Jim Kling

September 11, 2014

MUNICH, Germany — Stopping inhaled glucocorticoids in patients with chronic obstructive pulmonary disease (COPD) who were using bronchodilators has little effect on symptoms, and there is no WISDOM in continuing treatment, say researchers presenting the trial results here at the European Respiratory Society (ERS) International Congress 2014. The work was published simultaneously in the New England Journal of Medicine.

The double-blind study, known as the Withdrawal of Inhaled Steroids during Optimized Bronchodilator Management (WISDOM), includes more than 2400 patients receiving triple therapy combination of tiotropium (18 μg once daily), salmeterol (50 μg twice daily), and the inhaled glucocorticoid fluticasone propionate (500 μg twice daily). The study included a 6-week run-in period with all 3 medications, after which patients were randomly assigned to continue triple therapy or step down fluticasone in 3 stages over 12 weeks.

Current recommendations for patients with severe COPD and frequent exacerbations call for combination inhaled glucocorticoids and long-acting bronchodilators, but newer drugs have prompted some to question that recommendation.

"Now we have long-acting β-agonists and long-acting muscarinic antagonists," lead investigator Helgo Magnussen, MD, from the Pulmonary Research Institute at Lung Clinic Grosshansdorf in Germany, told Medscape Medical News. "Because dual bronchodilation therapy has been available for many years, we asked whether patients treated with dual bronchodilators plus inhaled glucocorticoids differ from patients treated with bronchodilators after stepwise withdrawal of inhaled glucocorticoids."

Previous studies have shown that withdrawal could worsen exacerbations, but in those cases, the withdrawal was abrupt, not stepwise, making the results "difficult to interpret," Peter Barnes, MD, head of respiratory medicine at Imperial College, London, United Kingdom, who was not involved in the study, pointed out during an interview.

The primary endpoint for WISDOM was time to the first moderate or severe COPD exacerbation. The researchers prespecified the noninferiority limit with an upper 95% confidence interval (CI) bound for the hazard ratio of 1.20 for the first moderate or severe exacerbation in the steroid withdrawal group compared with the continuation group. "Our idea was that there may be some patients who profit from inhaled steroids, so we performed a noninferiority study," said Dr. Magnussen.

Unnecessary Treatment

Analysis of the step-down group showed a hazard ratio of 1.06 (95% CI, 0.94 to 1.19). At week 18, when withdrawal was complete in the step-down group, the researchers noted a 38-mL larger adjusted mean reduction from baseline in forced expiratory volume in 1 second (FEV1) compared with the continuation group (P<.001). The difference persisted to week 52 (43 mL; P=.001). The 2 groups had no differences in dyspnea. There were minor changes in health status in the withdrawal group, such as slight reductions in the St. George's Respiratory Questionnaire, but the drop was just 1 point, well below any significant change, according to Dr. Magnussen.

The FEV1 difference "is statistically significant, no question, but it does not translate to changes in the exacerbation rate," he noted.

The results suggest that withdrawing inhaled glucocorticoids could be an option for many patients. "If you do not need these drugs, why should you take them?" Dr. Magnussen said. "By withdrawing, you prevent potential side effects and you save a lot of money."

The study result was predictable, Dr. Barnes told Medscape Medical News. "Although inhaled steroids are very widely used in the management of COPD because they're widely used in asthma treatment, we know that they have very poor efficacy in COPD. The steroid doesn't help them unless they happen to be a COPD patient who also has asthma." Most patients with COPD don't show beneficial responses to steroids, he noted, "and yet very high doses are used because I think people recognize patients are not responding. There's an increasing view that we should start withdrawing steroids from people because they aren't helping. I think it's a no-brainer, really," he said.

In an accompanying editorial, John Reilly, MD, from the University of Pittsburgh in Pennsylvania, wrote that the trial results, taken together with those from other studies, should encourage physicians to reconsider how they treat patients. "[T]he rationale for continuing glucocorticoid therapy in patients who are also taking long-acting bronchodilators should be based on symptomatic improvement attributable to the glucocorticoid rather on the prevention of exacerbations," he noted. "[A] trial of glucocorticoid withdrawal will not increase the risk of exacerbation, even in patients with severe COPD. The findings may prompt clinicians to consider other preventive interventions, such as daily azithromycin, in patients who continue to have frequent exacerbations while receiving long-acting bronchodilators."

This study was funded by Boehringer Ingelheim. Dr. Magnussen reports financial relationships with Boehringer Ingelheim, Almirall, AstraZeneca, BerlinChemie, Novartis, and Chiesi. Dr. Barnes has served on scientific advisory boards for Boehringer-Ingelheim, AstraZeneca, Chiesi, Cytokinetics, Cytos, DeepBreeze, GlaxoSmithKline, Glenmark, Johnson & Johnson, Novartis, Pfizer, Prosonix, Pulmatrix, Teva, Sun Pharmaceuticals, and UCB. Dr. Barnes has received research support from Aquinox Pharmaceuticals, Cempra, Daiichi-Sankyo, and Takeda/Nycomed. Dr. Reilly has disclosed no relevant financial relationships.

European Respiratory Society (ERS) International Congress 2014. Abstract 1890. Presented September 8, 2014.

N Engl J Med. Published online September 8, 2014. Abstract Editorial


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