Lucie Valembois

Etienne Audureau

Andrea Takeda

Witold Jarzebowski

Joël Belmin

Carmelo Lafuente-Lafuente
email: carmelo.lafuente@cfx.ap-hop.paris.fr

Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation

Background Description of the condition

Atrial fibrillation is the most common sustained arrhythmia and its incidence increases substantially with age [START_REF] Go | Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study[END_REF][START_REF] Knuiman | A cohort study examination of established and emerging risk factors for atrial fibrillation: the Busselton Health Study[END_REF][START_REF] Ruigomez | Incidence of chronic atrial fibrillation in general practice and its treatment pattern[END_REF]. Atrial fibrillation is associated with increased morbidity and mortality, due to stroke, other embolic complications and heart failure (Benjamin 1998;Heeringa 2006;Krahn 1995;Stewart 2002). In developed countries, atrial fibrillation has grown progressively in the last few decades as a contributing cause of hospitalisation and death (Chugh 2014;MMWR 2003;Wattigney 2003).

In people who have atrial fibrillation, normal sinus rhythm is interrupted by periods of atrial fibrillation that may be either symptomatic or asymptomatic. Symptoms can be mild (for example palpitations, breathlessness or reduced effort capacity) or severe, causing syncope, heart failure or acute coronary syndrome. Many of the symptoms caused by atrial fibrillation are related to the degree of tachycardia and can be improved by either controlling heart rate (rate control strategy) or converting atrial fibrillation to normal sinus rhythm by electrical or pharmacological means (rhythm control strategy).

Most patients alternate between atrial fibrillation and sinus rhythm. The frequency and duration of atrial fibrillation are highly variable, both within patients and between patients, and are employed to classify this arrhythmia (ESC 2016; ACC/AHA/ESC 2014; NICE 2014). If the arrhythmia terminates spontaneously, atrial fibrillation is designated as 'paroxysmal', and it may recur afterwards or not. When atrial fibrillation is sustained beyond seven days it is designated as 'persistent'. Termination with pharmacological or electrical intervention does not change the designation. When atrial fibrillation is first detected, and it is not known if it will resolve or persist, it is designated 'recent onset' or simply 'first detected' atrial fibrillation. Finally, 'permanent' atrial fibrillation refers to persistent atrial fibrillation where cardioversion has failed or has not been attempted because it is considered that there is no possibility to restore sinus rhythm. An individual patient can show different classes of atrial fibrillation over time.

Description of the intervention

Many patients recover sinus rhythm spontaneously after an episode of recent onset atrial fibrillation, as many as 70% in some studies [START_REF] Geleris | Spontaneous conversion to sinus rhythm of recent (within 24 hours) atrial fibrillation[END_REF]. Electrical and pharmacological cardioversion are very effective in restoring sinus rhythm, even in long-standing persistent atrial fibrillation. However, a major problem is that recurrence of atrial fibrillation occurs frequently. The risk of recurrence of atrial fibrillation is dependent on age, duration of the atrial fibrillation and the existence and severity of underlying heart disease (Flaker 1995;Frick 2001). The overall rate of recurrence of atrial fibrillation without treatment is high; of patients who have converted to sinus rhythm, only 20% to 30% will remain in sinus rhythm one year later (Gelder 1996;Golzari 1996;AFFIRM 2002).

Long-term antiarrhythmic therapy has been widely used to prevent the recurrence of atrial fibrillation. Antiarrhythmic drugs are usually grouped into four classes following the classification by Vaughan Williams (Vaughan Williams 1984). Class I drugs are those with a direct membrane action (sodium (Na) channel blockade), subdivided to Ia, Ib and Ic depending on specific effects on conduction and repolarization; class II drugs are betablockers; class III drugs are those that prolong repolarization; and class IV drugs are calcium channel blockers. There is evidence that several class I, class III and maybe class II antiarrhythmic drugs are more effective than placebo for maintaining sinus rhythm [START_REF] Miller | [END_REF]Nichol 2002). However, some questions remain concerning the long term use of antiarrhythmic drugs.

How the intervention might work

It has been assumed that keeping patients in sinus rhythm would improve their quality of life and reduce the risks of embolism, stroke, heart failure or increased mortality that are associated with atrial fibrillation (Anter 2009). However, this has not been proven and, unfortunately, many of the trials with antiarrhythmic drugs have focused only on maintenance of sinus rhythm and have not assessed other relevant outcomes (Connolly 2000). Overall, the rhythm control strategy, using antiarrhythmics to maintain sinus rhythm, has not shown any clear benefit on clinical outcomes (for example mortality or stroke) in randomised controlled trials compared to a rate control strategy (Caldeira 2012;Chatterjee 2013;Cordina 2005;[START_REF] De Denus | Rate vs rhythm control in patients with atrial fibrillation: a meta-analysis[END_REF]Testa 2005).

Chronic treatment with antiarrhythmic drugs can be associated with severe adverse effects, including the potential induction of life-threatening arrhythmias (a phenomenon called "proarrhythmia"). Adverse effects could compromise any benefits of maintaining sinus rhythm, or even outweigh them, leading to worse outcomes overall. In fact, the results of some trials show increased mortality associated with the long-term use of some antiarrhythmics, as in the case with quinidine (Coplen 1990;SPAF 1992) or flecainide (CAST 1991). Finally, it is not known if all antiarrhythmic drugs are equivalent in their effectiveness and safety in the treatment of atrial fibrillation.

Why it is important to do this review

Many trials have studied long-term treatment with diverse antiarrhythmic drugs for maintaining sinus rhythm, sometimes compared to placebo and sometimes compared to other antiarrhythmic drugs. Attempts to summarise this evidence in systematic reviews of trials or meta-analyses have been incomplete. They were combined in a narrative review (Golzari 1996); trials using different antiarrhythmics and with very dissimilar lengths of treatment were pooled together (Nichol 2002); and outcomes other than sinus rhythm maintenance were not evaluated [START_REF] Miller | [END_REF]. Consequently, we planned to conduct a more exhaustive systematic review of randomised controlled trials studying the long-term use of antiarrhythmic drugs to maintain sinus rhythm and aimed to determine their effects not only on the recurrence of atrial fibrillation but also on other important clinical outcomes.

After the first publication of this review, another meta-analysis on the same subject was published by Freementle et al (Freemantle 2011). This meta-analysis employed a mixed treatment comparison method, combining the estimates obtained from direct and indirect comparisons in a network of trials. Network meta-analysis represents an interesting extension of traditional pairwise meta-analyses and can potentially provide a more complete overview of a health set. However, appropriate use of these methods requires strict assumptions and standardization (Caldwell 2015). Although assumptions underlying classical pairwise metaanalyses are well understood, those concerning network meta-analysis are more complex and prone to misinterpretation. The conduction of network meta-analysis still poses multiple challenges that should be carefully considered when utilizing such methods (Cipriani 2013;

Measures of treatment effect

Risk ratio (RR) was determined for all outcomes as they are all dichotomous variables. If evidence of an effect appeared for any outcome and the control group rates of the outcomes were broadly similar, we calculated the number needed to treat to benefit (NNTB) or number needed to treat to harm (NNTH) to prevent or produce, respectively, one adverse outcome for the specified duration of treatment. We used the pooled RR and the pooled rate from the control groups.

Unit of analysis issues

There was no cross-over trial or cluster randomised trial included in this review. For trials with multiple timepoints, only data at one year (or the nearest timepoint) was included. For trials comparing two antiarrhythmics and placebo/no treatment, the placebo (or no treatment) group was spliced into two groups with smaller sample size, to include two different comparisons.

In addition, the worst-case scenario intention-to-treat-analysis (this is, considering all missing patients as having events) was also carried out for all outcomes to test if any potential difference might have arisen due to losses to follow up.

Results

Description of studies

Results of the search

We found a total of 6,332 references and assessed 205 articles in more detail for the previous publication of this review (Lafuente-Lafuente 2015. We retrieved, translated, when needed, and assessed articles in Chinese, English, French, German, Italian, Spanish and Swedish. Finally, 59 studies fulfilled the inclusion criteria and had useable data. They comprised 20,981 patients in total.

Compared with the previous publication of this review in 2015, which searched the medical literature until January 2014, we read 2185 additional references (LV, CLL, AT), assessed in detail 21 new articles (LV, EA, CLL, WJ), included one new randomised controlled trial [START_REF] Chun | Efficacy of dronedarone versus propafenone in the maintenance of sinus rhythm in patients with atrial fibrillation after electrical cardioversion[END_REF]) and identified one ongoing study (Park 2017). The new included trial compared dronedarone and propafenone, added 100 more patients and reported only AF recurrence rates, but not mortality or adverse events.

On the contrary, during our process of checking papers for double publication we became aware that the data from one study we had previously included, SVA-4 2008a, was already reported in another included publication (ASAP 2003) and we amended that.

Figure 1 illustrates the selection of articles, following the PRISMA model. Agreement between authors was good for both selecting studies and extracting the data. Details of each included study are shown in the Characteristics of included studies table, and the reasons for exclusion are shown in the Characteristics of excluded studies table.

Included studies

Patients

Entry criteria differed between studies in several aspects. In some trials atrial fibrillation was documented in the past history but patients were in sinus rhythm at the time of inclusion, while in other trials patients were in atrial fibrillation and needed to be converted to sinus rhythm (only those converted were included in the review). The duration of atrial fibrillation when persistent, or the time from the last documented episode of atrial fibrillation when paroxysmal, were highly variable (from one month to one year, or no time limit in some studies). Some of the studies required atrial fibrillation to be symptomatic while others did not. A few studies (six in total) enrolled both patients with atrial fibrillation or atrial flutter. When available, only data from patients with atrial fibrillation were used.

Regarding the type of atrial fibrillation, 8 studies included exclusively paroxysmal or recent onset atrial fibrillation, 28 studies included only persistent atrial fibrillation (i.e. lasting more than 7 days), and the remaining 23 studies included both types. Overall, 48% of the pooled population had persistent or permanent atrial fibrillation.

The mean age of patients varied from 46 to 72 years in the included studies and was 64.8 years in the pooled population. The proportion of patients having underlying heart disease varied widely, from 29% to 100%, with only one study selectively including patients without structural heart disease (FAPIS 1996). The most frequent diseases were coronary artery disease (5% to 50% of patients), hypertension, and valvular abnormalities (less frequent in recent studies). The mean left ventricle ejection fraction was greater than 50% in almost all trials but with five exceptions (DIAMOND 2001;[START_REF] Kalusche | Sotalol and quinidine/verapamil (Cordichin) in chronic atrial fibrillation -conversion and 12-month follow-up -a randomized comparison [Sotalol und Chinidin/Verapamil (Cordichin) bei chronischem Vorhoflimmern -Konversion und 12-Monats-Follow-up -ein randomisierter Vergleich[END_REF]Nergardh 2007;[START_REF] Plewan | Maintenance of sinus rhythm after electrical cardioversion of persistent atrial fibrillation; sotalol vs bisoprolol[END_REF]Vijayalaskshmi 2006).

Interventions

Twenty nine trials (accumulating 13,443 patients) compared an antiarrhythmic with a control, 12 trials (4536 patients) compared two different antiarrhythmics and a control, and 18 trials (3,002 patients) compared two or more antiarrhythmics with each other. The comparator used in the 41 trials with control groups was a placebo in 32 trials, a beta-blocker in 2 trials [START_REF] Daphne Study Investigators | The Drug And Pace Health cliNical Evaluation (DAPHNE) study: a randomized trial comparing sotalol versus beta-blockers to treat symptomatic atrial fibrillation in patients with brady-tachycardia syndrome implanted with an antitachycardia pacemaker[END_REF][START_REF] Plewan | Maintenance of sinus rhythm after electrical cardioversion of persistent atrial fibrillation; sotalol vs bisoprolol[END_REF], digoxin in 1 trial [START_REF] Steinbeck | Therapy of paroxysmal atrial fibrillation. Cardiac glycosides alone or combined with anti-arrhythmia agents? [Therapie des paroxysmalen Vorhofflimmerns. Herzglykoside allein oder in Kombination mit Antiarrhythmika?[END_REF] and no treatment in 6 trials (Flec-SL 2012;[START_REF] Hillestad | Quinidine in maintenance of sinus rhythm after electroconversion of chronic atrial fibrillation. A controlled clinical study[END_REF][START_REF] Santas | Early withdrawal of amiodarone after cardioversion in atrial fibrillation patients treated with irbesartan. A prospective randomized study[END_REF][START_REF] Sodermark | Effect of quinidine on maintaining sinus rhythm after conversion of atrial fibrillation or flutter. A multicentre study from Stockholm[END_REF]Van Gelder 1989;Vijayalaskshmi 2006).

Drugs included in this review, for which at least one well designed randomised controlled trial was found, were (a) class Ia: quinidine, disopyramide; (c) class Ic: flecainide, propafenone; (d) class II (beta-blockers): metoprolol; (e) class III: amiodarone, dofetilide, dronedarone and sotalol.

Follow up

The most frequent length of follow up was one year. It was shorter in 17 trials (6 to 9 months) and longuer in 6 trials (15 to 19 months). Five trials followed patients for two years or more (AFFIRM Substudy 2003;ATHENA 2009;Kochiadakis 2000;Kochiadakis 2004a;Kochiadakis 2004b). We extracted and pooled all outcomes at one year of follow up or the nearest time point available. For studies with shorter duration of follow up the last observation available was employed. Overall, the mean follow-up of the pooled population analysed was 10.2 months.

Excluded studies

Main reasons for exclusion of studies were not being actually controlled or randomized (43 studies), having a follow-up shorter than 6 months (16 studies) and including in the control group patients who did not revert to sinus ryhtm (10 studies). Additionnal details on excluded studies are given in the Characteristics of excluded studies table.

Risk of bias in included studies

Asymmetry was found in the funnel plot of withdrawals beacuse of adverse effects on treatment with sotalol (Figure 2). It showed fewer small studies on the left side (this is, there were more small studies showing a trend to more withdrawals on active treatment). However, funnel plots for other outcomes with sotalol were symmetric, so we think the risk of substantial publication bias is low. Funnel plots for the remaining drugs were symmetric.

The results of the assessment of the risk of bias of included studies across different domains are showed in Figure 3 and Figure 4.

Allocation (selection bias)

All included studies were described as randomised controlled trials. However, only a minority detailed how the random number sequence was generated (18 studies, 30.5%) or how the allocation of patients was concealed (17 studies, 28.8%). Because of lack of details, the risk of bias on these items is unclear for the remaining studies.

Blinding (performance bias and detection bias)

The majority of trials comparing an antiarrhythmic versus a control were described as blinded (of 41 trials: 25 were double-blind and 5 single-blind, the remaining 11 were open-label). In contrast, most trials comparing two or more different antiarrhythmics were open-label (15 out of 18). However, only 17 of the 25 studies said to be double-blind adequately reported the method of blinding (and it was adequate in all cases). Nonetheless, we think that the risk of bias associated to this lack of adequate blinding is not very high because: (a) most outcomes assessed in this review are objective ones: recurrence of AF and pro-arrhythmia were established by ECG records, mortality and stroke are hard outcomes; (b) results from adequately double-blind studies and open-label studies are very consistent; (c) well described, adequate blinding was more frequent in studies comparing an active drug with no active treatment, which is the main comparison of the review.

Incomplete outcome data (attrition bias)

Withrawals and dropouts were adequately reported in the majority of studies. The percentage of patients lost to follow up was detailed in 47 out of the 59 included trials and was small (5% to 10%). However, virtually all studies followed patients until atrial fibrillation recurred or until treatment was stopped for any reason, and no longer. Data for some outcomes, like mortality, were therefore not extensive.

Selective reporting (reporting bias)

All studies but three [START_REF] Chun | Efficacy of dronedarone versus propafenone in the maintenance of sinus rhythm in patients with atrial fibrillation after electrical cardioversion[END_REF][START_REF] Daphne Study Investigators | The Drug And Pace Health cliNical Evaluation (DAPHNE) study: a randomized trial comparing sotalol versus beta-blockers to treat symptomatic atrial fibrillation in patients with brady-tachycardia syndrome implanted with an antitachycardia pacemaker[END_REF][START_REF] Santas | Early withdrawal of amiodarone after cardioversion in atrial fibrillation patients treated with irbesartan. A prospective randomized study[END_REF] had data on all-cause mortality, all but two (ASAP 2003;PITAGORA 2008) on atrial fibrillation recurrence rates, and all but three (AFIB 1997;[START_REF] Chun | Efficacy of dronedarone versus propafenone in the maintenance of sinus rhythm in patients with atrial fibrillation after electrical cardioversion[END_REF][START_REF] Santas | Early withdrawal of amiodarone after cardioversion in atrial fibrillation patients treated with irbesartan. A prospective randomized study[END_REF] presented data for adverse effects, either withdrawals or pro-arrhythmia (Table 1). Other outcomes were less frequently reported: in studies with a placebo or no treatment arm, stroke was reported in 11 trials, heart failure in 2 trials and actual frequency of anticoagulation in none. All studies reported the outcomes they have prespecified in the way they had prespecified.

