Inhaled corticosteroids (ICS) are drugs that can reduce the occurrence of COPD flare-ups and improve quality of life. In COPD, ICS are commonly used alongside long-acting beta2-agonists (LABA). The most common combinations of ICS and LABA inhalers are fluticasone and salmeterol, and budesonide and formoterol, but fluticasone furoate is also used once daily with a new LABA called vilanterol. Lots of studies have shown benefits of ICS, but they can also increase the risk of pneumonia. Added to this concern, pneumonia can be difficult to diagnose, and the severity of pneumonia can be poorly reported in trials. Therefore even though we have reviews on inhaled steroids for COPD, we wanted to do a review exclusively on pneumonia, so we could take a closer look at the evidence.
The overall aim of this review is to assess the risk of pneumonia for people with COPD taking fluticasone or budesonide.
How did we answer the question?
We looked for all studies comparing budesonide or fluticasone versus a dummy inhaler (placebo), and all studies comparing their use in combination with a LABA (i.e. budesonide/formoterol, fluticasone propionate/salmeterol, and fluticasone furoate/vilanterol) versus the same dose of LABA alone. This allowed us to assess the risk of ICS used alone or in combination with LABA.
What did we find?
We found 43 studies including more than 30,000 people with COPD. More studies used fluticasone (26 studies; 21,247 people) than budesonide (17 studies; 10,150 people). A higher proportion of people in the studies were male (around 70%), and their COPD was generally classed as severe. The last search for studies to include in the review was done in September 2013.
We compared each drug against controls and assessed separately the results of studies that compared ICS versus placebo, and an ICS/LABA combination versus LABA alone. We also conducted an indirect comparison of budesonide and fluticasone based on their effects against placebo, to explore whether one drug was safer than the other.
Fluticasone increased 'serious' pneumonias (requiring hospital admission). Over 18 months, 18 more people of every 1000 treated with fluticasone were admitted to hospital for pneumonia.
Budesonide also increased pneumonias that were classed as 'serious'. Over nine months, six more hospital admissions were reported for every 1000 individuals treated with budesonide. A lower dose of budesonide (320 mcg) was associated with fewer serious pneumonias than a higher dose (640 mcg).
No more deaths overall were reported in the ICS groups compared with controls, and deaths related to pneumonia were too rare to tell either way.
When we compared fluticasone and budesonide versus each other, the difference between them was not clear enough to tell whether one was safer (for pneumonia, requiring a hospital stay, general adverse events and death). The risk of any pneumonia event (i.e. less serious cases that could be treated without going to hospital) was higher with fluticasone than with budesonide.
Evidence was rated to be of high or moderate quality for most outcomes. When anoutcome is rated of high quality, further research is very unlikely to change our confidence in the estimate of effect, but moderate ratings reflect some uncertainty in the findings. Results from the budesonide studies were generally less clear because they were based on fewer people, and the studies were shorter.
Conclusion
Budesonide and fluticasone, delivered alone or in combination with LABA, can increase serious pneumonias that result in hospitalisation of people. Neither has been shown to affect the chance of dying compared with not taking ICS. Comparison of the two drugs revealed no difference in serious pneumonias or risk of death. Fluticasone was associated with a higher risk of any pneumonia (i.e. cases that could be treated in the community) than budesonide, but potential differences in the definition used by the respective drug manufacturers reduced our confidence in this finding. These concerns need to be balanced with the known benefits of ICS (e.g. fewer exacerbations, improved lung function and quality of life).
Researchers should remain aware of the risks associated with ICS and should make sure that pneumonia is properly diagnosed in studies.
Authors' conclusions:
Budesonide and fluticasone, delivered alone or in combination with a LABA, are associated with increased risk of serious adverse pneumonia events, but neither significantly affected mortality compared with controls. The safety concerns highlighted in this review should be balanced with recent cohort dataand established randomised evidence of efficacy regarding exacerbations and quality of life. Comparison of the two drugs revealed no statistically significantdifference in serious pneumonias, mortality or serious adverse events. Fluticasone was associated with higher risk of any pneumonia when compared with budesonide (i.e. less serious cases dealt with in the community), but variation in the definitions used by the respective manufacturers is a potentialconfounding factor in their comparison.
Primary research should accurately measure pneumonia outcomes and should clarify both the definition and the method of diagnosis used, especially for new formulations and combinations for which little evidence of the associated pneumonia risk is currently available. Similarly, systematic reviews and cohorts should address the reliability of assigning 'pneumonia' as an adverse event or cause of death and should determine how this affects the applicability of findings.
