Meta-analyses of safety data: a comparison of exact versus asymptotic methods

The objectives of this study were to establish and describe a database of Cochrane and non-Cochrane meta-analyses of safety data and to determine under what conditions exact methods differ from asymptotic methods in meta-analyses of safety data. A sample of Cochrane (n = 500) and non-Cochrane (n = 200) systematic reviews was randomly selected and a database of safety meta-analyses established. Point estimates and confidence intervals for each meta-analysis were recalculated using exact methods and compared to the results of asymptotic methods. Cochrane reviews were nearly four times as likely as non-Cochrane reviews to contain meta-analyses of safety data (35% compared to 9%). More than 50% of safety meta-analyses contained an outcome with a rare event rate (<5%) and 30% contained at least one study with no events in one arm of the study. For rare event meta-analyses, exact point estimates differed substantially from asymptotic estimates 46% of the time, compared to 17% for those without rare events. Exact confidence intervals differed substantially from asymptotic ones 67% of the time compared to only 19% for those without rare events. The magnitude of differences was also correlated with the number of studies and the summary statistic used to combine the data. Asymptotic methods will not always be a good approximation for exact methods in safety meta-analyses. Event rates and number of studies should be closely examined when choosing the statistical method for combining rare event data.