Other potential sources of bias

Conflict of interest could exist as almost all the studies included in the review were funded by the company manufacturing the antiarrhythmic drug tested.

Effects of interventions

All outcomes were calculated at one year of follow up or the nearest time point (overall mean follow-up was 10.2 months).

Imputing missing patients as events (the worst-case intention-to-treat scenario) generally did not modify the results, so the best-case intention-to-treat analysis (missing patients counted as being free of events) was reported as the default; where differences existed details are given.

All-cause mortality

The all-cause mortality rate was low (0% to 5.1% at 1 year). The only exception to this generally low mortality rate was the DIAMOND study (DIAMOND 2001). This trial recruited patients with advanced heart failure and had an overall all-cause mortality of 31% at 1 year.

The quantity and quality of data on mortality varied markedly between drugs. We could not find any data on mortality with flecainide and very few data with disopyramide and propafenone.

More data was available for other drugs. We found evidence suggesting an increase in the risk of death with two drugs, quinidine and sotalol. For the remaining drugs studied, available evidence did not show any apparent effect in mortality.

No important heterogeneity between studies was detected for this outcome with any of the drugs studied.

Drugs with very few or no data on mortality

Disopyramide

Only one study reported all-cause mortality in people taking disopyramide compared with placebo/no treatment. It included only 92 participants and had a very wide confidence interval for mortality that includes both possible benefits and harms (Analysis 2.1: RR 5.00, 95% CI 0.25 to 101.37; I 2 = 0%, low-quality evidence).

Counting missing participants as having died did not change this finding (Analysis 2.2). No other sensitivity analysis could be carried out.

Propafenone

Of the five included trials (998 patients), only two studies reported any death, one each. The confidence interval was wide, including both possible benefits and harms, and the results varied markedly between the main analysis (Analysis 3.1) (RR 0.19, 95% CI 0.02 to 1.68; participants = 212; studies = 2; I 2 = 0%) and the sensitivity analysis which treated missing participants as having died (Analysis 3.2) (RR 1.28, 95% CI 0.45 to 3.62; participants = 406; studies = 3; I 2 = 19%). Restriciting the analysis to the only study at low risk of bias (Analysis 3.3) did not differ from the main analysis.

Overall, the evidence for this outcome is very low-quality, meaning that we are uncertain of the effect of propafenone on mortality.

Flecainide

None of the four trials we found studying flecainide (511 patients in total) reported any death from any cause. Thus, this outcome could not be analysed.

Drugs associated with an increase in mortality

Quinidine

All-cause mortality was reported by six studies which compared quinidine with placebo or no treatment (Analysis 1.1). The GRADE rating was low-quality for this outcome. The pooled RR suggested that risk of mortality was higher in people taking quinidine compared with placebo or no treatment, although the confidence interval also includes the possibility of a lower or similar mortality rate (RR 2.01, 95% CI 0.84 to 4.77; participants = 1646; studies = 6; I 2 = 0%).This corresponds to eight deaths per 1,000 in the control group and 15 per 1,000 (95% CI 6 to 36 per 1,000) in the quinidine group.

Sensitivity analysis which treated missing patients as having died (Analysis 1.2) increased the RR slightly, but was not substantially different to the main analysis (RR 2.12, 95% CI 0.96 to 4.67; participants = 1646; studies = 6; I 2 = 0%).

Conversely, sensitivity analysis of quinidine studies at low risk of bias (Analysis 1.5), or studies with more than 200 participants (Analysis 1.6), left only two studies (PAFAC 2004;SOPAT 2004) in which no difference in all-cause mortality was apparent compared with controls (RR 1.29, 95% CI 0.34 to 4.92; participants = 1234; studies = 2; I 2 = 0%). These two trials were more recent, employed a lower dose of quinidine (320 to 480 mg/day) than other studies (800 to 1800 mg/day) and combined quinidine with verapamil. However, when comparing those two studies against older, higher dose studies (Analysis 1.3), the test for subgroup differences did not indicate that the effect differed between those two groups (P=0.4).

Other sensitivity analysis did not differ from the main analysis (Analysis 1.4: persistent atrial fibrillation).

Sotalol

High-quality evidence from five RCTs indicated that people taking sotalol had a higher allcause mortality rate than those with placebo or no treatment (Analysis 9.1; RR 2.23, 95% CI 1.03 to 4.81; participants = 1882; studies = 5; I 2 = 0%) (Figure 7). This corresponds to eight deaths per 1,000 in the control group and 19 (95% Ci 9 to 40) in the sotalol group. The NNTH for sotalol was 102 patients treated for one year to have one excess death, with a wide 95% CI of 33 to 4167.

This association with increased mortality persisted in all sensitivity analyses undertaken, either counting missing patients as deaths (Analysis 9.2) (RR 2.02, 95% CI 1.28 to 3.20; participants = 2757; studies = 10; I 2 = 0%), restricting to those studies at low risk of bias (Analysis 9.4) or which included only persistent atrial fibrillation (Analysis 9.3), analysis which were identical since they both contained the same studies (RR 2.51, 95% CI 1.06 to 5.98; participants = 1311; studies = 3; I 2 = 0%). An even larger effect was seen when restricting the analysis to just those studies with at least 200 participants (Analysis 9.5) (RR 2.65, 95% CI 1.16 to 6.09; participants = 1826; studies = 4; I 2 = 0%).

Drugs with no apparent effect on mortality

For the remaining drugs studied, available evidence did not show any apparent difference in mortality with respect to placebo / no treatment. However, data for mortality was rarely extensive and the data obtained could be underpowered to detect mild differences in mortality for several of the drugs studied.

Metoprolol

Two studies (moderate-quality evidence) were pooled that compared metoprolol with placebo or no treatment. The main analysis obtained very wide confidence intervals (Analysis 5.1) (RR 2.02, 95% CI 0.37 to 11.05; participants = 562; studies = 2; I 2 = 47%). Results did not change in any of the sensitivity analyses (Analysis 5.2; Analysis 5.3; Analysis 5.4; Analysis 5.5).

Amiodarone

Moderate-quality evidence from two studies comparing amiodarone with placebo or no treatment (Analysis 6.1) produced wide confidence intervals (RR 1.66, 95% CI 0.55 to 4.99; participants = 444; studies = 2; I 2 = 10%). This finding did not change in any of the sensitivity analyses (Analysis 6.2; Analysis 6.3).

Dofetilide

Moderate-quality evidence from three RCTs Analysis 7.1 (RR 0.98, 95% CI 0.76 to 1.27; participants = 1183; studies = 3; I 2 = 0%) gave no evidence of a difference in all-cause mortality rate between dofetilide and placebo/ no treatment groups. Sensitivity analyses did not differ substantially from the main analysis (Analysis 7.2; Analysis 7.4; Analysis 7.3; Analysis 7.5).

Dronedarone

High-quality evidence from three RCTs (Analysis 8.1) showed no clear difference in allcause mortality between dronedarone and placebo/ no treatment (RR 0.86, 95% CI 0.68 to 1.09; participants = 6071; studies = 3; I 2 = 0%). The ATHENA 2009 study dominates this analysis, taking 97% of the weight in the meta-analysis.

There was very little difference between this main result and the different sensitivity analyses (Analysis 8.2; Analysis 8.3; Analysis 8.4; Analysis 8.5).

Head to head comparisons

In direct comparisons between antiarrhythmics, no differences in mortality was observed (Table 2).

Withdrawals due to adverse effects

Withdrawals due to adverse effects were more frequent with all studied drugs: Quinidine Moderate-quality evidence suggested a higher number of withdrawals due to adverse events in the quinidine group than in the placebo/no treatment controls (Analysis 1.7), although the confidence interval does include the possibilities of a slightly smaller number of withdrawals and also of no difference between groups (RR 1.56, 95% CI 0.87 to 2.78; participants = 1669; studies = 7; I 2 = 67%). This corresponds to 163 withdrawals per 1,000 people in the control group and 254 (95% CI 142 to 452) in the quinidine group.

There was high heterogeneity in the main analysis, which seemed to be related to two more recent studies (PAFAC 2004;SOPAT 2004) which employed lower doses of quinidine and combined it with verapamil. A subgroup analysis based in the age/dose of the studies (Analysis 1.8) suggested there is a real difference between these two studies and older studies which employed a higher dose of quinidine (test for subgroup differences, p=0.009). In older, higher-dose studies, approximately three times more people withdrew due to adverse effects, compared to placebo/no treatment (RR 3.05, 95% CI 1.29 to 7.22; participants = 435; studies = 5; I 2 = 29%). In more recent, lower-dose studies, there was no evidence of a difference in withdrawals (RR 0.88, 95% CI 0.61 to 1.27; participants = 1234; studies = 2; I 2 = 51%).

The results of sensitivity analysis varied depending on whether they included mostly older studies, as the analysis of studies on permanent atrial fibrillation, which showed an increase of withdrawals with quinidine (Analysis 1.9); or whether they included mainly the two more recent studies, which showed no difference with controls (Analysis 1.10, Analysis 1.11).

Disopyramide

Low-quality evidence from two RCTs indicated a more than three-fold higher risk of withdrawal due to adverse events among people taking disopyramide compared with placebo or no treatment, although the confidence interval also includes the possibility of similar risks of withdrawal due to adverse events (Analysis 2.4 RR 3.68, 95% CI 0.95 to 14.24; participants = 146; studies = 2; I 2 = 0%). This corresponds to 28 withdrawals per 1,000 people in the control group and 104 (95% CI 27 to 401) per 1,000 in the disopyramide group. The result of sensitivity Analysis 2.5 is identical to the main analysis. No further sensitivity analyses were possible.

Propafenone

Moderate-quality evidence indicated a higher risk of withdrawals due to adverse events in people taking propafenone compared with those in placebo/ no treatment groups (Analysis 3.4; RR 1.62, 95% CI 1.07 to 2.46; participants = 1098; studies = 5; I 2 = 0%). Corresponding numbers of withdrawals due to adverse events were 61 per 1,000 in the control group and 99 (95% CI 65 to 150) per 1,000 in the propafenone group. The NNTH for propafenone was 26 patients treated for one year to have one excess withdrawal (95%CI 11 to 234).

Restricting the analysis to the only study with more than 200 participants indicated a lack of evidence for a difference between groups (Analysis 3.5; RR 1.29, 95% CI 0.79 to 2.11; participants = 523; studies = 1).

Flecainide

Only one very small RCT ( Van Gelder 1989) reported withdrawals due to adverse events (Analysis 4.3) (RR 15.41, 95% CI 0.91 to 260.19; participants = 73; studies = 1; low-quality evidence). Seven people taking flecainide withdrew due to adverse events, compared with none in the control arm. The RR reflects a higher risk of withdrawal due to adverse events when taking flecainide, but the confidence interval is wide enough to include no difference between groups and even a small chance of a lower risk, but the very few people in this analysis limit the usefulness of this result. As there was just one study, all possible sensitivity analyses were identical to the main results.

Metoprolol

High-quality evidence from two RCTs found that the risk of withdrawing due to adverse events was more than three times higher among people taking metoprolol than people on placebo/ no treatment (Analysis 5.6; RR 3.47, 95% CI 1.48 to 8.15; participants = 562; studies = 2; I 2 = 0%). This represents 21 per 1,000 people on placebo/ no treatment withdrawing due to adverse effects, compared with 74 (95% CI 31 to 173 per 1,000 people on metoprolol. The NNTH was 19 patients treated for one year to have one excess withdrawal (95%CI 7 to 99).

All sensitivity analysis were similar to the main results (Analysis 5.7; Analysis 5.8; Analysis 5.9).

Amiodarone

Pooled analysis of four RCTs found low-quality evidence that the risk of withdrawing due to an adverse event was more than six times higher for people taking amiodarone than for people taking placebo/ no treatment (Analysis 6.4; RR 6.70, 95% CI 1.91 to 23.45; participants = 319; studies = 4; I 2 = 0%). This corresponds to seven people out of 1,000 taking placebo/ no treatment withdrawing, compared with 49 per 1,000 (95% CI 14 to 172) taking amiodarone. The NNTH for amiodarone was 25 patients treated for one year to have one excess withdrawal (95%CI 6 to 157).

Sensitivity analysis restricted to the only study at low risk of bias (Analysis 6.6) had a very wide confidence interval (RR 4.98,95% CI 0.65 to 38.29;participants = 99;studies = 1).

Dofetilide

Low-quality evidence from two RCTs suggested withdrawals due to adverse effects may be higher in people taking dofetilide, but the wide confidence interval also includes the possibility that there is the same risk (or a lower risk) as for people taking placebo/ no treatment (Analysis 7.6; RR 1.77, 95% CI 0.75 to 4.18; participants = 677; studies = 2; I 2 = 0%). The risk is 34 per 1,000 in the placebo/ no treatment group compared with 61 (95% CI 26 to 144) per 1,000 people taking dofetilide. Sensitivity analyses were identical to the main result (Analysis 7.7; Analysis 7.8).

Dronedarone

Three RCTs showed moderate-quality evidence of a higher risk of withdrawals due to adverse effects among people taking dronedarone (Analysis 8.6; RR 1.58, 95% CI 1.34 to 1.85; participants = 6071; studies = 3; I 2 = 31%). This corresponds to a risk of 77 withdrawals per 1,000 people in the placebo/ no treatment group and of 122 withdrawals per 1,000 people taking dronedarone (95% CI 104 to 143). The NNTH was 22 patients treated for one year to have one excess withdrawal (95%CI 15 to 38).

The ATHENA 2009 study had 82.5% of the weight in the main meta-analysis, so the sensitivity analyses are heavily influenced by this large study. When it was included, they were very similar to the main analysis (Analysis 8.8; Analysis 8.9). The analysis of studies on permanent atrial fibrillation did not include the ATHENA trial and and had a very wide confidence interval (Analysis 8.7; RR 14.51, 95% CI 0.90 to 234.74).

Sotalol

Results from 12 RCTs were pooled in Analysis 9.6 (RR 1.95, 95% CI 1.23 to 3.11; participants = 2688; studies = 12; I 2 = 56%). The risk of withdrawing due to an adverse event is almost twice as high in people taking sotalol as in people taking placebo or no treatment, with a risk of 94 withdrawals per 1,000 in the control group and 183 (95% CI 116 to 293) per 1,000 in the sotalol group. The corresponding NNTH was 11 patients treated for one year to have one excess withdrawal (95%CI 5 to 46).

Evidence was rated as moderate-quality due to suspected publication bias. Although there was an I 2 of 56% we did not downgrade for heterogeneity, because subgroup analysis Analysis 9.7 showed a difference between a subgroup containing the PAFAC 2004 and SOPAT 2004 studies, and a subgroup containing the other studies (p=0.009 from test for subgroup differences).

Sensitivity analyses all showed all an increase in withdrawals on sotalol, giving estimates which were very similar to the main analysis (permanent atrial fibrillation, Analysis 9.8), lower (low risk of bias studies, Analysis 9.9; RR 1.27, 95% CI 1.00 to 1.60; participants = 1686; studies = 4; I 2 = 78%), or slightly lower (studies with at least 200 participants, Analysis 9.10; RR 1.81, 95% CI 0.97 to 3.35; participants = 1900; studies = 5; I 2 = 79%)

Head to head comparisons

In direct comparisons between antiarrhythmics (Table 3), quinidine appeared to caused more withdrawals than flecainide or oher class I drugs. Amiodarone seemed to produce fewer withdrawals than class I drugs combined, but did not show any difference compared with dronedarone or sotalol. Sotalol, in turn, caused more withdrawals than dofetilide or betablockers.

Pro-arrhythmia

Virtually all studied antiarrhythmics showed increased pro-arrhythmic effects (counting both bradyarrhythmias and tachyarrhythmias attributable to treatment).

Ventricular arrhythmias (torsades, ventricular tachycardia (VT), ventricular fibrillation (VF), widening QRS or QT leading to stopping treatment, sudden death or unexplained syncope) were the most frequent pro-arrhythmic events reported with dofetilide (100% of all proarrhythmic events), quinidine (94%) and flecainide (69%), while symptomatic bradyarrhythmias (sinus bradycardia leading to stopping treatment, atrio-ventricular block) were more frequent with metoprolol (94% of all events) and amiodarone (69%). Others drugs demonstrated both types of pro-arrhythmic events: propafenone (63% ventricular events, 39% bradycardia), sotalol (61% ventricular events, 39% bradycardia) and dronedarone (41% ventricular events, 59% bradycardia).

