InforMing the PAthway of COPD Treatment (IMPACT) trial: fibrinogen levels predict risk of moderate or severe exacerbations

Abstract

Background: Fibrinogen is the first qualified prognostic/predictive biomarker for exacerbations in patients with chronic obstructive pulmonary disease (COPD). The IMPACT trial investigated fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy versus FF/VI and UMEC/VI in patients with symptomatic COPD at risk of exacerbations. This analysis used IMPACT trial data to examine the relationship between fibrinogen levels and exacerbation outcomes in patients with COPD.

Methods: 8094 patients with a fibrinogen assessment at Week 16 were included, baseline fibrinogen data were not measured. Post hoc analyses were performed by fibrinogen quartiles and by 3.5 g/L threshold. Endpoints included on-treatment exacerbations and adverse events of special interest (AESIs).

Results: Rates of moderate, moderate/severe, and severe exacerbations were higher in the highest versus lowest fibrinogen quartile (0.75, 0.92 and 0.15 vs 0.67, 0.79 and 0.10, respectively). The rate ratios (95% confidence interval [CI]) for exacerbations in patients with fibrinogen levels ≥ 3.5 g/L versus those with fibrinogen levels < 3.5 g/L were 1.03 (0.95, 1.11) for moderate exacerbations, 1.08 (1.00, 1.15) for moderate/severe exacerbations, and 1.30 (1.10, 1.54) for severe exacerbations. There was an increased risk of moderate/severe exacerbation (hazard ratio [95% CI]: highest vs lowest quartile 1.16 [1.04, 1.228]; ≥ 3.5 g/L vs < 3.5 g/L: 1.09 [1.00, 1.16]) and severe exacerbation (1.35 [1.09, 1.69]; 1.27 [1.08, 1.47], respectively) with increasing fibrinogen level. Cardiovascular AESIs were highest in patients in the highest fibrinogen quartile.

Conclusions: Rate and risk of exacerbations was higher in patients with higher fibrinogen levels. This supports the validity of fibrinogen as a predictive biomarker for COPD exacerbations, and highlights the potential use of fibrinogen as an enrichment strategy in trials examining exacerbation outcomes.

Trial registration: NCT02164513.

Keywords: COPD; COPD exacerbations; Fibrinogen; Pharmacotherapy.

Conflict of interest statement

DS reports personal fees from GSK, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Genentech, Glenmark, Menarini, Mundipharma, Novartis, Peptinnovate, Pfizer, Pulmatrix, Theravance and Verona, and grant support from AstraZeneca, Boehringer Ingelheim, Chiesi, Glenmark, Menarini, Mundipharma, Novartis, Pfizer, Pulmatrix, Theravance and Verona. GC has received personal fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, CSA Medical, Eolo, GSK, HGE Technologies, Novartis, Nuvaira, Olympus, Pulmonx and Verona. MD has received personal fees from AstraZeneca, Teva, Boehringer Ingelheim and GSK and contracted clinical trial support from AstraZeneca, Boehringer Ingelheim and GSK. DH reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis and Pfizer, and non-financial support Boehringer Ingelheim and Novartis. MH has received personal fees from AstraZeneca, Boehringer Ingelheim, Merck, Mylan and GSK, and research support from Novartis and Sunovion. PL reports personal fees and grant support from GSK, AstraZeneca and Boehringer Ingelheim. SL, DaLi, NM, and C-QZ are GSK employees and hold stock/shares in GSK. DM and BM are former GSK employees and hold stock/shares in GSK. FM has received personal fees and non-financial support from the American College of Chest Physicians, AstraZeneca, Boehringer Ingelheim, Chiesi, ConCert, Continuing Education, Genentech, GSK, Inova Fairfax Health System, Miller Communications, National Society for Continuing Education, Novartis, Pearl Pharmaceuticals, PeerView Communications, Potomac, Prime Communications, Puerto Rico Respiratory Society, Roche, Sunovion, Theravance, University of Alabama Birmingham, Physicians Education Resource, Canadian Respiratory Network and Teva, non-financial support from Gilead, Nitto, ProterrixBio and Zambon, personal fees from Columbia University, Integritas, MD magazine, Methodist Hospital Brooklyn, New York University, Unity, UpToDate, WedMD/MedScape, Western Connecticut Health Network, Academic CME, Patara, PlatformIQ, American Thoracic Society, Rockpointe and France Foundation, grant support from NIH, Rare Disease Health Communications and ProMedior, and is a member of steering committees for Afferent/Merck, Biogen, Veracyte, Prometic, Bayer and Bridge Biotherapeutics. RW has been a consultant for Circassia, Pneuma, Verona, Mylan/Theravance, Propeller Health, has received personal fees from AstraZeneca/Medimmune/Pearl, Boehringer Ingelheim, Contrafect, Roche-Genentech, GSK, Merck, AbbVie, ChemRx, Kiniska, Bristol Myers Squibb, Galderma, Kamada, Pulmonx, Kinevant and Puretech, has received research grants from Boehringer Ingelheim, Sanofi-Aventis and GSK. DaLo has received grant income, honoraria, and consultancy fees from GSK, and personal fees from Grifols, and chaired the GSK Respiratory Therapy Area Board 2012–2015.

