O3. Glucocorticoids

Indeed, caution in the long term use of systemic glucocorticoids is necessary because of limited efficacy and potential toxicity in elderly patients.

O3.1 Oral glucocorticoids

Some patients with stable COPD show a significant response to oral glucocorticoids (on spirometry or functional assessment). Therefore, a short course (two weeks) of prednisolone (20–50mg daily) may be tried with appropriate monitoring. Short courses of oral glucocorticoids (<14 days) do not require tapering. A negative bronchodilator response does not predict a negative steroid response.^7,71 If there is a response to oral steroids, continued treatment with inhaled glucocorticoids is indicated, but these may fail to maintain the response.^71,72 Patients who have a negligible response to glucocorticoids should not use them.

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.⁷³ A number of randomised controlled trials of high dose glucocorticoids have been published and these have been combined in a systematic review⁷⁴, 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 participants⁷⁵.

O3.2 Inhaled glucocorticoids

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, 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 FEV1⁷⁴, weighted mean difference = 5.8mls/year (95% CI -0.28 to 11.88, 2,333 participants), although this analysis did not include the TORCH study⁷⁵, which did find a significant benefit (weighted mean difference in FEV1 over three years = 47mls, 95% CI 31 to 64 mls, 3058 participants).

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.^71,72,76

In a large RCT in patients with milder COPD, medium-dose budesonide had no significant impact.⁷⁶ 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 and hoarseness or dysphonia. Pooling of studies longer than six months duration found an odds ratio of 2.49 (95% CI 1.78 to 3.49, 4380 participants) for candidiasis and 1.95 (95% CI 1.41 to 2.70) for hoarseness or dysphonia.

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 exacerbations⁷⁷ [evidence level II]. However, it is not clear whether this applies to patients who have not responded to oral steroids.

O4. Inhaled combination therapy

O4.1 Inhaled glucocorticoids and long-acting beta-agonists in combination

A systematic review of six randomised controlled trials involving 4,118 participants of combined glucocorticoid steroids and long-acting beta2-agonists in one inhaler⁷⁸ for COPD reached the following conclusion: Compared with placebo, combination therapy led to clinically meaningful differences in quality of life, symptoms and exacerbations. There was also a statistically significant difference in lung function. However, there were conflicting results when the different combination therapies were compared with the mono-components alone. There was a statistically significant reduction in exacerbation rate for budesonide and formoterol, or fluticasone and salmeterol when compared to placebo, rate ratio 0.76 (95% CI 0.68, 0.84). There was also a statistically significant reduction in exacerbation rate for combination therapy versus long-acting beta2-agonists, rate ratio 0.85 (0.77, 0.95) but not for combination therapy compared to inhaled glucocorticoids. There was a significant difference in the change from baseline in pre-dose FEV1, weighted mean difference 160mls (95% CI 120-200, 697 participants). There were conflicting results for quality of life and symptom scores for both treatment comparisons and combinations (budesonide and formoterol, or fluticasone and salmeterol).

Possible explanations for these conflicts include study design and differential drop outs for interventions between studies. Although there was no significant difference (or any adverse event, oral candidiasis was significantly more common with combination therapy, odds ratio 6.88 (95% CI 3.38 to 14, 1436 participants). More recent data from Calverley et al⁷⁵[evidence level II], and a study by Kardos et al⁷⁹ [evidence level II] confirm that combined therapy with salmeterol and fluticasone (in one inhaler) is superior to placebo or monotherapy with either drug alone for reducing exacerbations and improving health-related quality of life. These results were noted in patients with both moderate and severe COPD (FEV1<60%) in the Calverley study, and in patients with severe COPD in the study by Kardos et al (FEV1 <50%). In addition, in the Calverley study, combination therapy, compared with placebo, was associated with a 2.6% reduction in all cause mortality over three years (although this finding was of borderline statistical significance, p=0.052). In both studies, however, an increased rate of pneumonia (defined on clinical grounds) was noted in the inhaled corticosteroid arms. The pneumonia rates in the Calverley study were: 19.6% in the combination group, 18.3% in the fluticasone alone group and 12.3% in the placebo group (p<0.001 for both comparisons). These results contrast with the reductions in exacerbation rates induced by these drugs. A nested case control study from Canada⁸⁰ [evidence level III-2] using databases linking hospitalisations and drug dispensing information also found an increased risk of pneumonia and hospitalisation from pneumonia in those prescribed and dispensed inhaled glucocorticoids and that this appeared dose-related. Further prospective studies using objective pneumonia definitions may clarify the situation. Meantime, increased vigilance and patient education about prompt treatment of infections would seem prudent.

O4.2 Inhaled glucocorticoids and long-acting beta-agonists and long-acting anticholinergics in combination

A recent study comparing tiotropium and combination therapy with fluticasone/ salmeterol (500/50bd) in a double-blind, double dummy randomised controlled trial over two years⁸¹ [evidence level II] found no difference in exacerbation rate between the groups (the primary aim of the study). Probability of withdrawing from the study was higher in the tiotropium group and the combination therapy group achieved a small, statistically significant benefit in quality of life (as well as the unexpected benefit of fewer deaths) evidence level II.

In clinical practice, many patients with COPD receive multiple inhaled medications in order to try and optimize their lung function and improve symptoms. In order to determine whether combining therapies with different pharmacological properties provides added benefits, Aaron et al⁸² [evidence level II] randomised patients with moderate to severe COPD to receive placebo, salmeterol or combined salmeterol/ fluticasone in addition to tiotropium. Although combined “triple” therapy did not reduce the proportion of patients suffering at least one exacerbation during the one year of the study (the primary study endpoint), those in this group did experience fewer hospitalisations for COPD and for all causes than the tiotropium plus placebo group. The patients receiving “triple” therapy also experienced a clinically significant improvement in their quality of life compared with the tiotropium plus placebo group [evidence level II].

O5. Inhaler technique 

Inhaler devices must be explained and demonstrated for patients to achieve optimal benefit. It is necessary to check regularly that the patient has the correct inhaler technique. Elderly and frail patients, especially those with cognitive deficits, may have difficulty with some devices. The cost of inhaler devices varies between products. As there are no differences in patient outcomes for the different devices, the cheapest device the patient can use adequately should be prescribed as first line treatment.⁸³ The  range of devices currently available, the products and dosage, as well as their advantages or disadvantages, are listed in Appendix 2.