Inhaled steroids in COPD: When to use them – and when not to

Chronic obstructive pulmonary disease (COPD) is an important cause of disability and mortality in Canada and abroad. Many changes in the approach to disease management have occurred over the last number of years. These include new and more potent bronchodilators, vaccination with influenza and both pneumococcal vaccines, pulmonary rehabilitation programs and, of course, smoking cessation. With these changes, it behooves us to review the use of inhaled corticosteroids (ICS) in the management of COPD, as this is an area of controversy.ICS are prescribed for the majority of COPD patients, many of whom are low-risk and do not meet the criteria for ICS use set out by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 guidelines.1 Market research suggests ICS are used by more than 70% of COPD patients, and given as initial therapy to more than 50% of newly diagnosed patients, mostly in combination with a long-acting beta2 agonist (LABA).2Where did this come from? In the landmark TORCH (Towards a Revolution in COPD Health) trial, it was found that an ICS plus a LABA resulted in significantly fewer exacerbations, a slower rate of decline in lung function and improved health status. However, there was only a trend towards improved survival.3 These findings formed the initial basis for the inclusion of ICS-containing regimens in clinical guidelines.4,5 The importance of exacerbations as a key determinant of health status and their association with a faster decline in lung function were being recognized, and the prevention of exacerbations became a key objective of COPD management.What has changed? Subsequently, a post hoc analysis of the TORCH data, which evaluated the independent contributions of ICS and LABAs, showed that the benefits of ICS+LABA in TORCH were actually provided by the LABA.6 Soon after TORCH, the INSPIRE trial was the first to show that ICS+LABA was no more effective than a long-acting antimuscarinic agent (LAMA) in preventing exacerbations in patients with severe COPD.7 This was followed by a Cochrane meta-analysis that questioned the superiority of ICS+LABA combinations over LABAs alone in preventing exacerbations.8Adverse effectsSide-effects of prolonged use of ICS have become more recognized and clearly merit a review of the routine use of these drugs in patients with COPD. The local adverse events include pneumonia,9 oropharyngeal candidiasis and tuberculosis.10 The systemic adverse events include glaucoma and cataracts,11 osteoporosis and fractures,12 easy bruising, type 2 diabetes13 and even adrenal suppression.14A recent Canadian population-based cohort study of 103,386 COPD patients who were treated with ICS demonstrated that discontinuation of ICS was associated with a 37% reduction in the risk of serious pneumonia, indicating that this risk can be mitigated by stopping the ICS.15The landmark FLAME trial assessed the risk of exacerbations in patients with COPD, comparing the combination of the LABA indacaterol plus the LAMA glycopyrronium to the combination of the LABA salmeterol and the ICS fluticasone in patients with moderate to severe COPD who had at least one exacerbation in the previous year.16 The annual rate of COPD exacerbations was 11% lower in the LABA/LAMA arm than in the ICS/LABA arm, and the LABA/LAMA group also had a longer time to first exacerbation. The incidence of adverse events and deaths were similar in both groups. However, the incidence of pneumonia (a presumed side-effect from long-term ICS) was statistically higher in the ICS/LABA group (4.8% versus 3.2%). The study attempted to rule out asthmatic patients by excluding trial candidates with a blood eosinophil count greater than 600 cells per microlitre. This study has now brought into question the need for ICS to prevent COPD exacerbations in those who are adequately and aggressively bronchodilated—and should make one reconsider starting patients on ICS for their COPD.ICS withdrawalBut what about those patients who are already taking ICS? They currently make up the majority of COPD patients, as already mentioned. Can and should we remove ICS from their therapeutic regimen? The WISDOM (Withdrawal of Inhaled Steroids During Optimized Bronchodilator Management) trial was the first to assess stepwise withdrawal of an ICS (fluticasone) in COPD patients with a history of exacerbations who were also on dual bronchodilation (tiotropium/salmeterol).17 In this 12-month trial, 2,485 COPD patients received fluticasone/tiotropium/salmeterol during a six-week run-in period and were randomized to continue with triple therapy or have the ICS withdrawn in three steps over a 12-week period. There was no difference in the occurrence of moderate or severe exacerbations between the two groups. Nor was there any difference in exacerbations in various subgroup analyses. The cost of this was a small, but significant, reduction in lung function when the ICS was completely withdrawn, the clinical importance of which is unclear.Who should be on ICS?There are certainly some COPD patients who should be on ICS. These include patients who have an element of asthma, the so-called asthma-COPD overlap syndrome.18 Evidence has clearly shown that treating asthma with long-acting bronchodilators without ICS has the potential to do harm, likely due to the masking of worsening symptoms and the non-treatment of the asthma inflammation.19 As such, patients who have asthma or have a strong suggestion of asthma in their history, such as a history of atopy, allergic rhinitis or a strong asthma family history, should