70	2	75	3.21 (0.67 to 15.40)
Amiodarone vs dronedarone
DIONYSOS 2010	5	255	2	249	2.44 (0.48 to 12.47)
Amiodarone vs sotalol
AFFIRM Substudy 2003	15	131	24	125	0.60 (0.33 to 1.08)
PITAGORA 2008	6	70	0	31	5.86 (0.34 to 100.89)
SAFE‐T 2005	13	267	15	261	0.85 (0.41 to 1.75)
Sotalol vs class I drugs other than quinidine
AFFIRM Substudy 2003	13	88	17	95	0.83 (0.43 to 1.60)
Reimold 1993	2	50	0	50	5.00 (0.25 to 101.58)
Sotalol vs dofetilide
EMERALD 2000	0	108	1	321	0.98 (0.04 to 23.99)
CI: confidence interval; RR: risk ratio.

Table 2. Head‐to‐head trials: all‐cause mortality

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Table 3. Head‐to‐head trials: withdrawals due to adverse events

Drug 1 vs drug 2	Drug 1		Drug 2		RR (95% CI)
Drug 1 vs drug 2	Events	Total	Events	Total	RR (95% CI)
Disopyramide vs other class I drugs
Lloyd 1984	2	29	4	28	0.48 (0.10 to 2.43)
PRODIS 1996	4	31	8	25	0.40 (0.14 to 1.19)
Quinidine vs flecainide
Naccarelli 1996	35	117	22	122	1.66 (1.04 to 2.65)
Steinbeck 1988	2	15	0	15	5.00 (0.26 to 96.13)
Quinidine vs other class I drugs
Lloyd 1984	4	28	2	29	2.07 (0.41 to 10.43)
Naccarelli 1996	35	117	22	122	1.66 (1.04 to 2.65)
Richiardi 1992	23	98	10	102	2.39 (1.20 to 4.77)
Steinbeck 1988	2	15	0	15	5.00 (0.26 to 96.13)
Quinidine vs sotalol
Hohnloser 1995	10	25	1	25	10.00 (1.38 to 72.39)
Juul‐Moller 1990	22	85	11	98	2.31 (1.19 to 4.47)
Kalusche 1994	7	41	3	41	2.33 (0.65 to 8.40)
PAFAC 2004	94	377	96	383	0.99 (0.78 to 1.27)
SOCESP 1999	10	63	7	58	1.32 (0.54 to 3.23)
SOPAT 2004	87	518	53	264	0.84 (0.62 to 1.14)
Flecainide vs propafenone
Aliot 1996	2	48	9	49	0.23 (0.05 to 1.00)
FAPIS 1996	10	97	9	103	1.18 (0.50 to 2.78)
Amiodarone vs class I drugs
AFFIRM Substudy 2003	20	154	47	121	0.33 (0.21 to 0.53)
Kochiadakis 2004a	17	72	2	74	8.74 (2.09 to 36.46)
PITAGORA 2008	5	70	2	31	1.11 (0.23 to 5.40)
Villani 1992	3	35	10	41	0.35 (0.10 to 1.18)
Vitolo 1981	1	28	1	26	0.93 (0.06 to 14.09)
Amiodarone vs dronedarone
DIONYSOS 2010	45	255	32	249	1.37 (0.90 to 2.09)
Amiodarone vs sotalol
AFFIRM Substudy 2003	20	154	21	135	0.83 (0.47 to 1.47)
Kochiadakis 2000	11	65	3	61	3.44 (1.01 to 11.75)
Niu 2006	5	51	7	51	0.71 (0.24 to 2.10)
PITAGORA 2008	6	70	0	31	5.86 (0.34 to 100.89)
Vijayalakshmi 2006	1	22	4	33	0.38 (0.04 to 3.14)
Sotalol vs class I drugs other than quinidine
AFFIRM Substudy 2003	21	135	47	121	0.40 (0.25 to 0.63)
Kochiadakis 2004b	5	85	5	86	1.01 (0.30 to 3.37)
Reimold 1993	6	50	4	50	1.50 (0.45 to 4.99)
Sotalol vs dofetilide
EMERALD 2000	16	108	22	321	2.16 (1.18 to 3.96)
Sotalol vs other beta‐blockers
DAPHNE 2008	11	69	2	66	5.26 (1.21 to 22.84)
Plewan 2001	4	64	3	64	1.33 (0.31 to 5.72)
CI: confidence interval; RR: risk ratio.

