Mixed treatment comparison of dronedarone - Europace

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CLINICAL RESEARCHAtrial Fibrillation – Clinical Issues

Mixed treatment comparison of dronedarone,amiodarone, sotalol, flecainide, and propafenone,for the management of atrial fibrillationNick Freemantle 1, Carmelo Lafuente-Lafuente2, Stephen Mitchell 3,Laurent Eckert4*, and Matthew Reynolds5

1School of Health and Population Sciences, 90 Vincent Drive, University of Birmingham Edgbaston, Birmingham B15 2SP, UK; 2Service de Medecine Interne A. Hopital Lariboisiere, 2,rue Ambroise Pare, Paris 75010, France; 3Abacus International, 4 Market Square, Bicester, Oxfordshire OX26 6AA, UK; 4sanofi-aventis R&D, 182 avenue de France, 75013 Paris,France; and 5Division of Cardiology, Beth Israel Deaconess Medical Center, Harvard Clinical Research Institute, Boston, MA, USA

Received 16 July 2010; accepted after revision 17 November 2010; online publish-ahead-of-print 11 January 2011

Aims Mixed treatment comparisons (MTC) were performed to assess the relative efficacy and tolerability of the main anti-arrhythmic drugs used for the treatment of atrial fibrillation (AF)/flutter.

Methodsand results

Electronic databases were systematically searched to identify randomized controlled trials (RCTs) examining amiodar-one, dronedarone, flecainide, propafenone, sotalol, or placebo for the treatment of AF. Thirty-nine RCTs met inclusioncriteria and were combined using MTC models to provide direct and indirect comparisons in a single analysis. Resultsare presented vs. placebo. Amiodarone had the largest effect in reducing AF recurrence (OR 0.22, 95% CI 0.16–0.29).Amiodarone was associated with the highest rate of patients experiencing at least one serious adverse event (OR 2.41,95% CI 0.96–6.06) and treatment withdrawals due to adverse events (OR 2.91, 95% CI 1.66–5.11). Dronedaronewas associated with the lowest rate of proarrhythmic events including bradycardia (OR 1.45, 95% CI 1.02–2.08).Dronedarone significantly reduced the risk of stroke (OR 0.69, 95% CI 0.57–0.84). Trends towards increased mortalityfor sotalol (OR 3.44, 95% CI 1.02–11.59) and amiodarone (OR 2.17, 95% CI 0.63–7.51) were found, which werestronger when small studies randomizing ,100 subjects per group were excluded.

Conclusions Amiodarone has been demonstrated to be the most effective drug in maintaining sinus rhythm. Differences in out-comes between the anti-antiarrhythmic drugs were reported, with sotalol and possibly amiodarone increasing mor-tality and dronedarone possibly decreasing the incidence of serious adverse events and proarrhythmia.

IntroductionAtrial fibrillation (AF) is the most common sustained cardiacarrhythmia.1 –3 It is a progressive disease and is strongly associatedwith adverse clinical outcomes, including heart failure and stroke,resulting in considerable morbidity and mortality.4– 6

Despite efforts at both rhythm and rate control, patients withAF and atrial flutter (AFL) are at a markedly increased risk of car-diovascular hospitalizations and cardiovascular death, particularlyin older age groups. Atrial fibrillation is the most frequent arrhyth-mic cause of hospital admission in the USA, representing morethan one-third of all patient discharges with arrhythmia as a prin-cipal diagnosis.7

Pharmacological treatments for AF were reviewed in 2007 byLafuente-Lafuente et al.8 Endpoints evaluated included all-causemortality, AF recurrences, and withdrawals due to adverseevents (AEs) pro-arrhythmia and embolic complications. Theauthors concluded that amiodarone was the most effective drugin maintenance of sinus rhythm (SR), but the usefulness of thisagent may be limited by toxicity. In 2009, dronedarone, a newanti-arrhythmic drug (AAD) with multiple ion channel blockadeproperties demonstrated benefit in the composite outcome ofcardiovascular hospitalization or death from all causes in thetreatment of AF.9

To date, there are limited data directly describing the safety andeffectiveness of dronedarone compared with alternative AADs in

* Corresponding author. Tel: +33 153778521, Email: [email protected] and [email protected]

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2011. For permissions please email: [email protected].

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AF patients. In the absence of direct comparisons, there has beenincreasing interest in undertaking mixed treatment comparisons(MTCs) of networks of trials in order to provide best estimatesof the relative effectiveness and safety of alternative health-careinterventions.10 Although these analyses provide a lesser strengthof evidence than well designed and adequately powered directlyrandomized trials, they do provide a summary of the best availableevidence, borrowing weight from indirect comparisons.

In this paper, we present the results of MTCs for amiodarone,dronedarone, flecainide, propafenone, and sotalol, for the effectof treatment on outcomes of all-cause mortality, stroke, preven-tion of AF recurrence, withdrawals (all cause and specifically dueto AE), serious adverse events (SAEs), and incidence of proar-rhythmic events. We also provide conventional meta-analyses ofdirect comparisons.

Methods

Inclusion/exclusion criteria and searchstrategyTo identify relevant studies, electronic databases and conference pro-ceedings were searched: Medline, EMBASE, and the Cochrane CentralRegister of Controlled Trials were accessed on 8 April 2009. Therewere no restrictions by date of publication. The search combinedboth index and free-text terms for ‘AF/flutter’ with the interventions‘AADs’, pharmacological therapies, ‘ablation’ and publication type ‘pro-spective clinical study’ or ‘randomized clinical trial’ (RCT), or studiesreporting quality-of-life outcomes.

Only RCTs, which examined the effect of amiodarone, dronedar-one, flecainide, propafenone, or sotalol in patients with AF or AFL,were included. The class IA AADs (e.g. quinidine, procainamide, diso-pyramide) were not included as part of the search strategy because aprevious synthesis of evidence concluded that they are potentiallyharmful in AF patients,8 and they are no longer recommended in con-sensus guidelines.11 Randomized controlled trials which compared thetarget treatments with an inactive control (placebo or no treatment)or with each other were included. Studies enrolling patients withAF/AFL ≤3 months after cardiac surgery, with follow-up ≤3months, or with duration of treatment ,30 days were excluded.Identified studies were assessed independently by two reviewers inorder to ascertain whether they met the pre-defined inclusion/exclu-sion criteria, and discrepancies were resolved by a third party. Datawere extracted from included publications by a reviewer into anExcelw spreadsheet. A second reviewer checked the resulting extrac-tion and any discrepancies were resolved through discussion.