Quinidine

High-quality evidence from seven RCTs (Analysis 1.12) showed that the risk of proarrhythmia was twice as high in people taking quinidine compared with people in placebo/ no treatment groups, although the confidence interval doesn't exclude the possibility of no difference between groups (RR 2.05, 95% CI 0.95 to 4.41; participants = 1676; studies = 7; I 2 = 0%). This represents 11 cases per 1,000 in the control group and 22 (95% CI 10 to 48) in the quinidine group.

In a way very similar to the analysis of withdrawals due to adverse effects, the results of sensitivity analysis varied depending wether they included mostly older, higher-dose studies, as the analysis of studies on permanent atrial fibrillation, which showed an increase of proarrhythmia with quinidine (Analysis 1.14); or whether they included mainly the two more recent, lower-dose studies (PAFAC 2004, SOPAT 2004) which showed no difference with controls (Analysis 1.15, Analysis 1.16). However, a subgroup analysis comparing older studies with more recent ones did not find a difference between groups (test for difference between subgroups P = 0.41) for this outcome (Analysis 1.3).

Disopyramide

No disopyramide studies reported pro-arrhythmia.

Propafenone

Three RCTs reported pro-arrhythmia, but the very low-quality evidence and wide confidence intervals means that we are uncertain of the effect of propafenone on this outcome (Analysis 3.6 RR 1.32, 95% CI 0.39 to 4.47; participants = 381; studies = 3; I 2 = 8%). Sensitivity analysis restricted to the only study at low risk of bias (Analysis 3.7) shows a lack of evidence for a difference between groups (RR 0.49, 95% CI 0.09 to 2.75; participants = 102; studies = 1).

Flecainide

Risk of pro-arrhythmia was over four times higher among people taking flecainide than placebo/ no treatment (Analysis 4.6; RR 4.80, 95% CI 1.30 to 17.77; participants = 511; studies = 4; I 2 = 0%; moderate-quality evidence). This corresponds to a risk of six per 1,000 among people taking placebo or no treatment, compared with a risk of 30 (95% CI 8 to 112) for people taking flecainide. The NNTH for flecainide was 44 patients treated for one year to have one excess pro-arrhythmic event (95%CI 10 to 556).

All sensitivity analysis suggested an increased risk of pro-arrhythmia with flecainide, but their confidence intervals were wider and included the possibility of no difference between groups (Analysis 4.7; Analysis 4.8; Analysis 4.9).

Metoprolol

High-quality evidence showed and important increase of pro-arrhythmia with metoprolol, compared to placebo (Analysis 5.10; RR 18.14, 95% CI 2.42 to 135.66; participants = 562; studies = 2; I 2 = 0%) due mainly to symptomatic bradyarrhythmias (94% of all proarrhythmic events). In the pooled population, pro-arrhythmic events were reported in no patient on placebo and in 60 patients per 1,000 on treatment with metoprolol. The corresponding NNTH was 19 patients treated for one year to have one excess bradyarrhythmia (95%CI 2 to 235).

All sensitivity analyses showed results similar to the main analysis (Analysis 5.11; Analysis 5.12; Analysis 5.13)

Amiodarone

Moderate quality evidence suggested an increase in pro-arrhythmia with amiodarone compared to placebo/ no treatment, but the confidence interval included the possibility of no difference (or even a reduction) (Analysis 6.7; (RR 2.22, 95% CI 0.71 to 6.96; participants = 673; studies = 4; I 2 = 0%). This corresponds to a risk of eight per 1,000 with placebo/ no treatment and of 18 (95%CI 6 to 57) with amiodarone. Symptomatic bradyarrhythmias represented 69% of events with amiodarone.

Sensitivity analyses gave similar results, the only difference was that they pooled fewer studies and confidence intervals were larger (Analysis 6.8; Analysis 6.9; Analysis 6.10).

Dofetilide

Moderate-quality evidence found a five-fold increase in pro-arrhythmic events with dofetilide compared to placebo/no treatment (Analysis 7.9; RR 5.50, 95% CI 1.33 to 22.76; participants = 1183; studies = 3; I 2 = 0%). That corresponds to two cases per 1,000 in the control group and 13 (95%CI 3 to 53) with dofetilide. The NNTH for dofetilide was 111 patients treated for one year to have one excess pro-arrhythmic event (95%CI 23 to 1515).

Sensitivity analyses did not differ to the main analysis (Analysis 7.10; Analysis 7.11; Analysis 7.12)

Dronedarone

Moderate-quality evidence from two RCTs suggested and increase of pro-arrhythmia with dronedarone compared with placebo, but the confidence interval included the possibility of no difference or even a benefit on this outcome (Analysis 8.6; RR 1.95, 95% CI 0.77 to 4.98; participants = 5872; studies = 2; I 2 = 78%). This represents 18 cases per 1,000 in the placebo group and 36 (95%CI 14 to 91) in patients taking dronedarone.

In sensitivity analysis, there was only one study (ATHENA 2009) rated as low risk of bias or including more than 200 patients. This study found an increased risk of pro-arrhythmia with dronedarone compared to placebo (Analysis 8.11; Analysis 8.12; RR 2.94, 95% CI 2.08 to 4.15, participants = 4628)

Sotalol

Moderate-quality evidence showed increased pro-arrhythmia rates on sotalol compared to placebo/ no treatment (Analysis 9.11; RR 3.55, 95% CI 2.16 to 5.83; participants = 2989; studies = 12; I 2 = 20%). This corresponds to 12 cases per 1,000 in the control group and 41 (95%CI 25 to 68) in patients treated with sotalol. The corresponding NNTH was 33 patients treated for one year to have one excess pro-arrhythmic event (95%CI 17 to 72).

All sensitivity analyses were very similar to the main analysis (Analysis 9.13; Analysis 9.14; Analysis 9.15).

Head to head comparisons

In direct comparisons between antiarrhythmics (Table 4), amiodarone seemed to produce fewer pro-arrhythmic events than class I drugs combined, but did not show clear differences compared with dronedarone or sotalol. No other differences between drugs were observed.

Stroke

Data available for this outcome was limited. Only 11 of the 41 studies with a control group (placebo or no treatment arm) reported stroke outcomes (ATHENA 2009;Benditt 1999;[START_REF] Carunchio | A comparison between flecainide and sotalol in the prevention of recurrences of paroxysmal atrial fibrillation [Confronto tra flecainide e sotalolo nella profilassi delle recidive di fibrillazione atriale parossistica[END_REF][START_REF] Euridis | Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter[END_REF]Flec-SL 2012;[START_REF] Hillestad | Quinidine in maintenance of sinus rhythm after electroconversion of chronic atrial fibrillation. A controlled clinical study[END_REF]Karlson 1998;[START_REF] Lloyd | The efficacy of quinidine and disopyramide in the maintenance of sinus rhythm after electroconversion from atrial fibrillation. A double-blind study comparing quinidine, disopyramide and placebo[END_REF]SAFE-T 2005;[START_REF] Sodermark | Effect of quinidine on maintaining sinus rhythm after conversion of atrial fibrillation or flutter. A multicentre study from Stockholm[END_REF]SOPAT 2004) and we were uncertain that reporting of stroke was complete. The reported stroke rate was very low (1% to 2% at 1 year).

Drugs with no data on stroke

No data on stroke was reported in any included study for propafenone, metoprolol and dofetilide.

Drugs with no apparent effect on stroke

Low to very-low quality evidence showed no apparent effect on stroke rates -compared to placebo or no treatment -with the following drugs:

 Quinidine (Analysis 1.17; RR 0.97, 95% CI 0.25 to 3.83; participants = 1107; studies = 4; I 2 = 0%)  Dysopiramide (Analysis 2.7; RR 0.31, 95% CI 0.03 to 2.91; participants = 146; studies = 2; I 2 = 0%)  Flecainide (Analysis 4.10; RR 2.04, 95% CI 0.11 to 39.00; participants = 362; studies = 1; I 2 = 0%)  Amiodarone (Analysis 6.11; RR 1.15, 95% CI 0.30 to 4.39; participants = 399; studies = 1; I 2 = 0%)  Sotalol (Analysis 9.16; RR 1.47, 95% CI 0.48 to 4.51; participants = 1161; studies = 3; I 2 = 0%)

The corresponding sensitivity analyses, when these were possible, did not show any notable difference with the main analyses.

Dronedarone

High-quality evidence from two RCTs suggested that dronedarone may be associated with reduced risk of stroke (Analysis 8.13; RR 0.66, 95% CI 0.47 to 0.95; participants = 5872; studies = 2; I 2 = 0%). This corresponds to a risk of stroke of 27 per 1,000 on people receiving placebo and 18 per 1,000 (13 to 25) on people taking dronedarone. The corresponding NNTB would be 109 patients treated for one year to prevent one stroke (95%CI 70 to 741).

This result, however, is due to a single large study, ATHENA 2009, which accounted for 94,6% of the weight in the meta-analysis. Sensitivity analysis restricted to studies with more than 200 patients included the same two studies and produced identical results (Analysis 8.14).

Atrial fibrillation recurrence

All antiarrhythmic drugs included in this review, including metoprolol, reduced the risk of recurrence of atrial fibrillation. Recurrence rates of atrial fibrillation at 1 year were high: 69% to 84% in controls not receiving antiarrhythmic treatment, reduced to 43% to 67% in patients treated with antiarrhythmics.

Details for each individual drug are as follows:

Quinidine

High-quality evidence showed a reduction in atrial fibrillation recurrences with quinidine (Analysis 1.21; RR 0.83, 95% CI 0.78 to 0.88; participants = 1624; studies = 7; I 2 = 0%). Recurrence rates at one year were 80.5% in patients on placebo or no treatment and 66.8% (62.8 to 70.8) in patients on quinidine. The NNTB for quinidine was 7 patients treated for one year to avoid one recurrence (95%CI 6 to 10).

Results of sensitivity analyses did not differ from the main analysis (Analysis 1.22; Analysis 1.23; Analysis 1.24)

Disopyramide

Evidence for disopyramide was low-quality because it consisted of two small RCTs with unclear risk of bias. It suggests disopyramide reduces recurrences of atrial fibrillation (Analysis 2.9; RR 0.77, 95% CI 0.59 to 1.01; participants = 146; studies = 2; I 2 = 0%). This corresponds to a recurrence rate, at 6 months to 1 year, of 69.0% in the control group and 53.1% (40.7 to 69.7) in the group treated with disopyramide. Both studies included only patients with permanent atrial fibrillation (Analysis 2.10) and no other sensitivity analysis was possible.

Propafenone

Moderate-quality evidence from five RCTs indicated that propafenone reduced atrial fibrillation recurrences by about a third (Analysis 3.8; RR 0.67, 95% CI 0.61 to 0.74; participants = 1098; studies = 5; I 2 = 0%). Recurrence rate was 73.0% in controls and 48.9% (44.5 to 54.0) in patients treated with propafenone. The corresponding NNTB was 4 patients treated for one year to avoid one recurrence (95%CI 3 to 5).

Results from sensitivity analyses were very similar (Analysis 3.9; Analysis 3.10).

Flecainide

High-quality evidence showed that flecainide reduces atrial fibrillation recurrences also by about a third (Analysis 4.14; RR 0.65, 95% CI 0.55 to 0.77; participants = 511; studies = 4; I 2 = 29%). That corresponded to a recurrence rate of 69.8% in people not treated or on placebo and of 45.4% (38.4 to 53.8) in people taking flecainide. The NNTB for flecainide was 4 patients treated for one year to avoid one recurrence (95%CI 3 to 6).

Results from sensitivity analysis did not differ substantially (Analysis 4.15; Analysis 4.16; Analysis 4.17).

Metoprolol

Moderate-quality evidence from two RCTs suggests that metoprolol reduces recurrences of atrial fibrillation, compared with placebo, but the confidence interval includes the possibility of no difference (Analysis 5.14; RR 0.83, 95% CI 0.68 to 1.02; participants = 562; studies = 2; I 2 = 59%). The corresponding recurrence rates were 72.0% in people receiving placebo and 59.7% (49.0 to 73.4) in people treated with metoprolol. All sensitivity analyses included the same two trials and obtained identical results (Analysis 5.15; Analysis 5.12) except the analysis restricted to studies including more than 200 patients, which included only one study and showed no difference between metoprolol and placebo (Analysis 4.17).

Amiodarone

High-quality evidence showed a reduction of atrial fibrillation recurrences with amiodarone of about a half, compared to placebo or no treatment (Analysis 6.14; RR 0.52, 95% CI 0.46 to 0.58; participants = 812; studies = 6; I 2 = 33%). This corresponded to a recurrence rate of 81.2% in people not receiving active treatment and of 42.2% (37.3 to 47.1) in people receiving amiodarone. The NNTB for amiodarone was 3 patients treated for one year to avoid one recurrence (95%CI 2 to 4).

All sensitivity analyses obtained very similar results (Analysis 6.15; Analysis 6.16; Analysis 6.17).

Dofetilide

Moderate-quality evidence indicated that dofetilide reduces recurrences of atrial fibrillation, compared to placebo, by about a quarter (Analysis 7.13; RR 0.72, 95% CI 0.61 to 0.85; participants = 1183; studies = 3; I 2 = 79%). Recurrence rates were 84.2% in people taking placebo and 60.6% (51.4 to 71.6) in people taking dofetilide. The corresponding NNTB was 4 patients treated for one year to avoid one recurrence (95%CI 3 to 8).

Substantial heterogeneity existed between studies on dofetilide for this outcome (I 2 = 79%, P = 0.008). All studies showed the same direction of effect (that is, a reduction of atrial fibrillation recurrences) and the heterogeneity was probably caused by differences in the characteristics of recruited patients.

Sensitivity analyses did not differ from the main analysis (Analysis 7.14; Analysis 7.15; Analysis 7.16).

Dronedarone

Moderate-quality evidence from two RCTs showed a reduction of recurrences of atrial fibrillation with dronedarone of about 15% (Analysis 8.15; RR 0.85, 95% CI 0.80 to 0.91; participants = 1443; studies = 2; I 2 = 0%). This corresponded to a recurrence rate of 76.6% in people treated with placebo and of 65.1% (61.3 to 69.7) in people treated with dronedarone.

The NNTB for dronedarone was 9 patients treated for one year to avoid one recurrence (95%CI 7 to 15).

Results from sensitivity analyses were quasi identical (Analysis 8.16; Analysis 8.17).

Sotalol

High-quality evidence found a reduction of atrial fibrillation recurrences of about a fifth with sotalol compared with placebo or no treatment (Analysis 9.20; RR 0.83, 95% CI 0.80 to 0.87; participants = 3179; studies = 14; I 2 = 54%). The corresponding recurrence rates were 78.8% in patients not receiving an antiarrhythmic and 65.4% (63.1 to 68.6) in patients receiving sotalol. The NNTB for sotalol was 7 patients treated for one year to avoid one recurrence (95%CI 6 to 10).

No substantial difference with the main analysis appeared in any of the sensitivity analyses (Analysis 9.21; Analysis 9.22; Analysis 9.23).

Head to head comparisons

In direct comparisons between antiarrhythmics (Table 5), amiodarone appeared to reduce the recurrence of atrial fibrillation more than the combined class I drugs, more than dronedarone and more than sotalol. No other differences were apparent in head to head comparisons between antiarrhythmics.

Other outcomes

Chronic anticoagulation with warfarin was mandatory (that is, every patient received anticoagulation therapy throughout the whole follow-up period) in only three studies (Channer 2004;[START_REF] Hillestad | Quinidine in maintenance of sinus rhythm after electroconversion of chronic atrial fibrillation. A controlled clinical study[END_REF]Van Gelder 1989). In the rest of the studies the decision on anticoagulation use was left to the judgement of the attending physician. Unfortunately, no trial reported the actual frequency of anticoagulation in the different treatment groups during follow up.

Seven trials reported some data on the incidence of heart failure (ATHENA 2009;DYONISOS 2010;FAPIS 1996;[START_REF] Hohnloser | Efficacy and proarrhythmic hazards of pharmacologic cardioversion of atrial fibrillation: prospective comparison of sotalol versus quinidine[END_REF][START_REF] Kuhlkamp | Use of metoprolol CR/XL to maintain sinus rhythm after conversion from persistent atrial fibrillation: a randomized, double-blind, placebo-controlled study[END_REF]PRODIS 1996;[START_REF] Reimold | Propafenone versus sotalol for suppression of recurrent symptomatic atrial fibrillation[END_REF], which was low. There were no differences in those trials between patients receiving antiarrhythmics and patients receiving placebo or no treatment.

Subgroup analysis

Twenty-three of the studies with a control group (placebo or no treatment) included only patients with persistent atrial fibrillation. The mean duration of atrial fibrillation in those studies varied greatly, from 3 to 36 months. Only four studies exclusively included patients with paroxysmal atrial fibrillation. The remaining studies included patients with both paroxysmal and persistent atrial fibrillation; none reported outcomes separately by type of atrial fibrillation.

