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Clinical Trial
. 2025 Feb 6;65(2):2400171.
doi: 10.1183/13993003.00171-2024. Print 2025 Feb.

ECG-based risk factors for adverse cardiopulmonary events and treatment outcomes in COPD

R Chad Wade  1 , Fernando J Martinez  2 , Gerard J Criner  3 , Lee Tombs  4 , David A Lipson  5   6 , David M G Halpin  7 , MeiLan K Han  8 , Dave Singh  9 , Robert A Wise  10 , Ravi Kalhan  11 , Mark T Dransfield  12
Affiliations
Clinical Trial

ECG-based risk factors for adverse cardiopulmonary events and treatment outcomes in COPD

R Chad Wade et al. Eur Respir J. .

Abstract

Background: COPD has high mortality, compounded by comorbid cardiovascular disease. We investigated two ECG markers, Cardiac Infarction Injury Score (CIIS) and P pulmonale, as prognostic tools for adverse cardiopulmonary events in COPD.

Methods: This was a p ost hoc analysis of the IMPACT trial. Outcomes included odds (odds ratio, 95% confidence intervals) of adverse cardiopulmonary events stratified by CIIS threshold (<20 versus ≥20) and P pulmonale (baseline). Events included all-cause death, hospitalisation or death, cardiovascular adverse event of special interest, severe COPD exacerbations, and moderate/severe COPD exacerbations. We also assessed the effects of fluticasone furoate/umeclidinium/vilanterol versus fluticasone furoate/vilanterol or umeclidinium/vilanterol based on CIIS and P pulmonale.

Results: We included 9448 patients. Patients with CIIS ≥20 (versus CIIS <20) had greater odds of all-cause death (OR 1.73, 95% CI 1.27-2.37, p<0.001), hospitalisation or death (OR 1.33, 95% CI 1.17-1.50, p<0.001), cardiovascular adverse event of special interest (OR 1.27, 95% CI 1.08-1.48, p<0.005), severe COPD exacerbations (OR 1.41, 95% CI 1.21-1.64, p<0.001) and moderate/severe COPD exacerbations (OR 1.25, 95% CI 1.13-1.40, p<0.001). Patients with P pulmonale (versus without) had greater odds of all-cause death (OR 2.25, 95% CI 1.54-3.29, p<0.001), hospitalisation or death (OR 1.51, 95% CI 1.28-1.79, p<0.001), severe COPD exacerbations (OR 2.00, 95% CI 1.65-2.41, p<0.001) and moderate/severe COPD exacerbations (OR 1.25, 95% CI 1.08-1.46, p<0.001). A combined model demonstrated that patients with CIIS ≥20 and P pulmonale had increased risk of all-cause death (OR 3.38, 95% CI 1.23-9.30, p=0.019), hospitalisation or death (OR 1.61, 95% CI 1.14-2.22, p=0.004) and rate of severe COPD exacerbations (OR 1.89, 95% CI 1.22-2.91, p=0.004) and moderate/severe COPD exacerbations (OR 1.25, 95% CI 1.00-1.56, p=0.046). The risk of all-cause death and cardiovascular adverse events of special interest was reduced with fluticasone furoate/umeclidinium/vilanterol versus umeclidinium/vilanterol in patients with CIIS ≥20, but not CIIS <20.

Conclusions: These findings suggest the potential clinical relevance of CIIS and P pulmonale as risk indicators for adverse cardiopulmonary events in COPD.

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Conflict of interest statement