The methodological quality of the included RCTs was abstractedand assessed according to methods recommended in section six ofthe Cochrane Reviewer’s handbook version 4.2.6.12 In brief, the likeli-hood of bias was assessed according to three components: adequacyof randomization and allocation concealment procedures, adequacyof blinding procedures and completeness of follow-up. Descriptorsof the trial populations and interventions used were also abstracted.

OutcomesMortality, stroke, AF recurrence, incidence of SAEs, treatment with-drawals (all cause and due specifically to AEs) and proarrhythmicevents were analysed. For these analyses, AF recurrence was definedas the reported number of patients failing to maintain SR at anypoint within the study timeframe (SR maintenance data), or the

reported number of patients with a recurrence of AF within the time-frame of the study (AF recurrence data).

Serious adverse events were defined as those events reported to beserious in the publication by the investigator. It was not possible to dis-criminate between SAEs that were reported using a standard regulat-ory definition and other SAEs.

Proarrhythmic events were reported as per the Cochrane analysis8

and included sudden death, new symptomatic arrhythmia, bradycardia,and drug discontinuation due to new QRS or QT intervalprolongation.13

Statistical methodsPlacebo control arms were pooled with no treatment/untreatedcontrol arms. Trials with multiple arms of different doses of thesame drug were pooled into a single-treatment arm prior tometa-analysis across trials.

Direct meta-analysis of included trials was estimated using randomeffect models and the Peto odds ratio (OR).14 Data were analysedusing an intention-to-treat (ITT) approach, and were based on alldata on patients allocated to an intervention, including patients whowithdrew from the trial and those who did not complete treatment.The analysis of SAE and treatment discontinuations included datareported at the end of the study whatever the follow-up duration.These analyses were performed using STATA, version 10.1.

Random effects MTC models were developed which combineddirect and indirect information from clinical trials appropriately con-ditioning parameter variances through adding a multiplicative over dis-persion parameter on the trial stratum. The data analysis for this paperwas generated using SAS software. Copyright, SAS Institute, Inc., SASand all other SAS Institute, Inc., product or service names are regis-tered trademarks or trademarks of SAS Institute, Inc., Cary, NC,USA. The SAS code used to specify these models is described in theAppendix.

Bayesian methods have increasingly been used for indirect compari-sons. However, these models are known to rely heavily on the priorinformation when event rates are sparse.15 As this was anticipateddue to the particular nature of trials that were to be included, non-linear mixed models based upon pseudo-likelihood were preferred.The latter models derive their estimations solely from the data. Ingeneral, the non-linear mixed models were qualitatively very similarto those unconstrained Bayesian baseline models specified usingnumerical simulation techniques and described by Lu and Ades.10

In line with standard methods for conventional meta-analyses, weexcluded studies which reported no events in all groups from themeta-analysis for each respective endpoint.16,17 The between trial het-erogeneity derived from the covariance statistic and standard error onthat stratum was reported. When heterogeneity was present,additional analyses excluding small studies (,100 patients in eitherarm with at least one event in at least one arm) were conducted toexplore potential causes. Results are reported against placebo ineach case and described using Forest plots.

ResultsIn total, 10 743 references were identified through electronic data-base searching, of which 9322 were excluded on the basis of titleand abstract (Figure 1). On re-application of the review inclusioncriteria to the 1411 full-text papers, 1299 were excluded fordesign and/or comparator considerations (Figure 1).

Of the 113 remaining publications, 39 met the inclusion criteria,reported one of the outcomes of interest, and compared the

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target treatments with an inactive control (placebo or no treat-ment) or with each other. Data from the DIONYSOS trial weretaken from the FDA dossier;18 final results were recently pub-lished.19 The analyses were conducted using these 40 publications.Overall there was some variation in the quality of trials included inthe analysis data set (Appendix Table A1). The baseline character-istics of the data set analysed are presented in Table 1.

The number of patients randomized per study varied from 16 to4628. The mean age of subjects across studies was 62 years and59% of subjects were male. The majority of studies includedpatients with paroxysmal AF. Permanent AF patients were includedin addition to other types of AF in seven of the studies. A majorityof patients had structural heart disease, mean left ventricular ejec-tion fraction (LVEF) was 55% and left atrial diameter (LAD) atechocardiography was 42.9 mm.

For the purposes of contrast with the MTC, conventional directestimates of treatment effect are described in Tables 2 and 3. TheMTC analyses used the full network of trials to estimate the com-parison with placebo and not only the trials that compared a par-ticular treatment with placebo.

Direct meta-analysesIn the direct meta-analysis, there were few mortality and strokeevents leading to uncertainty in the estimation for these analyses.None of the studies that investigated flecainide or propafenone

reported stroke outcomes. Dronedarone had the highestnumber of patients investigated primarily due to the inclusion ofthe ATHENA trial. A large number of subjects in the trials experi-enced the outcome of AF recurrence, providing a good basis forthe estimation of the effect sizes.

10 630 references excluded

Title or abstract

1 411 potential references

1299 references excluded due to

study type, design, intervention, disease, duplicate, duration,

post surgery, population, ablation study

74 references excluded due to

no drug of interest analysed (32), comparator not correct (42)

40 references analysed (DYONISOS included)

*Mortality n = 18, *Stroke n = 4, *AF Recurrence n = 30

*Treatment discontinuation n = 34, *due to AE n = 29

*SAE n = 20,*proarrhythmic events n = 13

10 743 references identified

113 potential references

Figure 1 Diagram flow. *Number of studies that reported the event and at least 1 event was observed during follow-up.

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Table 1 Baseline characteristics summary of theincluded studies

Patient characteristics Range ofvalues

Mean(SD)

Number of patients randomized 16–4628 245 (580)

Age (years) 49–78 61.6 (5.2)

Gender (% male) 35–99 59.2 (12.6)

AF Type (paroxysmal)a 33 —

AF type (persistent)a 23 —

AF type (permanent)a 7 —

Structural heart disease (%) 0–100 60.1 (23.4)

Left ventricular ejection fraction(LVEF) (%)

30–68 55.1 (9.1)

Left atrium diameter (LAD) (mm) 34–50 42.9 (3.8)

aNumber of studies reported across the included studies.

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Table 2 Direct meta-analysis: efficacy summary results

Comparison Mortality Stroke AF recurrence

No. ofstudies

n/N OR (95% CI) No. ofstudies

n/N OR (95% CI) No. ofstudies

n/N OR (95% CI)a

Dronedarone vs.