It was not possible to compare subgroups of patients with permanent and paroxysmal atrial fibrillation for any given antiarrhythmic drug. Therefore, we analysed separately patients with permanent atrial fibrillation -for the outcomes and drugs that was possible -but as a sensitivity analysis.

Other planned subgroup analyses (patients with heart failure, studies where warfarin was mandatory versus those where it was discretionary, patients with a structurally normal heart) were not possible as separate data for each group of patients were seldom available. A more detailed analysis by left ventricular function or by the New York Heart Association (NYHA) class was not possible either, for the same reason.

Discussion

In the third update of this systematic review we have found and included just one new randomised controlled trial which added little additional information (100 patients, reported only AF recurrence rates). Conversely, we excluded a previously included study as we become aware its data were already reported in another included study. Additionnally, we have restructured the analysis of the review to treat each drug separately, in order to present all analysis and results in a clearer way. In the end, some of the results regarding specific antiarrhythmics and conclusions of the review have changed.

Summary of main results

The primary aim of this review was to determine if long-term treatment with antiarrhythmics carried any clinical benefit to patients in addition to maintenance of sinus rhythm. Consequently, we focused on all-cause mortality, stroke, embolism and also potential adverse effects of treatment as the main outcomes.

Concerning all-cause mortality, we found that no antiarrhythmic produced a benefit on mortality and that some antiarrhythmics, sotalol and very probably quinidine, actually were associated with an increase in all-cause mortality. Results for sotalol are particularly strong and the certainty of evidence is high: included studies had a low risk of bias for this outcome; results were consistent in all sensitivity analysis, replicating the results of the main analysis and indicating a clear association with increased mortality. The mortality rate in the pooled population was low, 0,8% in control patients (placebo or no treatment), but it was doubled in patients receiving sotalol. The mean NNTH was estimated at 102 patients treated for one year to have one excess death.

The results suggesting an increase in mortality also with quinidine are less solid. The confidence interval included the possibility of no difference and when the analysis was restricted to more recent, larger and high-quality studies, two studies remained (PAFAC 2004, SOPAT 2004) which showed no increase in all-cause mortality in the active treatment groups. A possible explanation is that both studies used a lower dose of quinidine than earlier trials and that quinidine was combined with verapamil, which has been shown to reduce some of the pro-arrhythmic effects of quinidine, such as accelerated atrio-ventricular conduction.

Finally, the proportion of patients having structural heart disease was lower in the PAFAC and SOPAT studies than in earlier trials. Therefore, he certainty of the evidence pointing to increased all-cause mortality with quinidine was rated as low.

It is important to note that our data does not allow us to exclude a small increase in mortality with other antiarrhythmics, similar to those observed with quinidine and sotalol. Pooled data for other drugs included fewer studies and patients than for quinidine or sotalol and could be underpowered to detect effects that are of small size. In particular, we found very few data on mortality with flecainide. This is concerning because this drug has been shown to induce an excess of mortality in some trials (CAST 1991) and it showed a high risk of pro-arrhythmia in our review, similar to that of sotalol. The combined flecainide data had only a fifth of the patients included for sotalol and, despite the fact that several of the included studies stated that they analysed mortality, no death at all was reported in any treatment group. Thus, we are very unsure about what the effect of long-term treatment with flecainide in mortality might be. Similarly, the combined data for amiodarone for this outcome included four times less patients than with sotalol, so our power to detect small increases in mortality was very limited. Amiodarone has a well known high toxicity profile, showed in our analysis one of the highest risk of withdrawing treatment due to adverse effects (RR 6.70, 95% CI 1.91 to 23.45) and was associated, in other meta-analysis employing different methods, to a possible increase in mortality (Freemantle 2011;Piccini 2009) (See below: Agreements and disagreements with other studies or reviews).

With respect to adverse effects, virtually all the antiarrhythmics showed more withdrawals from treatment due to adverse effects and were associated to increased pro-arrhythmic events, compared with patients receiving placebo or no treatment. It is important to remember that we employed an extended definition of pro-arrhythmia that included severe, symptomatic bradycardia and AV blocks. Metoprolol was associated with an increase in pro-arrhythmia, precisely because an increased incidence of severe bradycardias. Of all antiarrhythmics, quinidine at higher doses and sotalol appeared to be the drugs with more withdrawals because of adverse events both compared to controls and to other antiarrhythmics. Withdrawal rates with quinidine were as high as 25% in the pooled population anlysed. Amiodarone, even if it compared favourably with class I drugs combined, had a very high RR (6.70) for increasing withdrawals compared to placebo. Moreover, these were the results at one year follow up, and the adverse effects of amiodarone are known to increase in frequency over time (Harris 1983;Lafuente-Lafuente 2009).

Regarding other outcomes, our results show that all the antiarrhythmic drugs studied reduce the recurrence of atrial fibrillation. The effectiveness of antiarrhythmics, however, was limited: they reduced recurrences by 20% to 50% compared to controls, which means that atrial fibrillation still recurred in many patients (43% to 67%) treated with antiarrhythmics, at one year. Amiodarone seemed to be the most effective drug in preventing recurrences as it had the lowest RR and in head to head comparisons it was better than combined class I drugs, dronedarone or sotalol. In spite of this, atrial fibrillation recurred at one year in 43% of patients treated with amiodarone.

Avobe all, we did not found any evidence of any clinical benefit derived from this reduction of recurrences of atrial fibrillation. The results on mortality showed no benefit with any drug, rather the contrary, as we have already discussed. Much fewer data existed on stroke or heart failure, but what data we found showed no difference between patients receiving active antiarrhythmic treatment and those not receiving it. The only exception was a single study (ATHENA 2009) in which the stroke rate was lower in the dronedarone arm than in the placebo arm. This finding was not confirmed by other studies of dronedarone. This lack of observable clinical benefit from the reduction of atrial fibrillation recurrences can have several explanations: a) any potential benefit obtained with antiarrhythmics might be erased by the associated toxicity and increased pro-arrhythmic events; b) clinical evolution and prognosis might be determined in many patients mostly by their underlying heart disease, rather than by atrial fibrillation itself.

An interesting result of this review is that metoprolol, a beta-blocker, also showed a reduction in atrial fibrillation recurrence, based on the pooled data from two high-quality randomised controlled trials [START_REF] Kuhlkamp | Use of metoprolol CR/XL to maintain sinus rhythm after conversion from persistent atrial fibrillation: a randomized, double-blind, placebo-controlled study[END_REF]Nergardh 2007). Besides, no difference in preventing recurrences was found between beta-blockers and sotalol in two other trials (DAPHNE 2008 comparing sotalol against metoprolol or atenolol, and Plewan 2001 against bisoprolol). The effect of beta-blockers in reducing the recurrence of atrial fibrillation could be due to their ability to suppress atrial extrasystoles, known to be a frequent precipitant of paroxysmal atrial fibrillation (Haïssaguerre 1998). Beta-blocker effects might also relate to antihypertensive and anti-Ischaemic actions or to their effect in reducing cardiac remodelling associated with coronary artery disease or heart failure. Metoprolol was associated, however, like most active drugs here studied, to increased withdrawals due to adverse effects and increased cases of severe, symptomatic bradycardia.

Overall completeness and applicability of evidence

Data on all-cause mortality, recurrence of atrial fibrillation and main adverse drug events was reported by most of the included trials. We also intended to analyse other clinically relevant outcomes such as the frequency of systemic embolism and use of long-term anticoagulation, or the influence of heart failure and structural heart disease in the response to treatment. Unfortunately data on those outcomes were sparse, if reported at all. In the few trials where they were reported, the frequencies of stroke and heart failure were very low, perhaps because the populations that were included were low risk. The frequency of use of anticoagulants during the follow up was not reported in any study.

Similarly, we wanted to analyse the influence of structural heart disease on effectiveness, specially with respect to left ventricular ejection fraction and left atrial size, and the influence of duration of atrial fibrillation before cardioversion. These are factors well known to influence the risk of recurrence of atrial fibrillation. Unfortunately this analysis was not possible as separate data were not available for those patients subgroups.

This lack of data for some clinical outcomes is the main limitation of our review. Another limitation could be that in many studies patients were followed up until atrial fibrillation recurred, and not thereafter, hence additional events between that point and the complete one year of follow up might have been missed. Also, the populations included in most studies were at low risk of events, the mean age of included patients was 64 years old and most of them had a normal left ventricular ejection fraction. We do not know if our results can be extrapolated to other patient populations, especially older patients and those with a reduced left ventricular ejection fraction.

Finally, it is important to remember that maintaining sinus rhythm by using long-term antiarrhythmic drugs is only one possible step in the more general 'rhythm control' strategy, and antiarrhythmic drugs should be put within the perspective of the global strategy chosen for the patient (ACC/AHA/ESC 2014; NICE 2014). Other therapies have proven to be useful to prevent or reduce recurrence of atrial fibrillation in selected patients, especially catheter ablation (APAF 2006;[START_REF] Oral | Circumferential pulmonary-vein ablation for chronic atrial fibrillation[END_REF]Terasawa 2009); and antiarrhythmics have been occasionally used for terminating recurrences (Alboni 2004). However, the effects of these therapies on the important clinical endpoints of all-cause mortality, stroke, incidence of heart failure are still not well known. A different Cochrane review has studied the effectiveness of catheter ablation for paroxysmal and persistent atrial fibrillation (Chen 2012).

Quality of the evidence

Two areas of concern regarding the risk of bias of included studies were present: (a) a lack of details, in about 70% of studies, on the procedures followed for randomisation and for concealing the allocation of patients; and (b) a lack of double-blinding in approximately 60% of studies. The lack of details on the randomisation and concealing procedures can probably be explained, at least partly, by the fact that many of the studies were conducted in the eighties and nineties, when the standards for reporting research methods were less developed. Also, it was very difficult to obtain additional data from authors for studies so old. The lack of blinding concerned specially studies comparing two antiarrhythmics and much less studies comparing an antiarrhythmic with no active treatment. Nevertheless, these concerns did not allow us to consider the evidence as "high quality".

On the other hand, despite the potential sources of bias, there were two other characteristics that increased our confidence in the results of the review: (a) Consistency of results: for each analysis, there were always several studies available and results are very consistent across individual studies, despite their differences in blinding or in the description of the allocation procedures; (b) Objective outcomes: with the only exception of withdrawals because of adverse effects, the outcomes analysed were measured objectively (ECG records) or are hard outcomes (stroke, mortality), which reduces the risk of bias associated to the lack of blinding.

In the end, we judged the available evidence for most analysed outcomes (all-cause mortality, withdrawals dure to adverse effects, pro-arrhythmia and recurrence of atrial fibrillation) as of moderate quality.

Potential biases in the review process

We are not aware of any potential bias in the review process. There were very few disagreements between reviewers regarding the inclusion and exclusion of candidate studies. There were also few disagreements regarding the data extracted from included studies. Disagreements were easily resolved by discussion and consensus in all cases.

Agreements and disagreements with other studies or reviews

A previous meta-analysis by Coplen et al found that quinidine increased all-cause mortality (Coplen 1990). A meta-analysis by Nichol et al found no difference in all-cause mortality with any antiarrhythmic, but most of the trials that they pooled had very short follow-up periods (Nichol 2002).

A more recent network meta-analysis, using a mixed treatment comparison method (where the estimates obtained from direct and indirect comparisons are combined in a network of trials), also found an increase in all-cause mortality associated with sotalol (Freemantle 2011). This meta-analysis, as well as a different meta-analysis that compared amiodarone and dronedarone (Piccini 2009), raised the possibility of an increase in mortality associated with amiodarone treatment compared with placebo. This result, however, appeared in exploratory analysis (restricted to inclusion of larger studies) and not in the main analysis. Quinidine was not studied in the meta-analysis by Freemantle et al.

Authors' conclusions

Implications for practice

There is high-quality evidence of increased all-cause mortality associated with sotalol treatment. Consequently, this drug should not be used for this indication (maintaining sinus rhythm in patients who had atrial fibrillation). If employed, it should be with extreme caution and very closely monitored.

Similarly, quinidine should neither be employed for this indication, or used with extreme caution, as there is low-quality evidence suggesting that its use is also associated with increased mortality, as well as moderate-quality evidence of a marked increase in withdrawals due to adverse events and high-quality evidence of increased pro-arrhythmic events.

Caution should also be taken when using flecainide. This drug has been shown to induce an excess of mortality in some trials in other heart conditions (CAST 1991). Very few data on mortality is available for this drug when employed for maintaining sinus rhythm, making impossible any reliable estimation of mortality in patients with atrial fibrillation. It exists, however, moderate-quality evidence of an important increase in pro-arrhythmic events with flecainide.

Overall, given: a) the concerns regarding increased mortality with several drugs; b) the modest effectiveness of antiarrhythmic drugs for preventing recurrences of atrial fibrillation; c) the evidence of increased adverse events with all drugs studied; d) the evidence of increased pro-arrhythmic events with most drugs studied, and; e) the absence of evidence of any benefit obtained with these drugs on clinical endpoints; chronic treatment with antiarrhythmics drugs should not be considered as a first-line treatment for maintaining sinus rhythm in patients with atrial fibrillation. Other treatments, or strategies, with fewer associated adverse events, or higher effectiveness, should be considered before: no treatment at all, rate control strategy (Caldeira 2012, Chatterjee 2013), pulmonary veins catheter ablation [START_REF] Khan | [END_REF], CASTLE-AF 2018) or, in selected patients with paroxysmal atrial fibrillation, episodic, very short-term use of antiarrhythmics (in hospital or as a "pill-in-the pocket" approach, Alboni 2004[START_REF] Saborido | Systematic review and cost-effectiveness evaluation of 'pill-in-the-pocket' strategy for paroxysmal atrial fibrillation compared to episodic in-hospital treatment or continuous antiarrhythmic drug therapy[END_REF].

Implications for research

Adequate evidence exists for some outcomes (withdrawals, pro-arrhythmia and atrial fibrillation recurrences) for all drugs included in this review. There is good evidence regarding mortality for several antiarrhythmics, but there is an important lack of data on mortality for some drugs, specially flecainide and propafenone, and limited data for other drugs, like amiodarone, which does not allow to exclude small increases in mortality with them.

Available evidence is limited by the lack of systematic assessment in many studies of important clinical outcomes: stroke, heart failure, and functional measures (exercise capacity, quality of life). Trials studying antiarrhythmic drugs should measure their effects on these outcomes in addition to prevention of arrhythmia recurrences. Pending questions include the effects of antiarrhythmics on these clinical outcomes, and the effects in specific subgroups of patients, specifically patients with heart failure or reduced left ventricular ejection fraction, and older patients.

Finally, new drugs or other procedures that are more effective in preventing atrial fibrillation recurrence or are associated with fewer adverse effects, or both, would be desirable.

Other modifications included in the successive updates with respect to the original protocol were:

 Assessment of the risk of bias of included studies was expanded to comply with the new Cochrane MECIR methodological requirements;  We decided to report risk ratios instead Peto odds ratios, as originally done, because risk ratios are more interpretable by clinicians and non-statisticians. *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; RR: Risk ratio; OR: Odds 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 Footnotes 1 Downgraded 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) 2 Downgraded one level for imprecision: confidence interval includes no effect, the possibility of a beneficial effect, and a strong harmful effect.

3 Not downgraded for study limitations, as the 2 studies contributing majority of weight were at low risk for key domains (allocation concealment, blinding, incomplete outcome data) 4 Not downgraded for inconsistency: although heterogeneity was high for the main analysis, this was partially explained by subgroup analysis.

5 Downgraded one level for imprecision: confidence interval includes possibility of no effect or small beneficial effect as well as harmful effect.

6 Not downgraded for imprecision, although CI just includes null 7 Downgraded one level for imprecision: confidence interval includes both important benefits and harms, and event rate was very low. *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).

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

CI:

Confidence interval; RR: Risk ratio; OR: Odds 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 Footnotes 1 Not downgraded for study limitations: study had unclear blinding but this is less relevant for this outcome.

2 Downgraded by two levels for imprecision: very small sample size and wide confidence intervals including both important benefits and harms.

3 Downgraded by one level for study limitations: both studies had unclear risk of bias for one of the key domains.

4 Downgraded by one level for imprecision: very small sample size *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).

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

CI:

Confidence interval; RR: Risk ratio; OR: Odds 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 Footnotes 1 Downgraded by 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).

2 Downgraded by two levels for imprecision due to small sample size and confidence interval wide enough to include both important benefit and harm. 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 Footnotes 1 Not 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.

2 Downgraded by two levels for imprecision due to small sample size and wide confidence interval that included both possible harm and no effect.

