2nd October 2009
This meta-analysis of individual patient data found that budesonide treatment for 12-months does not increase the risk of pneumonia in people with COPD. However, other studies which considered all inhaled corticosteroids, including budesonide, have shown a significantly increased risk of pneumonia. Further research is necessary to establish if budesonide offers any long-term safety advantage over other inhaled steroids (e.g. fluticasone) in COPD.
Level of evidence:
Level 1 (good quality patient-oriented evidence) according to the SORT criteria.
Although this study suggests that budesonide is not associated with an increased risk of pneumonia in people with COPD, clinicians should not change their practice on the basis of these new data. When considering adding an inhaled steroid to treatment regimens for people with COPD, prescribers should still consider, and discuss with patients, the potential increased risk of pneumonia, as well as osteoporosis and other side effects.
Health professionals should continue to follow NICE guidance on COPD , which recommends that ICSs are only prescribed for certain patients with moderate or severe COPD (forced expiratory volume in one second [FEV1] <50% predicted). An inhaled steroid should be added in to treatment with a long-acting bronchodilator (salmeterol, formoterol or tiotropium) only in patients with moderate or severe COPD who have had two or more exacerbations requiring treatment with antibiotics or oral corticosteroids in a 12-month period. Adding an inhaled steroid 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 steroid should be discontinued if there is no benefit after four weeks.
What is the background to this?
As we discussed in a MeReC Bulletin on recent safety issues with inhaled treatments for COPD, there is no good evidence that inhaled corticosteroids ICSs improve survival in people with COPD, or reduce the rate of FEV1 decline. However, there is evidence to suggest that ICSs may reduce the frequency of COPD exacerbations, and may improve quality of life.
The potential risks of ICSs range from unpleasant local side effects, such as oral candidiasis and dysphonia, to less common systemic effects, such as adrenal suppression and osteoporosis. Recently, ICS treatment in patients with COPD has also been associated with an increased risk of pneumonia.
The TORCH study found that pneumonia occurred more frequently in the fluticasone and combination fluticasone/salmeterol groups, than in the salmeterol alone and placebo groups (19% vs. 13%). For every 17 people treated for three years with an inhaler containing fluticasone instead of salmeterol alone or placebo, one suffered from pneumonia. Similarly, the INSPIRE study found the risk of pneumonia was almost doubled in the fluticasone/salmeterol group, compared with the tiotropium group (8% vs. 4%, hazard ratio (HR) for time to pneumonia 1.94, 95%CI 1.19 to 3.17, P=0.008). A subsequent systematic review and meta-analysis by Drummond, et al, also found that patients receiving an ICS had a significantly higher incidence of pneumonia; 14.4% vs. 10.4%, relative risk 1.34, 95%CI 1.03 to 1.75, P=0.03, I2=72%a, number needed to harm (NNH) = 25.
Both TORCH and INSPIRE specifically studied the ICS fluticasone, and the Drummond meta-analysis was heavily weighted (approximately 70%) by fluticasone studies. This new meta-analysis of individual patient data from 7 RCTs (n=7,042) aimed to establish the effects of the inhaled ICS budesonide on the risk of pneumonia in patients with COPD.
a The I2 statistic measures heterogeneity in a meta-analysis. A value of 0% indicates no observed heterogeneity, and larger values show increasing heterogeneity.
What does this study claim?
There was no statistically significant difference between the inhaled budesonide and placebo groups for the occurrence of pneumonia as an adverse event (3% [n=122 patients] vs. 3% [n=103] adjusted HR 1.05, 95%CI 0.81 to 1.37) or a serious adverse event (1% [n=53] vs. 2% [n=50], adjusted HR 0.92, 95%CI 0.62 to 1.35), or for time to pneumonia as an adverse event (log-rank test 0.94) or a serious adverse event (log-rank test 0.61). Increasing age and decreasing % FEV1 were the only two variables that were significantly associated with the occurrence of pneumonia as an adverse event or a serious adverse event. The authors claim that 12 months treatment with inhaled budesonide is safe for clinical use in COPD patients during that time.