Placebo 4 136/3418 vs. 142/2891 0.86 (0.67–1.10) 2 50/3129 vs. 70/2736 0.69 (0.47–0.99) 2 700/1032 vs. 369/475 0.59 (0.45–0.76)

Amiodarone 1 2/249 vs. 5/255 0.40 (0.08–2.13) 1 2/249 vs. 2/255 1.02 (0.14–7.33) 1 158/249 vs. 107/255 2.38 (1.67–3.45)

Amiodarone vs.

Placebo 6 13/472 vs. 5/299 1.08 (0.12–9.42) 1 6/267 vs. 3/137 1.03 (0.25–4.17) 6 170/472 vs. 232/299 0.15 (0.10–0.22)

Sotalol 4 28/490 vs. 39/483 0.66 (0.40–1.11) 1 6/267 vs. 5/261 1.18 (0.35–3.90) 5 185/490 vs. 269/518 0.47 (0.36–0.62)

Flecainide — — — — — — 2 31/100 vs. 34/104 0.74 (0.40–1.38)

Propafenone 1 0/72 vs. 0/74 1.55 (0.26–9.17) — — — 1 29/72 vs. 35/74 0.75 (0.39–1.45)b

Sotalol vs.

Placebo 12 27/1686 vs. 5/1092 2.52 (0.96–6.64) 1 5/261 vs. 3/137 0.87 (0.21–3.71) 10 861/1424 vs. 677/1047 0.41 (0.28–0.59)

Flecainide 1 0/20 vs. 0/20 1.00 (0.06–16.50) — — — 1 8/20 vs. 6/20 1.56 (0.42–5.76)

Propafenone 3 2/241 vs. 0/238 5.20 (0.24–111.24) — — — 4 138/275 vs. 155/277 0.76 (0.52–1.09)

Flecainide vs.

Placebo 4 2/99 vs. 0/105 5.24 (0.24–112.45) — — — 3 30/71 vs. 56/78 0.25 (0.09–0.70)

Propafenone 2 0/145 vs. 1/152 2.29 (0.64–8.16) 1 2/48 vs. 1/49 2.09 (0.18–23.78) 1 30/97 vs. 30/103 1.09 (0.59–2.00)

Propafenone vs.

Placebo 7 2/945 vs. 3/492 0.42 (0.08–2.05) — — — 6 454/944 vs. 349/481 0.29 (0.16–0.55)

aOR for 12 month timepoint.b24 months data.

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Table 3 Direct meta-analysis: safety summary results

Treatment withdrawals Treatment withdrawals due to AE Serious adverse events Pro-arrhythmia events

Comparison Studies n/N OR (95% CI) Studies n/N OR (95% CI) Studies n/N OR (95% CI) Studies n/N OR (95% CI)

Dronedarone vs.

Placebo 4 883/3418 vs.787/2891

1.23 (0.85–1.77) 4 409/3418 vs.226/2891

1.63 (1.32–2.03) 3 492/2580 vs.501/2468a

1.22 (0.59–2.22) 4 244/3418 vs.153/2891

1.46 (1.18–1.80)

Amiodarone 1 96/249 vs.69/255

1.69 (1.16–2.44) 1 32/249 vs.45/255

0.69 (0.43–1.12) 1 32/249 vs.45/255

0.69 (0.43–1.12) 1 2/249 vs. 11/255

0.29 (0.10–0.90)

Amiodarone vs.

Placebo 6 70/472 vs.29/299

3.92 (0.64–24.02) 5 28/217 vs. 1/195

8.41 (2.17–32.63) 1 11/65 vs. 0/60

8.10 (2.36–27.81) 5 13/445 vs. 2/268

2.27 (0.74–6.99)

Sotalol 5 80/490 vs.70/518

1.12 (0.58–2.20) 4 38/281 vs.31/267

1.13 (0.35–3.68) 2 13/100 vs. 6/96

1.80 (0.31–10.42) 4 13/521 vs.22/492

0.56 (0.28–1.12)

Flecainide 2 8/100 vs. 6/104

1.81 (0.56–5.83) — — — — — — — — —

Propafenone 1 17/72 vs. 4/74

4.34 (1.73–10.91) 1 17/72 vs. 4/74

4.34 (1.73–10.91) 1 17/72 vs. 2/74

6.26 (2.39–16.37) 1 2/72 vs. 2/74 1.03 (0.13–7.45)

Sotalol vs.

Placebo 10 712/1424 vs.416/1047

0.91 (0.62–1.32) 10 238/1424 vs.96/1047

2.06 (1.18–3.62) 6 222/1482 vs.96/921

1.77 (0.95–1.30) 11 68/1650 vs.12/1061

2.21 (1.21–4.01)

Flecainide 1 0/20 vs. 0/20 1 (0.06–16.5) 1 0/20 vs. 0/20 1 (0.06–16.5) — — — 1 5/20 vs. 3/20 1.83 (0.39–8.49)

Propafenone 4 26/275 vs.20/277

1.32 (0.72–2.43) 4 26/275 vs.20/277

1.32 (0.72–2.43) 2 9/132 vs. 7/127

1.34 (0.48–3.78) 4 28/279 vs.20/279

1.47 (0.76–2.84)

Flecainide vs.

Placebo 3 7/71 vs. 0/78 2.92 (0.22–38.62) 3 7/71 vs. 0/78 8.45 (1.02–70.40) 2 9/79 vs. 0/80 10.36 (1.26–58.24) 4 15/114 vs. 1/121

6.60 (1.52–28.58)

Propafenone 2 48/145 vs.56/152

0.80 (0.40–1.61) 2 12/145 vs.18/152

0.54 (0.09–3.23) 1 2/48 vs. 9/49 0.25 (0.07–0.86) 2 3/145 vs. 6/152

0.60 (0.05–6.58)

Propafenone vs.

Placebo 7 155/955 vs.54/492

1.55 (1.08–2.22) 7 123/955 vs.27/492

2.00 (1.22–3.30) 4 74/493 vs.21/320

2.12 (0.80–5.60) 8 37/1067 vs.12/604

2.34 (0.76–7.27)

aWithout EURIDIS/ADONIS.

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Sotalol showed a trend towards an increased risk of mortalitycompared with placebo [OR 2.52, 95% confidence interval (CI)0.96–6.64]. All other comparisons were not statistically significant.Dronedarone was the only drug to show a statistically significantreduction in the risk of stroke. The estimated OR was 0.69, 95%CI 0.47–0.99.

All drugs were shown to be efficacious at reducing AF recur-rence. Amiodarone was associated with the highest efficacy withan OR of 0.15, 95% CI 0.10–0.22. Furthermore, amiodarone wasstatistically superior to both sotalol (OR 0.47, 95% CI 0.36–0.69) and dronedarone (OR 0.42, 95% CI 0.29–0.60) in directcomparisons.

