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Introduction: Clinically important deterioration (CID) is a multicomponent measure for assessing disease worsening in chronic obstructive pulmonary disease (COPD). This analysis investigated the prognostic value of a CID event on future clinical outcomes and the effect of single-inhaler triple versus dual therapy on reducing CID risk in patients in the IMPACT trial., Methods: IMPACT was a phase III, double-blind, 52-week, multicentre trial. Patients with symptomatic COPD and at least one moderate/severe exacerbation in the prior year were randomised 2:2:1 to fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 µg, FF/VI 100/25 µg or UMEC/VI 62.5/25 µg. CID at the time-point of interest was defined as a moderate/severe exacerbation, ≥100 mL decrease in trough forced expiratory volume in 1 s or deterioration in health status (increase of ≥4.0 units in St George's Respiratory Questionnaire total score or increase of ≥2.0 units in COPD Assessment Test score) from baseline. A treatment-independent post hoc prognostic analysis compared clinical outcomes up to week 52 in patients with/without a CID by week 28. A prospective analysis evaluated time to first CID with each treatment., Results: Patients with a CID by week 28 had significantly increased exacerbation rates after week 28, smaller improvements in lung function and health status at week 52 (all p<0.001), and increased risk of all-cause mortality after week 28 versus patients who were CID-free. FF/UMEC/VI significantly reduced CID risk versus dual therapies (all p<0.001)., Conclusions: Prevention of short-term disease worsening was associated with better long-term clinical outcomes. FF/UMEC/VI reduced CID risk versus dual therapies; this effect may improve long-term prognosis in this population., Competing Interests: Conflict of interest: M.K. Han personal fees from AstraZeneca, Boehringer Ingelheim and GlaxoSmithKline, research support from Novartis and Sunovion, and personal fees from Mylan, Merck and Verona, outside the submitted work. Conflict of interest: G.J. Criner personal fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, CSA Medical, Eolo Medical and GlaxoSmithKline, and ownership interest in HGE Health Care Solutions, and personal fees from Novartis, Nuvaira, Olympus, Pulmonx, Verona, Amgen, Broncus Medical, Gala Therapeutics, Helios Medical, Merck, Medtronic, Mereo BioPharma, NGM Biopharmaceuticals, Philips Respironics, Respivant Sciences and The Implementation Group, outside the submitted work. Conflict of interest: M.T. Dransfield grants from the Dept of Defense, personal fees and other support from Boehringer Ingelheim and GlaxoSmithKline, other support from Novartis, personal fees and other support from AstraZeneca, other support from Yungjin, personal fees and other support from PneumRx/BTG, other support from Pulmonx, personal fees from Genentech, other support from Boston Scientific, personal fees from Quark Pharmaceuticals, grants from NIH, personal fees from Mereo, and grants from the American Lung Association and the NIH, outside the submitted work. Conflict of interest: D.M.G. Halpin reports personal fees from AstraZeneca, personal fees and nonfinancial support from Boehringer Ingelheim, personal fees from Chiesi, personal fees and nonfinancial support from GlaxoSmithKline, and personal fees from Novartis, Pfizer and Sanofi, outside the submitted work. Conflict of interest: C.E. Jones is an employee of and holds shares/options in GlaxoSmithKline, outside the submitted work. Conflict of interest: S. Kilbride is an employee of and holds shares/options in GlaxoSmithKline, outside the submitted work. Conflict of interest: P. Lange personal fees from AstraZeneca, Boehringer Ingelheim and Chiesi, and grants and personal fees from GlaxoSmithKline, outside the submitted work. Conflict of interest: S. Lettis is an employee of and holds shares/options in GlaxoSmithKline outside the submitted work. Conflict of interest: D.A. Lipson is an employee of and holds shares/options in GlaxoSmithKline outside the submitted work. Conflict of interest: D.A. Lomas reports grants from GlaxoSmithKline and personal fees from Grifols, outside the submitted work. Conflict of interest: N. Martin is an employee of and holds shares/options in GlaxoSmithKline, outside the submitted work. Conflict of interest: F.J. Martinez reports personal fees, nonfinancial support and other support from AstraZeneca and Boehringer Ingelheim, nonfinancial support and other support from ProterrixBio, personal fees from Columbia University, personal fees and nonfinancial support from Genentech, GlaxoSmithKline and Inova Fairfax Health System, personal fees from MD Magazine and Methodist Hospital Brooklyn, personal fees and nonfinancial support from Miller Communications, the National Association for Continuing Education and Novartis, personal fees from New York University, personal fees and nonfinancial support from Pearl Pharmaceuticals, PeerView Communications, Prime Communications, the Puerto Rican Respiratory Society, Chiesi, Sunovion and Theravance, personal fees from UpToDate and WebMD/MedScape, other support from Afferent/Merck, nonfinancial support from Gilead and Nitto, personal fees and other support from Patara/Respivant, personal fees and nonfinancial support from Potomac, other support from Biogen, personal fees and nonfinancial support from the University of Alabama Birmingham, other support from Veracyte, nonfinancial support from Zambon, personal fees from