Patients with mild, persistent asthma and low eosinophil levels fare no better with inhaled corticosteroids than with placebo, results from the Steroids in Eosinophil Negative Asthma (SIENA) study (NCT02066298) show. "We've been sending the message that something bad is going to happen if you don't give steroids" to all patients with asthma, said researcher Stephen Lazarus, MD, from the University of California, San Francisco. But "this calls all of that into question." "We're pretty excited about these results," he told Medscape Medical News, but, he warned, clinicians should proceed with caution. "We don't want people throwing away their medicines; this is not the definitive study," Lazarus explained. However, "it does make an argument for paying closer attention to the way patients respond. Bottom line: we are moving to the realization that asthma is a heterogeneous disease." The study findings were presented at the American Thoracic Society 2019 International Conference in Dallas and published online simultaneously in the New England Journal of Medicine. In their 36-week randomized crossover trial, Lazarus and his colleagues examined three 12-week regimens — mometasone, an inhaled glucocorticoid; tiotropium, a long-acting muscarinic antagonist; and placebo — to compare the effects on patients with mild, persistent asthma. The SIENA Study The 295 study participants, all at least 12 years of age, underwent a sputum test to determine eosinophil levels. In the study cohort, 73% had low levels of eosinophils (below 2%) and 27% had high levels (at least 2%). "We had anticipated that only about half would have a low eosinophil level," Lazarus reported. To address this unexpected result, the researchers changed the trial protocol to refocus the primary outcome on the group with low levels of eosinophils; outcomes in patients with high levels of eosinophils became a secondary end point. Patients received mometasone 220 μg twice-daily, tiotropium 5 μg once daily, or placebo twice daily for a 12-week period, and then cycled through the next two treatments for the remaining 12-week periods. A two-sided P value of less than .025 denoted statistical significance. In the low-eosinophil group, there was no significant difference in asthma control between mometasone and placebo (57% vs 43%; P = .14). However, asthma control was better with tiotropium than with placebo (60% vs 40%; P = .029). Tiotropium as Monotherapy? When the researchers looked at tiotropium monotherapy in participants 18 years and older, the rate of response was better in the low-eosinophil group than in the high-eosinophil group (62% vs 54%; P = .025). For tiotropium, "we were close to statistical significance, suggesting this could be an alternative drug rather than an add-on," said Lazarus. "A strict biostatistician would say, 'you failed to show a difference.' But I would interpret this as being very suggestive. It could perhaps be a viable option for those with mild, persistent asthma who lack eosinophil inflammation." In the high-eosinophil group, the response rate was better with mometasone than with placebo (74% vs 26%), and was better with tiotropium than with placebo (57% vs 43%). Eosinophil Levels May Predict Treatment Response These results show that "not everyone should receive the same treatment," Lazarus told Medscape Medical News. A personalized-medicine approach would be ideal, if we had biomarkers to "show us what to give patients," he explained. But testing eosinophil levels is highly complicated and it is unlikely that a sputum test will ever become routine to determine eosinophil levels in patients with mild asthma. Someday, a test might be developed, using gene profiling or a blood sample, to test eosinophil levels. "Maybe some protein in the blood could be a powerful predictor," he suggested. In the meantime, he said he believes that doctors should continue standard care but watch carefully to see how patients respond to treatment. "If patients demonstrably do better on an enhanced steroid, then they should continue taking it," Lazarus said. But if they are adhering to the regimen and not responding, they might need something else. It might be worth trying drugs used in the pediatric population, he explained, although he acknowledged that, "in general, they're not as good as steroids." Not Ready for Prime Time "What this paper is saying is very interesting and potentially practice-changing," said Andrew Bush, MD, from Imperial College London. But it's preliminary evidence and not ready for prime time. "Steroids are life-saving," he told Medscape Medical News. "Don't throw out or stop your steroids on the basis of this paper." Still, the findings do challenge "the paradigm that you've got to give everyone steroids," said Bush. "If you're in doubt, ask your doctor what the implications are for your type of asthma, and think about joining a study." Source