Safety was investigated through four outcomes: treatment with-drawals for any reason; and treatment withdrawals due to AEs,SAEs, and proarrhythmia. Studies investigating dronedarone,sotalol, or propafenone enrolled .1000 patients compared withthose for amiodarone and flecainide which recruited only 472and 114 patients, respectively.

On the outcome of treatment withdrawals for any reason, pro-pafenone was the only AAD to show a significant increase vs.placebo. Dronedarone treatment significantly increased treatmentwithdrawals for any reason compared with amiodarone (OR 1.69,95% CI 1.16–2.44). Similarly, amiodarone significantly increasedtreatment withdrawals for any reason compared with propafenone(OR 4.34, 95% CI 1.73–10.91).

Treatment withdrawals specifically due to AEs were significantlyincreased for all AADs compared with placebo. Dronedarone pre-sented the lowest increase in the risk of events with an OR of 1.63,95% CI 1.32–2.03. The highest OR was reported for amiodaronecompared with placebo where the odds of withdrawal were esti-mated at 8.41, 95% CI 2.17–32.63. Amiodarone treatment resultedin significantly increased treatment withdrawals due to AEs whencompared with propafenone (OR 4.34, 95% CI 1.73–10.91).

Based on a limited number of patients both amiodarone and fle-cainide showed an increase in the risk of SAEs compared withplacebo; the ORs were 8.10, 95% CI 2.36–27.81 and 10.36, 95%CI 1.26–58.24, respectively. The OR for SAEs for sotalol

compared with placebo was estimated at 1.77, 95% CI 0.95–1.30. Amiodarone significantly increased the risk of SAEs com-pared with propafenone with an OR of 6.26, 95% CI 2.39–16.37.All drugs were associated with an increased risk of proarrhythmiacompared with placebo. The increase did not reach statistical sig-nificance for amiodarone OR: 2.27, 95% CI 0.74–6.99 or propafe-none (OR: 2.34, 95% CI 0.76–7.27). However, the risk ofproarrhythmia was statistically higher with amiodarone when com-pared with dronedarone (OR: 3.41, 95% CI 1.11–10.44).

Mixed treatment comparison analysis:all-cause mortalityIn total, 18 trials9,18,20– 35 reported mortality and included at leastone event in at least one relevant randomized group. In these trials,10 032 patients were randomized and 369 patients died. Trialsincluded 3614 patients randomized to dronedarone, 680 patientsrandomized to amiodarone, 1342 patients randomized to sotalol,468 patients randomized to propafenone, 90 patients randomizedto flecainide, and 3838 patients randomized to placebo. The effectof each AAD compared with placebo on all-cause mortality isdescribed in Figure 2.

Sotalol was associated with an increase in risk of mortality com-pared with placebo/control (P ¼ 0.046). The analysis containedseveral small trials which introduced substantial uncertainty—thebetween trials covariance parameter estimate was 1.71 (SE 0.63;P ¼ 0.006). This leads to wide CIs and imprecision in thebetween agent measures. A further sensitivity analysis restrictedthe sample to those trials comparing the target drug either withan untreated control condition or an alternative drug, with atleast 100 patients per randomized group and at least one eventin either group. In total 7 trials,9,18,20,26,29,31,32 were included, inwhich 8252 patients were randomized and in 349 patients died.Trials included 3378 patients randomized to dronedarone, 653patients randomized to amiodarone, 873 patients randomized tosotalol, and 3348 patients randomized to placebo. The betweentrials covariance parameter estimate was reduced to 0.5860 (SE0.3706; P ¼ 0.12).

0.01 0.1 0.2 0.5 1 2 5 10 100

Propafenone 0.56 (0.06, 5.26) P=0.588

Flecainide 1.70 (0.05, 58.18) P=0.754

Sotalol 3.44 (1.02, 11.59) P=0.046

Amiodarone 2.17 (0.63, 7.51) P=0.203

Dronedarone 0.86 (0.61, 1.22) P=0.378

Figure 2 Mixed treatment comparison analysis: effect of anti-arrhythmic drugs on all-cause mortality. Odds ratios and 95% confidence inter-vals. Note—odds ratio smaller than 1 indicates a benefit (lower mortality) for the active agent.


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The effect of each AAD compared with placebo on all-causemortality in this subset of larger trials is described in Figure 3.Both amiodarone and sotalol were associated with an increasedrisk of death in this restricted analysis.

Mixed treatment comparison analysis:strokeIn total, 4 trials were included9,18,31,32 in which 7034 patients wererandomized and 138 patients experienced a stroke. Trials included261 patients randomized to sotalol, 3378 patients randomized todronedarone, 522 patients randomized to amiodarone, and 2873patients randomized to placebo. The effect of each AAD com-pared with placebo on stroke is described in Figure 4.

Randomization to dronedarone was associated with statisticallysignificant reductions in stroke compared with control. Neitheramiodarone nor sotalol achieved statistically significant reductionsin stroke compared with placebo.

There was no evidence of heterogeneity between studies(covariance parameter 0.06, SE0.06, P ¼ 0.3173).

Mixed treatment comparison analysis:atrial fibrillation recurrenceIn total, 30 trials were included18,20,21,24,25,27,29– 52 in which 6629patients were randomized and 3775 patients experienced AFrecurrence. Trials included 1228 patients randomized to propafe-none, 1404 patients randomized to sotalol, 1131 patients random-ized to dronedarone, 978 patients randomized to amiodarone, 305patients randomized to flecainide, and 1583 patients randomizedto placebo. The effects of each AAD compared with placebo onAF recurrence are described in Figure 5.

All treatments showed statistically significant reductions in AFrecurrence compared with placebo. There was substantialbetween study variability (covariance parameter 1.59, SE0.42,P ¼ 0.0002). Limiting the analysis to trials including at least 100

Dronedarone

Amiodarone

Sotalol 4.32 (1.59, 11.70) P=0.013

2.73 (1.00, 7.41) P=0.049

0.85 (0.67, 1.09) P=0.165

0.5 1 2 5 10 100

Figure 3 Mixed treatment comparison analysis: effect of anti-arrhythmic drugs on all-cause mortality in studies involving .100 patients ineither arm. Odds ratios and 95% confidence intervals. Note—odds ratio smaller than 1 indicates a benefit (lower mortality) for the active agent.