3 Downgraded by one level for study limitations; all studies were at high or unclear risk of bias in at least one of the key domains.

4 Not 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. *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).

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

CI:

Confidence interval; RR: Risk ratio; OR: Odds 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 Footnotes 1 Downgraded by one level for imprecision: confidence interval includes both possible benefit and harm

2 Downgraded by one level for study limitations: majority of weight was from studies with unclear or high risk of bias in key domains.

3 Downgraded by one level for imprecision: small sample size 4 Not downgraded for study limitations, as the majority weight was from studies at low risk of bias in all key domains.

5 Downgraded by two levels for imprecision: small sample size and wide confidence interval which includes both possible benefit and harm. *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; RR: Risk ratio; OR: Odds 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 Footnotes 1 Downgraded by one level for study limitations: majority of studies had unclear risk of selection bias.

2 Downgraded by one level for imprecision: confidence interval includes both possible benefit and harm.

3 Not downgraded for study limitations as 51% of weight came from a study with low risk of bias across all domains (but other 2 studies had unclear risk of selection bias).

4 Downgraded by one level for heterogeneity due to very high I 2 value (79%) *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; RR: Risk ratio; OR: Odds 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 Footnotes 1 Downgraded by one level for study limitations: 83% of weight came from a study with unclear blinding, which could be relevant to this outcome.

2 Downgraded by one level for inconsistency due to very high I 2 of 78%.

3 Downgraded by one level for study limitations: most weight came from a study with unclear allocation concealment. *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).

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

CI:

Confidence interval; RR: Risk ratio; OR: Odds 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 Footnotes 1 Not 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.

2 Not downgraded for inconsistency. I 2 was 56% for the main analysis but this was partially explained by subgroup analysis.

3 Downgraded by one level for publication bias: forest plot appears to be asymmetrical.

4 Downgraded by one level for imprecision: confidence interval includes both possible benefit and harm 5 Not downgraded for publication bias: funnel plot appears to be broadly symmetrical. 6 Not downgraded for inconsistency. I 2 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. All-cause mortality with Sotalol compared with placebo / no treatment: Main analysis.

Additional tables 1 Number of studies assessing each primary outcome

Sources of support

Figures Figure 1

 1 Figures

Figure

  Figure (Analysis 9.6)

Figure

  Figure

Figure

  Figure

Figure 5 (

 5 Figure 5 (Analysis 9.11)

Figure 6 (

 6 Figure 6 (Analysis 9.20)

Figure 7 (

 7 Figure 7 (Analysis 9.1)



  Initially, we analysed data not only by each individual drug but also grouped by pharmacological class, following the classification of VaughanWilliams (Vaughan Williams 1984). However, individual antiarrhythmics are very different one from another even inside the same class and it is not clear what would be the clinical implications of grouping them by classes. Consequently, after discussion, we decided to analyze data only by individual drugs.  We decide to drop out several drugs that have never been marketed for this indication (never proved to be effective) : aprindine (class IB), bidisomide (class IB) and azimilide (class III).

	Summary

of findings tables 1 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

	adverse	1,000	1,000 (142	2.78)		3 4 5	main analysis,
	effects -main		to 452)				but the test for
	analysis						subgroup
	follow up:						differences
	median 12						indicated that the
	months						RR was higher in
							older studies
							which used a
							higher dose.
	Pro-arrhythmia -main analysis follow up: median 12	Study population 11 per 22 per 1,000 1,000 (10 to 48)	RR 2.05 (0.95 to 4.41)	1676 (7 RCTs)	⊕⊕⊕⊕ HIGH 3 6
	months
	Stroke -main analysis follow up: median 12 months	Study population 5 per 5 per 1,000 1,000 (1 to 19)	RR 0.97 (0.25 to 3.83)	1107 (4 RCTs)	⊕⊕⊝⊝ LOW 1 7
	Atrial fibrillation recurrence -main analysis follow up: median 12	Study population 80.5 per 66.8 per 100 100 (62.8 to 70.8)	RR 0.83 (0.78 to 0.88)	1624 (7 RCTs)	⊕⊕⊕⊕ HIGH 3
	months
			in sinus rhythm after cardioversion of atrial fibrillation
	Setting: Hospital / community
	Intervention: Quinidine
	Comparison: placebo or no treatment
	Outcomes Anticipated absolute	Relative	№ of	Certainty of	Comments
		effects * (95% CI)	effect	participants	the evidence
		Risk with	Risk with	(95%	(studies)	(GRADE)
		placebo or	Quinidine	CI)
		no
		treatment
	All-cause mortality -	Study population 8 per 15 per	RR 2.01 (0.84 to	1646 (6 RCTs)	⊕⊕⊝⊝ LOW 1 2
	main analysis follow up:	1,000	1,000 (6 to 36)	4.77)
	median 12
	months
	Withdrawals	Study population	1.56	1669	⊕⊕⊕⊝	Heterogeneity
	due to	163 per	254 per	(0.87,	(7 RCTs)	MODERATE	was high for the

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

  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:

	Atrial fibrillation recurrence -main analysis follow up: range 6 to 12	Study population 69.8 per 100 45.4 per 100 (38.4 to 53.8)	RR 0.65 (0.55 to 0.77)	511 (4 RCTs)	⊕⊕⊕⊕ HIGH 4
	months
	*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; RR: Risk ratio; OR: Odds ratio;
	GRADE Working Group grades of evidence
	High certainty:
	Outcomes	Anticipated absolute	Relative	№ of	Certainty of	Comments
		effects * (95% CI)	effect	participants	the evidence
		Risk with placebo or	Risk with Flecainide	(95% CI)	(studies)	(GRADE)
		no
		treatment
	All-cause	Study population	-	(0 RCTs)	-
	mortality -	see	see
	main analysis	comment	comment
	Withdrawals due to adverse effects -main analysis	Study population 0 per 1,000 194 per 1,000 (? to ?)	RR 15.41 (0.91 to 260)	73 (1 RCT)	⊕⊕⊝⊝ LOW 1 2
	follow up:
	mean 6 months
	Pro-arrhythmia	Study population	RR 4.80	511	⊕⊕⊕⊝
	-main analysis follow up: range 6 to 12 months	6 per 1,000 30 per 1,000 (8 to 112)	(1.30 to 17.7)	(4 RCTs)	MODERATE 3
	Stroke -main analysis	Study population 0 per 1,000 ? per 1,000	RR 2.04 (0.11 to	362 (1 RCT)	⊕⊕⊝⊝ LOW 1 2
	follow up: mean 6 months		(0 to 0)	39)

: adults in sinus rhythm after cardioversion of atrial fibrillation Setting: Hospital / community Intervention: Flecainide Comparison: placebo or no treatment

Metoprolol compared to placebo or no treatment for maintaining sinus rhythm after cardioversion of atrial fibrillation Patient or population

	Outcomes	Anticipated absolute	Relative	№ of	Certainty of	Comments
		effects * (95% CI)	effect	participants	the evidence
		Risk with placebo or	Risk with Metoprolol	(95% CI)	(studies)	(GRADE)
		no
		treatment
	All-cause	Study population	RR 2.02	562	⊕⊕⊕⊝
	mortality -main analysis follow up:	4 per 1,000 7 per 1,000 (1 to 39)	(0.37 to 11.1)	(2 RCTs)	MODERATE 1
	mean 6 months
	Withdrawals	Study population	RR 3.47	562	⊕⊕⊕⊕
	due to adverse	21 per	74 per 1,000	(1.48 to	(2 RCTs)	HIGH
	effects -main analysis	1,000	(31 to 173)	8.1)
	follow up:
	mean 6 months
	Pro-arrhythmia	Study population	RR 18.14	562	⊕⊕⊕⊕
	-main analysis follow up: mean 6 months	0 per 1,000 ? per 1,000 (0 to 0)	(2.42 to 135.6)	(2 RCTs)	HIGH
	Stroke -not	-	-	-	-	-
	reported
	Atrial	Study population	RR 0.83	562	⊕⊕⊕⊝
	fibrillation recurrence -main analysis follow up:	72.0 per 100	59.7 per 100 (49.0 to 73.4)	(0.68, 1.02)	(2 RCTs)	MODERATE 2
	mean 6 months

: adults in sinus rhythm after cardioversion of atrial fibrillation Setting: Hospital / community Intervention: Metoprolol Comparison: placebo or no treatment *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; RR: Risk ratio; OR: Odds 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 Downgraded by one level for imprecision. Confidence interval includes both possible harm and possible benefit. Downgraded by one level for inconsistency: high I 2 indicated heterogeneity and this could not be explored in subgroup analysis due to only 2 studies being included.

Footnotes 1 2 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

	fibrillation	81.2 per	42.2 per 100	(0.46 to	(6 RCTs)	HIGH 4
	recurrence -	100	(37.3 to 47.1)	0.58)
	Main analysis
	follow up:
	median 12
	months
	population: adults in sinus rhythm after cardioversion of atrial fibrillation
	Setting: Hospital / community
	Intervention: Amiodarone
	Comparison: placebo or no treatment
	Outcomes	Anticipated absolute	Relative	№ of	Certainty of	Comments
		effects * (95% CI)	effect	participants	the evidence
		Risk with placebo or	Risk with Amiodarone	(95% CI)	(studies)	(GRADE)
		no
		treatment
	All-cause	Study population	RR 1.66	444	⊕⊕⊕⊝
	mortality -Main analysis follow up:	26 per 1,000	43 per 1,000 (14 to 129)	(0.55 to 4.99)	(2 RCTs)	MODERATE 1
	range 6 to 12
	months
	Withdrawals due to adverse effects -Main	Study population 7 per 1,000 49 per 1,000 (14 to 172)	RR 6.70 (1.91 to 23.45)	319 (4 RCTs)	⊕⊕⊝⊝ LOW 2 3
	analysis
	follow up:
	range 6 to 16
	months
	Pro-	Study population	RR 2.22	673	⊕⊕⊕⊝
	arrhythmia -Main analysis	8 per 1,000 18 per 1,000 (6 to 57)	(0.71 to 6.96)	(4 RCTs)	MODERATE 1 4
	follow up:
	range 6 to 16
	months
	Stroke -Main analysis	Study population 23 per 26 per 1,000	RR 1.15 (0.30 to	399 (1 RCT)	⊕⊕⊝⊝ LOW 5
	follow up: mean 12	1,000	(7 to 100)	4.39)
	months
	Atrial	Study population	RR 0.52 812	⊕⊕⊕⊕

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

	Outcomes	Anticipated absolute	Relative	№ of	Certainty of	Comments
		effects * (95% CI)	effect	participants	the evidence
		Risk with placebo or	Risk with Dofetilide	(95% CI)	(studies)	(GRADE)
		no
		treatment
	All-cause	Study population	RR 0.98	1183	⊕⊕⊕⊝
	mortality -Main analysis follow up: mean 12 months	193 per 1,000	189 per 1,000 (146 to 245)	(0.76 to 1.27)	(3 RCTs)	MODERATE 1
	Withdrawals due to adverse effects -Main analysis follow up:	Study population 34 per 1,000 61 per 1,000 (26 to 144)	RR 1.77 (0.75 to 4.2)	677 (2 RCTs)	⊕⊕⊝⊝ LOW 1 2
	mean 12
	months
	Pro-arrhythmia	Study population	RR 5.50	1183	⊕⊕⊕⊝
	-Main analysis follow up: mean 12 months	2 per 1,000 13 per 1,000 (3 to 53)	(1.33 to 22.8)	(3 RCTs)	MODERATE 1
	Stroke -not	-	-	-	-	-
	reported
	Atrial	Study population	RR	1183	⊕⊕⊕⊝
	fibrillation recurrence -Main analysis follow up: mean 12	84.2 per 100 60.6 per 100 (51.4 to 71.6)	0.0.72 (0.61, 0.85)	(3 RCTs)	MODERATE 3 4
	months

: adults in sinus rhythm after cardioversion of atrial fibrillation Setting: Hospital / community Intervention: Dofetilide Comparison: placebo or no treatment

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

	mean 12
	months
	Stroke -Main	Study population	RR 0.66	5872	⊕⊕⊕⊕
	analysis follow up: mean 12	27 per 1,000	18 per 1,000 (13 to 25)	(0.47 to 0.95)	(2 RCTs)	HIGH
	months
	Atrial	Study population	RR 0.85	1443	⊕⊕⊕⊝
	fibrillation recurrence -Main analysis	76.6 per 100	65.1 per 100 (61.3 to 69.7)	(0.80 to 0.91)	(2 RCTs)	MODERATE 3
	follow up:
	range 6 to 12
	months
	Setting: Hospital / community
	Intervention: Dronedarone
	Comparison: placebo or no treatment
	Outcomes	Anticipated absolute	Relative	№ of	Certainty of	Comments
		effects * (95% CI)	effect	participants	the evidence
		Risk with placebo or	Risk with Dronedarone	(95% CI)	(studies)	(GRADE)
		no
		treatment
	All-cause	Study population	RR 0.86	6071	⊕⊕⊕⊕
	mortality -	51 per	44 per 1,000	(0.68 to	(3 RCTs)	HIGH
	Main analysis follow up:	1,000	(35 to 56)	1.09)
	range 6 to 12
	months
	Withdrawals	Study population	RR 1.58	6071	⊕⊕⊕⊝
	due to adverse effects -Main	77 per 1,000	122 per 1,000 (104 to 143)	(1.34 to 1.85)	(3 RCTs)	MODERATE 1
	analysis
	follow up:
	range 6 to 12
	months
	Pro-	Study population	RR 1.95	5872	⊕⊕⊕⊝
	arrhythmia -main analysis	18 per 1,000	36 per 1,000 (14 to 91)	(0.77, 4.98)	(2 RCTs)	MODERATE 2
	follow up:

: adults in 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

	Setting: Hospital / community
	Intervention: Sotalol
	Comparison: placebo or no treatment
	Outcomes	Anticipated	Relative	№ of	Certainty of	Comments
		absolute effects *	effect	participants	the evidence
		(95% CI)		(95%	(studies)	(GRADE)
		Risk with	Risk	CI)
		placebo or	with
		no	Sotalol
		treatment
	All-cause	Study population RR 2.23	1882	⊕⊕⊕⊕
	mortality -Main analysis	8 per 1,000 19 per 1,000	(1.03 to 4.81)	(5 RCTs)	HIGH
	follow up: range 6 to 12 months		(9 to 40)
	Withdrawals	Study population RR 1.95	2688	⊕⊕⊕⊝	Heterogeneity was
	due to adverse effects -Main analysis follow up:	94 per 1,000	183 per 1,000 (116 to 293)	(1.23, 3.11)	(12 RCTs)	MODERATE 1 2 3	high for the main analysis, but the test for subgroup differences indicated that the
	range 6 to 19						RR was higher in
	months;						older studies with
	median 12						sotalol.
	months
	Pro-	Study population RR 3.55	2989	⊕⊕⊕⊝
	arrhythmia -Main analysis follow up: median 12 months	12 per 1,000	41 per 1,000 (25 to 68)	(2.16 to 5.83)	(12 RCTs)	MODERATE 1 3
	Stroke -Main	Study population RR 1.47	1161	⊕⊕⊕⊝
	analysis follow up:	7 per 1,000 10 per 1,000	(0.48 to 4.51)	(3 RCTs)	MODERATE 4
	range 6 to 12 months		(3 to 30)
	Atrial fibrillation	Study population RR 0.83 (0.80 to 78.8 per 65.4	3179 (14 RCTs)	⊕⊕⊕⊕ HIGH 1 5 6
	recurrence -Main analysis follow up:	100	per 100 (63.1 to 68.6)	0.87)
	range 6 to 19
	months;
	median 12
	months

