Do inhaled corticosteroids slow FEV1 decline in COPD after all?
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《胸》
Department of Medicines Management, Keele, University, Staffordshire ST5 5BG, UK; martin@theduerdens.co.uk
Keywords: chronic obstructive pulmonary disease; inhaled corticosteroids; ethics; placebo controlled studies
I question the findings of the meta-analysis by Sunderland et al1 and the content of the associated editorial by Burge and Lewis.2 The meta-analysis has drawn from available long term data from randomised controlled studies (RCTs) of inhaled corticosteroids (ICS) in chronic obstructive airways disease (COPD). The whole purpose of meta-analysis is to analyse such data systematically to answer a question. This study seems to use the data selectively to demonstrate an effect. Another recent meta-analysis—in my opinion properly conducted—drew on the same studies and reached the opposite conclusion.3 The fact is that four long term, adequately powered RCTs have examined the effect of ICS. All of these studies showed no effect of ICS on the primary outcome measure of decline in forced expiratory volume in 1 second (FEV1). There may be a subset of people in whom the exacerbation rate is reduced, which was a secondary outcome in some of these studies.
In any case, as the authors point out, an annual difference of 7.7–9.9 ml in FEV1 decline compared with placebo is of "debatable clinical importance".1 It is hardly something to shout about, as occurred following this publication (probably egged on by the editorial) which was quoted in the GP press as suggesting that current widespread ICS use (albeit "off-label") was now clinically justified.5
Another major problem with this study is that it does not analyse harm. For example, the largest RCT showed a significant reduction in bone mineral density of the lumbar spine and femur in patients receiving inhaled triamcinolone.4 People with COPD likely to receive ICS are frail and have poor mobility, so this finding raises particular concern as they are more likely to fall and falls could result in fracture. Even if inhaled triamcinolone is not used in the UK, fluticasone is. Fluticasone has been the subject of particular cautionary advice because of its ability to cause systemic effects at high doses.6 If there is indeed a marginal clinical benefit from using these drugs, I think these people deserve a better assessment of risk and benefit than was presented in this meta-analysis and the accompanying editorial.2 The editorial claimed that it is no longer ethical to do more long term trials: surely the conclusion is the opposite? We need better data to justify the widespread use of ICS in COPD.
References
Sutherland ER, Allmers H, Ayas NT, et al. Inhaled corticosteroids reduce the progression of airflow limitation in chronic obstructive pulmonary disease: a meta-analysis. Thorax 2003;58:937–41.
Burge PS, Lewis SA. So inhaled steroids slow the rate of decline of FEV1 in patients with COPD after all? Thorax 2003;58:911–3.
Highland KB, Strange C, Heffner JE. Long-term effects of inhaled corticosteroids on FEV1 in patients with chronic obstructive pulmonary disease. A meta-analysis. Ann Intern Med 2003;138:969–73.
The Lung Health Study Research Group. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N Engl J Med 2000;343:1902–9.
News: NICE steroids advice for COPD thrown into doubt. Pulse 3 November 2003.
CSM/MCA. Reminder: Fluticasone propionate (Flixotide): use of high doses (>500 micrograms/twice daily). Current Problems in Pharmacovigilance August 2001.(M G Duerden)
Keywords: chronic obstructive pulmonary disease; inhaled corticosteroids; ethics; placebo controlled studies
I question the findings of the meta-analysis by Sunderland et al1 and the content of the associated editorial by Burge and Lewis.2 The meta-analysis has drawn from available long term data from randomised controlled studies (RCTs) of inhaled corticosteroids (ICS) in chronic obstructive airways disease (COPD). The whole purpose of meta-analysis is to analyse such data systematically to answer a question. This study seems to use the data selectively to demonstrate an effect. Another recent meta-analysis—in my opinion properly conducted—drew on the same studies and reached the opposite conclusion.3 The fact is that four long term, adequately powered RCTs have examined the effect of ICS. All of these studies showed no effect of ICS on the primary outcome measure of decline in forced expiratory volume in 1 second (FEV1). There may be a subset of people in whom the exacerbation rate is reduced, which was a secondary outcome in some of these studies.
In any case, as the authors point out, an annual difference of 7.7–9.9 ml in FEV1 decline compared with placebo is of "debatable clinical importance".1 It is hardly something to shout about, as occurred following this publication (probably egged on by the editorial) which was quoted in the GP press as suggesting that current widespread ICS use (albeit "off-label") was now clinically justified.5
Another major problem with this study is that it does not analyse harm. For example, the largest RCT showed a significant reduction in bone mineral density of the lumbar spine and femur in patients receiving inhaled triamcinolone.4 People with COPD likely to receive ICS are frail and have poor mobility, so this finding raises particular concern as they are more likely to fall and falls could result in fracture. Even if inhaled triamcinolone is not used in the UK, fluticasone is. Fluticasone has been the subject of particular cautionary advice because of its ability to cause systemic effects at high doses.6 If there is indeed a marginal clinical benefit from using these drugs, I think these people deserve a better assessment of risk and benefit than was presented in this meta-analysis and the accompanying editorial.2 The editorial claimed that it is no longer ethical to do more long term trials: surely the conclusion is the opposite? We need better data to justify the widespread use of ICS in COPD.
References
Sutherland ER, Allmers H, Ayas NT, et al. Inhaled corticosteroids reduce the progression of airflow limitation in chronic obstructive pulmonary disease: a meta-analysis. Thorax 2003;58:937–41.
Burge PS, Lewis SA. So inhaled steroids slow the rate of decline of FEV1 in patients with COPD after all? Thorax 2003;58:911–3.
Highland KB, Strange C, Heffner JE. Long-term effects of inhaled corticosteroids on FEV1 in patients with chronic obstructive pulmonary disease. A meta-analysis. Ann Intern Med 2003;138:969–73.
The Lung Health Study Research Group. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N Engl J Med 2000;343:1902–9.
News: NICE steroids advice for COPD thrown into doubt. Pulse 3 November 2003.
CSM/MCA. Reminder: Fluticasone propionate (Flixotide): use of high doses (>500 micrograms/twice daily). Current Problems in Pharmacovigilance August 2001.(M G Duerden)