0.2 0.5 1 2

Sotalol 0.80 (0.39, 1.63) P=0.306

Amiodarone 0.89 (0.48, 1.65) P=0.517

Dronedarone 0.69 (0.57, 0.84) P=0.015

Figure 4 Mixed treatment comparison analysis: effect of anti-arrhythmic drugs on stroke. Odds ratios and 95% confidence intervals. Note—odds ratio lower than 1 describes a lower rate of stroke for the active treatment.


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patients per group reduced heterogeneity (P ¼ 0.11), and led tothe exclusion of flecainide from the analysis, but otherwise hadno qualitative effect upon the results.

Mixed treatment comparison analysis:treatment discontinuationIn total, 34 trials were included9,18,21,23–28,30–36,39–49,51–56 in which12 239 patients were randomized and 3150 patients discontinued.Trials included 3667 patients randomized to dronedarone, 1416patients randomized to propafenone, 1302 patients randomized tosotalol, 1172 patients randomized to amiodarone, 429 patients ran-domized to flecainide, and 4253 patients randomized to placebo.The effect of each AAD compared with placebo on treatment dis-continuation is described in Figure 6.

Numerically sotalol was associated with the lowest rate of treat-ment discontinuation. However, there were no statistically signifi-

cant differences in tolerability between the agents comparedwith placebo. There was substantial heterogeneity betweenstudies (between study covariance parameter 2.96, SE0.70, P ,

0.0001). Limiting the analysis to trials including at least 100 patientsin each group reduced between study variability (covariance par-ameter 1.03, SE0.65, P ¼ 0.11), but did not affect the results ofthe analysis.

Mixed treatment comparison analysis:withdrawal due to adverse eventsIn total, 29 trials were included9,18,20,21,23 –30,32– 36,39–46,49,51,52,54,57

in which 11 763 patients were randomized and 1342 patientsexperienced at least one SAE. Trials included 1624 patients ran-domized to sotalol, 3667 patients randomized to dronedarone,716 patients randomized to amiodarone, 224 patients randomizedto flecainide, 1261 patients randomized to propafenone, and 4271

0.1 0.2 0.5 1

Flecainide 0.31 (0.19, 0.49, P<0.0001)

Sotalol 0.40 (0.31, 0.52, P<0.0001)

Amiodarone 0.22 (0.16, 0.29, P<0.0001)

Propafenone 0.36 (0.28, 0.48, P<0.0001)

Dronedarone 0.53 (0.40, 0.72, P=0.0002)

Figure 5 Mixed treatment comparison analysis: effect of anti-arrhythmic drugs on atrial fibrillation recurrence. Odds ratios and 95% confi-dence intervals. Note—odds ratio lower than 1 describes a lower rate of atrial fibrillation recurrence for the active treatment.

0.5 1 2 5

Propafenone 1.20 (0.74, 1.95) P=0.449

Flecainide 1.20 (0.57, 2.53) P=0.629

Sotalol 0.89 (0.56, 1.40) P=0.608

Amiodarone 1.08 (0.68, 1.71) P=0.732

Dronedarone 1.09 (0.89, 1.33) P=0.407

Figure 6 Mixed treatment comparison analysis: effect of anti-arrhythmic drugs on treatment discontinuation. Odds ratios and 95% confi-dence intervals. Note—odds ratio smaller than 1 indicates a benefit (lower discontinuation) for the active agent.


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patients randomized to placebo. The effect of each AAD com-pared with placebo on the incidence of withdrawal due to AEs isdescribed in Figure 7.

Treatment with amiodarone, dronedarone, or sotalol wasassociated with significantly increased odds of withdrawals dueto AEs compared with placebo. There was considerable evidenceof between study heterogeneity (covariance parameter 2.36,SE0.63, P ¼ 0.0002). Limiting the analysis to those patients withat least 100 patients in each group reduces between study hetero-geneity (P ¼ 0.16) but had no qualitative effect upon the results.

Mixed treatment comparison analysis:serious adverse eventsIn total, 20 trials were included9,18,21,23,25 –29,32– 34,42– 46,51,52 inwhich 9734 patients were randomized and 1716 patients experi-enced at least one SAE. Trials included 1113 patients randomized

to sotalol, 3657 patients randomized to dronedarone, 427 patientsrandomized to amiodarone, 231 patients randomized to flecainide,550 patients randomized to propafenone, and 3756 patients ran-domized to placebo. The effect of each agent compared withplacebo on the incidence of SAEs is described in Figure 8.

No agent was statistically different from placebo on the incidenceof SAEs. There was some evidence of between trial heterogeneity(covariance parameter 3.83, SE1.35, P ¼ 0.005). Limiting the trialsto those with at least 100 patients in each group resulted in hom-ogeneity between trials. This analysis excluded flecainide and propa-fenone, but otherwise had little effect upon the parameter estimates.

Proarrhythmic eventsIn total, 13 trials were included9,18,21,23,26– 28,32,37,42,46,48,53 in which7860 patients were randomized and 501 patients experienced atleast one proarrhythmic event as per Friedman definition13.

0.5 1 2 5 10

Flecainide 1.65 (0.51, 5.37) P=0.392

Sotalol 1.69 (1.14, 2.52) P=0.011

Amiodarone 2.91 (1.66, 5.11) P=0.001

Propafenone 1.63 (0.94, 2.83) P=0.078

Dronedarone 1.70 (1.30, 2.23) P=0.0004

Figure 7 Mixed treatment comparison analysis: effect of anti-arrhythmic drugs on withdrawal due to adverse events. Odds ratios and 95%confidence intervals.

0.2 0.5 1 2 5 10 100

Propafenone 1.56 (0.49, 4.98) P=0.429

Flecainide 2.02 (0.29, 13.81) P=0.450

Sotalol 1.28 (0.71, 2.31) P=0.338

Amiodarone 2.41 (0.96, 6.06) P=0.060

Dronedarone 0.95 (0.73, 1.24) P=0.699

Figure 8 Mixed treatment comparison analysis: effect of anti-arrhythmic drugs on incidence of serious adverse events. Odds ratios and 95%confidence intervals. Note—odds ratio lower than 1 describes a lower rate of serious adverse events for the active treatment.


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Trials included 296 patients randomized to sotalol, 3443 patientsrandomized to dronedarone, 307 patients randomized to amiodar-one, 90 patients randomized to flecainide, 412 patients randomizedto propafenone, and 3312 patients randomized to placebo. Theeffect of each AAD compared with placebo on the incidence ofproarrhythmic events is described in Figure 9.

Dronedarone, propafenone, sotalol, and flecainide were allassociated with statistically significant increased rates of proar-rhythmic events. There was some evidence of heterogeneitybetween studies (covariance parameter 2.11, SE1.05, P ¼ 0.046).Limiting the analysis to studies with at least 100 patients in eachgroup resolved the limited heterogeneity, but had no qualitativeimpact upon the results.