This meta-analysis did not show an increased risk of pneumonia in COPD patients treated with inhaled budesonide for 12 months. Other large RCTs and meta-analyses have demonstrated an increased risk of pneumonia with ICSs, although these were heavily weighted with studies of fluticasone. On the basis of this new study, budesonide could be considered a safer option than fluticasone with respect to the risk of pneumonia, but this should not change current practice. As pointed out in an accompanying Comment, health professionals should continue to follow current guideline recommendations on the management of COPD.
There are some important limitations to these new findings and further long-term research is needed that directly compares budesonide with other ICSs at comparative doses. Furthermore, the risk of pneumonia is only one of a number of important factors to consider when assessing the risks of prescribing an ICS for an individual patient with COPD e.g. local side-effects, adrenal suppression, osteoporosis.
The authors of this meta-analysis had access to individual patient data, so they were able to assess and adjust for potential confounders e.g. age, symptoms, lung function. However, they did not appear to consider the dose of inhaled budesonide as a potential confounder. The Drummond meta-analysis found that the risk of pneumonia was significantly higher in the ‘highest ICS dose’ (>1000 micrograms beclometasone equivalent) subgroup. All the RCTs included in this meta-analysis had a maximum observation period of 12 months, so we don’t know if any differences between the treatment groups would have been observed over a longer duration.
None of the studies in this meta-analysis were specifically designed or powered to detect pneumonia. The diagnosis of pneumonia was identified from adverse event reports submitted by the investigators, and not validated by chest radiograph. This is a particular concern as the differentiation between pneumonia and acute exacerbation of COPD is often difficult.
Design: Meta-analysis of individual patient data from 7 double-blind RCTs of at least 6 months follow-up. All studies were of high quality (Jadad score >4, range 0–5). Intention to treat analysis was conducted.
Patients: 7,042 patients (mean age 61.6 years) with stable COPD ― defined as either a clinical diagnosis of COPD, or a current/former smoker (>10 pack-years) with a FEV1:FVC (forced vital capacity) ratio of <0.7 from postbronchodilator spirometry. According to the GOLD classification, 22% had very severe COPD (<30% predicted FEV1), 52% had severe COPD (30–49% predicted FEV1), 16% had moderate COPD (50–79% predicted FEV1), and 10% had mild COPD (>80% of predicted FEV1).
Intervention and comparison: Inhaled budesonide (320–1280 micrograms/day, n=3,801), with or without formoterol, versus control regimen (formoterol alone or placebo, n=3,242).
Outcomes: The primary outcome was the risk of pneumonia as an adverse event, or serious adverse event during the trial or within 15 days of the trial end. An adverse event was defined as the development of an undesirable disorder, or deterioration of a pre-existing disorder, irrespective of severity, and was assessed by study investigators. A serious adverse event was defined as an adverse event that resulted in death or hospital admission, or fulfilled any other criteria described in an appendix.
Results: There was no statistically significant difference between treatment groups for the occurrence of pneumonia as an adverse event (3% [n=122 patients] vs. 3% [n=103], adjusted HR 1.05, 95%CI 0.81 to 1.37) or a serious adverse event (1% [n=53] vs. 2% [n=50], 0.92, 95%CI 0.62 to 1.35), or for time to pneumonia as an adverse event (log-rank test 0.94) or a serious adverse event (0.61). Adjustments for potential confounders such as age, baseline lung function, and smoking status did not affect the overall results related to both treatment selection and outcome. Increasing age and decreasing % predicted FEV1 were the only two variables that were significantly associated with an increased risk of pneumonia as an adverse event or a serious adverse event. The proportion of patients who withdrew from the study for any reason was higher in the control group, compared with the budesonide group (30% [n=961] vs. 23% [n=877]).
Sponsorship: Michael Smith Foundation for Health Research. Original data was provided by AstraZeneca, but no funding for the study was supplied.
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