Atrial Fibrillation Associated With Ivabradine Treatment
The study was performed in line with the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.
We included in our analysis all randomised controlled double-blind trials of ivabradine, for any indication and of any size, which followed patients up for at least 4 weeks. We did not exclude studies where AF incidence was not reported in the published manuscript, but attempted to identify that data wherever possible. We included both placebo-controlled studies and non-inferiority studies where an alternative drug treatment was used as a comparator. We excluded open or single-blinded studies, studies where the follow-up period was less than 4 weeks and studies where there was significant risk of bias, as assessed by the methods recommended by the Cochrane Collaboration.
We performed a systematic search, without language restriction, for randomised clinical trials of ivabradine treatment for any indication, using the search term 'ivabradine' and the document type 'clinical trial' or 'randomized controlled trial'. We searched Medline, Embase and Web of Knowledge from 1980 to October 2013, and the Cochrane Central Register of Controlled Trials. We also examined the reference lists of published trials, review articles and meta-analyses to identify other eligible trials. We read the scientific discussions of the EMeA to identify safety data that were not published in the original trial report. We also contacted directly the authors and in the case of industry-sponsored trials, the sponsors of studies which did not report the AF incidence in the original manuscript.
Studies were assessed on the basis of their title or abstract and those studies which appeared to meet the eligibility criteria were selected for full text review. Trials were assessed for eligibility and risk of bias using the components recommended by the Cochrane Collaboration: sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, incomplete outcome data, selective outcome reporting and other sources of bias. We considered any trial with a high or unclear risk of bias, by the Cochrane criteria, in sequence generation, allocation concealment and blinding to be at high risk of bias; all other studies were considered to be at low risk of bias.
The main outcome measure was incident AF reported during the trial follow-up period. Where data on AF incidence were not reported, we contacted the authors by email on at least two occasions. We also identified AF incidence reported in the EMeA scientific discussions where trials were submitted as evidence for licensing and, in the case of trials sponsored by the manufacturer, contacted the manufacturer directly. Study data were collected on data collection forms which recorded reference data, ethical approval, randomisation, blinding, control agent (placebo or other drug), follow-up duration, inclusion and exclusion criteria and sponsorship and funding information as well as numbers of patients in the ivabradine and control arms with incident AF.
We performed meta-analysis of intention to treat outcomes using a random effect model in the metafor package in R statistical software V.3.0.2. Detailed statistical methods are available in the online supplement http://heart.bmj.com/content/100/19/1506/suppl/DC1.
Methods
The study was performed in line with the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.
Eligibility Criteria, Information Sources and Search Protocol
We included in our analysis all randomised controlled double-blind trials of ivabradine, for any indication and of any size, which followed patients up for at least 4 weeks. We did not exclude studies where AF incidence was not reported in the published manuscript, but attempted to identify that data wherever possible. We included both placebo-controlled studies and non-inferiority studies where an alternative drug treatment was used as a comparator. We excluded open or single-blinded studies, studies where the follow-up period was less than 4 weeks and studies where there was significant risk of bias, as assessed by the methods recommended by the Cochrane Collaboration.
We performed a systematic search, without language restriction, for randomised clinical trials of ivabradine treatment for any indication, using the search term 'ivabradine' and the document type 'clinical trial' or 'randomized controlled trial'. We searched Medline, Embase and Web of Knowledge from 1980 to October 2013, and the Cochrane Central Register of Controlled Trials. We also examined the reference lists of published trials, review articles and meta-analyses to identify other eligible trials. We read the scientific discussions of the EMeA to identify safety data that were not published in the original trial report. We also contacted directly the authors and in the case of industry-sponsored trials, the sponsors of studies which did not report the AF incidence in the original manuscript.
Selection and Quality Assessment
Studies were assessed on the basis of their title or abstract and those studies which appeared to meet the eligibility criteria were selected for full text review. Trials were assessed for eligibility and risk of bias using the components recommended by the Cochrane Collaboration: sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, incomplete outcome data, selective outcome reporting and other sources of bias. We considered any trial with a high or unclear risk of bias, by the Cochrane criteria, in sequence generation, allocation concealment and blinding to be at high risk of bias; all other studies were considered to be at low risk of bias.
Outcome Measures and Data Collected
The main outcome measure was incident AF reported during the trial follow-up period. Where data on AF incidence were not reported, we contacted the authors by email on at least two occasions. We also identified AF incidence reported in the EMeA scientific discussions where trials were submitted as evidence for licensing and, in the case of trials sponsored by the manufacturer, contacted the manufacturer directly. Study data were collected on data collection forms which recorded reference data, ethical approval, randomisation, blinding, control agent (placebo or other drug), follow-up duration, inclusion and exclusion criteria and sponsorship and funding information as well as numbers of patients in the ivabradine and control arms with incident AF.
Statistical Analyses
We performed meta-analysis of intention to treat outcomes using a random effect model in the metafor package in R statistical software V.3.0.2. Detailed statistical methods are available in the online supplement http://heart.bmj.com/content/100/19/1506/suppl/DC1.