Impact of chronic obstructive pulmonary disease on prognosis after percutaneous coronary intervention and bypass surgery for left main coronary artery disease: an analysis from the EXCEL trial

Impact of chronic obstructive pulmonary disease on prognosis after percutaneous coronary... Abstract View largeDownload slide View largeDownload slide OBJECTIVES Percutaneous coronary intervention (PCI) is often favoured over coronary artery bypass grafting (CABG) surgery for revascularization in patients with chronic obstructive pulmonary disease (COPD). We studied whether COPD affected clinical outcomes according to revascularization in the Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial, in which PCI with everolimus-eluting stents was non-inferior to CABG for the treatment of patients with left main coronary artery disease and low or intermediate SYNTAX scores. METHODS Patients with a history of COPD were propensity score matched to those without COPD. Outcomes at 30 days and 3 years in both groups were compared in patients randomized to PCI versus CABG. RESULTS COPD status was available for 1901 of 1905 randomized patients (99.8%), 148 of whom had COPD (7.8%). Propensity score matching yielded 135 patients with COPD and 675 patients without COPD. Patients with COPD had higher 3-year rates of the primary composite end point of death, myocardial infarction or stroke (31.7% vs 14.5%, P < 0.0001), death (17.1% vs 7.5%, P = 0.0005) and myocardial infarction (18.3% vs 7.3%, P < 0.0001), but not stroke (3.3% vs 2.9%, P = 0.84). There were no statistically significant interactions in the relative risks of PCI versus CABG for the primary composite end point in patients with and without COPD at 30 days [hazard ratio (HR) 0.39, 95% confidence interval (CI) 0.12–1.21 vs HR 0.55, 95% CI 0.29–1.06; Pinteraction = 0.61] or at 3 years (HR 0.85, 95% CI 0.46–1.56 vs HR 1.28, 95% CI 0.84–1.94; Pinteraction = 0.27). CONCLUSIONS In the EXCEL trial, COPD was independently associated with poor prognosis after left main coronary artery disease revascularization. The relative risks of PCI versus CABG at 30 days and 3 years were consistent in patients with and without COPD. Clinical trial registration number http://www.clinicaltrials.gov; NCT01205776. Chronic obstructive pulmonary disease, Percutaneous coronary intervention, Coronary artery bypass grafting, Left main coronary artery disease INTRODUCTION In patients with chronic obstructive pulmonary disease (COPD), hypoxia, chronic inflammation, endothelial dysfunction, oxidative stress and heightened platelet reactivity accelerate the course of atherosclerotic coronary artery disease (CAD) [1, 2]. Patients with COPD have increased surgical risk and a worse prognosis after coronary artery bypass grafting (CABG) [3, 4]; however, COPD patients are also at increased risk for adverse cardiac events after percutaneous coronary intervention (PCI), including mortality [5]. Patients with COPD and CAD requiring revascularization thus represent a challenging subset of patients [1], and the optimal mode of revascularization for high-risk patients with COPD and complex CAD has not been established. The large-scale, international Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial demonstrated that in patients with left main CAD (LMCAD) of low or intermediate complexity (as assessed by a SYNTAX score ≤32), PCI with everolimus-eluting stents was non-inferior to CABG for the composite rate of death, stroke or myocardial infarction (MI) at 3 years [6]. We sought to assess the association between COPD and adverse outcomes after LMCAD treatment and determine whether the relative safety and efficacy of PCI versus CABG differ in patients with COPD versus without COPD. METHODS Study design The design of the EXCEL trial has been reported previously [6, 7]. In brief, the EXCEL trial was an international, multicentre, randomized trial that compared everolimus-eluting stents with CABG in patients with LMCAD and low or intermediate SYNTAX scores (≤32) in whom equipoise for revascularization with both techniques was present after the heart team review. The goal was complete revascularization of all ischaemic territories. PCI was done using fluoropolymer-based cobalt–chromium everolimus-eluting stents (XIENCE, Abbott Vascular, Santa Clara, CA, USA). CABG was performed with or without cardiopulmonary bypass according to the discretion of the operator; the use of multiple arterial grafts was strongly recommended. The investigation was approved by the institutional review board or ethics committee at each participating centre, and all patients signed their written informed consent. Major end points were adjudicated by an independent clinical events committee (Cardiovascular Research Foundation, New York, NY, USA). Angiographic analyses were performed at an angiographic core laboratory (Cardiovascular Research Foundation). Follow-up is presently complete for all patients through 3 years. Definitions and end points COPD at baseline was defined as a prior diagnosis of COPD and ongoing treatment with bronchodilators and/or oral or inhalational steroids. The primary end point was a composite of death from any cause, stroke or MI at 3 years. Major secondary end points included the primary composite end point at 30 days and the composite of death, stroke, MI or ischaemia-driven revascularization at 3 years. Additional secondary end points included the components of the primary and secondary end points at 30 days and 3 years and stent thrombosis and symptomatic graft stenosis or occlusion at 30 days and 3 years, all as previously defined [6, 7]. An additional prespecified secondary end point was periprocedural major adverse events (MAE), defined as the occurrence within 30 days of death, stroke, MI, ischaemia-driven revascularization, thrombolysis in myocardial infarction major or minor bleeding, transfusion of ≥2 units of blood, major arrhythmias, unplanned surgical or radiological procedures, renal failure, sternal wound dehiscence, infections requiring antibiotics, prolonged (>48 h) intubation or post-pericardiotomy syndrome. Statistical analysis Continuous variables are expressed as mean ± standard deviation and were compared using the Student’s t-test or the Mann–Whitney U-test, depending on whether they satisfied the normality assumption as assessed by the visual inspection of residuals and by the Shapiro–Wilk test. Categorical variables were compared using the χ2 test if the counts in 80% of cells exceeded 5, otherwise using the Fisher’s exact test. The Kaplan–Meier methods were used to estimate cumulative event rates at 30 days and 3 years; comparisons were made using the marginal effects Cox proportional hazards regression (the matched cohort) or the log-rank test (overall cohort). To adjust for potential confounders, patients with COPD were matched 1:5 to patients without COPD using propensity scores and a greedy matching algorithm. With COPD as the binary outcome, logistic regression containing the following covariate set was used to calculate the propensity score: age, sex, hypertension, hyperlipidaemia, current smoking, prior stroke or transient ischaemic attack, congestive heart failure, diabetes, anaemia, peripheral vascular disease, prior PCI, prior MI, clinical presentation, body mass index, heart rate, white blood cell count, left ventricular ejection fraction, renal insufficiency, treatment assignment and the SYNTAX score. The predicted probability for each patient from the logistic model was the propensity score. COPD patients were matched 1:5 to non-COPD patients based on their propensity scores. Standardized differences of baseline variables comparing COPD versus non-COPD in overall and matched populations were calculated to demonstrate the balance achieved by propensity score matching. In the matched cohort, the comparisons of continuous and categorical variables were performed using the generalized estimating equation method, and the comparisons of clinical events were performed by the marginal Cox models, to account for the dependence within each matched stratum. The risk of periprocedural adverse events was compared using the logistic regression. Interaction terms between COPD and treatment were included to assess whether the presence versus absence of COPD moderated the effect of treatment assignment on outcomes. Sensitivity analyses were conducted using the multivariable Cox proportional hazards regression in the overall population using the same covariate set included in the propensity score calculation. The present analysis is post hoc, although all statistical analyses were prespecified. A 2-sided P-value <0.05 was considered to be statistically significant for all tests. All statistical analyses were performed with the SAS software, version 9.4 (SAS Institute, Cary, NC, USA). RESULTS Patient characteristics COPD status was documented in 1901 of 1905 (99.8%) patients randomized in the EXCEL trial, 148 (7.8%) of whom had COPD. Baseline clinical and angiographic characteristics of patients with COPD versus without COPD are presented in Supplementary Material, Table S1. Patients with COPD had more cardiovascular risk factors, including a higher prevalence of diabetes mellitus and current smoking, and more comorbidities such as peripheral vascular disease and anaemia compared with those without COPD. In addition, patients with COPD on average had a lower left ventricular ejection fraction and a higher B-type natriuretic peptide level. Propensity score matching (PSM) yielded 135 patients with COPD (91% of all patients with COPD) matched with 675 patients without COPD (the mean caliper 0.03, standard deviation 0.03). Baseline clinical and angiographic characteristics were similar between the matched groups (Table 1), and all covariates used for PSM were non-significantly different. The