ArticlesBudesonide and the risk of pneumonia: a meta-analysis of individual patient data
Introduction
Inhaled corticosteroids, given with and without longacting β2 agonists, reduce the occurrence of disease exacerbation and improve quality of life for patients with chronic obstructive pulmonary disease (COPD), but they have also been associated with increased risk of pneumonia.1 Results from the largest clinical trial so far showed that inhaled corticosteroids increase the risk of pneumonia by nearly 50%.1 In an observational study of a large health database, Ernst and colleagues2 reported a 70% increase in the risk of hospital admission for pneumonia in patients who used inhaled corticosteroids. Findings from a meta-analysis indicated that on average, inhaled corticosteroids raised the risk of pneumonia by 34%;3 however, results differed widely between studies with some trials reporting increased risk,1, 4 whereas others reported reduced risk.5, 6 The excess risk seemed to be mainly restricted to patients who received doses of inhaled corticosteroids exceeding 1000 μg/day beclometasone or equivalent.3
Although these data are striking, several important limitations have affected this meta-analysis and previous meta-analyses.3, 7, 8 First, the trials included in the meta-analyses were heterogeneous in terms of study drug and duration, which will probably have contributed to the large variability in results. Indeed in one meta-analysis, use of a random-effects model to correct for heterogeneity across studies yielded a confidence interval that included the possibility of no difference.7 Second, none of the previous meta-analyses had access to data about patient characteristics and thus could not adequately adjust for potential confounders such as age, lung function, or other clinical features. Third, the previous analyses largely focused on any pneumonia event documented as an adverse event. However, the diagnostic accuracy of this endpoint is uncertain since many events were not validated with established criteria for pneumonia, including an opacity on chest radiographs.7 Moreover, many such events are not associated with significant morbidity or mortality.9 Conversely, hospital admissions for pneumonia are usually better documented with imaging studies and laboratory investigations, and are associated with substantial morbidity and mortality.10, 11 Since all hospital admissions due to pneumonia will be reported as serious adverse events, pneumonia as a serious adverse event might be a more accurate and clinically relevant endpoint.
To address these limitations, we pooled data for patient characteristics and results from seven large clinical trials of inhaled budesonide to establish the effects of treatment on the risk of any adverse and serious adverse events of pneumonia in patients with COPD.
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Data sources, search strategy, and study selection
US and AT searched Medline, EmBase, and an internal AstraZeneca product database of published studies, Planet, for randomised controlled trials of inhaled budesonide, with or without the longacting β2 agonist formoterol, compared with a control regimen (placebo or formoterol alone) for patients with COPD. We searched using the seach term “COPD” in combination with “budesonide”, “Pulmicort”, “budesonide and formoterol”, “Symbicort”, “placebo”, “formoterol”, “Oxis”, or “Foradil”. No language or
Results
Table 1 shows the baseline characteristics and follow-up of participants in the seven trials. We analysed data from more than 7000 participants who had more than 5000 patient-years of exposure. Table 2 shows the overall baseline characteristics of participants, which were included in the primary analysis. Mean age of participants was 61·6 years (SD 9·7), and mean postbronchodilator FEV1 was 45·5% (20·2) of predicted. Overall, 22% (n=1523 patients) of the cohort were in the Global initiative for
Discussion
In our study we have shown that budesonide, with or without a longacting β2 agonist, is not associated with increased risk of pneumonia reported as an adverse event or a serious adverse event. Adjustments for potential confounders such as age, baseline lung function, and smoking status did not affect overall results related to both treatment selection and outcome. Overall, the 1-year risk of pneumonia as an adverse event was low in both treatment groups at about 3%, which is consistent with
References (31)
- et al.
Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial
Lancet
(1999) - et al.
Patients hospitalized after initial outpatient treatment for community-acquired pneumonia
Ann Emerg Med
(1998) - et al.
Patients admitted to hospital with suspected pneumonia and normal chest radiographs: epidemiology, microbiology, and outcomes
Am J Med
(2004) - et al.
Assessing the quality of reports of randomized clinical trials: is blinding necessary?
Control Clin Trials
(1996) - et al.
Effect of fluticasone propionate/salmeterol (250/50 microg) or salmeterol (50 microg) on COPD exacerbations
Respir Med
(2008) - et al.
Long-term safety of once-daily budesonide in patients with early-onset mild persistent asthma: results of the Inhaled Steroid Treatment as Regular Therapy in Early Asthma (START) study
Ann Allergy Asthma Immunol
(2005) - et al.
Withdrawal from treatment as an outcome in the ISOLDE study of COPD
Chest
(2003) - et al.
Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease
N Engl J Med
(2007) - et al.
Inhaled corticosteroid use in chronic obstructive pulmonary disease and the risk of hospitalization for pneumonia
Am J Respir Crit Care Med
(2007) - et al.
Inhaled corticosteroids in patients with stable chronic obstructive pulmonary disease: a systematic review and meta-analysis
JAMA
(2008)
The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide
Am J Respir Crit Care Med
Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial
BMJ
Combined corticosteroid and long-acting beta-agonist in one inhaler versus long-acting beta-agonists for chronic obstructive pulmonary disease
Cochrane Database Syst Rev
Long-term use of inhaled corticosteroids and the risk of pneumonia in chronic obstructive pulmonary disease: a meta-analysis
Arch Intern Med
Treatment and outcomes of community-acquired pneumonia at Canadian hospitals
CMAJ
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