Mixed treatment comparison vs.dronedaroneAn advantage of the MTC approach is that the results may beexpressed against a comparator of choice from within thenetwork described. Table 4 describes the major outcomes foreach comparison listed above compared with dronedarone.

DiscussionThis MTC assessed the relative efficacy and tolerability of the mainAADs used for the treatment of AF/AFl. The MTC method devel-oped further the results from the conventional direct meta-analysisand the results of both methods remained internally consistent.The major findings from our analyses include a reduced risk ofstroke with dronedarone, but not with other drugs studied, andsome evidence towards increased mortality for sotalol and amio-darone compared with control/placebo therapy, that were mostevident when studies with ,100 subjects or with no events inany group were excluded from analysis.

Many of these results are also consistent with the systematicCochrane review published previously8 despite differences in theinclusion/exclusion criteria used and the inclusion of new dataon dronedarone. The eight trials that were included in the

Cochrane review but not in the present analyses considered com-parisons not involving amiodarone, dronedarone, propafenone, orflecainide. Compared with the data set investigated by the previousCochrane review, we included six studies published after theCochrane cut-off date and eight studies with a duration shorterthan 6 months.

Risk of deathIn the present analysis, results indicating an increased risk of deathassociated with sotalol were statistically significant and consistentin sensitivity analysis. The previous Cochrane systematic review8

also reported a trend towards increased mortality with sotalolcompared with placebo, which became significant in some of thesensitivity analysis only.

Results from the current review also raise the possibility of anincrease in mortality associated with amiodarone treatment com-pared with placebo. This result is less robust than that obtainedfor sotalol as it reached modest statistical significance only in theexploratory analysis which was restricted to inclusion of largerstudies. A recent meta-analysis by Piccini et al.,58 which compareddronedarone and amiodarone using indirect comparison methods,found results very similar to ours, including also a non-significanttrend towards greater all-cause mortality with amiodarone,despite minor differences in the inclusion criteria between thetwo reviews.

The Cochrane review8 and a different meta-analysis by Doyle etal.,59 found no evidence of an effect of amiodarone on mortality. Inthe analysis by Doyle et al., amiodarone was not shown to increasemortality (OR 0.95, 95% CI 0.81–1.16). However, the RCT by Royet al.,60 which was not conducted in an AF population accountedalone for 72% of the weight in the analysis. In addition, the datathat they used for the AFFIRM substudy are different from thosewe extracted from the publication. In indications other than AF(post-myocardial infarction and heart failure), the RCTs61– 63 alsofound no evidence of an effect of amiodarone on mortality.

In contrast to sotalol and amiodarone, there is robust evidenceto suggest that treatment with dronedarone is not associated with

0.5 1 2 5 10 100

Flecainide 6.77 (0.85, 54.02) P=0.067

Sotalol 6.44 (1.03, 40.24) P=0.047

Amiodarone 5.45 (0.69, 42.93) P=0.095

Propafenone 4.06 (1.13, 14.52) P=0.035

Dronedarone 1.45 (1.02, 2.08) P=0.043

Figure 9 Mixed treatment comparison analysis: effect of anti-arrhythmic drugs on incidence of proarrhythmic events, odds ratio, and 95%confidence intervals.


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an increase in mortality in patients with AF. This finding is consist-ent with the finding that dronedarone was associated with thelowest odds of proarrhythmic events. The number of patients ran-domized to dronedarone and compared with placebo is the largestof all AADs studied. Dronedarone may carry an increased risk ofmortality in the specific population of patients with severe, decom-pensated heart failure, as observed in the ANDROMEDA trial.64

However, in that study, the inclusion criteria were symptomaticheart failure and not AF.

Stroke and other outcomesOur analyses indicated that dronedarone may be associated with areduced risk of stroke, compared with placebo. The estimates foramiodarone and sotalol for this outcome are similar (OR 0.89 and0.80), but have wide CIs and are not significant. The analysis of thisoutcome is limited because this endpoint was reported in fewstudies, especially in larger and more recent studies, so it cannotbe excluded that others AAD actually had a significant effect inthis outcome. In addition, antithrombotic therapies may not havebeen held constant between arms in all studies. Results for drone-darone are very encouraging but cannot be considered conclusive.

All of the reviewed AADs appear better than placebo at main-taining SR but all are associated with a greater likelihood thanplacebo of discontinuation due to AEs. Amiodarone, comparedwith placebo, was associated with the largest treatment effect inreducing AF recurrence but also with the highest rate of withdra-wal due to AEs. Moreover, amiodarone was associated with thehighest rate of patients experiencing at least one SAE, althoughthis estimate was not statistically significant.

Practical value of differences betweendrugsThe ATHENA trial9 had an overall mortality rate in the placebogroup of 6%. Applying the results of the MTC to this mortalityrate implies a number needed to treat for an additional death of16 (95% CI 4 to 1) for amiodarone, and 8 (95% CI 3–891) forSotalol.

LimitationsConventional direct meta-analyses include only those trials whichprovide evidence for a specific comparison, and thus can provideinconsistent results. For example, in the reporting of the directmeta-analyses results, we note that dronedarone treatment signifi-cantly increased treatment withdrawals for any reason comparedwith amiodarone [OR 1.69 (95% CI 1.16–2.44)]. Yet in the nextparagraph when presenting only withdrawals secondary to AEs,we report that the highest OR was reported for amiodarone com-pared with placebo where the odds of withdrawal were estimatedat 8.41 (95% CI 2.17–32.63). Such limitations of directmeta-analysis are addressed by the MTC, which finds that therewere no differences between agents in overall withdrawal com-pared with placebo, but significantly increased withdrawal second-ary to AEs with amiodarone, sotalol, and dronedarone comparedwith placebo.

Thus the MTC approach may be argued to make optimal use ofthe available data in describing the relative effectiveness of different

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treatments. However, estimates derived indirectly from a MTC arenot as strong as those derived from a directly randomized trial.The MTC method we used has the advantage that it preservesthe integrity of randomization in the original trials, without resort-ing to the rather strong assumptions necessary in Bayesian analysesusing numerical simulation techniques. Estimates are calculatedusing pseudo-likelihood directly from the data, rather than simu-lated from a distribution which is open to misspecification. Differ-ences between trials are incorporated in the variances through theR side random effects, appropriately accounting for extra binomialvariability (clustering at the trial level) while preserving the triallevel effect estimates. However, supportive analysis conducted(not shown) using numerical simulation approaches providesimilar answers to those presented here.

