Determinants of response to roflumilast in severe chronic obstructive pulmonary disease: Pooled analysis of two randomized trials

Fernando J. Martinez, Klaus F. Rabe, Peter M.A. Calverley, Leonardo M. Fabbri, Sanjay Sethi, Emilio Pizzichini, Andrew McIvor, Antonio R Anzueto, Vijay K.T. Alagappan, Shahid Siddiqui, Colin Reisner, Sofia Zetterstrand, Jonas Román, Debasree Purkayastha, Nitin Bagul, Stephen I. Rennard

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


Rationale: Roflumilast 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. Objectives: Define characteristics that most robustly identify patients who derive greatest exacerbation risk reduction with roflumilast. Methods: Predefined, 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 Results: In the overall intention-totreat 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. Conclusions: This 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.

Original languageEnglish (US)
Pages (from-to)1268-1278
Number of pages11
JournalAmerican Journal of Respiratory and Critical Care Medicine
Issue number10
StatePublished - Nov 15 2018


  • Cigarette smoking
  • Cough
  • Glucocorticosteroids
  • Inflammation
  • Sputum

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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