be considered for continuation of ICS therapy. Spirometry has a place in this decision. Spirometric criteria for the asthma-COPD overlap syndrome include fixed obstruction and a post-bronchodilator increase in FEV1 greater than 12% and 400 ml from baseline.Patients with recurrent exacerbations are the group with the largest question regarding ICS. Past guidelines have said those with frequent exacerbations should be on ICS treatment. The FLAME trial has brought this into question, asking whether or not a good bronchodilator may do just as well. In addition, the new GOLD guidelines suggest ICS should no longer be an automatic step in patients with frequent exacerbations, and there may be some phenotyping involved to include other preventive strategies such as roflumilast or azithromycin.20 While the TORCH trial did suggest a 25% reduction in exacerbations between those treated with ICS/LABA versus placebo, this was at a time when LAMAs were not universally used.What should I do?It is prudent to do a risk-benefit analysis for starting or continuing ICS therapy in COPD patients. The benefits of exacerbation prevention need to be balanced against the adverse effects of ICS. Do not start ICS in patients with definitive spirometric evidence and history compatible with COPD unless there is a clear reason. For those who are already on ICS as part of their COPD regimen, consider, in the appropriate patient, withdrawing the ICS in a controlled manner. An algorithm described in the figure on this page shows how to gradually withdraw ICS by reducing the dose at six- to 12-week intervals, with careful followup to check for changes in symptoms, exacerbations and significant loss of lung function.21 One other potential biomarker that may be useful in predicting exacerbations after ICS withdawal is the blood eosinophil count after the ICS is withdrawn. In the WISDOM trial, the blood eosinophil count at nine months predicted who would exacerbate, with an increased risk at counts over 300 cells per microlitre that continued to rise at even higher counts.22The bottom lineNot all patients who have COPD will respond to or benefit from ICS. Those with a clinical suspicion of asthma should be given ICS. Those with recurrent exacerbations, especially if associated with hospitalizations, may also benefit from them. Otherwise, consider stepping up therapy to achieve adequate bronchodilation, perhaps with a LABA/LAMA as your first step. In those already on ICS, consider reducing the dose over time, while following the patient carefully.References1. Vestbo J, et al. Understanding the GOLD 2011 Strategy as applied to a real-world COPD population. Respir Med. 2014 May;108(5):729-36.2. Suissa S, Barnes PJ. Inhaled corticosteroids in COPD: the case against. Eur Respir J. 2009 Jul;34(1):13-6.3. Calverley PM, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007 Feb 22;356(8):775-89.4. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease; 2015.5. O’Donnell DE, et al. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease - 2008 update - highlights for primary care. Can Respir J. 2008 Jan-Feb;15 Suppl A:1A-8A.6. Ernst P, et al. Inhaled corticosteroids in COPD: the clinical evidence. Eur Respir J. 2015 Feb;45(2):525-37.7. Wedzicha JA, et al. The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am J Respir Crit Care Med. 2008 Jan 1;177(1):19-26.8. Nannini LJ, et al. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012 Sep 12;(9):CD006829.9. Suissa S, et al. Inhaled corticosteroids in COPD and the risk of serious pneumonia. Thorax. 2013 Nov;68(11):1029-36.10. Brassard P, et al. Inhaled corticosteroids and risk of tuberculosis in patients with respiratory diseases. Am J Respir Crit Care Med. 2011 Mar 1;183(5):675-8.11. Ernst P, et al. Inhaled corticosteroids in COPD: the clinical evidence. Eur Respir J. 2015 Feb;45(2):525-37.12. Loke YK, et al. Risk of fractures with inhaled corticosteroids in COPD: systematic review and meta-analysis of randomised controlled trials and observational studies. Thorax. 2011 Aug;66(8):699-708.13. Suissa S, et al. Inhaled corticosteroids and the risks of diabetes onset and progression. Am J Med. 2010 Nov;123(11):1001-6.14. Hay CM, et al. Adrenal insufficiency in a woman secondary to standard-dose inhaled fluticasone propionate therapy. Endocrinol Diabetes Metab Case Rep. 2014;2014:130080.15. Suissa S, et al. Discontinuation of inhaled corticosteroids in COPD and the risk reduction of pneumonia. Chest. 2015 Nov;148(5):1177-83.16. Wedzicha JA et al., Indacaterol-glycopyrronium versus salmeterol-fluticasone for COPD. N Engl J Med. 2016 Jun 9;374(23):2222-34.17. Magnussen H, et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med. 2014 Oct 2;371(14):1285-94.18. Sin DD, et al. What is asthma-COPD overlap syndrome? Towards a consensus definition from a round table discussion. Eur Respir J. 2016 Sep;48(3):664-73.19. Nelson HS, et al. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest. 2006 Jan;129(1):15-26.20. goldcopd.org/gold-2017-global-strategy-diagnosis-management-prevention-copd21. Kaplan AG. Applying the wisdom of stepping down inhaled corticosteroids in patients with COPD: a proposed algorithm for clinical practice. Int J Chron Obstruct Pulmon Dis. 2015 Nov 20;10:2535-48.22. Watz H, et al. Blood eosinophil count and exacerbations in severe chronic obstructive pulmonary disease after withdrawal of inhaled corticosteroids: a post-hoc analysis of the WISDOM trial. Lancet Respir Med. 2016 May;4(5):390-8.

Inhaled steroids in COPD: When to use them – and when not to

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