|Inhaled corticosteroids in patients with stable chronic obstructive pulmonary disease: a systematic review and meta-analysis
|Bradley-Drummond M, Dasenbrook E C, Pitz M W, Murphy D J, Fan E
The authors concluded that inhaled corticosteroid therapy is not associated with a decrease in all-cause mortality in patients with chronic obstructive pulmonary disease, but is associated with an increased risk of pneumonia. This is a generally well conducted review, however the presence of clinical heterogeneity limits the reliability of the pooled results and makes interpretation difficult.
To investigate the impact of inhaled corticosteroid (ICS) therapy on all-cause mortality and risk of fracture or pneumonia in patients with stable chronic obstructive pulmonary disease (COPD).
MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, CINAHL, Web of Science and PsycInfo were searched to February 2008 with no language restrictions. Search terms were reported. Bibliographies of retrieved articles were searched for further studies. The search was restricted to published articles.
Double-blind randomised controlled trials (RCT) comparing ICS used for 6 months or more to placebo or non-ICS inhaled medications in adults, 40 years old or more, with COPD were eligible for inclusion. Studies of patients with asthma or with evidence of reversibility by standard bronchodilator testing were excluded. The primary outcome of interest was all-cause mortality at one year follow up, with mortality at 6 months, 2 years and 3 years follow up and incidence of pneumonia and fractures also reported.
Included studies evaluated fluticasone, budesonide or triamcinolone alone or combined with a long acting β2-agonist (LABA) and/or anticholinergic bronchodilators, compared to placebo or LABA and/or anticholinergic bronchodilators. The mean dose of ICS in beclomethasone equivalents ranged from 250μg/daily to 4,800μg/daily. Participants had a mean forced expiratory volume (FEV1) ranging from 36% to 87%. The percentage of smokers in the treatment groups ranged from 21% to 100%. The definition of pneumonia varied between studies. The duration of studies ranged from 6 to 40 months.
Two reviewers independently screened studies for inclusion. Disagreements were resolved by consensus
Assessment of study quality
Methodological quality was assessed using the Jadad scale and the criteria identified in the Cochrane Handbook; areas assessed included randomisation, allocation concealment, blinding, patient spectrum, intervention details, withdrawals and completeness of data. The validity assessment was performed independently by two reviewers.
The number of events in each group were extracted in order to calculate the relative risk (RR) with corresponding 95% confidence intervals (CI).
Two reviewers independently extracted the data. Disagreements were resolved by consensus.
Methods of synthesis
Pooled RRs with corresponding 95% CI were calculated using a random-effects model unless heterogeneity was low (I2 less than 50%), then a fixed-effects model was used. Where studies involved multiple therapeutic groups, the different treatment conditions were treated as separate two group trials. Subgroup analyses were conducted investigating dosage of ICS therapy, duration of ICS therapy, baseline COPD severity and the use of monotherapy versus combination therapy. Sensitivity analyses were conducted restricting analysis to studies with explicit outcome blinding, no industry funding, assessment of bronchodilator reversibility and secular trends (i.e. publication after 2003). Publication bias was assessed using funnel plots and the Begg statistical test.
Results of the review
Eleven RCTs were included for review (n=14,426). The methodological quality of studies was judged to be generally good. Four trials scored five on the Jadad, two trials scored four and five trials scored three. The sequence generation and allocation concealment was unclear in four trials, but outcome assessor blinding was reported in all trials. Discontinuation of allocated study medication occurred in 25% to 43% of patients. There was no evidence of significant publication bias. Results of the sensitivity analyses were reported and did not alter the main findings.
ICS therapy was not associated with a decreased risk of death at 6 month (2 RCTs), one year (5 RCTs), two years (2 RCTs) or three years follow up (5 RCTs), or the incidence of fractures (3 RCTs) compared to placebo or LABA monotherapy. There was no evidence of significant heterogeneity for these outcomes. However, ICS therapy was associated with a significantly higher risk of pneumonia compared to placebo or LABA monotherapy (7 RTCs, n=10,776; RR 1.34, 95% CI:1.03, 1.75, p=0.03). Significant heterogeneity was observed (I2 = 72%, p<0.001).
ICS therapy is not associated with a decrease in all-cause mortality in COPD patients, but is associated with an increased risk of pneumonia.
The review addressed a clear question with well-defined inclusion criteria. Several relevant databases were searched for articles in any language, thereby minimising the risk of language bias. The search was restricted to published articles, potentially introducing publication bias. The authors investigated this and reported no evidence of publication bias for any pooled analysis. The study selection, data extraction and validity assessment processes were conducted independently and in duplicate, thereby minimising the risk of reviewer error and bias. A validity assessment was carried out using established criteria. The authors investigated the impact of a number of potential sources of heterogeneity on the pooled results. This is a generally well-conducted review; however clinical heterogeneity across studies may, as acknowledged by the authors, make interpretation of the pooled results difficult.
Implications of the review for practice and research
Practice: The authors stated that patients should receive the lowest possible effective dose of ICS in order to minimise the risk of adverse events.
Research: The authors stated that further research is needed with clearly defined pneumonia and exacerbation outcomes. Future research should focus on identifying the optimal subgroup of patients who may benefit from ICS therapy.
Individual authors were supported by funding from a range of sources.
Bradley-Drummond M, Dasenbrook E C, Pitz M W, Murphy D J, Fan E. Inhaled corticosteroids in patients with stable chronic obstructive pulmonary disease: a systematic review and meta-analysis. JAMA 2008; 300(20): 2407-2416
Subject indexing assigned by NLM
Administration, Inhalation; Anti-Inflammatory Agents /adverse effects /therapeutic use; Fractures, Bone /epidemiology; Glucocorticoids /adverse effects /therapeutic use; Humans; Mortality; Pneumonia /epidemiology; Pulmonary Disease, Chronic Obstructive /drug therapy; Randomized Controlled Trials as Topic; Risk
Database entry date
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.