Table 3. Head‐to‐head trials: withdrawals due to adverse events

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Table 4. Head‐to‐head trials: proarrhythmia

Drug 1 vs drug 2	Drug 1		Drug 2		RR (95% CI)
Drug 1 vs drug 2	Events	Total	Events	Total	RR (95% CI)
Disopyramide vs other class I drugs
Lloyd 1984	0	29	1	28	0.32 (0.01 to 7.59)
PRODIS 1996	1	31	1	25	0.81 (0.05 to 12.26)
Quinidine vs flecainide
Naccarelli 1996	10	117	7	122	1.49 (0.59 to 3.78)
Steinbeck 1988	2	15	1	15	2.00 (0.20 to 19.78)
Quinidine vs other class I drugs
Lloyd 1984	1	28	0	29	3.10 (0.13 to 73.12)
Naccarelli 1996	10	117	7	122	1.49 (0.59 to 3.78)
Richiardi 1992	2	98	2	102	1.04 (0.15 to 7.24)
Steinbeck 1988	2	15	1	15	2.00 (0.20 to 19.78)
Quinidine vs sotalol
Hohnloser 1995	3	25	1	25	3.00 (0.33 to 26.92)
Juul‐Moller 1990	1	85	1	98	1.15 (0.07 to 18.15)
Kalusche 1994	1	41	2	41	0.50 (0.05 to 5.30)
PAFAC 2004	17	377	20	383	0.86 (0.46 to 1.62)
SOCESP 1999	2	63	3	58	0.61 (0.11 to 3.54)
SOPAT 2004	8	518	2	264	2.04 (0.44 to 9.53)
Flecainide vs propafenone
Aliot 1996	0	48	4	49	0.11 (0.01 to 2.05)
FAPIS 1996	2	97	1	103	2.12 (0.20 to 23.05)
Amiodarone vs class I drugs
AFFIRM Substudy 2003	5	154	20	121	0.20 (0.08 to 0.51)
Kochiadakis 2004a	2	72	2	74	1.03 (0.15 to 7.10)
Vitolo 1981	1	28	1	26	0.93 (0.06 to 14.09)
Amiodarone vs dronedarone
DIONYSOS 2010	4	255	2	249	1.95 (0.36 to 10.57)
Amiodarone vs sotalol
AFFIRM Substudy 2003	5	154	9	135	0.49 (0.17 to 1.42)
Kochiadakis 2000	2	65	2	61	0.94 (0.14 to 6.46)
SAFE‐T 2005	6	267	9	261	0.65 (0.24 to 1.81)
Sotalol vs class I drugs other than quinidine
AFFIRM Substudy 2003	9	135	20	121	0.40 (0.19 to 0.85)
Carunchio 1995	5	20	3	20	1.67 (0.46 to 6.06)
Kochiadakis 2004b	3	85	2	86	1.52 (0.26 to 8.86)
Reimold 1993	9	50	6	50	1.50 (0.58 to 3.90)
Sotalol vs dofetilide
EMERALD 2000	2	108	7	321	0.85 (0.18 to 4.03)
Sotalol vs other beta‐blockers
Plewan 2001	4	64	3	64	1.33 (0.31 to 5.72)
CI: confidence interval; RR: risk ratio.

Table 4. Head‐to‐head trials: proarrhythmia

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Table 5. Head‐to‐head trials: recurrence of atrial fibrillation