the American Thoracic Society, grants from the NIH, personal fees and nonfinancial support from the Physicians Education Resource, personal fees from Rockpointe, other support from Prometic, personal fees from Rare Disease Healthcare Communications, other support from Bayer and Bridge Biotherapeutics, personal fees and nonfinancial support from the Canadian Respiratory Network, other support from ProMedior, personal fees and nonfinancial support from Teva, personal fees from the France Foundation, personal fees and nonfinancial support from Dartmouth, other support from Gala, and personal fees from the Physicians Education Resource, outside the submitted work. Conflict of interest: R.A. Wise reports grants and personal fees from AstraZeneca/Medimmune/Pearl and Boehringer Ingelheim, personal fees from Contrafect, Pulmonx, Roche, Spiration and Sunovion, grants from Pearl Therapeutics, personal fees from Merck, Circassia, Pneuma, Verona, Mylan/Theravance and Propeller Health, grants from Sanofi-Aventis, personal fees from AbbVie, and grants and personal fees from GSK, outside the submitted work. Conflict of interest: I.P. Naya holds shares/options in GlaxoSmithKline, outside the submitted work. Conflict of interest: D. Singh reports grants and personal fees from AstraZeneca, Boehringer Ingelheim and Chiesi, personal fees from Cipla and Genentech, grants and personal fees from Glenmark, personal fees from GlaxoSmithKline, grants and personal fees from Menarini and Mundipharma, personal fees from Peptinnovate, and grants and personal fees from Pfizer, Pulmatrix, Theravance and Verona, outside the submitted work., (Copyright ©ERS 2021.)

IMPACT, a 52-week, randomised, double-blind trial, assessed the efficacy and safety of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy versus FF/VI or UMEC/VI in patients with symptomatic COPD and a history of exacerbations.Subgroup analyses assessed whether the efficacy of FF/UMEC/VI versus FF/VI or UMEC/VI and UMEC/VI versus FF/VI varies according to prior exacerbation history, and the combined effects of exacerbation history and blood eosinophil counts. Three subgroups were defined: single moderate (1 moderate/no severe; n=3056 (30%)), frequent moderate (≥2 moderate/no severe; n=4628 (45%)) and severe (≥1 severe/any moderate; n=2671 (26%)). End-points included annual on-treatment moderate/severe exacerbation rate (pre-specified), lung function and health status (both post-hoc).Moderate/severe exacerbation rates (reduction % (95% CI)) were reduced in the FF/UMEC/VI group versus FF/VI (single moderate 20% (10-29), frequent moderate 11% (2-19), severe 17% (7-26)) and versus UMEC/VI (single moderate 18% (5-29), frequent moderate 29% (21-37), severe 26% (14-35)). Moderate/severe exacerbation rates were reduced in the FF/VI group versus UMEC/VI in the frequent moderate subgroup; a numerical reduction was observed in the severe subgroup (single moderate 2% (-12-18), frequent moderate 21% (11-29), severe 11% (-3-22)). Moderate/severe exacerbation rates were lower in the FF/VI group compared with UMEC/VI in patients with higher eosinophil counts. FF/UMEC/VI improved lung function and health status versus both dual therapies irrespective of exacerbation subgroup. UMEC/VI improved lung function versus FF/VI in all subgroups.Triple therapy was more effective than dual regardless of exacerbation history, consistent with results in the intent-to-treat population. Comparisons between dual therapies were influenced by prior exacerbation history and eosinophil counts., Competing Interests: Conflict of interest: D.M.G. Halpin reports other from GlaxoSmithKline, non-financial support from GlaxoSmithKline, during the conduct of the study; personal fees from AstraZeneca, personal fees and non-financial support from Boehringer Ingelheim, personal fees from Chiesi, personal fees from GlaxoSmithKline, personal fees and non-financial support from Novartis, personal fees from Pfizer, outside the submitted work. Conflict of interest: M.T. Dransfield reports other from GlaxoSmithKline, non-financial support from GlaxoSmithKline, during the conduct of the study; grants from Department of Defense, personal fees and other from Boehringer Ingelheim, personal fees and other from GlaxoSmithKline, other from Novartis, personal fees and other from AstraZeneca, other from Yungjin, personal fees and other from PneumRx/BTG, other from Pulmonx, personal fees from Genentech, other from Boston Scientific, personal fees from Quark Pharmaceuticals, grants from NIH, personal fees from Mereo, grants from American Lung Association, grants from NIH, outside the submitted work. Conflict of interest: M.K. Han reports other from GlaxoSmithKline, non-financial support from GlaxoSmithKline, during the conduct of the study; personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, other from Novartis, other from Sunovion, personal fees from Mylan, outside the submitted work. Conflict of interest: E. Jones reports other from GlaxoSmithKline, non-financial support from GlaxoSmithKline, during the conduct of the study; personal fees from GlaxoSmithKline, other from GlaxoSmithKline, outside the submitted work. Conflict of interest: S. Kilbride reports other from GlaxoSmithKline, non-financial support from GlaxoSmithKline, during the conduct of the study; personal fees from GlaxoSmithKline, other from GlaxoSmithKline, outside the submitted work. Conflict of interest: P. Lange reports other from GlaxoSmithKline, non-financial support from GlaxoSmithKline, during the conduct