An important limitation of this, and any similar meta-analysis ofAF trials, is that some of the outcomes we examined were sec-ondary endpoints and may not have been ascertained and adjudi-cated in a consistent and complete manner. Historically most AFstudies were designed with a focus on measuring rhythm-relatedendpoints (such as AF recurrence rates or time to first recur-rence) and may have examined other endpoints, including theones we reviewed, with less rigour. In addition, some of theseoutcomes (e.g. stroke and mortality) were rare in most ofthese trials. As a result, the findings in some cases are sensitiveto meta-analytic methodology, and this may reflect somedegree of uncertainty. In a small number of trials which random-ized to different doses (Appendix Table A1), the doses groupswere pooled which may introduce bias if some dosages weresuboptimal.

The trials included in this review were conducted over a periodof time which included substantial changes in patient managementwhich could affect estimates derived in individual studies. Addition-ally, the standards for clinical trials have changed over time towardslarger trials with longer follow-up. For example, the evidence forpropafenone and flecainide was based upon few, smaller trialswith fewer events compared with the other AADs. In additionthese agents are not recommended for use in patients at raisedcardiovascular risk and so the results are not as generalizable asthose for the other agents.

ConclusionsAll AADs included in this mixed treatment analysis are efficaciousin delaying recurrence of AF. Amiodarone has been demonstratedto be the most effective drug in maintaining SR in many head tohead comparison trials. However, there may also be differencesin other outcomes between AADs. We found an increase in mor-tality associated with the use of sotalol and possibly with amiodar-one. The use of dronedarone was associated with less serious AEsand less proarrhythmic events than the other anti-arrhythmics. TheMTC provides the best available evidence on comparative efficacyand safety of these agents. Further large-scale comparative ran-domized morbidity, mortality, and patient-reported-outcometrials would be necessary to refine these estimates, particularlyfor older agents which have more limited evidence base.

Conflict of interest: N.F. received funding for research and con-sulting from sanofi-aventis and several other companies who man-ufacture products for cardiovascular diseases. L.E. is an employeeof sanofi-aventis. S.M. received funding for research and consultingfrom sanofi-aventis. C.L.L. and M.R. received funding for consultingfrom sanofi-aventis.

FundingThe study was funded by sanofi-aventis.

AcknowledgementsMichelle Orme provided statistical support.

AppendixSample SAS Code for estimating MTC models

proc glimmix data ¼ work.stroke;Title stroke by Drug;class study;model R/N ¼ study Dronedarone Amiodarone Sotalol/dist ¼ B

solution CL;NLOPTIONS tech ¼ nrridg MAXITER ¼ 5000;random_residual_/sub¼study;run;


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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Table A1 Presentation of the studies analysed

Study Year Experimentaltreatment

Treatment details Codedoutcomesreported

Totalpatients

Number ofpatientsdiscontinuedprematurely

Studyduration

Quality ofrandomization

Level ofblinding

Type of AF

AFFIRM substudy20 2003 Amiodarone Amiodarone, 200 mg/day a;b;d;f 154 20 Up to 5 years Inadequate Open-label Non-paroxysmal AFSotalol Sotalol, 240 mg/day 135 21

Aliot (Flecainide AF FrenchStudy Group)21

1996 Flecainide Flecainide, 100–300 mg/day a;b;c;d;g 48 18 12 months Unclear Open-label Paroxysmal AF (n ¼ 44);flutter (n ¼ 4)

Propafenone Propafenone, 600–1200 mg/day

49 26 Paroxysmal AF (n ¼ 45);flutter (n ¼ 1); both(n ¼ 3)

Bellandi (2001)36 2001 Sotalol Sotalol, 120–240 mg/day a;b;d;f 106 11 12 months Unclear Unclear Persistent/paroxysmal AFPropafenone Propafenone, 450–900 mg/

day102 9

Control Control 92 3

Benditt et al.57 1999 Sotalol Sotalol, 160–320 mg/day a;b;c;d;f 184 139 12 months Adequate Inadequate Non-permanent AF/flutterControl Control 69 53

Boos et al.37 2008 Amiodarone Amiodarone 200–600 mg/day

a;b;d;g 17 0 16 months Unclear Open-label Persistent AF, .1 month


Brodsky et al.65 1994 Sotalol Sotalol, 80–160 mg/day a;b 39 2 4 months Unclear Unclear Chronic/persistent AFControl Control 21

Carunchio et al.38 1995 Sotalol Sotalol, 240 mg/day a;b;d 20 0 12 months Unclear Open-label Paroxysmal AFFlecainide Flecainide, 200 mg/day 20 0Control Control 26 0

Channer et al.39 2004 Amiodarone Amiodarone, 200–800 mg/day

a;b;d 61 11 12 months Adequate Unclear Persistent AF, .72 h


Chimienti et al. (FAPIS)40 1996 Flecainide Flecainide, 100–150 mg b.d. a;b;d;f 97 30 12 months Adequate Open-label Paroxysmal recurrent AFPropafenone Propafenone, 150–300 t.i.d. 103 30

Cobbe53 1995 Propafenone Propafenone, 600 mg/day(low-dose)

b;c;g 30 13 .12 months Unclear Unclear PSVT (n ¼ 52)

Control Placebo low-dose 22Propafenone Propafenone, 900 mg/day

(high-dose)25 11 PAF (n ¼ 48)

Control Placebo high-dose 18

Connolly and Hoffert22 1989 Propafenone Propafenone, 1200 mg/day a;c 18 7 Four 30-daytreatmentperiods

Unclear Adequate Paroxysmal AFControl Control

Davy et al. (ERATO)23 2008 Dronedarone Dronedarone, 400 mg b.d. a;b;c;f;g 85 17 6 months Unclear Adequate Permanent AFControl Control 89 10

DIONYSOS18 2009 Dronedarone Dronedarone 400 mg b.i.d. a;b;c;d;e;f;g249 96 7 months Unclear Unclear Documented AF

.72 hAmiodarone Amiodarone 200–600 mg/

day255 69

Continued

Mixed

treatment

comparison

ofanti-arrhythm

icdrugs

341D

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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Table A1 Continued

Study Year Experimentaltreatment

Treatment details Codedoutcomesreported

Totalpatients

Number ofpatientsdiscontinuedprematurely

Studyduration

Quality ofrandomization

Level ofblinding

Type of AF

Dogan et al.24 2004 Propafenone Propafenone, 150 mg t.i.d. a;b;d;f 58 4 15 months Unclear Unclear Persistent (n ¼ 14);Recent onset (n ¼ 37)AF