rates of use of antithrombotic agents, statins and other medications were similar between patients with and without COPD during the study duration (Supplementary Material, Table S2). Table 1: Baseline clinical and angiographic characteristics Characteristics COPD (n = 135) No COPD (n = 675) Standardized difference P-value Age (years), mean ± SD 67.4 ± 8.6 67.3 ± 9.5 0.010 0.91 Male sex (%) 96/135 (71.1) 478/675 (70.8) 0.007 0.94 Diabetes (%) 51/135 (37.8) 266/675 (39.4) −0.033 0.72  Insulin treated (%) 18/135 (13.3) 71/675 (10.5) 0.087 0.34 Hypertension (%) 106/135 (78.5) 538/675 (79.7) −0.029 0.75 Hyperlipidaemia (%) 92/135 (68.1) 497/675 (73.6) −0.121 0.19 Smoking status (%)  Former smoker 64/135 (47.4) 220/675 (32.6) 0.306 0.0005  Current smoker 51/135 (37.8) 222/675 (32.9) 0.102 0.20 Prior MI (%) 26/135 (19.3) 131/675 (19.4) −0.004 0.97 Prior PCI (%) 27/135 (20.0) 133/675 (19.7) 0.007 0.94 Prior CABG (%) 0/135 (0.0) 0/675 (0.0) Congestive heart failure (%) 11/135 (8.1) 61/675 (9.0) −0.032 0.72 Prior stroke or TIA (%) 9/135 (6.7) 45/675 (6.7) 0.000 1.00 Peripheral vascular disease (%) 27/135 (20.0) 103/675 (15.3) 0.125 0.12 Clinical presentation (%)  Recent MIa 25/135 (18.5) 129/675 (19.1) −0.015 0.87  Unstable angina 37/135 (27.4) 185/675 (27.4) 0.000 1.00  Stable angina 66/135 (48.9) 326/675 (48.3) 0.012 0.90  Silent ischaemia 5/135 (3.7) 25/675 (3.7) 0.000 1.00 Body mass index (kg/m2), mean ± SD 29.7 ± 6.7 29.6 ± 5.4 0.014 0.89 Heart rate (bpm), mean ± SD 71.7 ± 11.5 71.1 ± 12.7 0.051 0.53 Haemoglobin (g/dl), mean ± SD 13.3 ± 1.8 13.4 ± 1.6 −0.042 0.66 Anaemia (%)b 48/135 (35.6) 209/673 (31.1) −0.009 0.31 WBC count (×109/l), mean ± SD 8.3 ± 2.4 8.2 ± 2.2 0.066 0.47 Platelet count (×109/l), mean ± SD 226.6 ± 65.6 235.3 ± 65.0 −0.133 0.35 Thrombocytopenia (%)c 7/61 (11.5) 16/341 (4.7) 0.251 0.04 CrCl (ml/min)d, mean ± SD 87.6 ± 31.3 89.8 ± 34.3 −0.065 0.49 Renal insufficiency (%)e 22/135 (16.3) 115/675 (17.0) −0.020 0.84 BNP (pg/ml), mean ± SD 431.3 ± 761.1 288.4 ± 629.2 0.205 0.17 LVEF (%), mean ± SD 54.7 ± 10.8 54.9 ± 9.8 −0.021 0.83 Left main lesion location (%)  Ostium 49/134 (36.6) 248/655 (37.9) −0.027 0.78  Mid-shaft 47/134 (35.1) 284/655 (43.4) −0.170 0.08  Distal 101/134 (75.4) 505/655 (77.1) −0.041 0.66 SYNTAX score, mean ± SD 26.3 ± 10.2 26.2 ± 9.3 0.97  Low (≤22) (%) 48/135 (35.6) 248/675 (36.7) −0.025 0.80  Intermediate (23 − 32) (%) 56/135 (41.5) 269/675 (39.9) 0.033 0.72  High (>32) (%) 31/135 (23.0) 158/675 (23.4) −0.011 0.92 Characteristics COPD (n = 135) No COPD (n = 675) Standardized difference P-value Age (years), mean ± SD 67.4 ± 8.6 67.3 ± 9.5 0.010 0.91 Male sex (%) 96/135 (71.1) 478/675 (70.8) 0.007 0.94 Diabetes (%) 51/135 (37.8) 266/675 (39.4) −0.033 0.72  Insulin treated (%) 18/135 (13.3) 71/675 (10.5) 0.087 0.34 Hypertension (%) 106/135 (78.5) 538/675 (79.7) −0.029 0.75 Hyperlipidaemia (%) 92/135 (68.1) 497/675 (73.6) −0.121 0.19 Smoking status (%)  Former smoker 64/135 (47.4) 220/675 (32.6) 0.306 0.0005  Current smoker 51/135 (37.8) 222/675 (32.9) 0.102 0.20 Prior MI (%) 26/135 (19.3) 131/675 (19.4) −0.004 0.97 Prior PCI (%) 27/135 (20.0) 133/675 (19.7) 0.007 0.94 Prior CABG (%) 0/135 (0.0) 0/675 (0.0) Congestive heart failure (%) 11/135 (8.1) 61/675 (9.0) −0.032 0.72 Prior stroke or TIA (%) 9/135 (6.7) 45/675 (6.7) 0.000 1.00 Peripheral vascular disease (%) 27/135 (20.0) 103/675 (15.3) 0.125 0.12 Clinical presentation (%)  Recent MIa 25/135 (18.5) 129/675 (19.1) −0.015 0.87  Unstable angina 37/135 (27.4) 185/675 (27.4) 0.000 1.00  Stable angina 66/135 (48.9) 326/675 (48.3) 0.012 0.90  Silent ischaemia 5/135 (3.7) 25/675 (3.7) 0.000 1.00 Body mass index (kg/m2), mean ± SD 29.7 ± 6.7 29.6 ± 5.4 0.014 0.89 Heart rate (bpm), mean ± SD 71.7 ± 11.5 71.1 ± 12.7 0.051 0.53 Haemoglobin (g/dl), mean ± SD 13.3 ± 1.8 13.4 ± 1.6 −0.042 0.66 Anaemia (%)b 48/135 (35.6) 209/673 (31.1) −0.009 0.31 WBC count (×109/l), mean ± SD 8.3 ± 2.4 8.2 ± 2.2 0.066 0.47 Platelet count (×109/l), mean ± SD 226.6 ± 65.6 235.3 ± 65.0 −0.133 0.35 Thrombocytopenia (%)c 7/61 (11.5) 16/341 (4.7) 0.251 0.04 CrCl (ml/min)d, mean ± SD 87.6 ± 31.3 89.8 ± 34.3 −0.065 0.49 Renal insufficiency (%)e 22/135 (16.3) 115/675 (17.0) −0.020 0.84 BNP (pg/ml), mean ± SD 431.3 ± 761.1 288.4 ± 629.2 0.205 0.17 LVEF (%), mean ± SD 54.7 ± 10.8 54.9 ± 9.8 −0.021 0.83 Left main lesion location (%)  Ostium 49/134 (36.6) 248/655 (37.9) −0.027 0.78  Mid-shaft 47/134 (35.1) 284/655 (43.4) −0.170 0.08  Distal 101/134 (75.4) 505/655 (77.1) −0.041 0.66 SYNTAX score, mean ± SD 26.3 ± 10.2 26.2 ± 9.3 0.97  Low (≤22) (%) 48/135 (35.6) 248/675 (36.7) −0.025 0.80  Intermediate (23 − 32) (%) 56/135 (41.5) 269/675 (39.9) 0.033 0.72  High (>32) (%) 31/135 (23.0) 158/675 (23.4) −0.011 0.92 P-values were derived using generalized estimating equation models. Angiographic data are core laboratory assessed. a Within 7 days of randomization. b Defined according to the World Health Organization criteria (haematocrit value at the initial presentation, <39% for men and <36% for women). c Less than 150 000 cells/mm3 at baseline. d Calculated by means of the Cockcroft–Gault equation. e Creatinine clearance <60 ml/min. BNP: B-type natriuretic peptide; COPD: chronic obstructive pulmonary disease; CrCl: creatinine clearance; LVEF: left ventricular ejection fraction; MI: myocardial infarction; PCI: percutaneous coronary intervention; SD: standard deviation; TIA: transient ischaemic attack; WBC: white blood cell. Table 1: Baseline clinical and angiographic characteristics Characteristics COPD (n = 135) No COPD (n = 675) Standardized difference P-value Age (years), mean ± SD 67.4 ± 8.6 67.3 ± 9.5 0.010 0.91 Male sex (%) 96/135 (71.1) 478/675 (70.8) 0.007 0.94 Diabetes (%) 51/135 (37.8) 266/675 (39.4) −0.033 0.72  Insulin treated (%) 18/135 (13.3) 71/675 (10.5) 0.087 0.34 Hypertension (%) 106/135 (78.5) 538/675 (79.7) −0.029 0.75 Hyperlipidaemia (%) 92/135 (68.1) 497/675 (73.6) −0.121 0.19 Smoking status (%)  Former smoker 64/135 (47.4) 220/675 (32.6) 0.306 0.0005  Current smoker 51/135 (37.8) 222/675 (32.9) 0.102 0.20 Prior MI (%) 26/135 (19.3) 131/675 (19.4) −0.004 0.97 Prior PCI (%) 27/135 (20.0) 133/675 (19.7) 0.007 0.94 Prior CABG (%) 0/135 (0.0) 0/675 (0.0) Congestive heart failure (%) 11/135 (8.1) 61/675 (9.0) −0.032 0.72 Prior stroke or TIA (%) 9/135 (6.7) 45/675 (6.7) 0.000 1.00 Peripheral vascular disease (%) 27/135 (20.0) 103/675 (15.3) 0.125 0.12 Clinical presentation (%)  Recent MIa 25/135 (18.5) 129/675 (19.1) −0.015 0.87  Unstable angina 37/135 (27.4) 185/675 (27.4) 0.000 1.00  Stable angina 66/135 (48.9) 326/675 (48.3) 0.012 0.90  Silent ischaemia 5/135 (3.7) 25/675 (3.7) 0.000 1.00 Body mass index (kg/m2), mean ± SD 29.7 ± 6.7 29.6 ± 5.4 0.014 0.89 Heart rate (bpm), mean ± SD 71.7 ± 11.5 71.1 ± 12.7 0.051 0.53 Haemoglobin (g/dl), mean ± SD 13.3 ± 1.8 13.4 ± 1.6 −0.042 0.66 Anaemia (%)b 48/135 (35.6) 209/673 (31.1) −0.009 0.31 WBC count (×109/l), mean ± SD 8.3 ± 2.4 8.2 ± 2.2 0.066 0.47 Platelet count (×109/l), mean ± SD 226.6 ± 65.6 235.3 ± 65.0 −0.133 0.35 Thrombocytopenia (%)c 7/61 (11.5) 16/341 (4.7) 0.251 0.04 CrCl (ml/min)d, mean ± SD 87.6 ± 31.3 89.8 ± 34.3 −0.065 0.49 Renal insufficiency (%)e 22/135 (16.3) 115/675 (17.0) −0.020 0.84 BNP (pg/ml), mean ± SD 431.3 ± 761.1 288.4 ± 629.2 0.205 0.17 LVEF (%), mean ± SD 54.7 ± 10.8 54.9 ± 9.8 −0.021 0.83 Left main lesion location (%)  Ostium 49/134 (36.6) 248/655 (37.9) −0.027 0.78  Mid-shaft 47/134 (35.1) 284/655 (43.4) −0.170 0.08  Distal 101/134 (75.4) 505/655 (77.1) −0.041 0.66 SYNTAX score, mean ± SD 26.3 ± 10.2 26.2 ± 9.3 0.97  Low (≤22) (%) 48/135 (35.6) 248/675 (36.7) −0.025 0.80  Intermediate (23 − 32) (%) 56/135 (41.5) 269/675 (39.9) 0.033 0.72  High (>32) (%) 31/135 (23.0) 158/675 (23.4) −0.011 0.92 Characteristics COPD (n = 135) No COPD (n = 675) Standardized difference P-value Age (years), mean ± SD 67.4 ± 8.6 67.3 ± 9.5 0.010 0.91 Male sex (%) 96/135 (71.1) 478/675 (70.8) 0.007 0.94 Diabetes (%) 51/135 (37.8) 266/675 (39.4) −0.033 0.72  Insulin treated (%) 18/135 (13.3) 71/675 (10.5) 0.087 0.34 Hypertension (%) 106/135 (78.5) 538/675 (79.7) −0.029 0.75 Hyperlipidaemia (%) 92/135 (68.1) 497/675 (73.6) −0.121 0.19 Smoking status (%)  Former smoker 64/135 (47.4) 220/675 (32.6) 0.306 0.0005  Current smoker 51/135 (37.8) 222/675 (32.9) 0.102 0.20 Prior MI (%) 26/135 (19.3) 131/675 (19.4) −0.004 0.97 Prior PCI (%) 27/135 (20.0) 133/675 (19.7) 0.007 0.94 Prior CABG (%) 0/135 (0.0) 0/675 (0.0) Congestive heart failure (%) 11/135 (8.1) 61/675 (9.0) −0.032 0.72 Prior stroke or TIA (%) 9/135 (6.7) 45/675 (6.7) 0.000 1.00 Peripheral vascular disease (%) 27/135 (20.0) 103/675 (15.3) 0.125 0.12 Clinical presentation (%)  Recent MIa 25/135 (18.5) 129/675 (19.1) −0.015 0.87  Unstable angina 37/135 (27.4) 185/675 (27.4) 0.000 1.00  Stable angina 66/135 (48.9) 326/675 (48.3) 0.012 0.90  Silent ischaemia 5/135 (3.7) 25/675 (3.7) 0.000 1.00 Body mass index (kg/m2), mean ± SD 29.7 ± 6.7 29.6 ± 5.4 0.014 0.89 Heart rate (bpm), mean ± SD 71.7 ± 11.5 71.1 ± 12.7 0.051 0.53 Haemoglobin (g/dl), mean ± SD 13.3 ± 1.8 13.4 ± 1.6 −0.042 0.66 Anaemia (%)b 48/135 (35.6) 209/673 (31.1) −0.009 0.31 WBC count (×109/l), mean ± SD 8.3 ± 2.4 8.2 ± 2.2 0.066 0.47 Platelet count (×109/l), mean ± SD 226.6 ± 65.6 235.3 ± 65.0 −0.133 0.35 Thrombocytopenia (%)c 7/61 (11.5) 16/341 (4.7) 0.251 0.04 CrCl (ml/min)d, mean ± SD 87.6 ± 31.3 89.8 ± 34.3 −0.065 0.49 Renal insufficiency (%)e 22/135 (16.3) 115/675 (17.0) −0.020 0.84 BNP (pg/ml), mean ± SD 431.3 ± 761.1 288.4 ± 629.2 0.205 0.17 LVEF (%), mean ± SD 54.7 ± 10.8 54.9 ± 9.8 −0.021 0.83 Left main lesion location (%)  Ostium 49/134 (36.6) 248/655 (37.9) −0.027 0.78  Mid-shaft 47/134 (35.1) 284/655 (43.4) −0.170 0.08  Distal 101/134 (75.4) 505/655 (77.1) −0.041 0.66 SYNTAX score, mean ± SD 26.3 ± 10.2 26.2 ± 9.3 0.97  Low (≤22) (%) 48/135 (35.6) 248/675 (36.7) −0.025 0.80  