Key message: The addition of new evidence to this review has shown a significant reduction in asthma-related non-fatal serious adverse events in adults with asthma who are given regular formoterol as well as inhaled steroids.
When asthma is not well controlled by low-dose inhaled corticosteroids (ICS), many asthma guidelines recommend adding another type of medicine, a long-acting beta2-agonist, such as formoterol. These have been shown to improve lung function, quality of life and asthma symptoms but there are concerns about their safety when used regularly. One worry is that because they improve symptoms people may think an asthma attack is not as bad as it really is and this could lead to an increase in deaths from asthma if people don’t get treatment quickly enough or don’t get the right treatment.
A team from the Cochrane Airways Group has now updated their systematic review comparing regular formoterol plus ICS with ICS only (at the same dose) for risk of death and of other ‘serious adverse events’ or SAEs. SAEs are life-threatening problems for which the person needs to be admitted to hospital or stay there longer if already hospitalized, or which result in serious disability or a birth defect. Six new randomized controlled trials (RCTs) in adults have been added, bringing the total to 20 RCTs with over 10,000 adults and seven RCTs with 2788 children.
What did they find?
- In adults, there were significantly fewer asthma-related SAEs in those taking regular formoterol and ICS compared with ICS alone and no significant difference in all-cause SAEs
- In children, there were too few data and too few events to allow any clear conclusions to be drawn
- 7 deaths of adults were reported in over 13,000 people, one related to asthma. No conclusions can be drawn about possible differences in the risk of death relating to taking ICS alone or with formoterol
How good was the evidence?
The reviewers found the evidence to be of moderate quality for adults but low quality for children. There is not much evidence relating to children but there is a large study being done at the moment. The trials were all sponsored by drug manufacturers and it is possible that there was some bias in relation to deciding whether events were related to asthma, as there was no independent assessment of the cause of events.
What does this change?
Perhaps not very much. The reviewers stress that the evidence does not remove the possibility that regularly taking ICS plus formoterol carries an increased risk of death compared with taking ICS alone. However, they also say that there is no clear evidence of harm and only one asthma-related death was reported in over 4,200 patient-years of observing people taking formoterol. There is now stronger evidence that adding formoterol to ICS reduces the risk of asthma-related SAEs in adults. For now, decisions about taking formoterol regularly must consider both the known benefits and continued uncertainty about possible harms.
Lead author Chris Cates writes:
“The new trials added to this review give a clearer picture of the impact of regular formoterol when used in combination with inhaled corticosteroids in adults. We now see that fewer adults on formoterol were found to have a serious asthma event (which would usually lead to an admission to hospital). This is good news, but it is puzzling to see that this finding was not mirrored by a decrease in serious events of any cause. We therefore cannot be sure whether there was some kind of bias operating in whether the events were labelled as being due to asthma or not. There is also a shortage of information on the safety of formoterol in children and adolescents with asthma.
We hope that we will better understand the safety of regular formoterol in combination with inhaled corticosteroids (particularly in adolescents) when the large on-going studies commissioned by the Food and Drug Administration are completed and report their results.”
Cates CJ, Jaeschke R, Schmidt S, Ferrer M. Regular treatment with formoterol and inhaled steroids for chronic asthma: serious adverse events. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD006924. DOI: 10.1002/14651858.CD006924.pub3.