: adults in sinus rhythm after cardioversion of atrial fibrillation

Head to head trials: withdrawals due to adverse events

	Out of 41 studies comparing an active drug with a control group receiving no antiarrhythmic Vijayalaskshmi 2006 1 22 4 33 0.38 (0.04, 3.14) Kochiadakis 2004a 2 72 2 74 1.03 (0.15, 7.10) SOCESP 1999 25 63 20 1.15 (0.72, 1.84) [CRSSTD: 6980542] 1.8.1 Older studies, 5 435 Risk Ratio (M-H, Random, 3.05 [1.29, 7.22] recurrence -main analysis 95% CI)
	Primary outcomes All-cause mortality Cardiovascular mortality Stroke (total 17 979 patients) * Chun 2014, DAPHNE 2008, Santas 2012 N° Trials reporting (N° participants) 39 (17 586) same as total mortality same as total mortality N° Trials NOT reporting (N° participants) 3 * (393) 11 (9 139) 30 (8 840) ** AFIB 1997, Chun 2014, Santas 2012. Others studies did not reported pro-arhythmia but reported withdrawals: DAPHNE, Niu, Villani 2 Head to head trials: all cause mortality Drug 1 vs. drug 2 drug 1 drug 2 RR (95% CI) events total events total Disopyramide vs. other Class I drugs PRODIS 1996 1 31 0 25 2.44 (0.10, 57.37) Lloyd 1984 0 29 2 28 0.19 (0.01, 3.86) Quinidine vs. other Class I drugs Richiardi 1992 0 98 2 102 0.21 (0.01, 4.28) Lloyd 1984 2 28 0 29 5.17 (0.26, 103.18) Quinidine vs. Sotalol SOPAT 2004 2 518 2 264 0.51 (0.07, 3.60) SOCESP 1999 0 63 1 58 0.31 (0.01, 7.40) PAFAC 2004 9 377 13 383 0.70 (0.30, 1.63) Kalusche 1994 1 41 0 41 3.00 (0.13, 71.56) Juul-Moller 1990 1 85 1 98 1.15 (0.07, 18.15) Flecainide vs. Propafenone Aliot 1996 0 48 1 49 0.34 (0.01, 8.15) Amiodarone vs. Class I drugs PITAGORA 2008 6 70 2 75 3.21 (0.67, 15.40) AFFIRM Substudy 2003 10 106 26 116 0.42 (0.21, 0.83) Amiodarone vs. Dronedarone DYONISOS 2010 5 255 2 249 2.44 (0.48, 12.47) Amiodarone vs. Sotalol SAFE-T 2005 13 267 15 261 0.85 (0.41, 1.75) PITAGORA 2008 6 70 0 31 5.86 (0.34, 100.89) AFFIRM Substudy 2003 15 131 24 125 0.60 (0.33, 1.08) Sotalol vs. Class I drugs other than quinidine Reimold 1993 2 50 0 50 5.00 (0.25, 101.58) AFFIRM Substudy 2003 13 88 17 95 0.83 (0.43, 1.60) Drug 1 vs. drug 2 drug 1 drug 2 RR (95% CI) events total events total Disopyramide vs. other Class I drugs Lloyd 1984 2 29 Sotalol vs. Class I drugs other than quinidine AFFIRM Substudy 2003 21 135 47 121 0.40 (0.25, 0.63) Kochiadakis 2004b 5 85 5 86 1.01 (0.30, 3.37) Reimold 1993 6 50 4 50 1.50 (0.45, 4.99) Sotalol vs. Dofetilide EMERALD 2000 16 108 22 321 2.16 (1.18, 3.96) Vitolo 1981 1 28 1 26 0.93 (0.06, 14.09) Amiodarone vs. Dronedarone DYONISOS 2010 4 255 2 249 1.95 (0.36, 10.57) Amiodarone vs.. Sotalol AFFIRM Substudy 2003 5 154 9 135 0.49 (0.17, 1.42) Kochiadakis 2000 2 65 2 61 0.94 (0.14, 6.46) SOPAT 2004 375 518 198 0.97 (0.88, 1.05) Flecainide vs. Propafenone Aliot 1996 19 48 26 0.75 (0.48, 1.16) FAPIS 1996 30 97 30 1.06 (0.70, 1.62) Amiodarone vs. Class I drugs AFFIRM Substudy 2003 60 106 99 0.66 (0.55, 0.80) higher dose 95% CI) 1.22 Atrial fibrillation 5 825 Risk Ratio (M-H, Fixed, 0.77 [0.70, 0.85] A-COMET-I Investigators, Pritchett EL, Kowey P, Connolly S, Page RL, Kerr C, et al. Antiarrhythmic efficacy of azimilide in patients with atrial fibrillation. Maintenance of sinus 1.8.2 More recent studies, 2 1234 Risk Ratio (M-H, Random, 0.88 [0.61, 1.27] recurrence -sensitivity 95% CI) Lafuente-Lafuente 2015 lower dose 95% CI) analysis: Persistent atrial rhythm after conversion to sinus rhythm. American Heart Journal 2006 May;151(5):1043-9. [CRSREF: 6980543; PubMed: PMID: 16644334] A-COMET-II 2006 1.9 Withdrawals due to 5 877 Risk Ratio (M-H, Random, 2.19 [0.99, 4.87] fibrillation Lafuente-Lafuente C, Valembois L, Bergmann JF, Belmin J. Antiarrhythmics for maintaining adverse effects -sensitivity 95% CI) 1.23 Atrial fibrillation 2 1234 Risk Ratio (M-H, Fixed, 0.85 [0.80, 0.91] sinus rhythm after cardioversion of atrial fibrillation. Cochrane Database of Systematic analysis: Persistent atrial recurrence -Sensitivity 95% CI) Reviews 2015, Issue 3. Art. No.: CD005049. DOI: 10.1002/14651858.CD005049.pub4. fibrillation analysis: Low risk of bias 4 28 0.48 (0.10, 2.43) PRODIS 1996 4 31 8 25 0.40 (0.14, 1.19) Quinidine vs. Flecainide Naccarelli 1996 35 117 22 122 1.66 (1.04, 2.65) Steinbeck 1988 2 15 0 15 5.00 (0.26, 96.13) Quinidine vs. other Class I drugs Lloyd 1984 4 28 2 29 2.07 (0.41, 10.43) Naccarelli 1996 35 117 22 122 1.66 (1.04, 2.65) Richiardi 1992 23 98 10 102 2.39 (1.20, 4.77) Steinbeck 1988 2 15 0 15 5.00 (0.26, 96.13) Quinidine vs. Sotalol Hohnloser 1995 10 25 1 25 10.00 (1.38, 72.39) Juul-Moller 1990 22 85 11 98 2.31 (1.19, 4.47) Kalusche 1994 7 41 3 41 2.33 (0.65, 8.40) PAFAC 2004 94 377 96 383 0.99 (0.78, 1.27) SOCESP 1999 10 63 7 58 1.32 (0.54, 3.23) SOPAT 2004 87 518 53 264 0.84 (0.62, 1.14) Flecainide vs. Propafenone Aliot 1996 2 48 9 49 0.23 (0.05, 1.00) FAPIS 1996 10 97 9 103 1.18 (0.50, 2.78) Amiodarone vs. Class I drugs AFFIRM Substudy 2003 20 154 47 121 0.33 (0.21, 0.53) Kochiadakis 2004a 17 72 2 74 8.74 (2.09, 36.46) PITAGORA 2008 5 70 2 31 1.11 (0.23, 5.40) Villani 1992 3 35 10 41 0.35 (0.10, 1.18) Vitolo 1981 1 28 1 26 0.93 (0.06, 14.09) Amiodarone vs. Dronedarone DYONISOS 2010 45 255 32 249 1.37 (0.90, 2.09) Amiodarone vs. Sotalol AFFIRM Substudy 2003 20 154 21 135 0.83 (0.47, 1.47) Sotalol vs. Other Beta-blockers DAPHNE 2008 11 69 2 66 5.26 (1.21, 22.84) Plewan 2001 4 64 3 64 1.33 (0.31, 5.72) Drug 1 vs. drug 2 drug 1 drug 2 RR (95% CI) events total events total Disopyramide vs. other Class I drugs Lloyd 1984 0 29 1 28 0.32 (0.01, 7.59) PRODIS 1996 1 31 1 25 0.81 (0.05, 12.26) Quinidine vs. Flecainide Naccarelli 1996 10 117 7 122 1.49 (0.59, 3.78) Steinbeck 1988 2 15 1 15 2.00 (0.20, 19.78) Quinidine vs. other Class I drugs Lloyd 1984 1 28 0 29 3.10 (0.13, 73.12) Naccarelli 1996 10 117 7 122 1.49 (0.59, 3.78) Richiardi 1992 2 98 2 102 1.04 (0.15, 7.24) Steinbeck 1988 2 15 1 15 2.00 (0.20, 19.78) Quinidine vs. Sotalol Hohnloser 1995 3 25 1 25 3.00 (0.33, 26.92) Juul-Moller 1990 1 85 1 98 1.15 (0.07, 18.15) Kalusche 1994 1 41 2 41 0.50 (0.05, 5.30) PAFAC 2004 17 377 20 383 0.86 (0.46, 1.62) SOCESP 1999 2 63 3 58 0.61 (0.11, 3.54) SOPAT 2004 8 518 2 264 2.04 (0.44, 9.53) SAFE-T 2005 6 267 9 261 0.65 (0.24, 1.81) Sotalol vs. Class I drugs other than quinidine AFFIRM Substudy 2003 9 135 20 121 0.40 (0.19, 0.85) Carunchio 1995 5 20 3 20 1.67 (0.46, 6.06) Kochiadakis 2004b 3 85 2 86 1.52 (0.26, 8.86) Reimold 1993 9 50 6 50 1.50 (0.58, 3.90) Sotalol vs. Dofetilide EMERALD 2000 2 108 7 321 0.85 (0.18, 4.03) Sotalol vs. Other Beta-blockers Plewan 2001 4 64 3 64 1.33 (0.31, 5.72) Footnotes 5 Head to head trials: atrial fibrillation recurrence drug 1 vs. drug 2 drug 1 drug 2 RR (95% CI) events total events total Disopyramide vs. other Class I drugs Lloyd 1984 16 29 16 28 0.97 (0.61, 1.53) PRODIS 1996 10 31 Kochiadakis 2004a 20 72 32 0.64 (0.41, 1.01) PITAGORA 2008 42 70 54 0.83 (0.66, 1.06) Villani 1992 14 35 30 0.55 (0.35, 0.85) Vitolo 1981 6 28 14 0.40 (0.18, 0.88) Amiodarone vs. Dronedarone DYONISOS 2010 116 255 163 0.69 (0.59, 0.82) Amiodarone vs. Sotalol AFFIRM Substudy 2003 58 131 [CRSSTD: 6980544] 1.10 Withdrawals due to 2 1234 Risk Ratio (M-H, Fixed, 0.85 [0.66, 1.08] studies Classification pending references adverse effects -95% CI) 1.24 Atrial fibrillation 2 1234 Risk Ratio (M-H, Fixed, 0.86 [0.80, 0.92] A-COMET-II Investigators; Lombardi F, Borggrefe M, Ruzyllo W, Lüderitz B. Azimilide vs. Sensitivity analysis: Low recurrence -Sensitivity 95% CI) placebo and sotalol for persistent atrial fibrillation: the A-COMET-II (Azimilide-CardiOversion MaintEnance Trial-II) trial. European Heart Journal 2006 Sep;27(18):2224-risk of bias studies analysis: Studies > 200 Data and analyses 1.11 Withdrawals due to 2 1234 Risk Ratio (M-H, Fixed, 0.86 [0.67, 1.09] patients 31. [CRSREF: 6980545; PubMed: PMID: 16935870] adverse effects -95% CI) 1 Quinidine vs. placebo / no treatment Sensitivity analysis: AFFIRM Substudy 2003 [CRSSTD: 6980546] Outcome or Subgroup Studies Participants Statistical Method Studies > 200 patients 2 Disopyramide vs placebo/ no treatment Effect Estimate 1.12 Pro-arrhythmia -main 7 1676 Risk Ratio (M-H, Fixed, 2.05 [0.95, 4.41] 81 0.68 (0.54, 0.86) Kochiadakis 2000 27 65 39 0.65 (0.46, 0.92) Niu 2006 24 51 36 0.67 (0.47, 0.94) PITAGORA 2008 42 70 24 0.78 (0.59, 1.01) SAFE-T 2005 133 267 183 0.71 (0.62, 0.82) Vijayalaskshmi 2006 3 11 10 0.46 (0.16, 1.32) Dronedarone vs. Propafenone Chun 2014 36 50 37 0.97 (0.77, 1.24) Sotalol vs. Class I drugs other than quinidine AFFIRM Substudy 2003 67 88 81 0.89 (0.77, 1.03) Carunchio 1995 8 20 6 1.33 (0.57, 3.14) Kochiadakis 2004b 43 85 35 1.24 (0.89, 1.73) 1.1 All-cause mortality -6 1646 Risk Ratio (M-H, Fixed, 2.01 [0.84, 4.77] analysis 95% CI) Outcome or Subgroup Studies Participants Statistical Method Effect Estimate AFFIRM First Antiarrhythmic Drug Substudy Investigators. Maintenance of sinus rhythm in patients with atrial fibrillation: an AFFIRM substudy of the first antiarrhythmic drug. Journal of the American College of Cardiology 2003;42(1):20-9. [CRSREF: 6980547; MEDLINE: PMID: 12849654; Other: ISSN: 0735-1097] main analysis 95% CI) 1.2 All-cause mortality -sensitivity analysis ITT Worst case: missing patients counted as events 6 1646 Risk Ratio (M-H, Fixed, 95% CI) 2.12 [0.96, 4.67] 1.13 Pro-arrhythmia -subgroup analysis: older 7 1677 Risk Ratio (M-H, Fixed, 2.05 [0.96, 4.42] 2.1 All-cause mortality -1 92 Risk Ratio (M-H, Fixed, 5.00 [0.25, 95% CI) main analysis 95% CI) 101.37] and recent studies 1.13.1 Older studies, higher dose 5 442 Risk Ratio (M-H, Fixed, 2.2 All-cause mortality -2 146 Risk Ratio (M-H, Fixed, 5.55 [0.68, 45.09] 3.14 [0.87, 11.32] ITT Worst case: missing 95% CI) 95% CI) patients counted as events AFIB 1997 [CRSSTD: 6980548] The Atrial Fibrillation Investigation with Bidisomide (AFIB) Investigators. Treatment of atrial fibrillation and paroxysmal supraventricular tachycardia with bidisomide. Circulation 1.3 All-cause mortality -subgroup analysis: older and recent studies 6 1646 Risk Ratio (M-H, Fixed, 95% CI) 2.01 [0.84, 4.77] 1.3.1 Older studies, higher dose 4 412 Risk Ratio (M-H, Fixed, 95% CI) 2.74 [0.85, 8.83] 1.13.2 More recent studies, lower dose 2 1235 Risk Ratio (M-H, Fixed, 1.60 [0.61, 4.24] 2.4 Withdrawals due to 2 146 Risk Ratio (M-H, Fixed, 3.68 [0.95, 14.24] 95% CI) 1.14 Pro-arrhythmia -sensitivity analysis: 5 877 Risk Ratio (M-H, Fixed, adverse effects -main 95% CI) 2.64 [0.93, 7.53] analysis 95% CI) 2.5 Withdrawals due to 2 146 Risk Ratio (M-H, Fixed, 3.68 [0.95, 14.24] Persistent atrial fibrillation adverse effects -95% CI) 1997;96(8):2625-32. [CRSREF: 6980549; MEDLINE: PMID: 9355903; Other: ISSN 0009-1.3.2 More recent studies, 2 1234 Risk Ratio (M-H, Fixed, 1.29 [0.34, 4.92] 1.15 Pro-arrhythmia -2 1235 Risk Ratio (M-H, Fixed, 1.60 [0.61, 4.24] Sensitivity analysis: 7322] lower dose 95% CI) Sensitivity analysis: Low 95% CI) Persistent atrial fibrillation 11 25 0.73 (0.37, 1.44) Quinidine vs. Flecainide Naccarelli 1996 93 117 93 122 1.04 (0.91, 1.19) Steinbeck 1988 10 15 6 15 1.67 (0.81, 3.41) Quinidine vs. other Class I drugs Lloyd 1984 16 28 16 29 1.04 (0.65, 1.64) Naccarelli 1996 93 117 93 122 1.04 (0.91, 1.19) Richiardi 1992 57 98 53 102 1.12 (0.87, 1.44) Steinbeck 1988 10 15 Reimold 1993 32 50 35 0.91 (0.69, 1.20) Sotalol vs. Dofetilide EMERALD 2000 74 108 196 1.12 (0.96, 1.31) Sotalol vs. Beta-blockers DAPHNE 2008 57 69 54 1.01 (0.86, 1.18) Plewan 2001 31 64 29 1.07 (0.74, 1.55) Footnotes Aliot 1996 [CRSSTD: 6980550] 1.4 All-cause mortality -sensitivity analysis: Persistent atrial fibrillation 5 865 Risk Ratio (M-H, Fixed, 95% CI) 1.82 [0.73, 4.53] 1.5 All-cause mortality -2 1234 Risk Ratio (M-H, Fixed, 1.29 [0.34, 4.92] risk of bias studies 1.16 Pro-arrhythmia -Sensitivity analysis: 2 1235 Risk Ratio (M-H, Fixed, 2.7 Stroke -main analysis 2 146 Risk Ratio (M-H, Fixed, 0.31 [0.03, 2.91] 1.60 [0.61, 4.24] 95% CI) 95% CI) 2.8 Stroke -Subgroup 2 146 Risk Ratio (M-H, Fixed, 0.31 [0.03, 2.91] Studies > 200 patients analysis: Persistent atrial 95% CI) Aliot E, Denjoy I. The Flecainide AF French Study Group. Comparison of the safety and Sensitivity analysis: Low 95% CI) 1.17 Stroke -main analysis 4 1107 Risk Ratio (M-H, Fixed, 0.97 [0.25, 3.83] fibrillation efficacy of flecainide versus propafenone in hospital out-patients with symptomatic paroxysmal atrial fibrillation/flutter. American Journal of Cardiology 1996;77(3):66A-71A. [CRSREF: 6980551; MEDLINE: PMID: 8607394; Other: ISSN: 0002-9149] risk of bias studies 1.6 All-cause mortality -Sensitivity analysis: Studies > 200 patients 2 1234 Risk Ratio (M-H, Fixed, 95% CI) 1.29 [0.34, 4.92] 95% CI) 1.18 Stroke -sensitivity analysis: Persistent atrial 3 338 Risk Ratio (M-H, Fixed, 2.9 Atrial fibrillation 2 146 Risk Ratio (M-H, Fixed, 0.77 [0.59, 1.01] 0.88 [0.19, 4.01] recurrence -main analysis 95% CI) 95% CI) 2.10 Atrial fibrillation 2 146 Risk Ratio (M-H, Fixed, 0.77 [0.59, 1.01] fibrillation recurrence -sensitivity 95% CI) 6 15 1.67 (0.81, 3.41) 1.7 Withdrawals due to 7 1669 Risk Ratio (M-H, Random, 1.56 [0.87, 2.78] 1.19 Stroke -Sensitivity 1 Risk Ratio (M-H, Fixed, Subtotals only analysis: Persistent atrial Flecainide vs. Propafenone Aliot 1996 0 48 4 49 0.11 (0.01, 2.05) Quinidine vs. Sotalol Hohnloser 1995 7 25 adverse effects -main 95% CI) analysis: Low risk of bias 95% CI) fibrillation References to studies analysis studies 12 25 0.58 (0.28, 1.23) Adverse effects (Proarrhythmia and Withdrawals due to adverse effects) 39 (16 558) 3 ** (1 421) Footnotes Sotalol vs. Dofetilide EMERALD 2000 0 108 1 321 0.98 (0.04, 23.99) Kochiadakis 2000 11 65 3 61 3.44 (1.01, 11.75) Niu 2006 5 51 7 51 0.71 (0.24, 2.10) PITAGORA 2008 6 70 0 31 5.86 (0.34, 100.89) FAPIS 1996 2 97 1 103 2.12 (0.20, 23.05) Amiodarone vs.. Class I drugs AFFIRM Substudy 2003 5 154 20 121 0.20 (0.08, 0.51) Juul-Moller 1990 49 85 50 98 1.13 (0.87, 1.47) Kalusche 1994 15 41 21 41 0.71 (0.43, 1.18) PAFAC 2004 A-COMET-I 2006 studies 1.21 Atrial fibrillation 7 1624 Risk Ratio (M-H, Fixed, 0.83 [0.78, 0.88] 244 377 255 383 0.97 (0.88, 1.08) 1.8 Withdrawals due to 7 1669 Risk Ratio (M-H, Random, 1.56 [0.87, 2.78] 1.20 Stroke -Sensitivity 1 Risk Ratio (M-H, Fixed, Subtotals only Included studies adverse effects -subgroup analysis: older and recent 95% CI) analysis: Studies > 200 patients 95% CI) 3