Intermediate (23 − 32) (%) 56/135 (41.5) 269/675 (39.9) 0.033 0.72  High (>32) (%) 31/135 (23.0) 158/675 (23.4) −0.011 0.92 P-values were derived using generalized estimating equation models. Angiographic data are core laboratory assessed. a Within 7 days of randomization. b Defined according to the World Health Organization criteria (haematocrit value at the initial presentation, <39% for men and <36% for women). c Less than 150 000 cells/mm3 at baseline. d Calculated by means of the Cockcroft–Gault equation. e Creatinine clearance <60 ml/min. BNP: B-type natriuretic peptide; COPD: chronic obstructive pulmonary disease; CrCl: creatinine clearance; LVEF: left ventricular ejection fraction; MI: myocardial infarction; PCI: percutaneous coronary intervention; SD: standard deviation; TIA: transient ischaemic attack; WBC: white blood cell. Clinical outcomes Patients with COPD had significantly higher 30-day rates of mortality (including cardiovascular death) and MI compared with those without COPD (Tables 2 and 3, Supplementary Material, Tables S3 and S4). PSM patients with COPD also had higher rates of lower respiratory tract infections within 30 days (16/135 [11.9%] vs 38/675 [5.6%], P = 0.008) compared with those without COPD. At 3 years, patients with COPD versus without COPD had higher rates of the primary composite end point, driven by increased rates of death and MI (both periprocedural and non-periprocedural), but not stroke (Table 2, Fig. 1 and Supplementary Material, Table S5). The rates of definite stent thrombosis or graft occlusion were increased at 3 years in patients with COPD in the entire study population, although the difference was no longer statistically significant after PSM. Ischaemia-driven revascularization and major bleeding rates did not vary according to COPD status. Sensitivity analyses using the multivariable adjustment in the entire study population were consistent with the results from the PSM cohort (Supplementary Material, Table S6). Table 2: Clinical outcomes at 30 days and 3 years End point 30 days 3 years COPD (n = 135), % (n) No COPD (n = 675), % (n) P-value COPD (n = 135), % (n) No COPD (n = 675), % (n) P-value Death, myocardial infarction or stroke 11.9 (16) 5.9 (40) 0.01 31.7 (41) 14.5 (96) <0.0001 All-cause death 3.0 (4) 0.9 (6) 0.06 17.1 (22) 7.5 (49) 0.0005  Cardiovascular 3.0 (4) 0.7 (5) 0.04 7.8 (10) 4.5 (29) 0.10  Non-cardiovascular 0.0 (0) 0.1 (1) 10.1 (12) 3.1 (20) 0.0006 Myocardial infarction 10.5 (14) 4.3 (29) 0.004 18.3 (23) 7.3 (48) <0.0001  Periprocedural 10.5 (14) 3.7 (25) 0.0009 10.5 (14) 3.7 (25) 0.0009  Spontaneous 0.0 (0) 0.6 (4) 8.7 (10) 3.6 (23) 0.02 Stroke 1.5 (2) 1.3 (9) 0.88 3.3 (4) 2.9 (19) 0.84 Any revascularization 0.0 (0) 1.0 (7) 12.9 (15) 10.8 (69) 0.52  Ischaemia driven 0.0 (0) 0.9 (6) 12.9 (15) 10.4 (66) 0.41 Definite stent thrombosis or symptomatic graft occlusiona 0.8 (1) 0.3 (2) 0.45 5.8 (7) 3.0 (19) 0.12 BARC bleedingb  Any 15.0 (20) 10.1 (68) 0.07 20.7 (27) 13.2 (88) 0.02  Types 2–5 11.2 (15) 8.8 (59) 0.34 17.0 (22) 11.4 (76) 0.07  Types 3–5 6.8 (9) 6.3 (42) 0.80 7.5 (10) 7.3 (49) 0.89 Bleeding according to TIMI criteria  Major 4.5 (6) 2.4 (16) 0.16 4.5 (6) 3.2 (21) 0.39  Minor 4.5 (6) 3.9 (26) 0.73 7.0 (9) 4.5 (30) 0.27 Blood transfusion 8.2 (11) 8.5 (57) 0.97 End point 30 days 3 years COPD (n = 135), % (n) No COPD (n = 675), % (n) P-value COPD (n = 135), % (n) No COPD (n = 675), % (n) P-value Death, myocardial infarction or stroke 11.9 (16) 5.9 (40) 0.01 31.7 (41) 14.5 (96) <0.0001 All-cause death 3.0 (4) 0.9 (6) 0.06 17.1 (22) 7.5 (49) 0.0005  Cardiovascular 3.0 (4) 0.7 (5) 0.04 7.8 (10) 4.5 (29) 0.10  Non-cardiovascular 0.0 (0) 0.1 (1) 10.1 (12) 3.1 (20) 0.0006 Myocardial infarction 10.5 (14) 4.3 (29) 0.004 18.3 (23) 7.3 (48) <0.0001  Periprocedural 10.5 (14) 3.7 (25) 0.0009 10.5 (14) 3.7 (25) 0.0009  Spontaneous 0.0 (0) 0.6 (4) 8.7 (10) 3.6 (23) 0.02 Stroke 1.5 (2) 1.3 (9) 0.88 3.3 (4) 2.9 (19) 0.84 Any revascularization 0.0 (0) 1.0 (7) 12.9 (15) 10.8 (69) 0.52  Ischaemia driven 0.0 (0) 0.9 (6) 12.9 (15) 10.4 (66) 0.41 Definite stent thrombosis or symptomatic graft occlusiona 0.8 (1) 0.3 (2) 0.45 5.8 (7) 3.0 (19) 0.12 BARC bleedingb  Any 15.0 (20) 10.1 (68) 0.07 20.7 (27) 13.2 (88) 0.02  Types 2–5 11.2 (15) 8.8 (59) 0.34 17.0 (22) 11.4 (76) 0.07  Types 3–5 6.8 (9) 6.3 (42) 0.80 7.5 (10) 7.3 (49) 0.89 Bleeding according to TIMI criteria  Major 4.5 (6) 2.4 (16) 0.16 4.5 (6) 3.2 (21) 0.39  Minor 4.5 (6) 3.9 (26) 0.73 7.0 (9) 4.5 (30) 0.27 Blood transfusion 8.2 (11) 8.5 (57) 0.97 Data are presented as the Kaplan–Meier event rates and were compared by the marginal effect Cox proportional hazards regression. a Definite and probable stent thrombosis were defined according to the Academic Research Consortium criteria. b BARC types 2–5 indicate bleeding that requires medical attention and types 3–5 indicate severe or fatal bleeding. BARC: Bleeding Academic Research Consortium; COPD: chronic obstructive pulmonary disease; TIMI: thrombolysis in myocardial infarction. Table 2: Clinical outcomes at 30 days and 3 years End point 30 days 3 years COPD (n = 135), % (n) No COPD (n = 675), % (n) P-value COPD (n = 135), % (n) No COPD (n = 675), % (n) P-value Death, myocardial infarction or stroke 11.9 (16) 5.9 (40) 0.01 31.7 (41) 14.5 (96) <0.0001 All-cause death 3.0 (4) 0.9 (6) 0.06 17.1 (22) 7.5 (49) 0.0005  Cardiovascular 3.0 (4) 0.7 (5) 0.04 7.8 (10) 4.5 (29) 0.10  Non-cardiovascular 0.0 (0) 0.1 (1) 10.1 (12) 3.1 (20) 0.0006 Myocardial infarction 10.5 (14) 4.3 (29) 0.004 18.3 (23) 7.3 (48) <0.0001  Periprocedural 10.5 (14) 3.7 (25) 0.0009 10.5 (14) 3.7 (25) 0.0009  Spontaneous 0.0 (0) 0.6 (4) 8.7 (10) 3.6 (23) 0.02 Stroke 1.5 (2) 1.3 (9) 0.88 3.3 (4) 2.9 (19) 0.84 Any revascularization 0.0 (0) 1.0 (7) 12.9 (15) 10.8 (69) 0.52  Ischaemia driven 0.0 (0) 0.9 (6) 12.9 (15) 10.4 (66) 0.41 Definite stent thrombosis or symptomatic graft occlusiona 0.8 (1) 0.3 (2) 0.45 5.8 (7) 3.0 (19) 0.12 BARC bleedingb  Any 15.0 (20) 10.1 (68) 0.07 20.7 (27) 13.2 (88) 0.02  Types 2–5 11.2 (15) 8.8 (59) 0.34 17.0 (22) 11.4 (76) 0.07  Types 3–5 6.8 (9) 6.3 (42) 0.80 7.5 (10) 7.3 (49) 0.89 Bleeding according to TIMI criteria  Major 4.5 (6) 2.4 (16) 0.16 4.5 (6) 3.2 (21) 0.39  Minor 4.5 (6) 3.9 (26) 0.73 7.0 (9) 4.5 (30) 0.27 Blood transfusion 8.2 (11) 8.5 (57) 0.97 End point 30 days 3 years COPD (n = 135), % (n) No COPD (n = 675), % (n) P-value COPD (n = 135), % (n) No COPD (n = 675), % (n) P-value Death, myocardial infarction or stroke 11.9 (16) 5.9 (40) 0.01 31.7 (41) 14.5 (96) <0.0001 All-cause death 3.0 (4) 0.9 (6) 0.06 17.1 (22) 7.5 (49) 0.0005  Cardiovascular 3.0 (4) 0.7 (5) 0.04 7.8 (10) 4.5 (29) 0.10  Non-cardiovascular 0.0 (0) 0.1 (1) 10.1 (12) 3.1 (20) 0.0006 Myocardial infarction 10.5 (14) 4.3 (29) 0.004 18.3 (23) 7.3 (48) <0.0001  Periprocedural 10.5 (14) 3.7 (25) 0.0009 10.5 (14) 3.7 (25) 0.0009  Spontaneous 0.0 (0) 0.6 (4) 8.7 (10) 3.6 (23) 0.02 Stroke 1.5 (2) 1.3 (9) 0.88 3.3 (4) 2.9 (19) 0.84 Any revascularization 0.0 (0) 1.0 (7) 12.9 (15) 10.8 (69) 0.52  Ischaemia driven 0.0 (0) 0.9 (6) 12.9 (15) 10.4 (66) 0.41 Definite stent thrombosis or symptomatic graft occlusiona 0.8 (1) 0.3 (2) 0.45 5.8 (7) 3.0 (19) 0.12 BARC bleedingb  Any 15.0 (20) 10.1 (68) 0.07 20.7 (27) 13.2 (88) 0.02  Types 2–5 11.2 (15) 8.8 (59) 0.34 17.0 (22) 11.4 (76) 0.07  Types 3–5 6.8 (9) 6.3 (42) 0.80 7.5 (10) 7.3 (49) 0.89 Bleeding according to TIMI criteria  Major 4.5 (6) 2.4 (16) 0.16 4.5 (6) 3.2 (21) 0.39  Minor 4.5 (6) 3.9 (26) 0.73 7.0 (9) 4.5 (30) 0.27 Blood transfusion 8.2 (11) 8.5 (57) 0.97 Data are presented as the Kaplan–Meier event rates and were compared by the marginal effect Cox proportional hazards regression. a Definite and probable stent thrombosis were defined according to the Academic Research Consortium criteria. b BARC types 2–5 indicate bleeding that requires medical attention and types 3–5 indicate severe or fatal bleeding. BARC: Bleeding Academic Research Consortium; COPD: chronic obstructive pulmonary disease; TIMI: thrombolysis in myocardial infarction. Table 3: Periprocedural major adverse events (within 30 days) End points COPD, n (%) No COPD, n (%) P-value Periprocedural major adverse events (any) 28/135 (20.7) 103/675 (15.2) 0.11  Deatha 4/135 (3.0) 6/675 (0.9) 0.06  Myocardial infarctiona 14/135 (10.4) 29/675 (4.3) 0.005  Strokea 2/135 (1.5) 9/675 (1.3) 0.89  TIMI major or minor bleeding 12/135 (8.9) 41/675 (6.1) 0.24  Transfusion ≥2 units of blood 17/135 (12.6) 75/675 (11.1) 0.60  Major arrhythmiab 14/135 (10.4) 64/675 (9.5) 0.75  Ischaemia-driven revascularizationa 0/135 (0.0) 6/675 (0.9)  Any unplanned surgery or therapeutic radiological procedure 4/135 (3.0) 24/675 (3.4) 0.73  Renal failurec 4/135 (3.0) 15/675 (2.2) 0.61  Sternal wound dehiscence 0/135 (0.0) 11/675 (1.6)  Infection requiring antibiotics 10/135 (7.4) 77/675 (11.4) 0.17  Prolonged intubation (>48 h) 4/135 (3.0) 14/675 (2.1) 0.53  Post-pericardiotomy syndrome 1/135 (0.7) 1/675 (0.1) 0.26 End points COPD, n (%) No COPD, n (%) P-value Periprocedural major adverse events (any) 28/135 (20.7) 103/675 (15.2) 0.11  Deatha 4/135 (3.0) 6/675 (0.9) 0.06  Myocardial infarctiona 14/135 (10.4) 29/675 (4.3) 0.005  Strokea 2/135 (1.5) 9/675 (1.3) 0.89  TIMI major or minor bleeding 12/135 (8.9) 41/675 (6.1) 0.24  Transfusion ≥2 units of blood 17/135 (12.6) 75/675 (11.1) 0.60  Major arrhythmiab 14/135 (10.4) 64/675 (9.5) 0.75  Ischaemia-driven revascularizationa 0/135 (0.0) 6/675 (0.9)  Any unplanned surgery or therapeutic radiological procedure 4/135 (3.0) 24/675 (3.4) 0.73  Renal failurec 4/135 (3.0) 15/675 (2.2) 0.61  Sternal wound dehiscence 0/135 (0.0) 11/675 (1.6)  Infection requiring antibiotics 10/135 (7.4) 77/675 (11.4) 0.17  Prolonged intubation (>48 h) 4/135 (3.0) 14/675 (2.1) 0.53  Post-pericardiotomy syndrome 1/135 (0.7) 1/675 (0.1) 0.26 Data are expressed as binary event rates. P-values