Conflict of interest: R.C. Wade declares no conflicts of interest. F.J. Martinez is editor-in-chief for the American Journal of Respiratory and Critical Care Medicine and reports consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, Gala, GSK, Novartis, Polarean, Pulmonx, Sanofi/Regeneron, Sunovion, Teva, Theravance/Viatris and Verona; grant support from AstraZeneca, Chiesi, GSK and Sanofi/Regeneron; and payment or honoraria from UpToDate for participation in COPD CME activities; and participated in an event adjudication committee for MedTronic. F.J. Martinez states that AstraZeneca, Boehringer Ingelheim and GSK are partners of the SPIROMICS programme and partners in the NHLBI CAPTURE validation study; Novartis, Sanofi/Regeneron, Sunovion and Teva are partners of the SPIROMICS programme; and Theravance/Viatris are partners in the NHLBI CAPTURE validation study. G.J. Criner has received personal fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, CSA Medical, Eolo, GSK, HGE Technologies, Novartis, Nuvaira, Olympus, Pulmonx and Verona. L. Tombs is a consultant for Veramed and a director for Precise Approach Ltd, London; he was consulted by GSK to conduct the statistical analysis for this study but received no payment for manuscript development. D.A. Lipson is an employee of GSK and holds GSK stocks/shares. D.M.G. Halpin received personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis and Pfizer; and non-financial support from Boehringer Ingelheim and Novartis. M.K. Han has received either in kind research support or funds paid to the institution from National Institutes of Health, Sanofi, Novartis, Nuvaira, Sunovion, Gala Therapeutics, COPD Foundation, AstraZeneca, American Lung Association, Boehringer Ingelheim and Biodesix; consulting fees from AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Pulmonx, Teva, Verona, Merck, Mylan, Sanofi, DevPro, Aerogen, Polarian, Regeneron, Altesa BioSciences, Amgen, Roche, United Therapeutics, RS Biotherapeutics and Apreo Health; royalties from UpToDate, Norton Publishing and Penguin Random House; payment or honoraria for consultancy from Cipla, Chiesi, AstraZeneca, Boehringer Ingelheim, GSK, Medscape, Integrity, NACE and Medwiz; has served roles on boards or scientific committees for COPD Foundation Board, COPD Foundation Scientific Advisory Committee, American Lung Association advisory committee, American Thoracic Society (journal editor), American Lung Association (volunteer spokesperson), GOLD scientific committee and Emerson School Board (Ann Arbor, MI, USA); participated in data safety monitoring boards for Novartis and Medtronic with funds paid to the institution; holds stock options from Meissa Vaccines and Altesa BioSciences; and reports receipt of equipment, materials, drugs, medical writing, gifts or other services from GSK, Boehringer Ingelheim, AstraZeneca and Novartis. D. Singh declares consulting fees from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, CSL Behring, Epiendo, Genentech, Glenmark, GSK, Gossamerbio, Kinaset, Menarini, Novartis, Pulmatrix, Sanofi, Synairgen, Teva, Theravance and Verona. R.A. Wise served as a paid member of the IMPACT study data monitoring committee and is a member of the scientific advisory board; and has received personal fees from AstraZeneca, Boehringer Ingelheim, Beyond Air, Contrafect, Roche-Genentech, Bristol Myers Squibb, Merck, Verona, Theravance, AbbVie, GSK, Chemerx, Kiniksa, Savara, Galderma, Kamada, Pulmonx, Kinevant, Vaxart, Polarean, Chiesi, 4D Pharma and Puretech; grant support from AstraZeneca, Sanofi, Verona, Genentech, Boehringer Ingelheim and 4DX imaging; payment for expert testimony from the US Government and Genentech; and support for attending meetings and/or travel from AstraZeneca; additionally, he has received editorial support from GSK, AstraZeneca, Boehringer Ingelheim and Merck Foundation and has served on the Board of Directors/Medical and Scientific Advisory Committee for the COPD Foundation, and on a Scientific Advisory Board for the American Lung Association. R. Kalhan reports grants from NHLBI, Boehringer Ingelheim and Spiration; grants and personal fees from AstraZeneca; and personal fees from CVS Caremark and GSK. M.T. Dransfield received consulting fees from GSK, Genentech, Novartis, Pulmonx, AstraZeneca, Teva and Apreo; royalties or licences from UpToDate; support for attending meetings from GSK; and grant support from the American Lung Association, Department of Defense and NIH; he also serves on the Board of Directors for the COPD Foundation.