Footnotes 3 Footnotes 4 Head to head trials: pro-arrhythmia

Propafenone vs. placebo / no treatment Outcome or Subgroup Studies Participants

	analysis 5.3 All-cause mortality -recurrence -Sensitivity recurrence -Sensitivity 7.11 Pro-arrhythmia -8.8 Withdrawals due to Sensitivity analysis: Low	2 1 1	562 506 4628	Statistical Method 95% CI) Risk Ratio (M-H, Fixed, 95% CI) 95% CI) Risk Ratio (M-H, Fixed, Risk Ratio (M-H, Fixed, 95% CI) 95% CI)	Effect Estimate 2.02 [0.37, 11.05] 9.29 [0.50, 1.57 [1.32, 1.87]
	3.1 All-cause mortality -main analysis 3.2 All-cause mortality -ITT Worst case: missing patients counted as events 4.7 Pro-arrhythmia -Sensitivity analysis: Persistent atrial fibrillation Sensitivity analysis: Persistent atrial fibrillation 5.4 All-cause mortality -analysis: Studies > 200 patients analysis: Persistent atrial fibrillation 6.16 Atrial fibrillation Sensitivity analysis: Low risk of bias studies 7.12 Pro-arrhythmia -adverse effects -risk of bias studies 9.17 Stroke -Sensitivity Sensitivity analysis: Low 9.5 All-cause mortality -analysis: Persistent atrial risk of bias studies Sensitivity analysis: fibrillation 3.3 All-cause mortality -Sensitivity analysis: Low risk of bias studies 3.4 Withdrawals due to adverse effects -main analysis 3.5 Withdrawals due to adverse effects -Sensitivity analysis: Studies > 200 patients 3.6 Pro-arrhythmia -main analysis 3.7 Pro-arrhythmia -Sensitivity analysis: Low risk of bias studies 3.8 Atrial fibrillation recurrence -main analysis 3.9 Atrial fibrillation recurrence -Sensitivity analysis: Low risk of bias studies 3.10 Atrial fibrillation recurrence -Sensitivity analysis: Studies > 200 patients 4 Flecainide vs. placebo / no treatment 2 212 Risk Ratio (M-H, Fixed, 95% CI) 3 406 Risk Ratio (M-H, Fixed, 95% CI) 2 435 Risk Ratio (M-H, Fixed, 95% CI) 95% CI) 2 562 Risk Ratio (M-H, Fixed, 2 498 Risk Ratio (M-H, Fixed, 95% CI) 3 1183 Risk Ratio (M-H, Fixed, 95% CI) 1 393 Risk Ratio (M-H, Fixed, 4 1826 Risk Ratio (M-H, Fixed, 95% CI) 95% CI) 1 102 Risk Ratio (M-H, Fixed, 95% CI) 5 1098 Risk Ratio (M-H, Fixed, 95% CI) 1 523 Risk Ratio (M-H, Fixed, 95% CI) 3 381 Risk Ratio (M-H, Fixed, 95% CI) 1 102 Risk Ratio (M-H, Fixed, 95% CI) 5 1098 Risk Ratio (M-H, Fixed, 95% CI) 1 102 Risk Ratio (M-H, Fixed, 95% CI) 1 523 Risk Ratio (M-H, Fixed, 95% CI) Outcome or Subgroup Studies Participants Statistical Method 4.1 All-cause mortality -main analysis 0 0 Risk Ratio (M-H, Fixed, 95% CI) 4.2 All-cause mortality -ITT Worst case: missing patients counted as events 1 362 Risk Ratio (M-H, Fixed, 95% CI) 4.3 Withdrawals due to adverse effects -main analysis 1 73 Risk Ratio (M-H, Fixed, 95% CI) 4.6 Pro-arrhythmia -main 4 511 Risk Ratio (M-H, Fixed, 4.80 [1.30, 17.77] 0.19 [0.02, 1.68] 6.35 [0.91, 44.22] 2.02 [0.37, 11.05] 0.57 [0.50, 0.64] 171.62] 5.50 [1.33, 22.76] 1.35 [0.36, 5.00] 2.65 [1.16, 6.09] 1.28 [0.45, 3.62] 0.11 [0.00, 2.64] 1.62 [1.07, 2.46] 1.29 [0.79, 2.11] 1.32 [0.39, 4.47] 0.49 [0.09, 2.75] 0.67 [0.61, 0.74] 0.71 [0.50, 1.01] 0.71 [0.63, 0.79] Effect Estimate Not estimable 1.30 [0.45, 3.72] 15.41 [0.91, 260.19] 4.8 Pro-arrhythmia -Sensitivity analysis: Low risk of bias studies 2 435 Risk Ratio (M-H, Fixed, 95% CI) 6.35 [0.91, 44.22] 4.9 Pro-arrhythmia -Sensitivity analysis: Studies > 200 patients 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 4.10 Stroke -main analysis 1 362 Risk Ratio (M-H, Fixed, 95% CI) 2.04 [0.11, 39.00] 4.11 Stroke -Subgroup analysis: Persistent atrial fibrillation 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 4.12 Stroke -Sensitivity analysis: Low risk of bias studies 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 4.13 Stroke -Sensitivity analysis: Studies > 200 patients 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 4.14 Atrial fibrillation recurrence -main analysis 4 511 Risk Ratio (M-H, Fixed, 95% CI) 0.65 [0.55, 0.77] 4.15 Atrial fibrillation recurrence -Sensitivity analysis: Persistent atrial fibrillation 2 435 Risk Ratio (M-H, Fixed, 95% CI) 0.71 [0.60, 0.85] 4.16 Atrial fibrillation recurrence -Sensitivity analysis: Low risk of bias studies 2 435 Risk Ratio (M-H, Fixed, 95% CI) 0.71 [0.60, 0.85] 4.17 Atrial fibrillation recurrence -Sensitivity analysis: Studies > 200 patients 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 5 Metoprolol vs. placebo / no treatment Outcome or Subgroup Studies Participants Statistical Method Effect Estimate 5.1 All-cause mortality -main analysis 2 562 Risk Ratio (M-H, Fixed, 95% CI) 2.02 [0.37, 11.05] 5.2 All-cause mortality -ITT Worst case: missing patients counted as events 2 562 Risk Ratio (M-H, Fixed, 95% CI) 0.77 [0.41, 1.43] Sensitivity analysis: Low risk of bias studies 95% CI) 5.5 All-cause mortality -Sensitivity analysis: Studies > 200 patients 1 394 Risk Ratio (M-H, Fixed, 95% CI) 7.00 [0.36, 134.63] 5.6 Withdrawals due to adverse effects -main analysis 2 562 Risk Ratio (M-H, Fixed, 95% CI) 3.47 [1.48, 8.15] 5.7 Withdrawals due to adverse effects -Sensitivity analysis: Persistent atrial fibrillation 2 562 Risk Ratio (M-H, Fixed, 95% CI) 3.47 [1.48, 8.15] 5.8 Withdrawals due to adverse effects -Sensitivity analysis: Low risk of bias studies 2 562 Risk Ratio (M-H, Fixed, 95% CI) 3.47 [1.48, 8.15] 5.9 Withdrawals due to adverse effects -Sensitivity analysis: Studies > 200 patients 1 394 Risk Ratio (M-H, Fixed, 95% CI) 3.33 [1.37, 8.12] 5.10 Pro-arrhythmia -main analysis 2 562 Risk Ratio (M-H, Fixed, 95% CI) 18.14 [2.42, 135.66] 5.11 Pro-arrhythmia -Sensitivity analysis: Persistent atrial fibrillation 2 562 Risk Ratio (M-H, Fixed, 95% CI) 18.14 [2.42, 135.66] 5.12 Pro-arrhythmia -Sensitivity analysis: Low risk of bias studies 2 562 Risk Ratio (M-H, Fixed, 95% CI) 18.14 [2.42, 135.66] 5.13 Pro-arrhythmia -Sensitivity analysis: Studies > 200 patients 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 5.14 Atrial fibrillation recurrence -main analysis 2 562 Risk Ratio (M-H, Random, 95% CI) 0.83 [0.68, 1.02] 5.15 Atrial fibrillation recurrence -Sensitivity analysis: Persistent atrial fibrillation 2 562 Risk Ratio (M-H, Random, 95% CI) 0.83 [0.68, 1.02] 5.16 Atrial fibrillation recurrence -Sensitivity analysis: Low risk of bias studies 2 562 Risk Ratio (M-H, Random, 95% CI) 0.83 [0.68, 1.02] 5.17 Atrial fibrillation 1 Risk Ratio (M-H, Fixed, Subtotals only 6 Amiodarone vs. placebo / no treatment Outcome or Subgroup Studies Participants Statistical Method Effect Estimate 6.1 All-cause mortality -Main analysis 2 444 Risk Ratio (M-H, Fixed, 95% CI) 1.66 [0.55, 4.99] 6.2 All-cause mortality -ITT Worst case: missing patients counted as events 2 444 Risk Ratio (M-H, Fixed, 95% CI) 1.35 [0.64, 2.82] 6.3 All-cause mortality -Sensitivity analysis: 2 444 Risk Ratio (M-H, Fixed, 95% CI) 1.66 [0.55, 4.99] recurrence -Sensitivity analysis: Low risk of bias studies 95% CI) 6.17 Atrial fibrillation recurrence -Sensitivity analysis: Studies > 200 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only Sensitivity analysis: Studies > 200 patients 95% CI) 7.13 Atrial fibrillation recurrence -Main analysis 3 1183 Risk Ratio (M-H, Random, 95% CI) 0.72 [0.61, 0.85] 7.14 Atrial fibrillation recurrence -sensitivity 3 1183 Risk Ratio (M-H, Random, 95% CI) 0.72 [0.61, 0.85] 8.9 Withdrawals due to adverse effects -2 5872 Risk Ratio (M-H, Fixed, 1.53 [1.31, 1.80] Studies > 200 patients 9.18 Stroke -Sensitivity 2 768 Risk Ratio (M-H, Fixed, 1.85 [0.20, 16.71] 95% CI) 9.6 Withdrawals due to 12 2688 Risk Ratio (M-H, Random, 1.95 [1.23, 3.11] analysis: Low risk of bias 95% CI) Sensitivity analysis: adverse effects -Main 95% CI) studies Studies > 200 patients 8.10 Pro-arrhythmia -main analysis 2 5872 Risk Ratio (M-H, Random, analysis 9.19 Stroke -Sensitivity 3 1161 Risk Ratio (M-H, Fixed, 1.47 [0.48, 4.51] 1.95 [0.77, 4.98] 9.7 Withdrawals due to 12 2688 Risk Ratio (M-H, Random, 1.95 [1.23, 3.11] analysis: Studies > 200 95% CI) 95% CI) adverse effects -Sotalol: 95% CI) patients patients 7 Dofetilide vs. placebo / no treatment Outcome or Subgroup Studies Participants Statistical Method Effect Estimate analysis: Persistent atrial fibrillation 7.15 Atrial fibrillation recurrence -Sensitivity analysis: Low risk of bias studies 1 506 Risk Ratio (M-H, Fixed, 95% CI) 0.62 [0.54, 0.70] 8.11 Pro-arrhythmia -Sensitivity analysis: Low 1 Risk Ratio (M-H, Fixed, Subtotals only heterogeneity study 9.20 Atrial fibrillation 14 3179 Risk Ratio (M-H, Fixed, 0.83 [0.80, 0.87] 95% CI) 9.7.1 PAFAC and 2 987 Risk Ratio (M-H, Random, 0.96 [0.74, 1.25] recurrence -Main analysis 95% CI) risk of bias studies 8.12 Pro-arrhythmia -Sensitivity analysis: 1 Risk Ratio (M-H, Fixed, SOPAT trials 95% CI) 9.21 Atrial fibrillation 7 1743 Risk Ratio (M-H, Fixed, 0.81 [0.77, 0.86] Subtotals only 9.7.2 Rest of studies 10 1701 Risk Ratio (M-H, Random, 2.77 [1.81, 4.22] recurrence -Sensitivity 95% CI) 95% CI) 95% CI) analysis: Persistent atrial Studies > 200 patients 9.8 Withdrawals due to 6 1350 Risk Ratio (M-H, Fixed, 1.75 [1.28, 2.41] fibrillation Persistent atrial fibrillation 6.4 Withdrawals due to adverse effects -Main analysis 4 319 Risk Ratio (M-H, Fixed, 95% CI) 6.70 [1.91, 23.45] 6.6 Withdrawals due to adverse effects -Sensitivity analysis: Low risk of bias studies 1 99 Risk Ratio (M-H, Fixed, 6.7 Pro-arrhythmia -Main analysis 4 673 Risk Ratio (M-H, Fixed, 95% CI) 6.8 Pro-arrhythmia -Sensitivity analysis: Persistent atrial fibrillation 2 498 Risk Ratio (M-H, Fixed, 6.9 Pro-arrhythmia -Sensitivity analysis: Low risk of bias studies 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 6.10 Pro-arrhythmia -Sensitivity analysis: Studies > 200 patients 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 6.11 Stroke -Main analysis 1 399 Risk Ratio (M-H, Fixed, 6.12 Stroke -Sensitivity analysis: Persistent atrial fibrillation 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 6.13 Stroke -Sensitivity analysis: Studies > 200 patients 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 6.14 Atrial fibrillation recurrence -Main analysis 6 812 Risk Ratio (M-H, Fixed, 95% CI) 0.52 [0.46, 0.58] 6.15 Atrial fibrillation 5 687 Risk Ratio (M-H, Fixed, 0.52 [0.46, 0.58] Persistent atrial fibrillation 7.8 Withdrawals due to adverse effects -Sensitivity analysis: Studies > 200 patients 2 677 Risk Ratio (M-H, Fixed, 95% CI) 1.77 [0.75, 4.18] 7.9 Pro-arrhythmia -Main analysis 3 1183 Risk Ratio (M-H, Fixed, 95% CI) 5.50 [1.33, 22.76] 7.10 Pro-arrhythmia -Sensitivity analysis: Persistent atrial fibrillation 3 1183 Risk Ratio (M-H, Fixed, 95% CI) 5.50 [1.33, 22.76] 8.5 All-cause mortality -Sensitivity analysis: Studies > 200 patients 2 5872 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.68, 1.09] 8.6 Withdrawals due to adverse effects -Main analysis 3 6071 Risk Ratio (M-H, Fixed, 95% CI) 1.58 [1.34, 1.85] 8.7 Withdrawals due to adverse effects -Sensitivity analysis: Persistent atrial fibrillation 1 199 Risk Ratio (M-H, Fixed, 95% CI) 14.51 [0.90, 234.74] 9.1 All-cause mortality -Main analysis 5 1882 Risk Ratio (M-H, Fixed, 9.2 All-cause mortality -ITT Worst case: missing 9.3 All-cause mortality -Sensitivity analysis: 9.4 All-cause mortality -3 1311 9.16 Stroke -Main analysis 3 1161 Risk Ratio (M-H, Fixed, 1.47 [0.48, 4.51] Risk Ratio (M-H, Fixed, 2.51 [1.06, 5.98] Studies > 200 patients Persistent atrial fibrillation 3 1311 Risk Ratio (M-H, Fixed, Sensitivity analysis: 95% CI) 95% CI) 9.15 Pro-arrhythmia -6 2293 Risk Ratio (M-H, Fixed, 3.00 [1.77, 5.06] 2.51 [1.06, 5.98] risk of bias studies patients counted as events 10 2757 Risk Ratio (M-H, Fixed, Sensitivity analysis: Low 95% CI) 95% CI) 9.14 Pro-arrhythmia -4 1686 Risk Ratio (M-H, Fixed, 3.05 [1.73, 5.40] 2.02 [1.28, 3.20] Persistent atrial fibrillation 95% CI) Sensitivity analysis: 95% CI) 2.23 [1.03, 4.81] 9.13 Pro-arrhythmia -6 1687 Risk Ratio (M-H, Fixed, 4.37 [2.25, 8.52] 95% CI) 1.15 [0.30, 4.39] 7.5 All-cause mortality -Sensitivity analysis: Studies > 200 patients 3 1183 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.76, 1.27] 7.6 Withdrawals due to adverse effects -Main analysis 2 677 Risk Ratio (M-H, Fixed, 95% CI) 1.77 [0.75, 4.18] 7.7 Withdrawals due to adverse effects -Sensitivity analysis: 2 677 Risk Ratio (M-H, Fixed, 95% CI) 1.77 [0.75, 4.18] 8.2 All-cause mortality -ITT Worst case: missing 8.3 All-cause mortality -Sensitivity analysis: 8.4 All-cause mortality -Sensitivity analysis: Low risk of bias studies 1 4628 Risk Ratio (M-H, Fixed, Outcome or Subgroup Studies Participants Statistical Method Effect Estimate 95% CI) 95% CI) 9.12.2 Rest of studies 9 1840 Risk Ratio (M-H, Fixed, 4.32 [2.40, 7.76] 0.84 [0.66, 1.07] 9 Sotalol vs. placebo / no treatment SOPAT trials 95% CI) Persistent atrial fibrillation 1 199 Risk Ratio (M-H, Fixed, 9.12.1 PAFAC and 2 986 Risk Ratio (M-H, Fixed, 1.49 [0.51, 4.37] 95% CI) study 0.97 [0.04, 23.36] Sotalol: heterogeneity 95% CI) patients patients counted as events 3 6071 Risk Ratio (M-H, Fixed, 9.12 Pro-arrhythmia -11 2826 Risk Ratio (M-H, Fixed, 3.43 [2.07, 5.67] analysis: Studies > 200 95% CI) recurrence -Sensitivity 95% CI) Main analysis 95% CI) 0.85 [0.67, 1.07] 8.17 Atrial fibrillation 1 Risk Ratio (M-H, Fixed, Subtotals only 9.11 Pro-arrhythmia -12 2989 Risk Ratio (M-H, Fixed, 3.55 [2.16, 5.83] 95% CI) 2.03 [0.52, 7.96] 7.4 All-cause mortality -Sensitivity analysis: Low risk of bias studies 1 506 Risk Ratio (M-H, Fixed, 95% CI) 8.1 All-cause mortality -Main analysis 3 6071 Risk Ratio (M-H, Fixed, 95% CI) fibrillation Studies > 200 patients 0.86 [0.68, 1.09] analysis: Persistent atrial Sensitivity analysis: 0.99 [0.77, 1.29] Outcome or Subgroup Studies Participants Statistical Method Effect Estimate recurrence -Sensitivity 95% CI) adverse effects -95% CI) 2.22 [0.71, 6.96] 7.3 All-cause mortality -Sensitivity analysis: Persistent atrial fibrillation 3 1183 Risk Ratio (M-H, Fixed, 8.16 Atrial fibrillation 1 Risk Ratio (M-H, Fixed, Subtotals only 9.10 Withdrawals due to 5 1900 Risk Ratio (M-H, Random, 1.81 [0.97, 3.35] patients 95% CI) 0.98 [0.76, 1.27] recurrence -Main analysis 95% CI) risk of bias studies analysis: Studies > 200 8 Dronedarone vs. placebo / no treatment 8.15 Atrial fibrillation 2 1443 Risk Ratio (M-H, Fixed, 0.85 [0.80, 0.91] Sensitivity analysis: Low recurrence -Sensitivity 95% CI) 95% CI) 4.98 [0.65, 38.29] 7.1 All-cause mortality -Main analysis 3 1183 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.76, 1.27] 7.2 All-cause mortality -ITT Worst case: missing patients counted as events 3 1183 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.79, 1.31] 7.16 Atrial fibrillation recurrence -Sensitivity 3 1183 Risk Ratio (M-H, Random, 95% CI) 0.72 [0.61, 0.85] 8.13 Stroke -Main analysis 2 5872 Risk Ratio (M-H, Fixed, 0.66 [0.47, 0.95] adverse effects -95% CI) 9.22 Atrial fibrillation 4 1686 Risk Ratio (M-H, Fixed, 0.86 [0.82, 0.91] 95% CI) Sensitivity analysis: recurrence -Sensitivity 95% CI) analysis: Studies > 200 8.14 Stroke -Sensitivity 2 5872 Risk Ratio (M-H, Fixed, 0.66 [0.47, 0.95] Persistent atrial fibrillation analysis: Low risk of bias patients analysis: Studies > 200 95% CI) 9.9 Withdrawals due to 4 1686 Risk Ratio (M-H, Random, studies 1.52 [0.82, 2.81] patients adverse effects -95% CI) 9.23 Atrial fibrillation 6 2293 Risk Ratio (M-H, Fixed, 0.85 [0.81, 0.89]

