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RofLumilast or Azithromycin to preveNt COPD Exacerbations (RELIANCE)

Chronic obstructive pulmonary disease (COPD) affects at least 12 million Americans and is the third leading cause of death in the U.S. COPD is disproportionately prevalent in elderly, low-income and minority populations. COPD exacerbations are often debilitating, disrupting the lives of patients and their caregivers for days to weeks or longer. COPD exacerbations lead to about 750,000 hospitalizations in the U.S. each year, with 30-day and 90-day all-cause re-hospitalization rates of 20% and 30% respectively. In recognition of the growing burden of COPD in the U.S., reductions in morbidity, mortality, and acute care utilization for COPD are listed as specific objective in the US Healthy People 2020 initiative (RD-9 to RD-12) and the Centers for Medicare & Medicaid Services (CMS) added COPD to the list of conditions in the Hospital Readmissions Reductions Program. Systematic reviews of efficacy trials conducted by the Cochrane Collaboration and the recently published 2015 ACCP/CTS guidelines indicate that chronic use of either roflumilast (PDE-4 inhibitor; 15 trials, 12,654 patients) or azithromycin (macrolide antibiotic with putative anti-inflammatory effects; 3 trials, 1,262 patients) significantly reduces the risk of COPD exacerbations, compared to placebo. No studies to date have directly compared chronic roflumilast to azithromycin in patients with COPD, so their relative effectiveness is unclear. Also, post-hoc analyses of placebo-controlled trials suggest that roflumilast reduces the risk of COPD exacerbations in both current and past smokers, whereas the efficacy of azithromycin may be limited to past smokers. These reports highlight the need for head-to-head comparisons of azithromycin to roflumilast in "real-world" high-risk COPD populations and in prospectively defined subgroups based on smoking status. Stakeholder engagement activities we have conducted indicate substantial clinician practice variation in the use of chronic roflumilast or azithromycin, uncertainty about which of the two medications to use in which patients, and sufficient clinical equipoise to conduct a trial. We have also documented substantial support for head-to-head studies to better understand the role of these two medications in the patient/caregiver community. Understanding the relative effectiveness of chronic azithromycin vs. roflumilast therapy can also inform public health efforts to promote antibiotic stewardship.


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