Drug 1 vs drug 2	Drug 1		Drug 2		RR (95% CI)
Drug 1 vs drug 2	Events	Total	Events	Total	RR (95% CI)
Disopyramide vs other class I drugs
Lloyd 1984	16	29	16	28	0.97 (0.61 to 1.53)
PRODIS 1996	10	31	11	25	0.73 (0.37 to 1.44)
Quinidine vs flecainide
Naccarelli 1996	93	117	93	122	1.04 (0.91 to 1.19)
Steinbeck 1988	10	15	6	15	1.67 (0.81 to 3.41)
Quinidine vs other class I drugs
Lloyd 1984	16	28	16	29	1.04 (0.65 to 1.64)
Naccarelli 1996	93	117	93	122	1.04 (0.91 to 1.19)
Richiardi 1992	57	98	53	102	1.12 (0.87 to 1.44)
Steinbeck 1988	10	15	6	15	1.67 (0.81 to 3.41)
Quinidine vs sotalol
Hohnloser 1995	7	25	12	25	0.58 (0.28 to 1.23)
Juul‐Moller 1990	49	85	50	98	1.13 (0.87 to 1.47)
Kalusche 1994	15	41	21	41	0.71 (0.43 to 1.18)
PAFAC 2004	244	377	255	383	0.97 (0.88 to 1.08)
SOCESP 1999	25	63	20	58	1.15 (0.72 to 1.84)
SOPAT 2004	375	518	198	264	0.97 (0.88 to 1.05)
Flecainide vs propafenone
Aliot 1996	19	48	26	49	0.75 (0.48 to 1.16)
FAPIS 1996	30	97	30	103	1.06 (0.70 to 1.62)
Amiodarone vs class I drugs
AFFIRM Substudy 2003	60	106	99	116	0.66 (0.55 to 0.80)
Kochiadakis 2004a	20	72	32	74	0.64 (0.41 to 1.01)
PITAGORA 2008	42	70	54	75	0.83 (0.66 to 1.06)
Villani 1992	14	35	30	41	0.55 (0.35 to 0.85)
Vitolo 1981	6	28	14	26	0.40 (0.18 to 0.88)
Amiodarone vs dronedarone
DIONYSOS 2010	116	255	163	249	0.69 (0.59 to 0.82)
Amiodarone vs sotalol
AFFIRM Substudy 2003	58	131	81	125	0.68 (0.54 to 0.86)
Kochiadakis 2000	27	65	39	61	0.65 (0.46 to 0.92)
Niu 2006	24	51	36	51	0.67 (0.47 to 0.94)
PITAGORA 2008	42	70	24	31	0.78 (0.59 to 1.01)
SAFE‐T 2005	133	267	183	261	0.71 (0.62 to 0.82)
Vijayalakshmi 2006	3	11	10	17	0.46 (0.16 to 1.32)
Dronedarone vs propafenone
Chun 2014	36	50	37	50	0.97 (0.77 to 1.24)
Sotalol vs class I drugs other than quinidine
AFFIRM Substudy 2003	67	88	81	95	0.89 (0.77 to 1.03)
Carunchio 1995	8	20	6	20	1.33 (0.57 to 3.14)
Kochiadakis 2004b	43	85	35	86	1.24 (0.89 to 1.73)
Reimold 1993	32	50	35	50	0.91 (0.69 to 1.20)
Sotalol vs dofetilide
EMERALD 2000	74	108	196	321	1.12 (0.96 to 1.31)
Sotalol vs beta‐blockers
DAPHNE 2008	57	69	54	66	1.01 (0.86 to 1.18)
Plewan 2001	31	64	29	64	1.07 (0.74 to 1.55)
CI: confidence interval; RR: risk ratio.

Table 5. Head‐to‐head trials: recurrence of atrial fibrillation

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Comparison 1. Quinidine versus placebo or no treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause mortality – main analysis Show forest plot	6	1646	Risk Ratio (M‐H, Fixed, 95% CI)	2.01 [0.84, 4.77]

2 All‐cause mortality – sensitivity analysis intention to treat (ITT) worse case: missing participants counted as events Show forest plot	6	1646	Risk Ratio (M‐H, Fixed, 95% CI)	2.12 [0.96, 4.67]

3 All‐cause mortality – subgroup analysis: older and recent studies Show forest plot	6	1646	Risk Ratio (M‐H, Fixed, 95% CI)	2.01 [0.84, 4.77]

3.1 Older studies, higher dose	4	412	Risk Ratio (M‐H, Fixed, 95% CI)	2.74 [0.85, 8.83]
3.2 More recent studies, lower dose	2	1234	Risk Ratio (M‐H, Fixed, 95% CI)	1.29 [0.34, 4.92]
4 All‐cause mortality – sensitivity analysis: persistent atrial fibrillation Show forest plot	5	865	Risk Ratio (M‐H, Fixed, 95% CI)	1.82 [0.73, 4.53]

5 All‐cause mortality – sensitivity analysis: low risk of bias studies Show forest plot	2	1234	Risk Ratio (M‐H, Fixed, 95% CI)	1.29 [0.34, 4.92]

6 All‐cause mortality – sensitivity analysis: studies > 200 participants Show forest plot	2	1234	Risk Ratio (M‐H, Fixed, 95% CI)	1.29 [0.34, 4.92]

7 Withdrawals due to adverse effects – main analysis Show forest plot	7	1669	Risk Ratio (M‐H, Random, 95% CI)	1.56 [0.87, 2.78]

8 Withdrawals due to adverse effects – subgroup analysis: older and recent studies Show forest plot	7	1669	Risk Ratio (M‐H, Random, 95% CI)	1.56 [0.87, 2.78]