Figures

None
Overview of the IMPACT post hoc analysis examining ECG-derived risk factors for adverse cardiopulmonary outcomes in patients with COPD. CVAESI: cardiovascular adverse event of special interest; FF: fluticasone furoate; UMEC: umeclidinium; VI: vilanterol. #: analysed using Cox proportional hazards models.
FIGURE 1
FIGURE 1
Odds of experiencing an adverse cardiopulmonary event stratified by Cardiac Infarction Injury Score (CIIS) threshold (<20 or ≥20). CVAESI: cardiovascular adverse event of special interest. #: n=7815; : n=1633.
FIGURE 2
FIGURE 2
Odds of experiencing adverse cardiopulmonary events stratified by P pulmonale presence. CVAESI: cardiovascular adverse event of special interest. #: n=8704; : n=744.
FIGURE 3
FIGURE 3
Risk of on-treatment all-cause death, hospitalisation or death, and cardiovascular adverse event of special interest (CVAESI), and rate of severe and moderate/severe exacerbations stratified by Cardiac Infarction Injury Score (CIIS) threshold (<20 or ≥20) and P pulmonale presence. Risk of on-treatment all-cause death, hospitalisation or death and CVAESI were calculated using Cox proportional hazards models with covariates of treatment group, sex (excluding CVAESI), age (excluding CVAESI), geographical region, five cardiovascular comorbidities (coronary artery disease/angina pectoris/myocardial infarction, arrhythmia, congestive heart failure, cerebrovascular accident, carotid/aorto-femoral vascular disease; recorded as yes/no), baseline P pulmonale, baseline CIIS and the interactions of treatment group by baseline CIIS, treatment group by baseline P pulmonale and baseline CIIS by baseline P pulmonale. The model assessing risk of all-cause death also contained the covariate smoking status at screening. The rate of on-treatment severe COPD exacerbations and moderate/severe COPD exacerbations was analysed using a generalised linear model assuming a negative binomial distribution with covariates of treatment group, sex, geographical region, smoking status at screening, five cardiovascular comorbidities (coronary artery disease/angina pectoris/myocardial infarction, arrhythmia, congestive heart failure, cerebrovascular accident, carotid/aorto-femoral vascular disease, recorded as yes/no), exacerbation history (≤1, ≥2 moderate/severe), post-bronchodilator forced expiratory volume in 1 s (% predicted) at screening, baseline P pulmonale, baseline CIIS and the interactions of treatment group by baseline CIIS, treatment group by baseline P pulmonale and baseline CIIS by baseline P pulmonale. HR: hazard ratio; RR: rate ratio. #: n=7222; : n=151.
FIGURE 4
FIGURE 4
Risk of all-cause death, hospitalisation or death, and cardiovascular adverse event of special interest (CVAESI), and rate of severe and moderate/severe exacerbations stratified by treatment type and Cardiac Infarction Injury Score (CIIS) threshold a) ≥20 or b) <20. Dual therapy refers to fluticasone furoate (FF)/vilanterol (VI) or umeclidinium (UMEC)/VI. Risk of on-treatment all-cause death, hospitalisation or death and CVAESI were analysed using Cox proportional hazards models with covariates of treatment group, sex (excluding CVAESI), age (excluding CVAESI), geographical region (excluding all-cause mortality), baseline CIIS and treatment group by baseline CIIS interaction. The rate of on-treatment severe COPD exacerbations and moderate/severe COPD exacerbations was analysed using generalised linear models assuming a negative binomial distribution with covariates of treatment group, sex, exacerbation history (≤1, ≥2 moderate/severe), smoking status at screening, geographical region, post-bronchodilator % predicted forced expiratory volume in 1 s at screening, baseline CIIS and treatment group by baseline CIIS interaction. HR: hazard ratio; RR: rate ratio.
FIGURE 5
FIGURE 5
Risk of all-cause death, hospitalisation or death, and cardiovascular adverse event of special (CVAESI), and rate of severe and moderate/severe exacerbations stratified by treatment type and P pulmonale presence a) yes or b) no. Dual therapy refers to fluticasone furoate (FF)/vilanterol (VI) or umeclidinium (UMEC)/VI. Risk of on-treatment all-cause death, hospitalisation or death and CVAESI were analysed using Cox proportional hazards models with covariates of treatment group, sex (excluding CVAESI), age (excluding CVAESI), geographical region (excluding all-cause mortality), baseline P pulmonale and treatment group by baseline P pulmonale interaction. The rate of on-treatment severe COPD exacerbations and moderate/severe COPD exacerbations was analysed using generalised linear models assuming a negative binomial distribution with covariates of treatment group, sex, exacerbation history (≤1, ≥2 moderate/severe), smoking status at screening, geographical region, post-bronchodilator % predicted forced expiratory volume in 1 s at screening, baseline P pulmonale and treatment group by baseline P pulmonale interaction. HR: hazard ratio; RR: rate ratio.
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