were derived using generalized estimating equation models. P-values were determined by the χ2 or the Fisher’s exact test and, thus, may vary slightly from those in Table 2 for the same events. a Adjudicated events; others are site reported. b Supraventricular tachycardia requiring cardioversion, ventricular tachycardia or fibrillation requiring treatment or bradyarrhythmia requiring temporary or permanent pacemaker. c Serum creatinine increased by ≥0.5 mg/dl from baseline or the need for dialysis. COPD: chronic obstructive pulmonary disease; TIMI: thrombolysis in myocardial infarction. Table 3: Periprocedural major adverse events (within 30 days) End points COPD, n (%) No COPD, n (%) P-value Periprocedural major adverse events (any) 28/135 (20.7) 103/675 (15.2) 0.11  Deatha 4/135 (3.0) 6/675 (0.9) 0.06  Myocardial infarctiona 14/135 (10.4) 29/675 (4.3) 0.005  Strokea 2/135 (1.5) 9/675 (1.3) 0.89  TIMI major or minor bleeding 12/135 (8.9) 41/675 (6.1) 0.24  Transfusion ≥2 units of blood 17/135 (12.6) 75/675 (11.1) 0.60  Major arrhythmiab 14/135 (10.4) 64/675 (9.5) 0.75  Ischaemia-driven revascularizationa 0/135 (0.0) 6/675 (0.9)  Any unplanned surgery or therapeutic radiological procedure 4/135 (3.0) 24/675 (3.4) 0.73  Renal failurec 4/135 (3.0) 15/675 (2.2) 0.61  Sternal wound dehiscence 0/135 (0.0) 11/675 (1.6)  Infection requiring antibiotics 10/135 (7.4) 77/675 (11.4) 0.17  Prolonged intubation (>48 h) 4/135 (3.0) 14/675 (2.1) 0.53  Post-pericardiotomy syndrome 1/135 (0.7) 1/675 (0.1) 0.26 End points COPD, n (%) No COPD, n (%) P-value Periprocedural major adverse events (any) 28/135 (20.7) 103/675 (15.2) 0.11  Deatha 4/135 (3.0) 6/675 (0.9) 0.06  Myocardial infarctiona 14/135 (10.4) 29/675 (4.3) 0.005  Strokea 2/135 (1.5) 9/675 (1.3) 0.89  TIMI major or minor bleeding 12/135 (8.9) 41/675 (6.1) 0.24  Transfusion ≥2 units of blood 17/135 (12.6) 75/675 (11.1) 0.60  Major arrhythmiab 14/135 (10.4) 64/675 (9.5) 0.75  Ischaemia-driven revascularizationa 0/135 (0.0) 6/675 (0.9)  Any unplanned surgery or therapeutic radiological procedure 4/135 (3.0) 24/675 (3.4) 0.73  Renal failurec 4/135 (3.0) 15/675 (2.2) 0.61  Sternal wound dehiscence 0/135 (0.0) 11/675 (1.6)  Infection requiring antibiotics 10/135 (7.4) 77/675 (11.4) 0.17  Prolonged intubation (>48 h) 4/135 (3.0) 14/675 (2.1) 0.53  Post-pericardiotomy syndrome 1/135 (0.7) 1/675 (0.1) 0.26 Data are expressed as binary event rates. P-values were derived using generalized estimating equation models. P-values were determined by the χ2 or the Fisher’s exact test and, thus, may vary slightly from those in Table 2 for the same events. a Adjudicated events; others are site reported. b Supraventricular tachycardia requiring cardioversion, ventricular tachycardia or fibrillation requiring treatment or bradyarrhythmia requiring temporary or permanent pacemaker. c Serum creatinine increased by ≥0.5 mg/dl from baseline or the need for dialysis. COPD: chronic obstructive pulmonary disease; TIMI: thrombolysis in myocardial infarction. Figure 1: View largeDownload slide The Kaplan–Meier failure rates in the propensity score-matched cohort stratified according to the presence of COPD. (A) Primary composite end point of death, stroke or myocardial infarction; (B) all-cause death; (C) myocardial infarction and (D) stroke. P-values are derived from a marginal effects Cox proportional hazards model. COPD: chronic obstructive pulmonary disease; HR: hazard ratio. Figure 1: View largeDownload slide The Kaplan–Meier failure rates in the propensity score-matched cohort stratified according to the presence of COPD. (A) Primary composite end point of death, stroke or myocardial infarction; (B) all-cause death; (C) myocardial infarction and (D) stroke. P-values are derived from a marginal effects Cox proportional hazards model. COPD: chronic obstructive pulmonary disease; HR: hazard ratio. There was no significant interaction between COPD status and randomization to revascularization with PCI versus CABG in regard to primary composite end point at 30 days [6.6% vs 16.4%, respectively, in patients with COPD; hazard ratio (HR) 0.39, 95% confidence interval (CI) 0.12–1.21 and 4.4% vs 5.8%, respectively, in patients without COPD; HR 0.55, 95% CI 0.29–0.1.06] (Pinteraction = 0.61). Similarly, the risk of periprocedural MAE in patients randomized to PCI versus CABG was consistent in those with versus without COPD (Table 4). Lower respiratory tract infections within 30 days after randomization to PCI versus CABG in the PSM cohorts occurred in 4 of 61 (6.6%) vs 12 of 74 (16.2%) patients, respectively, with COPD [odds ratio (OR) 0.36, 95% CI 0.11–1.18] and in 31 of 314 (3.5%) vs 27 of 361 (7.5%) patients, respectively, without COPD (OR 0.44, 95% CI 0.22–0.90) (Pinteraction = 0.77). Finally, the 3-year risks of the primary composite end point and other adverse events after PCI versus CABG were consistent in patients with and without COPD, both in the PSM cohorts and the entire population after multivariable adjustment (Fig. 2, Supplementary Material, Table S7 and Fig. S1). Table 4: Periprocedural major adverse events according to revascularization modality and the presence of COPD End points COPD No COPD PCI, n (%) CABG, n (%) P-value PCI, n (%) CABG, n (%) P-value Pinteraction Periprocedural major adverse events (any) 6/61 (9.8) 22/74 (29.7) 0.007 26/314 (8.3) 77/361 (21.3) <0.0001 0.63  Deatha 1/61 (1.6) 3/74 (4.1) 0.43 1/314 (0.3) 5/361 (1.4) 0.18 0.74  Myocardial infarctiona 4/61 (6.6) 10/74 (13.5) 0.20 11/314 (3.5) 18/361 (5.0) 0.34 0.56  Strokea 1/61 (1.6) 1/74 (1.4) 0.89 2/314 (0.6) 7/361 (1.9) 0.17 0.42  TIMI major or minor bleeding 4/61 (6.6) 8/74 (10.8) 0.39 9/314 (2.9) 32/361 (8.9) 0.003 0.40  Transfusion ≥2 units of blood 3/61 (4.9) 14/74 (18.9) 0.02 16/314 (5.1) 59/361 (16.3) <0.0001 0.75  Major arrhythmiab 1/61 (1.6) 13/74 (17.6) 0.02 5/314 (1.6) 59/361 (16.3) <0.0001 0.99  Ischaemia-driven revascularizationa 0/61 (0.0) 0/74 (0.0) 2/314 (0.6) 4/361 (1.1) 0.53  Any unplanned surgery or therapeutic radiological procedure 0/61 (0.0) 4/74 (5.4) 0.13 3/314 (1.0) 21/361 (5.8) 0.003 0.97a  Renal failurec 3/61 (4.9) 1/74 (1.4) 0.26 2/314 (0.6) 13/361 (3.6) 0.02 0.04  Sternal wound dehiscence 0/61 (0.0) 0/74 (0.0) 0/314 (0.0) 11/361 (3.0)  Infection requiring antibiotics 2/61 (3.3) 8/74 (10.8) 0.12 9/314 (2.9) 68/361 (18.8) <0.0001 0.37  Prolonged intubation (>48 h) 2/61 (3.3) 2/74 (2.7) 0.84 0/314 (0.0) 14/361 (3.9) 0.93a  Post-pericardiotomy syndrome 0/61 (0.0) 1/74 (1.4) 0/314 (0.0) 1/361 (0.3) 1.00a End points COPD No COPD PCI, n (%) CABG, n (%) P-value PCI, n (%) CABG, n (%) P-value Pinteraction Periprocedural major adverse events (any) 6/61 (9.8) 22/74 (29.7) 0.007 26/314 (8.3) 77/361 (21.3) <0.0001 0.63  Deatha 1/61 (1.6) 3/74 (4.1) 0.43 1/314 (0.3) 5/361 (1.4) 0.18 0.74  Myocardial infarctiona 4/61 (6.6) 10/74 (13.5) 0.20 11/314 (3.5) 18/361 (5.0) 0.34 0.56  Strokea 1/61 (1.6) 1/74 (1.4) 0.89 2/314 (0.6) 7/361 (1.9) 0.17 0.42  TIMI major or minor bleeding 4/61 (6.6) 8/74 (10.8) 0.39 9/314 (2.9) 32/361 (8.9) 0.003 0.40  Transfusion ≥2 units of blood 3/61 (4.9) 14/74 (18.9) 0.02 16/314 (5.1) 59/361 (16.3) <0.0001 0.75  Major arrhythmiab 1/61 (1.6) 13/74 (17.6) 0.02 5/314 (1.6) 59/361 (16.3) <0.0001 0.99  Ischaemia-driven revascularizationa 0/61 (0.0) 0/74 (0.0) 2/314 (0.6) 4/361 (1.1) 0.53  Any unplanned surgery or therapeutic radiological procedure 0/61 (0.0) 4/74 (5.4) 0.13 3/314 (1.0) 21/361 (5.8) 0.003 0.97a  Renal failurec 3/61 (4.9) 1/74 (1.4) 0.26 2/314 (0.6) 13/361 (3.6) 0.02 0.04  Sternal wound dehiscence 0/61 (0.0) 0/74 (0.0) 0/314 (0.0) 11/361 (3.0)  Infection requiring antibiotics 2/61 (3.3) 8/74 (10.8) 0.12 9/314 (2.9) 68/361 (18.8) <0.0001 0.37  Prolonged intubation (>48 h) 2/61 (3.3) 2/74 (2.7) 0.84 0/314 (0.0) 14/361 (3.9) 0.93a  Post-pericardiotomy syndrome 0/61 (0.0) 1/74 (1.4) 0/314 (0.0) 1/361 (0.3) 1.00a Data are expressed as binary event rates. P-values were derived using generalized estimating equation models. a Adjudicated events; others are site reported. b Supraventricular tachycardia requiring cardioversion, ventricular tachycardia or fibrillation requiring treatment or bradyarrhythmia requiring temporary or permanent pacemaker. c Serum creatinine increased by ≥0.5 mg/dl from baseline or the need for dialysis. CABG: coronary artery bypass grafting; COPD: chronic obstructive pulmonary disease; PCI: percutaneous coronary intervention; TIMI: thrombolysis in myocardial infarction. Table 4: Periprocedural major adverse events according to revascularization modality and the presence of COPD End points COPD No COPD PCI, n (%) CABG, n (%) P-value PCI, n (%) CABG, n (%) P-value Pinteraction Periprocedural major adverse events (any) 6/61 (9.8) 22/74 (29.7) 0.007 26/314 (8.3) 77/361 (21.3) <0.0001 0.63  Deatha 1/61 (1.6) 3/74 (4.1) 0.43 1/314 (0.3) 5/361 (1.4) 0.18 0.74  Myocardial infarctiona 4/61 (6.6) 10/74 (13.5) 0.20 11/314 (3.5) 18/361 (5.0) 0.34 0.56  Strokea 1/61 (1.6) 1/74 (1.4) 0.89 2/314 (0.6) 7/361 (1.9) 0.17 0.42  TIMI major or minor bleeding 4/61 (6.6) 8/74 (10.8) 0.39 9/314 (2.9) 32/361 (8.9) 0.003 0.40  Transfusion ≥2 units of blood 3/61 (4.9) 14/74 (18.9) 0.02 16/314 (5.1) 59/361 (16.3) <0.0001 0.75  Major arrhythmiab 1/61 (1.6) 13/74 (17.6) 0.02 5/314 (1.6) 59/361 (16.3) <0.0001 0.99  Ischaemia-driven revascularizationa 0/61 (0.0) 0/74 (0.0) 2/314 (0.6) 4/361 (1.1) 0.53  Any unplanned surgery or therapeutic radiological procedure 0/61 (0.0) 4/74 (5.4) 0.13 3/314 (1.0) 21/361 (5.8) 0.003 0.97a  Renal failurec 3/61 (4.9) 1/74 (1.4) 0.26 2/314 (0.6) 13/361 (3.6) 0.02 0.04  Sternal wound dehiscence 0/61 (0.0) 0/74 (0.0) 0/314 (0.0) 11/361 (3.0)  Infection requiring antibiotics 2/61 (3.3) 8/74 (10.8) 0.12 9/314 (2.9) 68/361 (18.8) <0.0001 0.37  Prolonged intubation (>48 h) 2/61 (3.3) 2/74 (2.7) 0.84 0/314 (0.0) 14/361 (3.9) 0.93a  Post-pericardiotomy