8.1 Older studies, higher dose	5	435	Risk Ratio (M‐H, Random, 95% CI)	3.05 [1.29, 7.22]
8.2 More recent studies, lower dose	2	1234	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.61, 1.27]
9 Withdrawals due to adverse effects – sensitivity analysis: persistent atrial fibrillation Show forest plot	5	877	Risk Ratio (M‐H, Random, 95% CI)	2.19 [0.99, 4.87]

10 Withdrawals due to adverse effects – sensitivity analysis: low risk of bias studies Show forest plot	2	1234	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.66, 1.08]

11 Withdrawals due to adverse effects – sensitivity analysis: studies > 200 participants Show forest plot	2	1234	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.67, 1.09]

12 Proarrhythmia – main analysis Show forest plot	7	1676	Risk Ratio (M‐H, Fixed, 95% CI)	2.05 [0.95, 4.41]

13 Proarrhythmia – subgroup analysis: older and recent studies Show forest plot	7	1677	Risk Ratio (M‐H, Fixed, 95% CI)	2.05 [0.96, 4.42]

13.1 Older studies, higher dose	5	442	Risk Ratio (M‐H, Fixed, 95% CI)	3.14 [0.87, 11.32]
13.2 More recent studies, lower dose	2	1235	Risk Ratio (M‐H, Fixed, 95% CI)	1.60 [0.61, 4.24]
14 Proarrhythmia – sensitivity analysis: persistent atrial fibrillation Show forest plot	5	877	Risk Ratio (M‐H, Fixed, 95% CI)	2.64 [0.93, 7.53]

15 Proarrhythmia – sensitivity analysis: low risk of bias studies Show forest plot	2	1235	Risk Ratio (M‐H, Fixed, 95% CI)	1.60 [0.61, 4.24]

16 Proarrhythmia – sensitivity analysis: studies > 200 participants Show forest plot	2	1235	Risk Ratio (M‐H, Fixed, 95% CI)	1.60 [0.61, 4.24]

17 Stroke – main analysis Show forest plot	4	1107	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.25, 3.83]

18 Stroke – sensitivity analysis: persistent atrial fibrillation Show forest plot	3	338	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.19, 4.01]

19 Stroke – sensitivity analysis: low risk of bias studies Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

20 Stroke – sensitivity analysis: studies > 200 participants Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

21 Atrial fibrillation recurrence – main analysis Show forest plot	7	1624	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.78, 0.88]

22 Atrial fibrillation recurrence – sensitivity analysis: persistent atrial fibrillation Show forest plot	5	825	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.70, 0.85]

23 Atrial fibrillation recurrence – sensitivity analysis: low risk of bias studies Show forest plot	2	1234	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.80, 0.91]

24 Atrial fibrillation recurrence – sensitivity analysis: studies > 200 participants Show forest plot	2	1234	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.80, 0.92]

Comparison 1. Quinidine versus placebo or no treatment

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Comparison 2. Disopyramide versus placebo or no treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause mortality – main analysis Show forest plot	1	92	Risk Ratio (M‐H, Fixed, 95% CI)	5.0 [0.25, 101.37]

2 All‐cause mortality – intention to treat (ITT) worse case: missing participants counted as events Show forest plot	2	146	Risk Ratio (M‐H, Fixed, 95% CI)	5.55 [0.68, 45.09]

3 Withdrawals due to adverse effects – main analysis Show forest plot	2	146	Risk Ratio (M‐H, Fixed, 95% CI)	3.68 [0.95, 14.24]

4 Withdrawals due to adverse effects – sensitivity analysis: persistent atrial fibrillation Show forest plot	2	146	Risk Ratio (M‐H, Fixed, 95% CI)	3.68 [0.95, 14.24]

5 Stroke – main analysis Show forest plot	2	146	Risk Ratio (M‐H, Fixed, 95% CI)	0.31 [0.03, 2.91]

6 Stroke – subgroup analysis: persistent atrial fibrillation Show forest plot	2	146	Risk Ratio (M‐H, Fixed, 95% CI)	0.31 [0.03, 2.91]

7 Atrial fibrillation recurrence – main analysis Show forest plot	2	146	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.59, 1.01]

8 Atrial fibrillation recurrence – sensitivity analysis: persistent atrial fibrillation Show forest plot	2	146	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.59, 1.01]

Comparison 2. Disopyramide versus placebo or no treatment

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Comparison 3. Propafenone versus placebo or no treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause mortality – main analysis Show forest plot	2	212	Risk Ratio (M‐H, Fixed, 95% CI)	0.19 [0.02, 1.68]

2 All‐cause mortality – intention to treat (ITT) worse case: missing participants counted as events Show forest plot	3	406	Risk Ratio (M‐H, Fixed, 95% CI)	1.28 [0.45, 3.62]

