O3.2 Inhaled glucocorticoids

Inhaled glucocorticoids should be considered in patients with moderate to severe COPD and frequent exacerbations [evidence level I]

Acute exacerbations have a detrimental effect on quality of life, and patients with severe disease and frequent exacerbations have an accelerated decline in their quality of life. (Miravitlles et al., 2004) A number of randomised controlled trials of high dose glucocorticoids have been published and these have been combined in a systematic review (Yang et al., 2007), mainly involving subjects without bronchodilator reversibility or bronchial hyper-responsiveness. Unfortunately, this review does not include all the data from a recently published large randomised controlled trial involving 6000 participants. (Calverley et al., 2007)

Inhaled glucocorticoids decrease the exacerbation rate compared to placebo in studies longer than a year, weighted mean difference  -0.26 exacerbations per participant, per year (95% CI -0.37 to -0.14, 2586 participants). They also show the rate of decline in quality of life slowed, the weighted mean difference in rate of change for the St George’s Respiratory Questionnaire was -1.22 units/year (95% CI  -1.83 to -0.60, 2507 participants).

Inhaled glucocorticoids do not improve mortality. Pooled results from nine studies involving 8,390 participants found an odds ratio of death of 0.98 (95% CI 0.83 to 1.16). The effect of inhaled glucocorticoids on the decline in lung function remains unclear. Pooled results from studies of two years duration or longer, found no significant difference in the rate of decline in post-bronchodilator FEV₁ (Yang et al., 2007), weighted mean difference = 5.8mls/year (95% CI -0.28 to 11.88, 2,333 participants), although this analysis did not include the TORCH study (Calverley et al., 2007) , which did find a significant benefit (weighted mean difference in FEV₁ over three years = 47mls, 95% CI 31 to 64 mls, 2,617 participants). In a large RCT in patients with milder COPD, medium-dose budesonide had no significant impact.(Pauwels et al., 1999)

Patients with clinically significant acute bronchodilator reversibility may benefit from long-term inhaled glucocorti­coid therapy. Long term inhaled therapy with glucocorti­coids is also indicated in patients with COPD who have significant reversibility of airway function after a more prolonged trial of bronchodilators or glucocorticoids, as these patients probably have mixed asthma and COPD. (Senderovitz et al., 1999, Vestbo et al., 1999, Pauwels et al., 1999)

Some systemic absorption may occur, so the modest benefits of inhaled glucocorticoids must be weighed against the potential risks of local oropharyngeal adverse effects, easy bruising, cataract forma­tion and possible contribution to osteoporosis. Local adverse effects include oral candidiasis with a NNH of 38 (95% CI 23-71) and hoarseness or dysphonia with a NNH of 35 (95% CI 20-79). (Yang et al., 2007) In addition to local adverse effects, two subsequent meta-analyses have found an increase in the risk of pneumonia associated with inhaled glucocorticoid treatment. (Drummond et al., 2008), (Singh et al., 2009) Using data from the study by Drummond et al, which only included studies of greater than six months duration, gives a NNH of 34 (95% CI 16 to 372) [evidence level I]. Whether this is a dose or class effect is unclear, as these positive meta-analyses included studies of fluticasone and budesonide, whereas a more recent meta-analysis of individual patient data did not find a significant increase in risk of pneumonia for treatment with budesonide compared to placebo (adjusted hazard ratio=1.05, 95% CI 0.81-1.37,n=7042) [evidence level I]

In people with COPD and diabetes mellitus, particular care should be taken not to exceed the recommended dose of glucocorticoids as there is some evidence of a direct relationship between glucocorticoid dose and glucose levels in such patients(Slatore et al., 2009) [evidence level III-2]. The response should be assessed with spirometry and measures of performance status, quality of life or both. They should be trialled for three to six months in patients with moderate to severe COPD, and continued if there is objec­tive benefit.  Withdrawal of inhaled steroids may be associated with a decline of FEV₁, increased symptoms and a greater rate of mild exacerbations (Wouters et al., 2005)  [evidence level II]. However, it is not clear whether this applies to patients who have not responded to oral steroids.