article327

WISDOM

"Inhaled Glucocorticoids in Triple Therapy for Severe COPD"
The New England Journal of Medicine. 2014.

1 Clinical Question
2 Bottom Line
3 Major Points
4 Guidelines
5 Design
6 Population
6.1 Inclusion Criteria
6.2 Exclusion Criteria
6.3 Baseline Characteristics
7 Interventions
8 Outcomes
8.1 Primary Outcome
8.2 Secondary Outcomes
9 Criticisms
10 Funding
11 Further Reading

Clinical Question

In patients with severe chronic obstructive pulmonary disease (COPD) and a history of exacerbation, does withdrawal of inhaled glucocorticoid from triple therapy increase the risk of moderate or severe exacerbations?

Bottom Line

In patients with severe COPD and a history of exacerbations on triple therapy (tiotropium, salmeterol, and fluticasone), gradually withdrawing inhaled glucocorticoids does not increase the risk of moderate or severe exacerbations but is associated with a greater decrease in lung function.

Major Points

Previous studies suggest inhaled glucocorticoids, when used with long-acting bronchodilators, can reduce exacerbations in COPD. The role of continuing inhaled glucocorticoids in addition to dual bronchodilation therapy in severe COPD was evaluated in this trial. Withdrawing inhaled glucocorticoids gradually over 12 weeks did not increase the risk of moderate/severe exacerbations but led to a greater reduction in FEV1.

Guidelines

As of 2014, guidelines generally recommend triple therapy, including an inhaled glucocorticoid, for patients with COPD with a history of exacerbations.

Design

Multicenter, double-blind, parallel-group, randomized, active-control study.
N=2,485 patients with severe COPD with exacerbation history.
Intervention: Continuous triple therapy (n=1,242) or withdrawal of inhaled glucocorticoids (n=1,243).
Duration: 52 weeks with a 6-week run-in period.
Setting: 200 centers in 23 countries.
Enrollment: February 2009 to July 2013.

Population

Inclusion Criteria: Patients ≥40 years of age with a smoking history of ≥10 pack-years, severe or very severe COPD, a FEV1 <50% of the predicted post-bronchodilation volume, a FEV1/FVC <70% post-bronchodilation, and ≥1 exacerbation in the past year.

Exclusion Criteria: Current use of maintenance oral glucocorticoids or other relevant exclusion factors.

Baseline Characteristics: Mean age 63.8 years, 82.5% male, mean post-bronchodilation FEV1 0.93 liters (32.8% of predicted volume).

Interventions

All patients received a run-in period of triple therapy: tiotropium, salmeterol, and fluticasone. After the run-in period, patients were randomized to continue triple therapy or to have inhaled glucocorticoids withdrawn in three steps over 12 weeks.

Outcomes

Primary Outcome: Time to the first moderate or severe COPD exacerbation. Hazard ratio for glucocorticoid withdrawal vs. continuous use was 1.06 (95% CI, 0.94 to 1.19), demonstrating noninferiority.

Secondary Outcomes: There was a greater reduction from baseline in trough FEV1 in the glucocorticoid-withdrawal group at week 18 (38ml greater reduction, P<0.001) and week 52 (43ml greater reduction, P=0.001). Minor changes in health status and no change in dyspnea were observed in the withdrawal group.

Criticisms

The majority of the study population were white males, limiting generalizability across genders and ethnicities. The duration of the study may not reflect longer-term effects of inhaled glucocorticoid withdrawal.

Funding

Funded by Boehringer Ingelheim Pharma.