3 All‐cause mortality – sensitivity analysis: low risk of bias studies Show forest plot	1	102	Risk Ratio (M‐H, Fixed, 95% CI)	0.11 [0.00, 2.64]

4 Withdrawals due to adverse effects – main analysis Show forest plot	5	1098	Risk Ratio (M‐H, Fixed, 95% CI)	1.62 [1.07, 2.46]

5 Withdrawals due to adverse effects – sensitivity analysis: studies > 200 participants Show forest plot	1	523	Risk Ratio (M‐H, Fixed, 95% CI)	1.29 [0.79, 2.11]

6 Proarrhythmia – main analysis Show forest plot	3	381	Risk Ratio (M‐H, Fixed, 95% CI)	1.32 [0.39, 4.47]

7 Proarrhythmia – sensitivity analysis: low risk of bias studies Show forest plot	1	102	Risk Ratio (M‐H, Fixed, 95% CI)	0.49 [0.09, 2.75]

8 Atrial fibrillation recurrence – main analysis Show forest plot	5	1098	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.61, 0.74]

9 Atrial fibrillation recurrence – sensitivity analysis: low risk of bias studies Show forest plot	1	102	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.50, 1.01]

10 Atrial fibrillation recurrence – sensitivity analysis: studies > 200 participants Show forest plot	1	523	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.63, 0.79]

Comparison 3. Propafenone versus placebo or no treatment

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Comparison 4. Flecainide versus placebo or no treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Withdrawals due to adverse effects – main analysis Show forest plot	1	73	Risk Ratio (M‐H, Fixed, 95% CI)	15.41 [0.91, 260.19]

2 Proarrhythmia – main analysis Show forest plot	4	511	Risk Ratio (M‐H, Fixed, 95% CI)	4.80 [1.30, 17.77]

3 Proarrhythmia – sensitivity analysis: persistent atrial fibrillation Show forest plot	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	6.35 [0.91, 44.22]

4 Proarrhythmia – sensitivity analysis: low risk of bias studies Show forest plot	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	6.35 [0.91, 44.22]

5 Proarrhythmia – sensitivity analysis: studies > 200 participants Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6 Stroke – main analysis Show forest plot	1	362	Risk Ratio (M‐H, Fixed, 95% CI)	2.04 [0.11, 39.00]

7 Stroke – subgroup analysis: persistent atrial fibrillation Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

8 Stroke – sensitivity analysis: low risk of bias studies Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

9 Stroke – sensitivity analysis: studies > 200 participants Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

10 Atrial fibrillation recurrence – main analysis Show forest plot	4	511	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.55, 0.77]

11 Atrial fibrillation recurrence – sensitivity analysis: persistent atrial fibrillation Show forest plot	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.60, 0.85]

12 Atrial fibrillation recurrence – sensitivity analysis: low risk of bias studies Show forest plot	2	435	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.60, 0.85]

13 Atrial fibrillation recurrence – sensitivity analysis: studies > 200 participants Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

Comparison 4. Flecainide versus placebo or no treatment

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Comparison 5. Metoprolol versus placebo or no treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause mortality – main analysis Show forest plot	2	562	Risk Ratio (M‐H, Fixed, 95% CI)	2.02 [0.37, 11.05]

2 All‐cause mortality – intention to treat (ITT) worse case: missing participants counted as events Show forest plot	2	562	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.41, 1.43]

3 All‐cause mortality – sensitivity analysis: persistent atrial fibrillation Show forest plot	2	562	Risk Ratio (M‐H, Fixed, 95% CI)	2.02 [0.37, 11.05]

4 All‐cause mortality – sensitivity analysis: low risk of bias studies Show forest plot	2	562	Risk Ratio (M‐H, Fixed, 95% CI)	2.02 [0.37, 11.05]

5 All‐cause mortality – sensitivity analysis: studies > 200 participants Show forest plot	1	394	Risk Ratio (M‐H, Fixed, 95% CI)	7.0 [0.36, 134.63]

6 Withdrawals due to adverse effects – main analysis Show forest plot	2	562	Risk Ratio (M‐H, Fixed, 95% CI)	3.47 [1.48, 8.15]

7 Withdrawals due to adverse effects – sensitivity analysis: persistent atrial fibrillation Show forest plot	2	562	Risk Ratio (M‐H, Fixed, 95% CI)	3.47 [1.48, 8.15]

8 Withdrawals due to adverse effects – sensitivity analysis: low risk of bias studies Show forest plot	2	562	Risk Ratio (M‐H, Fixed, 95% CI)	3.47 [1.48, 8.15]

