Study Summary: WISDOM
Magnussen H, Disse B, Rodriguez-Roisin R, et al; WISDOM Investigators. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. New Engl J Med. 2014;371(14):1285-1294. doi:10.1056/nejmoa1407154.
Patients with chronic obstructive pulmonary disease (COPD) may experience exacerbations, episodes of worsening of COPD symptoms that may necessitate changes in treatment. Although various monotherapies have been shown to prevent exacerbations, individuals with severe COPD who experience frequent exacerbations are recommended a potent treatment regimen of an inhaled corticosteroid (ICS) in combination with a long-acting bronchodilator, such as a long-acting beta-agonist (LABA) or a long-acting muscarinic antagonist (LAMA).
The Withdrawal of Inhaled Steroids during Optimized Bronchodilator Management (WISDOM) trial was conducted to evaluate exacerbation risk with different combination treatment regimens among patients with severe or very severe COPD, according to Global Initiative for Chronic Obstructive Lung Disease criteria (GOLD stage 3-4) and a history of at least 1 exacerbation within the past year. The investigators hypothesized that triple therapy with 2 long-acting bronchodilators (a LAMA and a LABA) plus an ICS would yield similar exacerbation risk prevention, whether the ICS was withdrawn via a stepwise dosage reduction over several weeks (LAMA/LABA dual therapy) or continued as part of triple therapy (LAMA/LABA/ICS).
During this 52-week trial, patients within the glucocorticoid-continuation group received triple combination therapy of 18 mcg tiotropium (LAMA) once daily, 50 mcg salmeterol (LABA) twice daily, and 500 mcg fluticasone propionate (ICS) twice daily. Patients within the glucocorticoid-withdrawal group were treated with triple therapy with a systematic dosage reduction of the ICS (fluticasone propionate) every 6 weeks (1000 mcg à 500 mcg à 200 mcg à0 mcg).
The primary end point was defined by time to first moderate or severe COPD exacerbation during which patients experienced new or increased onset of respiratory tract symptoms related to COPD. As the WISDOM study aimed to demonstrate that the exacerbation rate is similar with continuation or withdrawal of an inhaled corticosteroid, a prespecified noninferiority margin of 1.20 was defined. A hazard ratio of 1.06 was determined by the primary end point for a first moderate or severe COPD exacerbation with ICS withdrawal compared with patients who continued the ICS. The investigators concluded that outcomes in patients who were in the withdrawal-of-ICS group were not inferior to outcomes among patients who continued to take the ICS as part of triple therapy with a LAMA and a LABA. The increase in risk of exacerbation did not exceed the upper limit of the 95% confidence interval, 1.19, in the withdrawal group compared with the continuation group (HR, 1.06; 95% CI, 0.94-1.19).
Analysis of the secondary end point showed that the adjusted event rate of moderate to severe exacerbations over the year demonstrated that patients who continued treatment with the ICS had an event rate of 0.91 per patient and those who had withdrawal of the glucocorticoid had an event rate of 0.95 per patient. From this data, investigators concluded that there were no significant differences in the risk and frequency of exacerbation in patients with COPD given LAMA/LABA/ICS initially and who were withdrawn from the ICS during the 52-week study compared with patients who continued with the ICS.
Interestingly, Magnussen et al reported that patients in whom ICS therapy was withdrawn experienced a statistically significant decrease in lung function compared with patients who continued triple therapy including the ICS. Results indicate that at week 18, the patients withdrawn from the ICS had a significant adjusted mean reduction (P <0.001) from baseline in FEV1 of 38 mL compared with patients who continued the ICS. By week 52, a similar decline in FEV1 of 43 mL was observed, confirming the previous observation of a modest but statistically significant (P = 0.001) change in lung function favoring continuation of fluticasone propionate (ICS) in addition to tiotropium and salmeterol (triple therapy).
Adverse event rates were similar in both treatment groups: 70.8% in the group that continued the ICS and 71.7% in the group that was withdrawn from the ICS. Serious adverse events occurred in 23.5% of patients receiving triple therapy and 24.2% of patients withdrawn from ICS treatment. Serious fatal adverse events were reported in 5.8% of patients treated with LAMA/LABA/ICS and 6.7% of patients withdrawn from the ICS, including fatalities within the follow-up period after study treatment was discontinued.
Adverse events of special interest to the WISDOM study population included cardiac events, pneumonia, and stroke, all of which occurred at similar rates between the 2 treatment groups. Major adverse cardiac events were reported in 2.2% of patients who continued ICS treatment and 2.0% of patients withdrawn from ICS, and fatal cardiac events were reported in 1.5% and 1.1% of patients, respectively. Pneumonia was reported 5.8% of patients treated with LAMA/LABA/ICS, and in 5.5% of patients withdrawn from ICS. The incidence of stroke was 0.5% among patients withdrawn from the ICS and 0.7% among patients who received the triplet.
Based on the results of the WISDOM study, investigators concluded that the treatment of patients with severe or very severe COPD at risk of exacerbation with a combination therapy of dual bronchodilators, tiotropium and salmeterol, has similar effects on exacerbation risk modulation whether the ICS (fluticasone propionate) is continued or withdrawn. Additional studies are necessary to further evaluate whether withdrawal of the ICS affects lung function and other markers of health status.