Regular treatment with formoterol and an inhaled corticosteroid versus regular treatment with salmeterol and an inhaled corticosteroid for chronic asthma: serious adverse events

Orlagh O'Shea, who is an ESI fellow, published a new review with Chris Cates and Liz Stovold from the Cochrane Airways Editroial base team. Orlagh said that the take-home message from the review is "As long as salmeterol or formoterol are in a combined inhaler with an inhaled steroid we did not identify any safety issues which would affect the choice of any combination". Below we have reproduced the plain language summary. The full review can be read here.

Do people with asthma have fewer serious adverse events when taking formoterol and inhaled corticosteroids compared to salmeterol and inhaled corticosteroids?


Asthma is a condition that affects the airways – the small tubes that carry air into and out of the lungs. When a person with asthma comes into contact with an asthma trigger, the airways become irritated and the muscles around the walls of the airways tighten, so that the airways become narrower (bronchoconstriction) and the lining of the airways becomes inflamed and starts to swell. Sometimes, sticky mucus or phlegm builds up, which can further narrow the airways. These reactions cause the airways to become narrower and irritated - making it difficult to breathe, and leading to coughing, wheezing, shortness of breath, and tightness in the chest. People with asthma are generally advised to take inhaled steroids to combat the underlying inflammation, but if asthma is still not controlled, current clinical guidelines for people with asthma recommend the introduction of an additional medication to help. A common strategy in these situations is to use a long-acting beta-agonist: formoterol or salmeterol. A long-acting beta-agonist is an inhaled drug that opens the airways (bronchodilator), making it easier to breathe. Inhaled steroids can be added to these bronchodilators in the same inhaler. A variety of inhaled steroids are used in combined inhalers with either formoterol or salmeterol.

We know from previous Cochrane Reviews that there is a small increase in serious adverse events (such as very severe asthma attacks, as well as other life-threatening events) when regular formoterol or regular salmeterol is taken without inhaled steroids, but this increase was not seen when these drugs were used with an inhaled steroid in a single combined inhaler. This review sought information from trials that compared the two treatments (i.e. when people taking salmeterol with an inhaled corticosteroid were compared directly with people taking formoterol and an inhaled corticosteroid) to see if we could determine which drug was safer.

Study characteristics

We carried out a search for studies in February 2021. In total, we included in this review 23 randomised controlled trials comparing formoterol and inhaled corticosteroids with salmeterol and inhaled corticosteroids. Twenty-one studies with 11,572 participants included adults and adolescents. The lower age in these 21 studies varied from 12 to 16 or 18. Eight of these studies (7730 adults) compared formoterol/budesonide combination inhalers with salmeterol/fluticasone, with smaller numbers (1472, 1126, and 1075 adults) comparing the other formoterol combinations with salmeterol/fluticasone. Only 229 adults were available in studies comparing formoterol/budesonide with salmeterol/budesonide. Two studies of 723 participants included children; the age ranges in these studies were 4 to 12 and 5 to 12; both compared formoterol/fluticasone with salmeterol/fluticasone inhalers.

Key results

No certain differences could be detected between combination formoterol/inhaled corticosteroids and salmeterol/inhaled corticosteroids for all-cause mortality nor for all-cause or asthma-related non-fatal adverse events. No deaths from asthma were reported. The included studies had enough participants to assess the benefits of treatment, but they did not include enough people to determine the comparative safety of these treatments.

Quality of the evidence

In general, the included studies had low levels of bias, but there was a low incidence of mortality and serious adverse events, which reduced the certainty of the evidence for different outcomes. The quality of evidence for all-cause mortality and all-cause non-fatal serious adverse events was graded as low and moderate, respectively. The quality of evidence for asthma-related serious adverse events varied from low to very low due to small numbers of asthma-related events and lack of independent assessment of the causation of events.


We found no safety issues that would affect the choice between salmeterol and formoterol combination inhalers used for regular maintenance therapy in adults and children with asthma.

The full review can be found here.