of the study; grants and personal fees from GlaxoSmithKline, personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Chiesi, outside the submitted work. Conflict of interest: D.A. Lipson reports other from GlaxoSmithKline, non-financial support from GlaxoSmithKline, during the conduct of the study; personal fees from GlaxoSmithKline, other from GlaxoSmithKline, outside the submitted work. Conflict of interest: D.A. Lomas reports personal fees and other from GlaxoSmithKline, non-financial support from GlaxoSmithKline, during the conduct of the study; grants from GlaxoSmithKline, personal fees and other from GlaxoSmithKline, personal fees from Grifols, outside the submitted work. Conflict of interest: F.J. Martinez reports grants, personal fees and non-financial support from GlaxoSmithKline, non-financial support from GlaxoSmithKline, during the conduct of the study; personal fees and non-financial support from American College of Chest Physicians, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Boehringer Ingelheim, non-financial support from ProterrixBio, personal fees from Columbia University, personal fees and non-financial support from ConCert, personal fees and non-financial support from Genentech, personal fees and non-financial support from GlaxoSmithKline, personal fees and non-financial support from Inova Fairfax Health System, personal fees from Integritas, personal fees from MD Magazine, personal fees from Methodist Hospital Brooklyn, personal fees and non-financial support from Miller Communicatinos, personal fees and non-financial support from National Association for Continuing Education, personal fees and non-financial support from Novartis, personal fees from New York University, personal fees and non-financial support from Pearl Pharmaceuticals, personal fees and non-financial support from PeerView Communications, personal fees and non-financial support from Prime Communications, personal fees and non-financial support from Puerto Rican Respiratory Society, personal fees and non-financial support from Chiesi, personal fees and non-financial support from Sunovion, personal fees and non-financial support from Theravance, personal fees from UpToDate, personal fees from WebMD/MedScape, personal fees from Western Connecticut Health Network, other from Afferent/Merck, non-financial support from Gilead, non-financial support from Nitto, personal fees from Patara/Respivant, personal fees from PlatformIQ, personal fees and non-financial support from Potomac, other from Biogen, personal fees and non-financial support from University of Alabama Birmingham, other from Veracyte, non-financial support from Zambon, personal fees from American Thoracic Society, grants from NIH, personal fees and non-financial support from Physicians Education Resource, personal fees from Rockpointe, other from Prometic, personal fees from Rare Disease Healthcare Communications, other from Bayer, other from Bridge Biotherapeutics, personal fees and non-financial support from Canadian Respiratory Network, other from ProMedior, personal fees and non-financial support from Teva, personal fees from France Foundation, personal fees and non-financial support from Dartmouth, outside the submitted work. Conflict of interest: S. Pascoe reports other from GlaxoSmithKline, non-financial support from GlaxoSmithKline, during the conduct of the study; personal fees from GlaxoSmithKline, other from GlaxoSmithKline, outside the submitted work. Conflict of interest: D. Singh reports other from GlaxoSmithKline, non-financial support from GlaxoSmithKline, during the conduct of the study; personal fees from GlaxoSmithKline, grants and personal fees from AstraZeneca, grants and personal fees from Boehringer Ingelheim, grants and personal fees from Chiesi, personal fees from Cipla, personal fees from Genentech, grants and personal fees from Glenmark, grants and personal fees from Menarini, grants and personal fees from Mundipharma, grants and personal fees from Novartis, personal fees from Peptinnovate, grants and personal fees from Pfizer, grants and personal fees from Pulmatrix, grants and personal fees from Therevance, grants and personal fees from Verona, outside the submitted work. Conflict of interest: R. Wise reports personal fees, non-financial support and other from GlaxoSmithKline, during the conduct of the study; grants and personal fees from AstraZeneca / Medimmune / Pearl, grants and personal fees from Boehringer Ingelheim, personal fees from Contrafect, personal fees from Pulmonx, personal fees from Roche, personal fees from Spiration, personal fees from Sunovion, grants from Pearl Therapeutics, personal fees from Merck, personal fees from Circassia, personal fees from Pneuma, personal fees from Verona, personal fees from Mylan/Theravance, personal fees from Propeller Health, grants from Sanofi-Aventis, personal fees from AbbVie, grants and personal fees from GSK, outside the submitted work. Conflict of interest: G.J. Criner reports other from GlaxoSmithKline, non-financial support from GlaxoSmithKline, during the conduct of the study; personal fees from Almirall, personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Chiesi, personal fees from CSA Medical, personal fees from Eolo, personal fees from GlaxoSmithKline, personal fees from HGE Technologies, personal fees from Novartis, personal fees from Nuvaira, personal fees from Olympus, personal fees from Pulmonx, personal fees from Verona, personal fees from NGM Bio, outside the submitted work., (Copyright ©ERS 2020.)