9 Withdrawals due to adverse effects – sensitivity analysis: studies > 200 participants Show forest plot	1	394	Risk Ratio (M‐H, Fixed, 95% CI)	3.33 [1.37, 8.12]

10 Proarrhythmia – main analysis Show forest plot	2	562	Risk Ratio (M‐H, Fixed, 95% CI)	18.14 [2.42, 135.66]

11 Proarrhythmia – sensitivity analysis: persistent atrial fibrillation Show forest plot	2	562	Risk Ratio (M‐H, Fixed, 95% CI)	18.14 [2.42, 135.66]

12 Proarrhythmia – sensitivity analysis: low risk of bias studies Show forest plot	2	562	Risk Ratio (M‐H, Fixed, 95% CI)	18.14 [2.42, 135.66]

13 Proarrhythmia – sensitivity analysis: studies > 200 participants Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

14 Atrial fibrillation recurrence – main analysis Show forest plot	2	562	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.68, 1.02]

15 Atrial fibrillation recurrence – sensitivity analysis: persistent atrial fibrillation Show forest plot	2	562	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.68, 1.02]

16 Atrial fibrillation recurrence – sensitivity analysis: low risk of bias studies Show forest plot	2	562	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.68, 1.02]

17 Atrial fibrillation recurrence – sensitivity analysis: studies > 200 participants Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

Comparison 5. Metoprolol versus placebo or no treatment

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Comparison 6. Amiodarone versus placebo or no treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause mortality – main analysis Show forest plot	2	444	Risk Ratio (M‐H, Fixed, 95% CI)	1.66 [0.55, 4.99]

2 All‐cause mortality – intention to treat (ITT) worse case: missing participants counted as events Show forest plot	2	444	Risk Ratio (M‐H, Fixed, 95% CI)	1.35 [0.64, 2.82]

3 All‐cause mortality – sensitivity analysis: persistent atrial fibrillation Show forest plot	2	444	Risk Ratio (M‐H, Fixed, 95% CI)	1.66 [0.55, 4.99]

4 Withdrawals due to adverse effects – main analysis Show forest plot	4	319	Risk Ratio (M‐H, Fixed, 95% CI)	6.70 [1.91, 23.45]

5 Withdrawals due to adverse effects – sensitivity analysis: low risk of bias studies Show forest plot	1	99	Risk Ratio (M‐H, Fixed, 95% CI)	4.98 [0.65, 38.29]

6 Proarrhythmia – main analysis Show forest plot	4	673	Risk Ratio (M‐H, Fixed, 95% CI)	2.22 [0.71, 6.96]

7 Proarrhythmia – sensitivity analysis: persistent atrial fibrillation Show forest plot	2	498	Risk Ratio (M‐H, Fixed, 95% CI)	2.03 [0.52, 7.96]

8 Proarrhythmia – sensitivity analysis: low risk of bias studies Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

9 Proarrhythmia – sensitivity analysis: studies > 200 participants Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

10 Stroke – main analysis Show forest plot	1	399	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.30, 4.39]

11 Stroke – sensitivity analysis: persistent atrial fibrillation Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

12 Stroke – sensitivity analysis: studies > 200 participants Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

13 Atrial fibrillation recurrence – main analysis Show forest plot	6	812	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.46, 0.58]

14 Atrial fibrillation recurrence – sensitivity analysis: persistent atrial fibrillation Show forest plot	5	687	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.46, 0.58]

15 Atrial fibrillation recurrence – sensitivity analysis: low risk of bias studies Show forest plot	2	498	Risk Ratio (M‐H, Fixed, 95% CI)	0.57 [0.50, 0.64]

16 Atrial fibrillation recurrence – sensitivity analysis: studies > 200 participants Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

Comparison 6. Amiodarone versus placebo or no treatment

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Comparison 7. Dofetilide versus placebo or no treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause mortality – main analysis Show forest plot	3	1183	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.76, 1.27]

2 All‐cause mortality – intention to treat (ITT) worse case: missing participants counted as events Show forest plot	3	1183	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.79, 1.31]

3 All‐cause mortality – sensitivity analysis: persistent atrial fibrillation Show forest plot	3	1183	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.76, 1.27]

4 All‐cause mortality – sensitivity analysis: low risk of bias studies Show forest plot	1	506	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.77, 1.29]

5 All‐cause mortality – sensitivity analysis: studies > 200 participants Show forest plot	3	1183	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.76, 1.27]