  Unité de Recherches Thérapeutiques, Hôpital Lariboisière, Paris, France  Assistance Publique -Hôpitaux de Paris, France  Sorbonne Université, Paris, France or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17) 27 (#18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26) 28 (#26 or #27) 29 (#6 and #28) Arrhythmia Agents" (mh) OR antiarrhythmi* (tw) OR anti-arrhythmi* (tw) OR procainamide (tw) OR disopyramide (tw) OR quinidine (tw) OR mexiletine (tw) OR flecainide (tw) propafenone (tw) OR bisoprolol (tw) OR esmolol (tw) OR amiodarone (tw) OR dofetilide (tw) OR sotalol (tw) OR ibutilide (tw) OR azimilide (tw) OR moricizine (tw) OR cibenzoline (tw)) AND ("randomized controlled trial" (pt) OR "controlled clinical trial" (pt) OR "randomized controlled trials" (mh) OR "random allocation" (mh) OR "double-blind method" (mh) OR "single-blind method" (mh) OR "clinical trial" (pt) OR "clinical trials" (mh) OR ("clinical trial" (tw)) OR ((singl* (tw) OR doubl* (tw) OR trebl* (tw) OR tripl* (tw)) AND (mask* (tw) OR blind* (tw))) OR ( placebos (mh) OR placebo* (tw) OR random* (tw) OR "research design" (mh:noexp) OR "comparative study" (mh) OR "evaluation studies" (mh) OR "followup studies" (mh) OR "prospective studies" (mh) OR control* (tw) OR prospectiv* (tw) OR volunteer* (tw)) NOT (animal (mh) NOT human (mh)))Notes: The strategy to locate randomized controlled trials is the Cochrane highly sensitive search strategy (all phases), as contained in the Cochrane Reviewer's Handbook (ref: CR Handbook 2003). The "related articles" feature of PubMed MEDLINE was also used. 1 (atrial OR 'atrium'/exp OR auricular) AND fibrillat* # 2 'anti-arrhythmic' OR antiarrhythmi* OR 'procainamide'/exp OR 'disopyramide'/exp OR 'quinidine'/exp OR 'mexiletine'/exp OR 'flecainide'/exp OR 'propafenone'/exp OR 'bisoprolol'/exp OR 'esmolol'/exp OR 'amiodarone'/exp OR 'dofetilide'/exp OR 'sotalol'/exp OR 'ibutilide'/exp OR 'azimilide'/exp OR 'dronedarone'/exp OR 'moricizine'/exp OR 'cibenzoline'/exp # 3 'randomized controlled trial'/exp OR 'controlled clinical trial'/exp OR 'randomized controlled trials'/exp OR 'random allocation'/exp OR 'double-blind method'/exp OR 'singleblind method'/exp OR 'clinical trial'/exp OR 'clinical trials'/exp OR ((singl* OR doubl* OR trebl* OR tripl*) AND (mask* OR blind*)) OR ('placebos'/exp OR placebo* OR random* OR 'comparative study'/exp OR 'evaluation studies'/exp OR 'follow-up studies'/exp OR 'prospective studies'/exp OR control* OR prospectiv* OR volunteer*) Atrial Fibrillation OR atrial fibrillat* OR atrium fibrillat* OR auricular fibrillat* Other terms: antiarrhythmi* OR anti-arrhythmi* OR dronedarone OR amiodarone OR bisoprolol OR disopyramide OR dofetilide OR azimilide OR ibutilide OR flecainide OR propafenone OR quinidine OR cibenzoline OR moricizine OR mexiletine OR procainamide OR sotalol Filters: Recruiting: All ; Country: All Atrial Fibrillation OR atrial fibrillat* OR atrium fibrillat* OR auricular fibrillat* Intervention: antiarrhythmi* OR anti-arrhythmi* OR dronedarone OR amiodarone OR bisoprolol OR disopyramide OR dofetilide OR azimilide OR ibutilide OR flecainide OR propafenone OR quinidine OR cibenzoline OR moricizine OR mexiletine OR procainamide OR sotalol Filters: Recruiting: All ; Country: All ; Phases: All

	azimilide.tw. cibenzoline.tw. exp heart atrium fibrillation/ 5 and 25
	ibutilide.tw.
	flecainide.tw. moricizine.tw. atrial fibrillation.tw. random$.tw.
	propafenone.tw. Internal sources External sources  No sources of support provided Appendices Search strategies 2005 CENTRAL ATRIAL FIBRILLATION (atrial near fibrillat*) (auricular* near fibrillat*) (atrium near fibrillat*) (atrial next arrhythmi*) (#1 or #2 or #3 or #4 or #5) ANTI-ARRHYTHMIA AGENTS antiarrhythmi* anti-arrhythmi* (anti next arrhythmi*) procainamide disopyramide quinidine mexiletine flecainide propafenone bisoprolol esmolol amiodarone dofetilide sotalol azimilide ibutilide cibenzoline moricizine ("Atrial Fibrillation" (mh) OR ((atrial OR atrium OR auricular) AND fibrillat*)) AND # 4 #1 AND #2 AND #3 Note: The "related articles" feature was also used. quinidine.tw. cibenzoline.tw. moricizine.tw. mexiletine.tw. or/36-43 44 not 34 35 or 45 26 and 46 limit 47 to yr="2005 -2010" EMBASE on Ovid to 2010 Week 06 heart atrium fibrillation/ atrial fibrillation.tw. atrium fibrillation.tw. auricular fibrillation.tw. or/1-4 exp antiarrhythmic agent/ antiarrhythmi$.tw. anti-arrhythmi$.tw. dronedarone.tw. amiodarone.tw. bisoprolol.tw. disopyramide.tw. mexiletine.tw. procainamide.tw. groups.ab. 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 exp animals/ not humans.sh. 35 not 36 26 and 37 (2014* or 2015* or 2016* or 2017* or 2018* or 2019*).ed. 38 and 39 38 not (1* or 2*).ed. 40 or 41 Embase Ovid atrium fibrillation.tw. auricular fibrillation.tw. flecainide.tw. propafenone.tw. quinidine.tw. cibenzoline.tw. moricizine.tw. mexiletine.tw. procainamide.tw. sotalol.tw. esmolol.tw. or/6-24 factorial$.tw. crossover$.tw. single blind procedure/ 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 (animal/ or nonhuman/) not human/ 42 not 43 26 and 44 (2014* or 2015* or 2016* or 2017* or 2018* or 2019*).em. (2014* or 2015* or 2016* or 2017* or 2018* or 2019*).dd. 46 or 47 45 and 48 ClinicalTrials.gov Condition or disease: WHO ICTRP (#7 Search strategy for MEDLINE in PubMed procainamide.tw. sotalol.tw. esmolol.tw. 5 and 25 randomized controlled trial.pt. controlled clinical trial.pt. Randomized controlled trials/ random allocation/ double blind method/ single-blind method/ or/27-32 exp animal/ not humans/ 33 not 34 clinical trial.pt. exp Clinical Trials as Topic/ (clin$ adj25 trial$).ti,ab. placebos/ placebo$.ti,ab. random$.ti,ab. research design/ sotalol.tw. esmolol.tw. or/6-24 5 and 25 randomized controlled trial.pt. controlled clinical trial.pt. randomized.ab. placebo.ab. drug therapy.fs. randomly.ab. trial.ab. or/1-4 exp antiarrhythmic agent/ antiarrhythmi$.tw. anti-arrhythmi$.tw. dronedarone.tw. amiodarone.tw. bisoprolol.tw. disopyramide.tw. dofetilide.tw. azimilide.tw. ibutilide.tw. cross over$.tw. cross-over$.tw. placebo$.tw. (doubl$ adj blind$).tw. (singl$ adj blind$).tw. assign$.tw. allocat$.tw. volunteer$.tw. crossover procedure/ double blind procedure/ randomized controlled trial/ Advanced Search: title: atrial fibrillation ("Anti-Search strategy for EMBASE.com or/6-24 Condition:



# ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).ti,ab.

Acknowledgements

We thank all the trial authors who answered our request for additional data; Professor Charles Caulin for his most valuable suggestions; Dr Barbara Stadler for translating articles from German, Lone Gale for helping with articles in Swedish, Dr Qian Zhang for translating from Chinese; Dr Miguel Angel Longas-Tejero, Pr Stéphane Mouly and Pr Jean-François Bergmann for their help in previous versions of this review; and all the staff of Cochrane Heart Group for their most important help and support.

Contributions of authors

CL-L and JB: prepared and designed the review, CL-L: searched for primary studies and contacted authors of primary studies when needed.

LV, AT, WJ: screened search results, and retrieved papers.

LV, EA, WJ, JB and CL-L: assessed papers for inclusion and risk of bias.

LV, EA, WJ and CL-L: extracted data.

CL-L and AT performed analysis and interpreted data.

LV and WJ: interpreted data and reviewed the manuscript.

CL-L, AT and JB: wrote the review.

Declarations of interest

Lucie Valembois: none known.

Etienne Audureau: none known Andrea Takeda: none known Witold Jarzebowski: none known Joël Belmin: none known Carmelo Lafuente-Lafuente has received consultant fees (less than EUR 5000 total) from Sanofi-Aventis, in 2009 and 2010, for helping to conduct a study (a mixed treatment comparison meta-analysis) on several antiarrhythmic drugs for the management of atrial fibrillation. Sanofi-Aventis is the manufacturer of amiodarone and dronedarone, two of the antiarrhythmics studied in this review. He also received personal fees from Bayer Healthcare and BMS, outside this work.

Differences between protocol and review

Some of the original planned outcomes and planned subgroup analyses could not be performed because the data needed were not recorded or not reported in the original studies. Some planned outcomes were thus modified:

Van