TY - JOUR
T1 - Determinants of response to roflumilast in severe chronic obstructive pulmonary disease
T2 - Pooled analysis of two randomized trials
AU - Martinez, Fernando J.
AU - Rabe, Klaus F.
AU - Calverley, Peter M.A.
AU - Fabbri, Leonardo M.
AU - Sethi, Sanjay
AU - Pizzichini, Emilio
AU - McIvor, Andrew
AU - Anzueto, Antonio
AU - Alagappan, Vijay K.T.
AU - Siddiqui, Shahid
AU - Reisner, Colin
AU - Zetterstrand, Sofia
AU - Román, Jonas
AU - Purkayastha, Debasree
AU - Bagul, Nitin
AU - Rennard, Stephen I.
N1 - Publisher Copyright:
© 2018 by the American Thoracic Society.
PY - 2018/11/15
Y1 - 2018/11/15
N2 - 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.
AB - 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.
KW - Cigarette smoking
KW - Cough
KW - Glucocorticosteroids
KW - Inflammation
KW - Sputum
UR - http://www.scopus.com/inward/record.url?scp=85055005656&partnerID=8YFLogxK
U2 - 10.1164/rccm.201712-2493OC
DO - 10.1164/rccm.201712-2493OC
M3 - Article
SN - 1073-449X
VL - 198
SP - 1268
EP - 1278
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
IS - 10
ER -