6 Withdrawals due to adverse effects – main analysis Show forest plot	2	677	Risk Ratio (M‐H, Fixed, 95% CI)	1.77 [0.75, 4.18]

7 Withdrawals due to adverse effects – sensitivity analysis: persistent atrial fibrillation Show forest plot	2	677	Risk Ratio (M‐H, Fixed, 95% CI)	1.77 [0.75, 4.18]

8 Withdrawals due to adverse effects – sensitivity analysis: studies > 200 participants Show forest plot	2	677	Risk Ratio (M‐H, Fixed, 95% CI)	1.77 [0.75, 4.18]

9 Proarrhythmia – main analysis Show forest plot	3	1183	Risk Ratio (M‐H, Fixed, 95% CI)	5.50 [1.33, 22.76]

10 Proarrhythmia – sensitivity analysis: persistent atrial fibrillation Show forest plot	3	1183	Risk Ratio (M‐H, Fixed, 95% CI)	5.50 [1.33, 22.76]

11 Proarrhythmia – sensitivity analysis: low risk of bias studies Show forest plot	1	506	Risk Ratio (M‐H, Fixed, 95% CI)	9.29 [0.50, 171.62]

12 Proarrhythmia – sensitivity analysis: studies > 200 participants Show forest plot	3	1183	Risk Ratio (M‐H, Fixed, 95% CI)	5.50 [1.33, 22.76]

13 Atrial fibrillation recurrence – main analysis Show forest plot	3	1183	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.61, 0.85]

14 Atrial fibrillation recurrence – sensitivity analysis: persistent atrial fibrillation Show forest plot	3	1183	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.61, 0.85]

15 Atrial fibrillation recurrence – sensitivity analysis: low risk of bias studies Show forest plot	1	506	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.54, 0.70]

16 Atrial fibrillation recurrence – sensitivity analysis: studies > 200 participants Show forest plot	3	1183	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.61, 0.85]

Comparison 7. Dofetilide versus placebo or no treatment

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Comparison 8. Dronedarone versus placebo or no treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause mortality – main analysis Show forest plot	3	6071	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.68, 1.09]

2 All‐cause mortality – intention to treat (ITT) worse case: missing participants counted as events Show forest plot	3	6071	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.67, 1.07]

3 All‐cause mortality – sensitivity analysis: persistent atrial fibrillation Show forest plot	1	199	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.04, 23.36]

4 All‐cause mortality – sensitivity analysis: low risk of bias studies Show forest plot	1	4628	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.66, 1.07]

5 All‐cause mortality – sensitivity analysis: studies > 200 participants Show forest plot	2	5872	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.68, 1.09]

6 Withdrawals due to adverse effects – main analysis Show forest plot	3	6071	Risk Ratio (M‐H, Fixed, 95% CI)	1.58 [1.34, 1.85]

7 Withdrawals due to adverse effects – sensitivity analysis: persistent atrial fibrillation Show forest plot	1	199	Risk Ratio (M‐H, Fixed, 95% CI)	14.51 [0.90, 234.74]

8 Withdrawals due to adverse effects – sensitivity analysis: low risk of bias studies Show forest plot	1	4628	Risk Ratio (M‐H, Fixed, 95% CI)	1.57 [1.32, 1.87]

9 Withdrawals due to adverse effects – sensitivity analysis: studies > 200 participants Show forest plot	2	5872	Risk Ratio (M‐H, Fixed, 95% CI)	1.53 [1.31, 1.80]

10 Proarrhythmia – main analysis Show forest plot	2	5872	Risk Ratio (M‐H, Random, 95% CI)	1.95 [0.77, 4.98]

11 Proarrhythmia – sensitivity analysis: low risk of bias studies Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

12 Proarrhythmia – sensitivity analysis: studies > 200 participants Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

13 Stroke – main analysis Show forest plot	2	5872	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.47, 0.95]

14 Stroke – sensitivity analysis: studies > 200 participants Show forest plot	2	5872	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.47, 0.95]

15 Atrial fibrillation recurrence – main analysis Show forest plot	2	1443	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.80, 0.91]

16 Atrial fibrillation recurrence – sensitivity analysis: persistent atrial fibrillation Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

17 Atrial fibrillation recurrence – sensitivity analysis: studies > 200 participants Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

Comparison 8. Dronedarone versus placebo or no treatment

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Comparison 9. Sotalol versus placebo or no treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause mortality – main analysis Show forest plot	5	1882	Risk Ratio (M‐H, Fixed, 95% CI)	2.23 [1.03, 4.81]

