Comment

Estimation and application of the minimum clinically important difference in COPD

Treatment with inhaled glucocorticoids in combination with long-acting bronchodilators is recommended in patients with frequent exacerbations of severe chronic obstructive pulmonary disease (COPD). However, the benefit of inhaled glucocorticoids in addition to two long-acting bronchodilators has not been fully explored.

In this 12-month, double-blind, parallel-group study, 2485 patients with a history of exacerbation of COPD received triple therapy consisting of tiotropium (at a dose of 18 μg once daily), salmeterol (50 μg twice daily), and the inhaled glucocorticoid fluticasone propionate (500 μg twice daily) during a 6-week run-in period. Patients were then randomly assigned to continued triple therapy or withdrawal of fluticasone in three steps over a 12-week period. The primary end point was the time to the first moderate or severe COPD exacerbation. Spirometric findings, health status, and dyspnea were also monitored.

As compared with continued glucocorticoid use, glucocorticoid withdrawal met the prespecified noninferiority criterion of 1.20 for the upper limit of the 95% confidence interval (CI) with respect to the first moderate or severe COPD exacerbation (hazard ratio, 1.06; 95% CI, 0.94 to 1.19). At week 18, when glucocorticoid withdrawal was complete, the adjusted mean reduction from baseline in the trough forced expiratory volume in 1 second was 38 ml greater in the glucocorticoid-withdrawal group than in the glucocorticoid-continuation group (P<0.001); a similar between-group difference (43 ml) was seen at week 52 (P=0.001). No change in dyspnea and minor changes in health status occurred in the glucocorticoid-withdrawal group.

In patients with severe COPD receiving tiotropium plus salmeterol, the risk of moderate or severe exacerbations was similar among those who discontinued inhaled glucocorticoids and those who continued glucocorticoid therapy. However, there was a greater decrease in lung function during the final step of glucocorticoid withdrawal. (Funded by Boehringer Ingelheim Pharma; WISDOM ClinicalTrials.gov number, NCT00975195.)

In patients with severe COPD receiving inhaled glucocorticoids and two classes of long-acting bronchodilators, glucocorticoid withdrawal was noninferior to continuation with respect to exacerbations but was associated with a slight worsening in lung function and symptoms.

Exacerbations of chronic obstructive pulmonary disease (COPD) are symptomatically defined, acute events that lead to a change in treatment1, 2 and are associated with an accelerated decline in lung function and health status.³ Treatment with inhaled glucocorticoids reduces the exacerbation rate, especially when the drugs are used in combination with a long-acting β-agonist (LABA).4, 5 Consequently, combination therapy with an inhaled glucocorticoid and a LABA is recommended in patients with severe COPD or a history of frequent exacerbations.² Long-acting muscarinic antagonists (LAMAs) have also been shown to prevent exacerbations.6, 7, 8 However, in patients with severe or very severe COPD and . . .