Therapeutics

For preventing exacerbations of COPD, withdrawal of inhaled glucocorticoids was noninferior to continuation Clinical impact ratings:

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Magnussen H, Disse B, Rodriguez-Roisin R, et al; WISDOM Investigators. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med. 2014;371:1285-94.

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Question In adults with chronic obstructive pulmonary disease (COPD) who use long-acting muscarinic antagonists (LAMAs), long-acting ␤-agonists, and inhaled corticosteroids (ICSs), is withdrawal of ICSs noninferior to continuing ICSs for preventing exacerbations?

Patient follow-up: 81% (modified intention-to-treat analysis of patients who had ≥ 1 dose of study drug).

Main results

Design: Randomized controlled noninferiority trial (Withdrawal of Inhaled Steroids during Optimized Bronchodilator Management [WISDOM] study). ClinicalTrials.com NCT00975195.

ICS withdrawal was noninferior to ICS continuation for moderate or severe COPD exacerbation (Table). Groups did not differ for severe exacerbations (hazard ratio 1.20, 95% CI 0.98 to 1.48) or for change in dyspnea or health status (Table). ICS withdrawal had a 43-mL greater reduction in trough FEV1 than did ICS continuation (P = 0.001).

Allocation: {Concealed}*.†

Conclusions

Methods

Blinding: Blinded† {patients, clinicians, data collectors, statisticians, and manuscript writers}*. Follow-up period: 1 year. Setting: 200 clinical centers in 23 countries. Patients: 2488 adults ≥ 40 years of age (mean age 64 y, 83% men, mean FEV1 after bronchodilation 0.93 L) who had severe or very severe COPD and ≥ 1 exacerbation in the past year; were current or past smokers; and successfully completed a 6-week run-in period with tiotropium, salmeterol xinafoate, and fluticasone propionate. Exclusion criteria included significant illnesses other than COPD, including asthma; oxygen dependence; cancer requiring treatment; hypersensitivity to study therapies; recent pulmonary rehabilitation or steroid use; previous lung resection; or unstable cardiac conditions. Intervention: ICS withdrawal (n = 1244) or ICS continuation (n = 1244). The withdrawal group received tiotropium and salmeterol as per run-in, but fluticasone was reduced from 1000 μg/d to 0 μg/d by week 12, with placebo given in its place. The continuation group received tiotropium, salmeterol, and fluticasone at the doses used in the run-in. Outcomes: Moderate or severe COPD exacerbation at 1 year. Secondary endpoints included severe COPD exacerbation, change in trough FEV1, health status (St. George's Respiratory Questionnaire), and dyspnea (modified Medical Research Council scale). 2234 patients were needed to determine noninferiority of ICS withdrawal compared with ICS continuation for moderate or severe COPD exacerbation (upper limit of noninferiority margin 1.20, 90% power, 1-sided ␣ = 0.025).

Withdrawal vs continuation of inhaled glucocorticoids in COPD treated with long-acting muscarinic antagonists and long-acting ␤-agonists‡ Outcomes

Moderate or severe exacerbation§

Event rates Withdrawal

Continuation

47%

44%

Hazard ratio (95% CI) at 1 y

In adults with chronic obstructive pulmonary disease who receive both long-acting muscarinic antagonists, long-acting ␤-agonists, and inhaled corticosteroids (ICSs), withdrawal of ICSs was noninferior to continuing ICSs for preventing exacerbations. ICS withdrawal reduced FEV1 by a small amount compared with ICS continuation. *Information provided by author. †See Glossary. Source of funding: Boehringer Ingelheim Pharma. For correspondence: Dr. H. Magnussen, Pulmonary Research Institute at Lung Clinic Grosshansdorf, Grosshansdorf, Germany. E-mail [email protected] 

Commentary In an earlier era when ICSs were used alone in COPD and before LAMAs became available, withdrawal of ICSs in COPD caused exacerbations and worsened quality of life (1). The contrasting findings of the WISDOM trial suggest that dual long-acting bronchodilators provide sufficient protection to mitigate adverse effects of ICS withdrawal. Perhaps the same explanation accounts for the finding that the ICS continuation did not increase risk for pneumonia as has been observed in most other large trials of ICSs (2)—a hypothesis that deserves further testing. Tapering of ICSs, rather than stopping them abruptly as in previous trials, may also have been relevant to successful outcomes in WISDOM. The greater reduction in FEV1 with ICS withdrawal reminds us that ICSs potentiate the effects of bronchodilators, but the small difference is of doubtful clinical relevance. If we apply the noninferiority criterion to one component of the primary outcome— severe exacerbations requiring hospitalization—ICS withdrawal fails to show noninferiority to continuation. Also, WISDOM excluded COPD patients with features of asthma, in whom ICSs could have a more important role (3). Overall, WISDOM suggests that ICSs can usually be discontinued safely when perceived risks exceed anticipated benefits in patients with COPD. Matthew B. Stanbrook, MD, PhD University Health Network, University of Toronto Toronto, Ontario, Canada

1.06 (0.94 to 1.19)||

Change from baseline

P value

Health status¶

1.15

⫺0.07

0.047

References

Dyspnea**

0.035

⫺0.028

0.06

1. van der Valk P, Monninkhof E, van der Palen J, Zielhuis G, van Herwaarden C. Effect of discontinuation of inhaled corticosteroids in patients with chronic obstructive pulmonary disease: the COPE study. Am J Respir Crit Care Med. 2002;166:1358-63.

‡CI defined in Glossary. Exacerbation event rates provided by author. §Groups did not differ for severe exacerbations only (hazard ratio 1.20, CI 0.98 to 1.48). ||Criterion for noninferiority was met because upper CI of the hazard ratio was < 1.20). ¶St. George's Respiratory Questionnaire. Possible score range 0 to 100, higher scores = worse functioning; minimally important difference is 4. **Modified Medical Research Council scale. Possible score range 0 to 4, higher scores = more severe dyspnea.

2. Kew KM, Seniukovich A. Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014;3: CD010115. 3. Gershon AS, Campitelli MA, Croxford R, et al. Combination long-acting ␤-agonists and inhaled corticosteroids compared with long-acting ␤-agonists alone in older adults with chronic obstructive pulmonary disease. JAMA. 2014;312:1114-21.

17 March 2015 Annals of Internal Medicine ACP Journal Club Downloaded From: http://annals.org/ by a Univ of Co Hlth Sci Ctr User on 03/30/2015

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ACP journal club. For preventing exacerbations of COPD, withdrawal of inhaled glucocorticoids was noninferior to continuation.

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