Determinants of Response to Roflumilast in Severe Chronic Obstructive Pulmonary Disease Pooled Analysis of Two Randomized Trials

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 (RESPOND)-S-2 (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-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/mu l (0.81; 0.71-0.93; P = 0.0020), >= 150 to < 300 cells/mu l (0.84; 0.71-0.98; P = 0.0282), or >= 300 cells/mu l (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/mu l (0.65; 0.52-0.82; P = 0.0003) and 42.7% at >= 300 cells/mu l (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/mu l, >= 150 to < 300 cells/mu l, or >= 300 cells/mu l) baseline blood eosinophil count.