syndrome 0/61 (0.0) 1/74 (1.4) 0/314 (0.0) 1/361 (0.3) 1.00a End points COPD No COPD PCI, n (%) CABG, n (%) P-value PCI, n (%) CABG, n (%) P-value Pinteraction Periprocedural major adverse events (any) 6/61 (9.8) 22/74 (29.7) 0.007 26/314 (8.3) 77/361 (21.3) <0.0001 0.63  Deatha 1/61 (1.6) 3/74 (4.1) 0.43 1/314 (0.3) 5/361 (1.4) 0.18 0.74  Myocardial infarctiona 4/61 (6.6) 10/74 (13.5) 0.20 11/314 (3.5) 18/361 (5.0) 0.34 0.56  Strokea 1/61 (1.6) 1/74 (1.4) 0.89 2/314 (0.6) 7/361 (1.9) 0.17 0.42  TIMI major or minor bleeding 4/61 (6.6) 8/74 (10.8) 0.39 9/314 (2.9) 32/361 (8.9) 0.003 0.40  Transfusion ≥2 units of blood 3/61 (4.9) 14/74 (18.9) 0.02 16/314 (5.1) 59/361 (16.3) <0.0001 0.75  Major arrhythmiab 1/61 (1.6) 13/74 (17.6) 0.02 5/314 (1.6) 59/361 (16.3) <0.0001 0.99  Ischaemia-driven revascularizationa 0/61 (0.0) 0/74 (0.0) 2/314 (0.6) 4/361 (1.1) 0.53  Any unplanned surgery or therapeutic radiological procedure 0/61 (0.0) 4/74 (5.4) 0.13 3/314 (1.0) 21/361 (5.8) 0.003 0.97a  Renal failurec 3/61 (4.9) 1/74 (1.4) 0.26 2/314 (0.6) 13/361 (3.6) 0.02 0.04  Sternal wound dehiscence 0/61 (0.0) 0/74 (0.0) 0/314 (0.0) 11/361 (3.0)  Infection requiring antibiotics 2/61 (3.3) 8/74 (10.8) 0.12 9/314 (2.9) 68/361 (18.8) <0.0001 0.37  Prolonged intubation (>48 h) 2/61 (3.3) 2/74 (2.7) 0.84 0/314 (0.0) 14/361 (3.9) 0.93a  Post-pericardiotomy syndrome 0/61 (0.0) 1/74 (1.4) 0/314 (0.0) 1/361 (0.3) 1.00a Data are expressed as binary event rates. P-values were derived using generalized estimating equation models. a Adjudicated events; others are site reported. b Supraventricular tachycardia requiring cardioversion, ventricular tachycardia or fibrillation requiring treatment or bradyarrhythmia requiring temporary or permanent pacemaker. c Serum creatinine increased by ≥0.5 mg/dl from baseline or the need for dialysis. CABG: coronary artery bypass grafting; COPD: chronic obstructive pulmonary disease; PCI: percutaneous coronary intervention; TIMI: thrombolysis in myocardial infarction. Figure 2: View largeDownload slide The association between COPD, randomized revascularization modality and 3-year adverse clinical events in the propensity score-matched groups. Marginal effects Cox proportional hazards regression. BARC: Bleeding Academic Research Consortium; CI: confidence interval; COPD: chronic obstructive pulmonary disease; HR: hazard ratio; PCI: percutaneous coronary intervention. Figure 2: View largeDownload slide The association between COPD, randomized revascularization modality and 3-year adverse clinical events in the propensity score-matched groups. Marginal effects Cox proportional hazards regression. BARC: Bleeding Academic Research Consortium; CI: confidence interval; COPD: chronic obstructive pulmonary disease; HR: hazard ratio; PCI: percutaneous coronary intervention. DISCUSSION The major finding of this analysis from the randomized, multicentre EXCEL trial is that patients with LMCAD undergoing revascularization in whom COPD was present had higher 30-day and 3-year rates of mortality and MAE compared with those without COPD, regardless of whether they were treated with PCI or CABG. Similar to prior studies in patients without LMCAD [4, 8–13], in the EXCEL trial, the hazard curves for patients with COPD compared with those without COPD diverged early after LMCAD revascularization (signifying increased periprocedural risk) and continued to spread throughout the 3-year duration of follow-up. The significantly higher 30-day rates of periprocedural MI, lower respiratory tract infections and cardiovascular and all-cause mortality in patients with COPD compared to those without COPD in the EXCEL trial are consistent with previous reports of an increased risk of in-hospital complications, cardiogenic shock and death in non-LMCAD patients with COPD with medical or surgical management [10, 11]. Our finding of a long-term COPD-associated risk of adverse outcomes is also consistent with previous studies reporting a greater long-term risk of recurrent MI and death in patients with COPD versus patients without COPD after PCI [9] and CABG [4, 11, 12]. The mechanisms underlying the increased rates of periprocedural and spontaneous MI associated with COPD are unknown and may be multifactorial. COPD is associated with other cardiovascular risk factors, which may in part explain its association with MI. Previous studies have also suggested that more severe coronary calcification and a higher prevalence of high-risk plaque features are present in patients with COPD which may contribute to an increased risk of MI [14, 15]. However, COPD in the EXCEL trial was not associated with the extent of CAD as assessed by the SYNTAX score. In addition to higher rates of MI, the greater risk of in-hospital infections [16] and difficulties in weaning patients with COPD from mechanical ventilation [16] may contribute to increased mortality in patients with COPD, especially after CABG. Of note, however, in the EXCEL trial, COPD was not associated with prolonged intubation after CABG (although lower respiratory tract infections were increased). Our findings are consistent with recent nationwide data from Sweden reporting a significantly increased adjusted risk of pneumonia but not of prolonged mechanical ventilation after CABG in patients with COPD versus without COPD [13]. COPD is considered by many to be a greater risk factor for patients undergoing CABG compared to PCI. COPD portends worse outcomes after CABG [17] and is an independent predictor of operative mortality in the Society of Thoracic Surgeons (STS) and the European System for Cardiac Operative Risk Evaluation (EuroSCORE) risk scores [17–20]. COPD is, therefore, incorporated in both these scores, which are used to assess the surgical risk of patients who are candidates for CABG as noted in the 2018 ESC/EACTS guidelines on myocardial revascularization [21]. In the SYNTAX trial, COPD was independently associated with 4-year mortality after CABG but not after PCI [22, 23]. Conversely, the outcomes of PCI versus CABG were consistent in patients with and without COPD in the DELTA [23, 24] and SWEDEHEART registries [13]. In this large-scale randomized trial, no significant interactions were present between revascularization strategy and COPD status regarding the risk of periprocedural MAE or lower respiratory tract infections; however, treatment with PCI compared with CABG resulted in greater absolute reductions in lower respiratory tract infections in patients with COPD versus without COPD. Nonetheless, no significant interactions between COPD and treatment modality (PCI versus CABG) were present for the 3-year primary composite end point or any of its components. Thus, the principal finding from the EXCEL trial is that PCI and CABG result in comparable 3-year outcomes after revascularization of patients with LMCAD, and low or intermediate SYNTAX scores apply to patients with and without COPD who are acceptable candidates for both procedures. Study strengths and limitations As the largest randomized trial to date of patients with LMCAD undergoing revascularization, the EXCEL trial provides relevant insights into the association between medically treated COPD and the risk of adverse outcomes after contemporary LMCAD therapies; however, several limitations should be considered. First, this analysis was post hoc and should thus be considered as hypothesis generating. Second, the number of subjects with COPD was modest, and not all confounders in the described relationships may have been identified. Third, some of the outcomes were uncommon, resulting in imprecise effect sizes. The reported differences in the relative risk of PCI versus CABG for these infrequent events are inconclusive. Fourth, we do not have detailed data available on pulmonary function tests or other parameters reflecting the severity of COPD that might have provided greater insights as to whether certain COPD patients might selectively benefit from treatment with PCI versus CABG. Finally, equipoise for randomization may not have been present in patients with severe COPD including those with markedly reduced lung volumes or requiring continuous oxygen therapy. A review of the EXCEL screening registry demonstrates that COPD was present in only a slightly greater proportion of patients who were excluded compared to those who were randomized in the trial (9.8% vs 7.1%, P = 0.05) [6]; unfortunately, the severity of COPD in excluded versus randomized patients was not collected nor were clinical outcomes in registry patients. It is likely that patients with very severe COPD were not randomized, and thus, these results apply to patients with less severe COPD in whom the risk of general anaesthesia is acceptable. The results of the present study, thus, do not inform the optimal treatments or outcomes of the most severely impaired COPD patients. Nevertheless, our study confirms that patients with COPD are at increased risk of early mortality and late mortality irrespective of the revascularization therapy. CONCLUSIONS Patients with LMCAD undergoing PCI or CABG in whom medically treated COPD is present are at increased risk of periprocedural and long-term adverse events, including death and MI, irrespective of revascularization modality. In the EXCEL trial, the relative early and late risk: the benefit profile of PCI versus CABG was consistent in patients with and without COPD who were candidates for both procedures. Further studies are required to determine which COPD patients requiring revascularization, if any, might have a relatively improved prognosis with PCI compared with CABG. Funding The EXCEL trial was supported by Abbott Vascular (Santa Clara, CA, USA). Conflict of interest: David E. Kandzari: grant support—Abbott Vascular, Boston Scientific and Medtronic; consultant—Boston Scientific, Medtronic and Micell Technologies. Bela