A recent systematic review and meta-analysis found that while inhaled corticosteroid use in COPD did not significantly affect mortality, there was a significantly increased incidence of pneumonia (NNH=25).
Clinicians should follow NICE guidance and only prescribe inhaled corticosteroids for certain patients with moderate or severe COPD (FEV1 <50% predicted). When considering inhaled corticosteroids in COPD, clinicians should weigh the possible benefits such as reduced exacerbations, with the potential adverse effects, particularly an increased risk of pneumonia.
What is the background to this?
There is no good evidence that inhaled corticosteroids (ICS) improve survival in patients with COPD, or reduce the rate of FEV1 decline. However, there is evidence to suggest that ICS use may reduce the frequency of COPD exacerbations, and may improve quality of life.
In 2007, the TORCH study was published, which was the first randomised controlled trial (RCT) to have mortality as its primary outcome. It found that after 3 years, there was no statistically significant reduction in mortality with fluticasone/salmeterol compared with salmeterol alone or placebo. Fluticasone/salmeterol reduced moderate to severe exacerbations, but not exacerbations requiring hospitalisation, compared with salmeterol alone. Furthermore, pneumonia occurred more frequently in the combination and fluticasone groups, than in the salmeterol and placebo groups (19% vs. 13%). This means that, for every 17 people treated for three years with an inhaler containing fluticasone instead of salmeterol alone or placebo, one suffered pneumonia.
Current NICE guidance on COPD recommends adding an ICS to treatment with a long-acting bronchodilator (salmeterol, formoterol or tiotropium) only in patients with moderate or severe COPD (FEV1 <50% predicted) who have had two or more exacerbations requiring treatment with antibiotics or oral corticosteroids in a 12-month period. Adding an ICS could also be considered in patients with moderate or severe COPD who are still breathless despite monotherapy with a long-acting beta-agonist, but the ICS should be discontinued if there is no benefit after four weeks.
What does this review claim?
This was a systematic review and meta-analysis of 11 double blind RCTs (n=14,426) that compared ICS therapy for >6 months with placebo or non-steroid therapy in patients with COPD. In trials with mortality data (N=5, n=9,233), there was no statistically significant difference in 1-year all cause mortality (the primary outcome) between the ICS and control groups; relative risk (RR) 0.86, 95% confidence interval (CI) 0.68 to 1.09; P=0.20; I2=0%*).
In trials with data on pneumonia (N=7, n=10,776), patients receiving ICS therapy had a significantly higher incidence of pneumonia; 14.4% vs. 10.4%, RR 1.34, 95%CI 1.03 to 1.75; P=0.03; I2=72%; number needed to harm (NNH) = 25. Three studies (n=8,131) reported fracture events, and there was no significant difference in the risk of fracture between ICS users vs. non-users; RR 1.09, 95%CI 0.89 to 1.33; P=0.40; I2=29%.
* The I2 statistic measures heterogeneity in a meta-analysis. A value of 0% indicates no observed heterogeneity, and larger values show increasing heterogeneity.
This meta-analysis of RCTs found that ICS use in stable COPD was not associated with improved survival during any of the follow-up periods ranging from 6 months to 3 years. However, there is no good evidence that any pharmaceutical treatments reduce mortality in COPD. It is also important to consider other patient-oriented outcomes e.g. reducing exacerbations, breathlessness, and improving quality of life, which this meta-analysis did not consider. There is evidence to suggest that ICS use may reduce the frequency of COPD exacerbations, and may improve quality of life. However, for the individual patient these benefits must be balanced against the known harms of ICS.
ICS therapy was associated with a 34% relative risk increase in pneumonia. This risk may be greatest in patients with: the lowest baseline FEV1; the highest ICS dose; the shortest duration of ICS; and combination therapy, although further studies with clearly defined pneumonia and exacerbation outcomes would be needed to confirm this. There was no increased risk of fracture with ICS use in this study, although the total number of fracture events was low.