Control Control 52 1 Persistent (n ¼ 15);Recent onset (n ¼ 33)AF

Fetsch et al. (PAFAC)25 2004 Sotalol Sotalol, 320 mg/day a;b;c;d;f 383 255 12 months Adequate Unclear Persistent AF (.7 days)Quinidine + Verapamil Quinidine,

160 mg + Verapamil,80 mg bid

377 244


Galperin et al. (GEFACA)41 2001 Amiodarone Amiodarone, 200 mg/day a;b;d;f 35 1 16 months Unclear Unclear Permanent AFControl Control 15 0

Hohnloser et al.(ATHENA)9

2009 Dronedarone Dronedarone, 400 mg b.d. a;b;e;f;g 2301 696 Meanfollow-up21 months(1–2.5years)

Unclear Unclear Paroxysmal/persistentAF/flutter


Kochiadakis et al.42 1998 Amiodarone Amiodarone 200 mg/day b;c;d;f;g 35 2 12 months Unclear Unclear Chronic or paroxysmalAFSotalol Sotalol 360 mg/day 35 2

Kochiadakis et al.43 2000 Amiodarone Amiodarone, 200 mg/day a;b;c;d;f 65 15 ≤2 years Unclear Unclear Paroxysmal(n ¼ 42);Chronic (n ¼ 23)

Sotalol Sotalol, 160–480 mg/day 61 3 Paroxysmal (n ¼ 39);Chronic (n ¼ 22)

Control Control 60 0 Paroxysmal(n ¼ 40);Chronic (n ¼ 20)

Kochiadakis et al.44 2004 Amiodarone Amiodarone, 200 mg/day a;b;c;d;f 72 17 �24 months Adequate Unclear Persistent (n ¼ 29);Paroxysmal (n ¼ 43)

Propafenone Propafenone, 150 mg t.i.d. 74 4 Persistent (n ¼ 25);Paroxysmal (n ¼ 49)

Kochiadakis et al.45 2004b Sotalol Sotalol, 160–480 mg/day a;b;c;d;f 85 5 ,48 months Unclear Unclear Persistent (n ¼ 35);Paroxysmal (n ¼ 50)

Propafenone Propafenone, 150 mg t.i.d. 86 5 Persistent (n ¼ 34);Paroxysmal (n ¼ 52)

Control Control 83 0 Persistent (n ¼ 34);Paroxysmal (n ¼ 49)

Lau et al.54 1992 Flecainide Flecainide 200 mg/day b 19 3 6 months Unclear Unclear Paroxysmal AFQuinidine Quinidine 1200 gm/dayControl Control

Lee et al. 199746 1997 Propafenone Propafenone b;c;d;f;g 41 2 3 months Unclear Unclear Symptomatic, paroxysmalAFSotalol Sotalol 38 4

Lombardi et al.(A-COMET-II)26

2006 Sotalol Sotalol, 160 mg b.d. a;b;c;f;g 223 196 6 months Adequate Adequate Persistent AF (.48 h, ,

6 months)Azimilide Azimilide, 125 mg b.d. 211 179Control Control 224 198

N.Freem

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Manios et al.55 2003 Diltiazem Diltiazem b 35 3 3 months Adequate Open-label Persistent AFAmiodarone Amiodarone 34 1Control No antiarrhythmic 37 0

Massacci et al.47 1992 Amiodarone Amiodarone 200–400 mg/day

b;d 18 6 18 months Unclear Open-label Paroxysmal AF

Flecainide Flecainide 200–300 mg/day 24 4

Meinertz et al. (ERAFT)27 2002 Propafenone Propafenone, SR, 325 or425 b.d.

a;b;c;d;f;g 200 29 3 months Unclear Unclear Paroxysmal AF


Pietersen and Hellemann(Danish-NorwegianFlecainide MulticenterStudy Group)28

1991 Flecainide Flecainide, 150 mg b.d. a;b;c;f;g 43 2 3 months Unclear Unclear Paroxysmal AF/flutterControl Control 43 2

Patten et al. (SOPAT)29 2004 Sotalol Sotalol, 160 mg b.d. a;b;c;d;f 264 53 12 months Unclear Unclear Paroxysmal AF(documented inprevious month)

Quinidine + Verapamil Quinidine + verapamil(high dose)

263 68

Quinidine + Verapamil Quinidine + verapamil (lowdose)

255 60


Pritchett et al.48 1991 Propafenone Propafenone 300 mg b.d.,t.i.d., or o.d.

b;d;g 23 11 4 months withextensionphase

Unclear Open-label Paroxysmalsupraventriculartachycardia orparoxysmal AF


Pritchett et al. (RAFT)49 2003 Propafenone Propafenone SR, 225–425 mg b.d.

a;b;d;f 397 69 ≤39 weeks Unclear Adequate Symptomatic AF


Reimold et al.30 1993 Sotalol Sotalol, ≤480 mg b.d. a;b;d;f 50 6 12 months Inadequate Open-label Paroxysmal (n ¼ 22);Chronic (n ¼ 28)

Propafenone Propafenone, ≤300 mgt.i.d.

50 4 Paroxysmal (n ¼ 25);Chronic (n ¼ 25)

Roy et al. (The CanadianTrial of AtrialFibrillation)50

2000 Amiodarone Amiodarone �200 mg/day a;b;c;d;e 201 68 36 months Unclear Open-label Persistent AFSotalol or propafenone Sotalol or propafenone 202 93

Singh et al. (SAFE-T)31 2003 Amiodarone Amiodarone, 200–800 mg/day

a;b;d;e;g 267 42 12 months Adequate Unclear Persistent AF

Sotalol Sotalol, 160–320 mg/day 261 39Control Control 137 28

Singh et al.51 1991 Sotalol Sotalol, 80–320 mg/day a;b;c;d;f 24 12 6 months Unclear Unclear Persistent (chronic) AF(2–52 weeks)Control Control 10 4

Singh et al. (EURIDISADONIS)32

2007 Dronedarone Dronedarone, 400 mg b.d. a;b;d;e;f 828 148 12 months Adequate Unclear Non-permanent AFControl Control 409 61

Stroobandt et al.33 1997 Propafenone Propafenone, 150 mg t.i.d. a;b;c;d;f 101 18 6 months Unclear Unclear Chronic (n ¼ 51); Recentonset (n ¼ 49) AF

Control Control 35 4 Chronic (n ¼ 60); Recentonset (n ¼ 40) AF

Touboul et al. (DAFNE)34 2003 Dronedarone Dronedarone, 400, 600,800 b.d.

a;b;c;d;f 204 22 6 months Unclear Unclear Persistent AF


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