Figures

Fig. 1

Rate of on-treatment exacerbations by quartiles. a Moderate; b moderate/severe; c severe. Rate of exacerbations from Week 16 by Week 16 fibrinogen quartiles. Quartile 1, fibrinogen value < 25th percentile; Quartile 2, fibrinogen value > 25th percentile and < median; Quartile 3, fibrinogen value ≥ median and < 75th percentile; Quartile 4, fibrinogen value ≥ 75th percentile; interaction of treatment with fibrinogen quartile p-values for a–c are 0.494, 0.515 and 0.916 respectively. CI confidence interval

Fig. 2

Rate ratio for on-treatment exacerbations by quartile. a Moderate; b moderate/severe; c severe. Rate ratio (FF/UMEC/VI vs dual therapies) for on-treatment exacerbations by Week 16 fibrinogen quartile. Quartile 1, fibrinogen value < 25th percentile; Quartile 2, fibrinogen value > 25th percentile and < median; Quartile 3, fibrinogen value ≥ median and < 75th percentile; Quartile 4, fibrinogen value ≥ 75th percentile. CI confidence interval; FF fluticasone furoate; n number of patients in the analysis in each subgroup; UMEC umeclidinium; VI vilanterol

Fig. 3

Rate of on-treatment exacerbations by 3.5 g/L threshold. Rate of on-treatment exacerbations from Week 16 by Week 16 fibrinogen 3.5 g/L threshold. CI confidence interval

Fig. 4

Rate ratio for on-treatment exacerbations by 3.5 g/L threshold. a Moderate; b moderate/severe; c severe. Rate ratio (FF/UMEC/VI vs dual therapies) for on-treatment exacerbations by Week 16 fibrinogen 3.5 g/L threshold. CI confidence interval; FF fluticasone furoate; n number of patients in the analysis in each subgroup; UMEC umeclidinium; VI vilanterol

Fig. 5

Time-to-first on-treatment exacerbation by quartile. a Moderate; b moderate/severe; c severe. Time-to-first on-treatment exacerbation from Week 16 by Week 16 fibrinogen quartile. Interaction of treatment with fibrinogen quartile p-values for a–c are 0.695, 0.599 and 0.783 respectively: Quartile 1: < 2.780 g/L; Quartile 2: ≥ 2.780 g/L; Quartile 3: < 3.830 g/L; Quartile 4: ≥ 3.830 g/L

Fig. 6

All-cause mortality on and off-treatment by a fibrinogen quartile; b fibrinogen 3.5 g/L threshold. Quartile 1: < 2.780 g/L; Quartile 2: ≥ 2.780 g/L; Quartile 3: < 3.830 g/L; Quartile 4: ≥ 3.830 g/L