Merkely: lecture fees and grant support (to institution)—Abbott. Joseph F. Sabik III: consultant—Medtronic, Edwards and Sorin; advisory board—Medtronic (cardiac surgery). Patrick W. Serruys: consultant—Abbott, Biosensors, Cardialysis, Micell Technologies, Medtronic, Sinomed Science Technologies, Stentys France, Svelte Medical Systems, Philips/Volcano, St. Jude Medical and Xeltis. Arie Pieter Kappetein: employee—Medtronic. Gregg W. Stone: Columbia University (employer) receives royalties from Abbott Vascular for the sale of the MitraClip. All other authors have no conflict of interest. REFERENCES 1 Campo G , Pavasini R , Malagu M , Mascetti S , Biscaglia S , Ceconi C et al. Chronic obstructive pulmonary disease and ischemic heart disease comorbidity: overview of mechanisms and clinical management . Cardiovasc Drugs Ther 2015 ; 29 : 147 – 57 . Google Scholar Crossref Search ADS PubMed 2 Decramer M , Janssens W , Miravitlles M. Chronic obstructive pulmonary disease . Lancet 2012 ; 379 : 1341 – 51 . Google Scholar Crossref Search ADS PubMed 3 Roques F , Nashef SA , Michel P , Gauducheau E , de Vincentiis C , Baudet E et al. Risk factors and outcome in European cardiac surgery: analysis of the EuroSCORE multinational database of 19030 patients . Eur J Cardiothorac Surg 1999 ; 15 : 816 – 22 ; discussion 22–3. Google Scholar Crossref Search ADS PubMed 4 O'Boyle F , Mediratta N , Chalmers J , Al-Rawi O , Mohan K , Shaw M et al. Long-term survival of patients with pulmonary disease undergoing coronary artery bypass surgery . 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The DELTA registry: a multicenter registry evaluating percutaneous coronary intervention versus coronary artery bypass grafting for left main treatment . JACC Cardiovasc Interv 2012 ; 5 : 718 – 27 . Google Scholar Crossref Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Cardio-Thoracic Surgery Oxford University Press

Impact of chronic obstructive pulmonary disease on prognosis after percutaneous coronary intervention and bypass surgery for left main coronary artery disease: an analysis from the EXCEL trial

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
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1010-7940
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Abstract

Abstract View largeDownload slide View largeDownload slide OBJECTIVES Percutaneous coronary intervention (PCI) is often favoured over coronary artery bypass grafting (CABG) surgery for revascularization in patients with chronic obstructive pulmonary disease (COPD). We studied whether COPD affected clinical outcomes according to revascularization in the Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial, in which PCI with everolimus-eluting stents was non-inferior to CABG for the treatment of patients with left main coronary artery disease and low or intermediate SYNTAX scores. METHODS Patients with a history of COPD were propensity score matched to those without COPD. Outcomes at 30 days and 3 years in both groups were compared in patients randomized to PCI versus CABG. RESULTS COPD status was available for 1901 of 1905 randomized patients (99.8%), 148 of whom had COPD (7.8%). Propensity score matching yielded 135 patients with COPD and 675 patients without COPD. Patients with COPD had higher 3-year rates of the primary composite end point of death, myocardial infarction or stroke (31.7% vs 14.5%, P < 0.0001), death (17.1% vs 7.5%, P = 0.0005) and myocardial infarction (18.3% vs 7.3%, P < 0.0001), but not stroke (3.3% vs 2.9%, P = 0.84). There were no statistically significant interactions in the relative risks of PCI versus CABG for the primary composite end point in patients with and without COPD at 30 days [hazard ratio (HR) 0.39, 95% confidence interval (CI) 0.12–1.21 vs HR 0.55, 95% CI 0.29–1.06; Pinteraction = 0.61] or at 3 years (HR 0.85, 95% CI 0.46–1.56 vs HR 1.28, 95% CI 0.84–1.94; Pinteraction = 0.27). CONCLUSIONS In the EXCEL trial, COPD was independently associated with poor prognosis after left main coronary artery disease revascularization. The relative risks of PCI versus CABG at 30 days and 3 years were consistent in patients with and without COPD. Clinical trial registration number http://www.clinicaltrials.gov; NCT01205776. Chronic obstructive pulmonary disease, Percutaneous coronary intervention, Coronary artery bypass grafting, Left main coronary artery disease INTRODUCTION In patients with chronic obstructive pulmonary disease (COPD), hypoxia, chronic inflammation, endothelial dysfunction, oxidative stress and heightened platelet reactivity accelerate the course of atherosclerotic coronary artery disease (CAD) [1, 2]. Patients with COPD have increased surgical risk and a worse prognosis after coronary artery bypass grafting (CABG) [3, 4]; however, COPD patients are also at increased risk for adverse cardiac events after percutaneous coronary intervention (PCI), including mortality [5]. Patients with COPD and CAD requiring revascularization thus represent a challenging subset of patients [1], and the optimal mode of revascularization for high-risk patients with COPD and complex CAD has not been established. The large-scale, international Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial demonstrated that in patients with left main CAD (LMCAD) of low or intermediate complexity (as assessed by a SYNTAX score ≤32), PCI with everolimus-eluting stents was non-inferior to CABG for the composite rate of death, stroke or myocardial infarction (MI) at 3 years [6]. We sought to assess the association between COPD and adverse outcomes after LMCAD treatment and determine whether the relative safety and efficacy of PCI versus CABG differ in patients with COPD versus without COPD. METHODS Study design The design of the EXCEL trial has been reported previously [6, 7]. In brief, the EXCEL trial was an international, multicentre, randomized trial that compared everolimus-eluting stents with CABG in patients with LMCAD and low or intermediate SYNTAX scores (≤32) in whom equipoise for revascularization with both techniques was present after the heart team review. The goal was complete revascularization of all ischaemic territories. PCI was done using fluoropolymer-based cobalt–chromium everolimus-eluting stents (XIENCE, Abbott Vascular, Santa Clara, CA, USA). CABG was performed with or without cardiopulmonary bypass according to the discretion of the operator; the use of multiple arterial grafts was strongly recommended. The investigation was approved by the institutional review board or ethics committee at each participating centre, and all patients signed their written informed consent. Major end points were adjudicated by an independent clinical events committee (Cardiovascular Research Foundation, New York, NY, USA). Angiographic analyses were performed at an angiographic core laboratory (Cardiovascular Research Foundation). Follow-up is presently complete for all patients through 3 years. Definitions and end points COPD at baseline was defined as a prior diagnosis of COPD and ongoing treatment with bronchodilators and/or oral or inhalational steroids. The primary end point was a composite of death from any cause, stroke or MI at 3 years. Major secondary end points included the primary composite end point at 30 days and the composite of death, stroke, MI or ischaemia-driven revascularization at 3 years. Additional secondary end points included the components of the primary and secondary end points at 30 days and 3 years and stent thrombosis and symptomatic graft stenosis or occlusion at 30 days and 3 years, all as previously defined [6, 7]. An additional prespecified secondary end point was periprocedural major adverse events (MAE), defined as the occurrence within 30 days of death, stroke, MI, ischaemia-driven revascularization, thrombolysis in myocardial infarction major or minor bleeding, transfusion of ≥2 units of blood, major arrhythmias, unplanned surgical or radiological procedures, renal failure, sternal wound dehiscence, infections requiring antibiotics, prolonged (>48 h) intubation or post-pericardiotomy syndrome. Statistical analysis Continuous variables are expressed as mean ± standard deviation and were compared using the Student’s t-test or the Mann–Whitney U-test, depending on whether they satisfied the normality assumption as assessed by the visual inspection of residuals and by the Shapiro–Wilk test. Categorical variables were compared using the χ2 test if the counts in 80% of cells exceeded 5, otherwise using the Fisher’s exact test. The Kaplan–Meier methods were used to estimate cumulative event rates at 30 days and 3 years; comparisons were made using the marginal effects Cox proportional hazards regression (the matched cohort) or the log-rank test (overall cohort). To adjust for potential confounders, patients with COPD were matched 1:5 to patients without COPD using propensity scores and a greedy matching algorithm. With COPD as the binary outcome, logistic regression containing the following covariate set was used to calculate the propensity score: age, sex, hypertension, hyperlipidaemia, current smoking, prior stroke or transient ischaemic attack, congestive heart failure, diabetes, anaemia, peripheral vascular disease, prior PCI, prior MI, clinical presentation, body mass index, heart rate, white blood cell count, left ventricular ejection fraction, renal insufficiency, treatment assignment and the SYNTAX score. The predicted probability for each patient from the logistic model was the propensity score. COPD patients were matched 1:5 to non-COPD patients based on their propensity scores. Standardized differences of baseline variables comparing COPD versus non-COPD in overall and matched populations were calculated to demonstrate the balance achieved by propensity score matching. In the matched cohort, the