Regular treatment with formoterol for chronic asthma: serious adverse events.

BACKGROUND: Epidemiological evidence has suggested a link between beta-agonists and increases in asthma mortality. There has been much debate about possible causal links for this association, and whether regular (daily) long-acting beta(2)-agonists are safe.

OBJECTIVES: The aim of this review is to assess the risk of fatal and non-fatal serious adverse events in trials that randomised patients with chronic asthma to regular formoterol versus placebo or regular short-acting beta(2)-agonists.

SEARCH STRATEGY: Trials were identified using the Cochrane Airways Group Specialised Register of trials. Web sites of clinical trial registers were checked for unpublished trial data and Food and Drug Administration (FDA) submissions in relation to formoterol were also checked. The date of the most recent search was July 2008.

SELECTION CRITERIA: Controlled parallel design clinical trials on patients of any age and severity of asthma were included if they randomised patients to treatment with regular formoterol and were of at least 12 weeks duration. Concomitant use of inhaled corticosteroids was allowed, as long as this was not part of the randomised treatment regimen.

DATA COLLECTION AND ANALYSIS: Two authors independently selected trials for inclusion in the review. Outcome data were extracted by one author and checked by the second author. Unpublished data on mortality and serious adverse events were sought.

MAIN RESULTS: The review includes 22 studies (8,032 participants) comparing regular formoterol to placebo and salbutamol. Non-fatal serious adverse event data could be obtained for all participants from published studies comparing formoterol and placebo but only 80% of those comparing formoterol with salbutamol or terbutaline.Three deaths occurred on regular formoterol and none on placebo; this difference was not statistically significant. It was not possible to assess disease specific mortality in view of the small number of deaths. Non-fatal serious adverse events were significantly increased when regular formoterol was compared with placebo (Odds Ratio 1.57 [95% CI: 1.05 to 2.37]). One extra serious adverse event occurred over 16 weeks for every 179 people treated with regular formoterol [95% CI: 75 to 2022]. The increase was larger in children than in adults, but the impact of age was not statistically significant. Data submitted to the FDA indicates that the increase in asthma-related serious adverse events remained significant in patients taking regular formoterol who were also on inhaled corticosteroids.No significant increase in fatal or non-fatal serious adverse events was found when regular formoterol was compared with regular salbutamol or terbutaline.

AUTHORS' CONCLUSIONS: In comparison with placebo, we have found an increased risk of serious adverse events with regular formoterol, and this does not appear to be abolished in patients taking inhaled corticosteroids. The effect on serious adverse events of regular formoterol in children was greater than the effect in adults, but the difference between age-groups was not significant.Data on all-cause serious adverse events should be more fully reported in journal articles, and not combined with all adverse events or limited to those events that are thought by the investigator to be drug-related.