• Fernando J Martinez, Klaus F Rabe, Calverley Peter M A PMA 3 Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom., Leonardo M Fabbri, Sanjay Sethi, Emilio Pizzichini, Andrew McIvor, Antonio Anzueto, Alagappan Vijay K T VKT 10 AstraZeneca, Gaithersburg, Maryland., Shahid Siddiqui, Colin Reisner, Sofia Zetterstrand, Jonas Román, Debasree Purkayastha, Nitin Bagul, and Stephen I Rennard.
• 1 Weill Cornell Medicine, New York, New York.
• Am. J. Respir. Crit. Care Med. 2018 Nov 15; 198 (10): 1268-1278.

RationaleRoflumilast reduces exacerbations in patients with severe chronic obstructive pulmonary disease associated with chronic bronchitis and a history of exacerbations. Further characterization of patients most likely to benefit is warranted.ObjectivesDefine characteristics that most robustly identify patients who derive greatest exacerbation risk reduction with roflumilast.MethodsPredefined, pooled analyses of REACT (Roflumilast in the Prevention of COPD Exacerbations While Taking Appropriate Combination Treatment; NCT01329029) and RE2SPOND (Roflumilast Effect on Exacerbations in Patients on Dual [LABA/ICS] Therapy; NCT01443845) multicenter, randomized, double-blind, placebo-controlled studies. The primary endpoint was rate of moderate or severe exacerbations per patient per year.Measurements And Main ResultsIn the overall intention-to-treat population (n = 4,287), roflumilast reduced moderate or severe exacerbations by 12.3% (rate ratio, 0.88, 95% confidence interval, 0.80-0.97; P = 0.0086) and severe exacerbations by 16.1% (0.84; 0.71-0.99; P = 0.0409) versus placebo. The reduction in moderate or severe exacerbations with roflumilast was most pronounced in patients who had been hospitalized for an exacerbation in the prior year (0.74; 0.63-0.88; P = 0.0005); had more than two exacerbations in the prior year (0.79; 0.65-0.96; P = 0.0160); or had baseline eosinophils ≥150 cells/μl (0.81; 0.71-0.93; P = 0.0020), ≥150 to <300 cells/μl (0.84; 0.71-0.98; P = 0.0282), or ≥300 cells/μl (0.77; 0.61-0.97; P = 0.0264). Similar subgroup results were noted for severe exacerbations. In patients with prior hospitalization and higher baseline blood eosinophil concentrations, roflumilast reduced moderate or severe exacerbations by 34.5% at ≥150 cells/μl (0.65; 0.52-0.82; P = 0.0003) and 42.7% at ≥300 cells/μl (0.57; 0.37-0.88; P = 0.0111) versus placebo.ConclusionsThis prespecified, pooled analysis confirms the benefit of roflumilast in decreasing exacerbations in patients with prior hospitalization for exacerbation, greater exacerbation frequency, and higher (≥150 cells/μl, ≥150 to <300 cells/μl, or ≥300 cells/μl) baseline blood eosinophil count.

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