comparisons of continuous and categorical variables were performed using the generalized estimating equation method, and the comparisons of clinical events were performed by the marginal Cox models, to account for the dependence within each matched stratum. The risk of periprocedural adverse events was compared using the logistic regression. Interaction terms between COPD and treatment were included to assess whether the presence versus absence of COPD moderated the effect of treatment assignment on outcomes. Sensitivity analyses were conducted using the multivariable Cox proportional hazards regression in the overall population using the same covariate set included in the propensity score calculation. The present analysis is post hoc, although all statistical analyses were prespecified. A 2-sided P-value <0.05 was considered to be statistically significant for all tests. All statistical analyses were performed with the SAS software, version 9.4 (SAS Institute, Cary, NC, USA). RESULTS Patient characteristics COPD status was documented in 1901 of 1905 (99.8%) patients randomized in the EXCEL trial, 148 (7.8%) of whom had COPD. Baseline clinical and angiographic characteristics of patients with COPD versus without COPD are presented in Supplementary Material, Table S1. Patients with COPD had more cardiovascular risk factors, including a higher prevalence of diabetes mellitus and current smoking, and more comorbidities such as peripheral vascular disease and anaemia compared with those without COPD. In addition, patients with COPD on average had a lower left ventricular ejection fraction and a higher B-type natriuretic peptide level. Propensity score matching (PSM) yielded 135 patients with COPD (91% of all patients with COPD) matched with 675 patients without COPD (the mean caliper 0.03, standard deviation 0.03). Baseline clinical and angiographic characteristics were similar between the matched groups (Table 1), and all covariates used for PSM were non-significantly different. The rates of use of antithrombotic agents, statins and other medications were similar between patients with and without COPD during the study duration (Supplementary Material, Table S2). Table 1: Baseline clinical and angiographic characteristics Characteristics COPD (n = 135) No COPD (n = 675) Standardized difference P-value Age (years), mean ± SD 67.4 ± 8.6 67.3 ± 9.5 0.010 0.91 Male sex (%) 96/135 (71.1) 478/675 (70.8) 0.007 0.94 Diabetes (%) 51/135 (37.8) 266/675 (39.4) −0.033 0.72  Insulin treated (%) 18/135 (13.3) 71/675 (10.5) 0.087 0.34 Hypertension (%) 106/135 (78.5) 538/675 (79.7) −0.029 0.75 Hyperlipidaemia (%) 92/135 (68.1) 497/675 (73.6) −0.121 0.19 Smoking status (%)  Former smoker 64/135 (47.4) 220/675 (32.6) 0.306 0.0005  Current smoker 51/135 (37.8) 222/675 (32.9) 0.102 0.20 Prior MI (%) 26/135 (19.3) 131/675 (19.4) −0.004 0.97 Prior PCI (%) 27/135 (20.0) 133/675 (19.7) 0.007 0.94 Prior CABG (%) 0/135 (0.0) 0/675 (0.0) Congestive heart failure (%) 11/135 (8.1) 61/675 (9.0) −0.032 0.72 Prior stroke or TIA (%) 9/135 (6.7) 45/675 (6.7) 0.000 1.00 Peripheral vascular disease (%) 27/135 (20.0) 103/675 (15.3) 0.125 0.12 Clinical presentation (%)  Recent MIa 25/135 (18.5) 129/675 (19.1) −0.015 0.87  Unstable angina 37/135 (27.4) 185/675 (27.4) 0.000 1.00  Stable angina 66/135 (48.9) 326/675 (48.3) 0.012 0.90  Silent ischaemia 5/135 (3.7) 25/675 (3.7) 0.000 1.00 Body mass index (kg/m2), mean ± SD 29.7 ± 6.7 29.6 ± 5.4 0.014 0.89 Heart rate (bpm), mean ± SD 71.7 ± 11.5 71.1 ± 12.7 0.051 0.53 Haemoglobin (g/dl), mean ± SD 13.3 ± 1.8 13.4 ± 1.6 −0.042 0.66 Anaemia (%)b 48/135 (35.6) 209/673 (31.1) −0.009 0.31 WBC count (×109/l), mean ± SD 8.3 ± 2.4 8.2 ± 2.2 0.066 0.47 Platelet count (×109/l), mean ± SD 226.6 ± 65.6 235.3 ± 65.0 −0.133 0.35 Thrombocytopenia (%)c 7/61 (11.5) 16/341 (4.7) 0.251 0.04 CrCl (ml/min)d, mean ± SD 87.6 ± 31.3 89.8 ± 34.3 −0.065 0.49 Renal insufficiency (%)e 22/135 (16.3) 115/675 (17.0) −0.020 0.84 BNP (pg/ml), mean ± SD 431.3 ± 761.1 288.4 ± 629.2 0.205 0.17 LVEF (%), mean ± SD 54.7 ± 10.8 54.9 ± 9.8 −0.021 0.83 Left main lesion location (%)  Ostium 49/134 (36.6) 248/655 (37.9) −0.027 0.78  Mid-shaft 47/134 (35.1) 284/655 (43.4) −0.170 0.08  Distal 101/134 (75.4) 505/655 (77.1) −0.041 0.66 SYNTAX score, mean ± SD 26.3 ± 10.2 26.2 ± 9.3 0.97  Low (≤22) (%) 48/135 (35.6) 248/675 (36.7) −0.025 0.80  Intermediate (23 − 32) (%) 56/135 (41.5) 269/675 (39.9) 0.033 0.72  High (>32) (%) 31/135 (23.0) 158/675 (23.4) −0.011 0.92 Characteristics COPD (n = 135) No COPD (n = 675) Standardized difference P-value Age (years), mean ± SD 67.4 ± 8.6 67.3 ± 9.5 0.010 0.91 Male sex (%) 96/135 (71.1) 478/675 (70.8) 0.007 0.94 Diabetes (%) 51/135 (37.8) 266/675 (39.4) −0.033 0.72  Insulin treated (%) 18/135 (13.3) 71/675 (10.5) 0.087 0.34 Hypertension (%) 106/135 (78.5) 538/675 (79.7) −0.029 0.75 Hyperlipidaemia (%) 92/135 (68.1) 497/675 (73.6) −0.121 0.19 Smoking status (%)  Former smoker 64/135 (47.4) 220/675 (32.6) 0.306 0.0005  Current smoker 51/135 (37.8) 222/675 (32.9) 0.102 0.20 Prior MI (%) 26/135 (19.3) 131/675 (19.4) −0.004 0.97 Prior PCI (%) 27/135 (20.0) 133/675 (19.7) 0.007 0.94 Prior CABG (%) 0/135 (0.0) 0/675 (0.0) Congestive heart failure (%) 11/135 (8.1) 61/675 (9.0) −0.032 0.72 Prior stroke or TIA (%) 9/135 (6.7) 45/675 (6.7) 0.000 1.00 Peripheral vascular disease (%) 27/135 (20.0) 103/675 (15.3) 0.125 0.12 Clinical presentation (%)  Recent MIa 25/135 (18.5) 129/675 (19.1) −0.015 0.87  Unstable angina 37/135 (27.4) 185/675 (27.4) 0.000 1.00  Stable angina 66/135 (48.9) 326/675 (48.3) 0.012 0.90  Silent ischaemia 5/135 (3.7) 25/675 (3.7) 0.000 1.00 Body mass index (kg/m2), mean ± SD 29.7 ± 6.7 29.6 ± 5.4 0.014 0.89 Heart rate (bpm), mean ± SD 71.7 ± 11.5 71.1 ± 12.7 0.051 0.53 Haemoglobin (g/dl), mean ± SD 13.3 ± 1.8 13.4 ± 1.6 −0.042 0.66 Anaemia (%)b 48/135 (35.6) 209/673 (31.1) −0.009 0.31 WBC count (×109/l), mean ± SD 8.3 ± 2.4 8.2 ± 2.2 0.066 0.47 Platelet count (×109/l), mean ± SD 226.6 ± 65.6 235.3 ± 65.0 −0.133 0.35 Thrombocytopenia (%)c 7/61 (11.5) 16/341 (4.7) 0.251 0.04 CrCl (ml/min)d, mean ± SD 87.6 ± 31.3 89.8 ± 34.3 −0.065 0.49 Renal insufficiency (%)e 22/135 (16.3) 115/675 (17.0) −0.020 0.84 BNP (pg/ml), mean ± SD 431.3 ± 761.1 288.4 ± 629.2 0.205 0.17 LVEF (%), mean ± SD 54.7 ± 10.8 54.9 ± 9.8 −0.021 0.83 Left main lesion location (%)  Ostium 49/134 (36.6) 248/655 (37.9) −0.027 0.78  Mid-shaft 47/134 (35.1) 284/655 (43.4) −0.170 0.08  Distal 101/134 (75.4) 505/655 (77.1) −0.041 0.66 SYNTAX score, mean ± SD 26.3 ± 10.2 26.2 ± 9.3 0.97  Low (≤22) (%) 48/135 (35.6) 248/675 (36.7) −0.025 0.80  Intermediate (23 − 32) (%) 56/135 (41.5) 269/675 (39.9) 0.033 0.72  High (>32) (%) 31/135 (23.0) 158/675 (23.4) −0.011 0.92 P-values were derived using generalized estimating equation models. Angiographic data are core laboratory assessed. a Within 7 days of randomization. b Defined according to the World Health Organization criteria (haematocrit value at the initial presentation, <39% for men and <36% for women). c Less than 150 000 cells/mm3 at baseline. d Calculated by means of the Cockcroft–Gault equation. e Creatinine clearance <60 ml/min. BNP: B-type natriuretic peptide; COPD: chronic obstructive pulmonary disease; CrCl: creatinine clearance; LVEF: left ventricular ejection fraction; MI: myocardial infarction; PCI: percutaneous coronary intervention; SD: standard deviation; TIA: transient ischaemic attack; WBC: white blood cell. Table 1: Baseline clinical and angiographic characteristics Characteristics COPD (n = 135) No COPD (n = 675) Standardized difference P-value Age (years), mean ± SD 67.4 ± 8.6 67.3 ± 9.5 0.010 0.91 Male sex (%) 96/135 (71.1) 478/675 (70.8) 0.007 0.94 Diabetes (%) 51/135 (37.8) 266/675 (39.4) −0.033 0.72  Insulin treated (%) 18/135 (13.3) 71/675 (10.5) 0.087 0.34 Hypertension (%) 106/135 (78.5) 538/675 (79.7) −0.029 0.75 Hyperlipidaemia (%) 92/135 (68.1) 497/675 (73.6) −0.121 0.19 Smoking status (%)  Former smoker 64/135 (47.4) 220/675 (32.6) 0.306 0.0005  Current smoker 51/135 (37.8) 222/675 (32.9) 0.102 0.20 Prior MI (%) 26/135 (19.3) 131/675 (19.4) −0.004 0.97 Prior PCI (%) 27/135 (20.0) 133/675 (19.7) 0.007 0.94 Prior CABG (%) 0/135 (0.0) 0/675 (0.0) Congestive heart failure (%) 11/135 (8.1) 61/675 (9.0) −0.032 0.72 Prior stroke or TIA (%) 9/135 (6.7) 45/675 (6.7) 0.000 1.00 Peripheral vascular disease (%) 27/135 (20.0) 103/675 (15.3) 0.125 0.12 Clinical presentation (%)  Recent MIa 25/135 (18.5) 129/675 (19.1) −0.015 0.87  Unstable angina 37/135 (27.4) 185/675 (27.4) 0.000 1.00  Stable angina 66/135 (48.9) 326/675 (48.3) 0.012 0.90  Silent ischaemia 5/135 (3.7) 25/675 (3.7) 0.000 1.00 Body mass index (kg/m2), mean ± SD 29.7 ± 6.7 29.6 ± 5.4 0.014 0.89 Heart rate (bpm), mean ± SD 71.7 ± 11.5 71.1 ± 12.7 0.051 0.53 Haemoglobin (g/dl), mean ± SD 13.3 ± 1.8 13.4 ± 1.6 −0.042 0.66 Anaemia (%)b 48/135 (35.6) 209/673 (31.1) −0.009 0.31 WBC count (×109/l), mean ± SD 8.3 ± 2.4 8.2 ± 2.2 0.066 0.47 Platelet count (×109/l), mean ± SD 226.6 ± 65.6 235.3 ± 65.0 −0.133 0.35 Thrombocytopenia (%)c 7/61 (11.5) 16/341 (4.7) 0.251 0.04 CrCl (ml/min)d, mean ± SD 87.6 ± 31.3 89.8 ± 34.3 −0.065 0.49 Renal insufficiency (%)e 22/135 (16.3) 115/675 (17.0) −0.020 0.84 BNP (pg/ml), mean ± SD 431.3 ± 761.1 288.4 ± 629.2 0.205 0.17 LVEF (%), mean ± SD 54.7 ± 10.8 54.9 ± 9.8 −0.021 0.83 Left main lesion location (%)  Ostium 49/134 (36.6) 248/655 (37.9) −0.027 0.78  Mid-shaft 47/134 (35.1) 284/655 (43.4) −0.170 0.08  Distal 101/134 (75.4) 505/655 (77.1) −0.041 0.66 SYNTAX score, mean ± SD 26.3 ± 10.2 26.2 ± 9.3 0.97  Low (≤22) (%) 48/135 (35.6) 248/675 (36.7) −0.025 0.80  Intermediate (23 − 32) (%) 56/135 (41.5) 269/675 (39.9) 0.033 0.72  High (>32) (%) 31/135 (23.0) 158/675 (23.4) −0.011 0.92 Characteristics COPD (n = 135) No COPD (n = 675) Standardized difference P-value Age (years), mean ± SD 67.4 ± 