Maintenance ICS Use in Severe COPD: Will It Reduce Exacerbations?

Nicholas Gross, MD, PhD


December 01, 2014

Withdrawal of Inhaled Glucocorticoids and Exacerbations of COPD

Magnussen H, Disse B, Rodriguez-Roisin R, et al; WISDOM Investigators
N Engl J Med. 2014;371:1285-1294

Study Summary

Many patients with moderately severe or worse chronic obstructive pulmonary disease (COPD) are receiving an inhaled corticosteroid (ICS) in addition to a long-acting beta-agonist (LABA) and/or a long-acting muscarinic antagonist (LAMA). This is in accordance with current guidelines.[1] Because prolonged use of an ICS may carry a risk for adverse events, the question is raised of whether these agents provide benefit above that of the bronchodilators.

This study addressed the question by giving triple therapy with a LABA, a LAMA, and an ICS (fluticasone propionate 500 μg twice daily) to patients with severe COPD and a history of exacerbations.

After 6 weeks, the investigators began to discontinue or continue treatment with the ICS in randomly selected patients; discontinuation was achieved in three steps over a 12-week period. The control group was given placebo inhalations. All treatments were given in a double-blind manner.

The primary outcome was time to first moderate or severe acute exacerbation of COPD; secondary outcomes were symptoms, health status, and spirometry values. Observations were continued for 52 weeks from the onset of ICS withdrawal.

The primary outcome, time to first exacerbation, did not differ between the group that continued ICS therapy and the group from whom ICS was withdrawn. Among secondary outcomes, the trough FEV1 (the FEV1 24 hours after the previous dose) was an average of 38 mL higher (ie, better) in the ICS group than the placebo group; this difference was statistically significant, but not clinically meaningful. A dyspnea measurement, the modified Medical Research Council (mMRC) scale, did not differ between the treatment groups.

A COPD health status score, the St George's Respiratory Questionnaire (SGRQ), did not differ between treatment groups until the last measurement at the end of the study, when the ICS withdrawal group was statistically worse—but, again, this difference was not meaningful. The incidence of adverse events and serious adverse events was similar between the treatment groups.


The short-term use of corticosteroids as part of the treatment for an acute exacerbation of COPD is well established and not in question.[1] The question here is whether ICSs should be given as maintenance treatment for COPD. The rationale for using maintenance ICS therapy in COPD is that it reduces the frequency of acute exacerbations, which are major events both medically and financially.

ICSs also improve health-related quality of life, but have only a slight and nonsignificant effect on improvement in spirometry values. However, they have never been shown to decrease the rate of decline of lung function.

ICSs have well-documented adverse effects that include a small but definite increase in the frequency of pneumonia and a decrease in bone density. Reversible changes due to ICS use include oral thrush, dysphonia, and easy bruising. Unfortunately, corticosteroids, whether administered systemically or by inhalation, have only a marginal effect on airway inflammation, unlike in asthma. No medications have been shown to address the type of inflammation that is present in COPD.[2]

One might conclude from the present, well-conducted trial that maintenance ICS use adds little or nothing to the use of a combination of a LAMA and a LABA. In patients who have never experienced an acute exacerbation, that would be a reasonable conclusion. The present trial was therefore appropriately limited to persons who had experienced at least one acute exacerbation.

Before concluding that use of an ICS was ineffective and could be avoided when patients are already receiving a LABA and a LAMA, one needs to consider the pitfalls of the present study. First, the protocol was not how one uses an ICS in practice in COPD: We do not administer an ICS and then withdraw it. Perhaps, therefore, use of the ICS at its full dose for 6 weeks to maximize therapy and then slowly removing it over the next 3 months was sufficient to protect the airways from acute exacerbations for the next 9 months.

The ICS that was used, fluticasone propionate, is one of the most potent ICSs available, and its dosage, 500 µg twice daily, is twice that approved in the United States. In addition, the change in trough FEV1 from baseline began as soon as the ICS dose is decreased and continued stepwise throughout the remaining study period. Perhaps, therefore, if the study duration had been longer (as would be the case in clinical practice), there would have been an increase in acute exacerbations and a clinically significant decline in trough FEV1 after, say, 18 months without ICS use. In addition, a different and less potent ICS may have revealed a different result.

The authors and the accompanying editorial[3] do not recommend any change in maintenance therapy for COPD at present. However, it remains the case that an inhaled corticosteroid should not be used in COPD until and unless the patient starts to experience acute exacerbations, or if there is an asthmatic component to the patient's disease.



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