2 All‐cause mortality – intention to treat (ITT) worse case: missing participants counted as events Show forest plot	10	2757	Risk Ratio (M‐H, Fixed, 95% CI)	2.02 [1.28, 3.20]

3 All‐cause mortality – sensitivity analysis: persistent atrial fibrillation Show forest plot	3	1311	Risk Ratio (M‐H, Fixed, 95% CI)	2.51 [1.06, 5.98]

4 All‐cause mortality – sensitivity analysis: low risk of bias studies Show forest plot	3	1311	Risk Ratio (M‐H, Fixed, 95% CI)	2.51 [1.06, 5.98]

5 All‐cause mortality – sensitivity analysis: studies > 200 participants Show forest plot	4	1826	Risk Ratio (M‐H, Fixed, 95% CI)	2.65 [1.16, 6.09]

6 Withdrawals due to adverse effects – main analysis Show forest plot	12	2688	Risk Ratio (M‐H, Random, 95% CI)	1.95 [1.23, 3.11]

7 Withdrawals due to adverse effects – sotalol: heterogeneity study Show forest plot	12	2688	Risk Ratio (M‐H, Random, 95% CI)	1.95 [1.23, 3.11]

7.1 PAFAC and SOPAT trials	2	987	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.74, 1.25]
7.2 Rest of studies	10	1701	Risk Ratio (M‐H, Random, 95% CI)	2.77 [1.81, 4.22]
8 Withdrawals due to adverse effects – sensitivity analysis: persistent atrial fibrillation Show forest plot	6	1350	Risk Ratio (M‐H, Fixed, 95% CI)	1.75 [1.28, 2.41]

9 Withdrawals due to adverse effects – sensitivity analysis: low risk of bias studies Show forest plot	4	1686	Risk Ratio (M‐H, Random, 95% CI)	1.52 [0.82, 2.81]

10 Withdrawals due to adverse effects – sensitivity analysis: studies > 200 participants Show forest plot	5	1900	Risk Ratio (M‐H, Random, 95% CI)	1.81 [0.97, 3.35]

11 Proarrhythmia – main analysis Show forest plot	12	2989	Risk Ratio (M‐H, Fixed, 95% CI)	3.55 [2.16, 5.83]

12 Proarrhythmia – sotalol: heterogeneity study Show forest plot	11	2826	Risk Ratio (M‐H, Fixed, 95% CI)	3.43 [2.07, 5.67]

12.1 PAFAC and SOPAT trials	2	986	Risk Ratio (M‐H, Fixed, 95% CI)	1.49 [0.51, 4.37]
12.2 Rest of studies	9	1840	Risk Ratio (M‐H, Fixed, 95% CI)	4.32 [2.40, 7.76]
13 Proarrhythmia – sensitivity analysis: persistent atrial fibrillation Show forest plot	6	1687	Risk Ratio (M‐H, Fixed, 95% CI)	4.37 [2.25, 8.52]

14 Proarrhythmia – sensitivity analysis: low risk of bias studies Show forest plot	4	1686	Risk Ratio (M‐H, Fixed, 95% CI)	3.05 [1.73, 5.40]

15 Proarrhythmia – sensitivity analysis: studies > 200 participants Show forest plot	6	2293	Risk Ratio (M‐H, Fixed, 95% CI)	3.00 [1.77, 5.06]

16 Stroke – main analysis Show forest plot	3	1161	Risk Ratio (M‐H, Fixed, 95% CI)	1.47 [0.48, 4.51]

17 Stroke – sensitivity analysis: persistent atrial fibrillation Show forest plot	1	393	Risk Ratio (M‐H, Fixed, 95% CI)	1.35 [0.36, 5.00]

18 Stroke – sensitivity analysis: low risk of bias studies Show forest plot	2	768	Risk Ratio (M‐H, Fixed, 95% CI)	1.85 [0.20, 16.71]

19 Stroke – sensitivity analysis: studies > 200 participants Show forest plot	3	1161	Risk Ratio (M‐H, Fixed, 95% CI)	1.47 [0.48, 4.51]

20 Atrial fibrillation recurrence – main analysis Show forest plot	14	3179	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.80, 0.87]

21 Atrial fibrillation recurrence – sensitivity analysis: persistent atrial fibrillation Show forest plot	7	1743	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.77, 0.86]

22 Atrial fibrillation recurrence – sensitivity analysis: low risk of bias studies Show forest plot	4	1686	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.82, 0.91]

23 Atrial fibrillation recurrence – sensitivity analysis: studies > 200 participants Show forest plot	6	2293	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.81, 0.89]

Comparison 9. Sotalol versus placebo or no treatment

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