This review confirms that clinicians should continue to follow NICE guidance and only prescribe inhaled corticosteroids for certain patients with moderate or severe COPD (FEV1 <50% predicted). When considering inhaled corticosteroids in COPD, clinicians should weigh the possible benefits such as reduced exacerbations and improved quality of life, with the potential adverse effects, particularly and increased risk of pneumonia.
Citation: Drummond MB, Dasenbrook EC, Pitz MW, et al. Inhaled corticosteroids in patients with stable chronic obstructive pulmonary disease. A systematic review and meta-analysis. JAMA 2008; 300(20): 2407–16
Design: Systematic review and meta-analysis of 11 double-blind RCTs (mean duration 24 months, range 6–40 months). Allocation concealment was adequately described in 7 studies. Nine studies reported intention-to-treat analysis.
Patients: Adults >40 years with COPD and an FEV1:FVC ratio <0.70. Mean baseline FEV1 was 51% predicted (range 36–86%). Trials enrolling patients with asthma or evidence of reversibility were excluded. All studies excluded patients with recent exacerbations.
Intervention & comparison: ICS therapy (>6 months) was compared with control therapy (placebo or non-ICS inhaled medications). Mean ICS dose was 930 micrograms/day beclometasone equivalent (range 250–4800 micrograms). The primary outcome was all-cause mortality 1 year after initiation of ICS therapy. Secondary outcomes included pneumonia, fractures, and mortality at 6-month, 2-year and 3-year follow-up. Pre-specified subgroup analyses were performed to investigate associations of ICS therapy with outcomes according to the following characteristics:
- High vs. low dose ICS
- Shorter vs. longer duration of ICS
- Severity of COPD
- ICS monotherapy vs. ICS/bronchodilator combination
Mortality — at 1-year follow-up (N=5, n=9233) there was no significant difference between the treatment and control groups (RR 0.86, 95%CI 0.68 to 1.09; P=0.20; I2=0%). Only 2 studies reported 6-month follow-up (n=6557), which limited pooled analysis. Neither study demonstrated a survival difference with ICS use. Only 2 studies (n=7435) reported 2-year follow-up. When combined, there was no difference for ICS therapy vs. no ICS therapy (RR 0.90, 95%CI, 0.69 to 1.12; P=0.45; I2=55%). At 3-year follow-up (N=5, n=9537) there was also no significant difference for ICS therapy vs. no ICS therapy (RR 0.98, 95%CI, 0.87 to 1.10; P=0.70; I2=0%).
Pneumonia — Seven studies (n=10 776) reported pneumonia outcomes. There were 777 events among 5405 patients in the treatment group and 561 events among 5371 patients in the control group. Patients receiving ICS therapy had a significantly higher incidence of pneumonia (14.4% vs. 10.4%, RR 1.34, 95%CI 1.03 to 1.75; P=0.03; I2=72%; number needed to harm [NNH] = 25).
Fracture — Three studies (n=8131 patients) reported fracture events. There was no statistically significant difference in the risk of fracture between ICS users vs. nonusers (RR 1.09, 95%CI 0.89 to 1.33; P=0.40; I2=29%).
Subgroup analyses — No effect modification was demonstrated for 1-year all-cause mortality or fracture risk in any of the 4 explored subgroups. However, there was a significantly higher risk of pneumonia in the following subgroups: highest ICS dose (RR 1.46, 95%CI 1.10 to 1.92; P=0.008; I2=78%); shorter (2 years) duration of ICS use (RR 2.12, 95%CI 1.47 to 3.05; P=0.001; I2=0%); higher baseline COPD severity (mean FEV1<40% predicted) (RR 1.90, 95%CI 1.26 to 2.85; P=0.002; I2=0%); and combination therapy (RR 1.57 95%CI 1.35 to 1.82; P=0.001; I2=24%).
Sponsorship: Eight studies reported industry funding. All studies reported some involvement with industry sponsors.