8.6 67.3 ± 9.5 0.010 0.91 Male sex (%) 96/135 (71.1) 478/675 (70.8) 0.007 0.94 Diabetes (%) 51/135 (37.8) 266/675 (39.4) −0.033 0.72  Insulin treated (%) 18/135 (13.3) 71/675 (10.5) 0.087 0.34 Hypertension (%) 106/135 (78.5) 538/675 (79.7) −0.029 0.75 Hyperlipidaemia (%) 92/135 (68.1) 497/675 (73.6) −0.121 0.19 Smoking status (%)  Former smoker 64/135 (47.4) 220/675 (32.6) 0.306 0.0005  Current smoker 51/135 (37.8) 222/675 (32.9) 0.102 0.20 Prior MI (%) 26/135 (19.3) 131/675 (19.4) −0.004 0.97 Prior PCI (%) 27/135 (20.0) 133/675 (19.7) 0.007 0.94 Prior CABG (%) 0/135 (0.0) 0/675 (0.0) Congestive heart failure (%) 11/135 (8.1) 61/675 (9.0) −0.032 0.72 Prior stroke or TIA (%) 9/135 (6.7) 45/675 (6.7) 0.000 1.00 Peripheral vascular disease (%) 27/135 (20.0) 103/675 (15.3) 0.125 0.12 Clinical presentation (%)  Recent MIa 25/135 (18.5) 129/675 (19.1) −0.015 0.87  Unstable angina 37/135 (27.4) 185/675 (27.4) 0.000 1.00  Stable angina 66/135 (48.9) 326/675 (48.3) 0.012 0.90  Silent ischaemia 5/135 (3.7) 25/675 (3.7) 0.000 1.00 Body mass index (kg/m2), mean ± SD 29.7 ± 6.7 29.6 ± 5.4 0.014 0.89 Heart rate (bpm), mean ± SD 71.7 ± 11.5 71.1 ± 12.7 0.051 0.53 Haemoglobin (g/dl), mean ± SD 13.3 ± 1.8 13.4 ± 1.6 −0.042 0.66 Anaemia (%)b 48/135 (35.6) 209/673 (31.1) −0.009 0.31 WBC count (×109/l), mean ± SD 8.3 ± 2.4 8.2 ± 2.2 0.066 0.47 Platelet count (×109/l), mean ± SD 226.6 ± 65.6 235.3 ± 65.0 −0.133 0.35 Thrombocytopenia (%)c 7/61 (11.5) 16/341 (4.7) 0.251 0.04 CrCl (ml/min)d, mean ± SD 87.6 ± 31.3 89.8 ± 34.3 −0.065 0.49 Renal insufficiency (%)e 22/135 (16.3) 115/675 (17.0) −0.020 0.84 BNP (pg/ml), mean ± SD 431.3 ± 761.1 288.4 ± 629.2 0.205 0.17 LVEF (%), mean ± SD 54.7 ± 10.8 54.9 ± 9.8 −0.021 0.83 Left main lesion location (%)  Ostium 49/134 (36.6) 248/655 (37.9) −0.027 0.78  Mid-shaft 47/134 (35.1) 284/655 (43.4) −0.170 0.08  Distal 101/134 (75.4) 505/655 (77.1) −0.041 0.66 SYNTAX score, mean ± SD 26.3 ± 10.2 26.2 ± 9.3 0.97  Low (≤22) (%) 48/135 (35.6) 248/675 (36.7) −0.025 0.80  Intermediate (23 − 32) (%) 56/135 (41.5) 269/675 (39.9) 0.033 0.72  High (>32) (%) 31/135 (23.0) 158/675 (23.4) −0.011 0.92 P-values were derived using generalized estimating equation models. Angiographic data are core laboratory assessed. a Within 7 days of randomization. b Defined according to the World Health Organization criteria (haematocrit value at the initial presentation, <39% for men and <36% for women). c Less than 150 000 cells/mm3 at baseline. d Calculated by means of the Cockcroft–Gault equation. e Creatinine clearance <60 ml/min. BNP: B-type natriuretic peptide; COPD: chronic obstructive pulmonary disease; CrCl: creatinine clearance; LVEF: left ventricular ejection fraction; MI: myocardial infarction; PCI: percutaneous coronary intervention; SD: standard deviation; TIA: transient ischaemic attack; WBC: white blood cell. Clinical outcomes Patients with COPD had significantly higher 30-day rates of mortality (including cardiovascular death) and MI compared with those without COPD (Tables 2 and 3, Supplementary Material, Tables S3 and S4). PSM patients with COPD also had higher rates of lower respiratory tract infections within 30 days (16/135 [11.9%] vs 38/675 [5.6%], P = 0.008) compared with those without COPD. At 3 years, patients with COPD versus without COPD had higher rates of the primary composite end point, driven by increased rates of death and MI (both periprocedural and non-periprocedural), but not stroke (Table 2, Fig. 1 and Supplementary Material, Table S5). The rates of definite stent thrombosis or graft occlusion were increased at 3 years in patients with COPD in the entire study population, although the difference was no longer statistically significant after PSM. Ischaemia-driven revascularization and major bleeding rates did not vary according to COPD status. Sensitivity analyses using the multivariable adjustment in the entire study population were consistent with the results from the PSM cohort (Supplementary Material, Table S6). Table 2: Clinical outcomes at 30 days and 3 years End point 30 days 3 years COPD (n = 135), % (n) No COPD (n = 675), % (n) P-value COPD (n = 135), % (n) No COPD (n = 675), % (n) P-value Death, myocardial infarction or stroke 11.9 (16) 5.9 (40) 0.01 31.7 (41) 14.5 (96) <0.0001 All-cause death 3.0 (4) 0.9 (6) 0.06 17.1 (22) 7.5 (49) 0.0005  Cardiovascular 3.0 (4) 0.7 (5) 0.04 7.8 (10) 4.5 (29) 0.10  Non-cardiovascular 0.0 (0) 0.1 (1) 10.1 (12) 3.1 (20) 0.0006 Myocardial infarction 10.5 (14) 4.3 (29) 0.004 18.3 (23) 7.3 (48) <0.0001  Periprocedural 10.5 (14) 3.7 (25) 0.0009 10.5 (14) 3.7 (25) 0.0009  Spontaneous 0.0 (0) 0.6 (4) 8.7 (10) 3.6 (23) 0.02 Stroke 1.5 (2) 1.3 (9) 0.88 3.3 (4) 2.9 (19) 0.84 Any revascularization 0.0 (0) 1.0 (7) 12.9 (15) 10.8 (69) 0.52  Ischaemia driven 0.0 (0) 0.9 (6) 12.9 (15) 10.4 (66) 0.41 Definite stent thrombosis or symptomatic graft occlusiona 0.8 (1) 0.3 (2) 0.45 5.8 (7) 3.0 (19) 0.12 BARC bleedingb  Any 15.0 (20) 10.1 (68) 0.07 20.7 (27) 13.2 (88) 0.02  Types 2–5 11.2 (15) 8.8 (59) 0.34 17.0 (22) 11.4 (76) 0.07  Types 3–5 6.8 (9) 6.3 (42) 0.80 7.5 (10) 7.3 (49) 0.89 Bleeding according to TIMI criteria  Major 4.5 (6) 2.4 (16) 0.16 4.5 (6) 3.2 (21) 0.39  Minor 4.5 (6) 3.9 (26) 0.73 7.0 (9) 4.5 (30) 0.27 Blood transfusion 8.2 (11) 8.5 (57) 0.97 End point 30 days 3 years COPD (n = 135), % (n) No COPD (n = 675), % (n) P-value COPD (n = 135), % (n) No COPD (n = 675), % (n) P-value Death, myocardial infarction or stroke 11.9 (16) 5.9 (40) 0.01 31.7 (41) 14.5 (96) <0.0001 All-cause death 3.0 (4) 0.9 (6) 0.06 17.1 (22) 7.5 (49) 0.0005  Cardiovascular 3.0 (4) 0.7 (5) 0.04 7.8 (10) 4.5 (29) 0.10  Non-cardiovascular 0.0 (0) 0.1 (1) 10.1 (12) 3.1 (20) 0.0006 Myocardial infarction 10.5 (14) 4.3 (29) 0.004 18.3 (23) 7.3 (48) <0.0001  Periprocedural 10.5 (14) 3.7 (25) 0.0009 10.5 (14) 3.7 (25) 0.0009  Spontaneous 0.0 (0) 0.6 (4) 8.7 (10) 3.6 (23) 0.02 Stroke 1.5 (2) 1.3 (9) 0.88 3.3 (4) 2.9 (19) 0.84 Any revascularization 0.0 (0) 1.0 (7) 12.9 (15) 10.8 (69) 0.52  Ischaemia driven 0.0 (0) 0.9 (6) 12.9 (15) 10.4 (66) 0.41 Definite stent thrombosis or symptomatic graft occlusiona 0.8 (1) 0.3 (2) 0.45 5.8 (7) 3.0 (19) 0.12 BARC bleedingb  Any 15.0 (20) 10.1 (68) 0.07 20.7 (27) 13.2 (88) 0.02  Types 2–5 11.2 (15) 8.8 (59) 0.34 17.0 (22) 11.4 (76) 0.07  Types 3–5 6.8 (9) 6.3 (42) 0.80 7.5 (10) 7.3 (49) 0.89 Bleeding according to TIMI criteria  Major 4.5 (6) 2.4 (16) 0.16 4.5 (6) 3.2 (21) 0.39  Minor 4.5 (6) 3.9 (26) 0.73 7.0 (9) 4.5 (30) 0.27 Blood transfusion 8.2 (11) 8.5 (57) 0.97 Data are presented as the Kaplan–Meier event rates and were compared by the marginal effect Cox proportional hazards regression. a Definite and probable stent thrombosis were defined according to the Academic Research Consortium criteria. b BARC types 2–5 indicate bleeding that requires medical attention and types 3–5 indicate severe or fatal bleeding. BARC: Bleeding Academic Research Consortium; COPD: chronic obstructive pulmonary disease; TIMI: thrombolysis in myocardial infarction. Table 2: Clinical outcomes at 30 days and 3 years End point 30 days 3 years COPD (n = 135), % (n) No COPD (n = 675), % (n) P-value COPD (n = 135), % (n) No COPD (n = 675), % (n) P-value Death, myocardial infarction or stroke 11.9 (16) 5.9 (40) 0.01 31.7 (41) 14.5 (96) <0.0001 All-cause death 3.0 (4) 0.9 (6) 0.06 17.1 (22) 7.5 (49) 0.0005  Cardiovascular 3.0 (4) 0.7 (5) 0.04 7.8 (10) 4.5 (29) 0.10  Non-cardiovascular 0.0 (0) 0.1 (1) 10.1 (12) 3.1 (20) 0.0006 Myocardial infarction 10.5 (14) 4.3 (29) 0.004 18.3 (23) 7.3 (48) <0.0001  Periprocedural 10.5 (14) 3.7 (25) 0.0009 10.5 (14) 3.7 (25) 0.0009  Spontaneous 0.0 (0) 0.6 (4) 8.7 (10) 3.6 (23) 0.02 Stroke 1.5 (2) 1.3 (9) 0.88 3.3 (4) 2.9 (19) 0.84 Any revascularization 0.0 (0) 1.0 (7) 12.9 (15) 10.8 (69) 0.52  Ischaemia driven 0.0 (0) 0.9 (6) 12.9 (15) 10.4 (66) 0.41 Definite stent thrombosis or symptomatic graft occlusiona 0.8 (1) 0.3 (2) 0.45 5.8 (7) 3.0 (19) 0.12 BARC bleedingb  Any 15.0 (20) 10.1 (68) 0.07 20.7 (27) 13.2 (88) 0.02  Types 2–5 11.2 (15) 8.8 (59) 0.34 17.0 (22) 11.4 (76) 0.07  Types 3–5 6.8 (9) 6.3 (42) 0.80 7.5 (10) 7.3 (49) 0.89 Bleeding according to TIMI criteria  Major 4.5 (6) 2.4 (16) 0.16 4.5 (6) 3.2 (21) 0.39  Minor 4.5 (6) 3.9 (26) 0.73 7.0 (9) 4.5 (30) 0.27 Blood transfusion 8.2 (11) 8.5 (57) 0.97 End point 30 days 3 years COPD (n = 135), % (n) No COPD (n = 675), % (n) P-value COPD (n = 135), % (n) No COPD (n = 675), % (n) P-value Death, myocardial infarction or stroke 11.9 (16) 5.9 (40) 0.01 31.7 (41) 14.5 (96) <0.0001 All-cause death 3.0 (4) 0.9 (6) 0.06 17.1 (22) 7.5 (49) 0.0005  Cardiovascular 3.0 (4) 0.7 (5) 0.04 7.8 (10) 4.5 (29) 0.10  Non-cardiovascular 0.0 (0) 0.1 (1) 10.1 (12) 3.1 (20) 0.0006 Myocardial infarction 10.5 (14) 4.3 (29) 0.004 18.3 (23) 7.3 (48) <0.0001  Periprocedural 10.5 (14) 3.7 (25) 0.0009 10.5 (14) 3.7 (25) 0.0009  Spontaneous 0.0 (0) 0.6 (4) 8.7 (10) 3.6 (23) 0.02 Stroke 1.5 (2) 1.3 (9) 0.88 3.3 (4) 2.9 (19) 0.84 Any revascularization 0.0 (0) 1.0 (7) 12.9 (15) 10.8 (69) 0.52  Ischaemia driven 0.0 (0) 0.9 (6) 12.9 (15) 10.4 (66) 0.41 Definite stent thrombosis or symptomatic graft occlusiona 0.8 (1) 0.3 (2) 0.45 5.8 (7) 3.0 (19) 0.12 BARC bleedingb  Any 15.0 (20) 10.1 (68) 0.07 20.7 (27) 13.2 (88) 0.02  Types 2–5 11.2 (15) 8.8 (59) 0.34 17.0 (22) 11.4 (76) 0.07  Types 3–5 6.8 (9) 6.3 (42) 0.80 7.5 (10) 7.3 (49) 0.89 Bleeding according to TIMI criteria  Major 4.5 (6) 2.4 (16) 0.16 4.5 (6) 3.2 (21) 0.39  Minor 4.5 (6) 3.9 (26) 0.73 7.0 (9) 4.5 (30) 0.27 Blood transfusion 8.2 (11) 8.5 (57) 0.97 Data are presented as the Kaplan–Meier event rates and were compared by the marginal effect Cox proportional hazards regression. a Definite and probable stent thrombosis were defined according to the Academic Research Consortium criteria. b BARC types 2–5 indicate bleeding that requires medical attention and types 3–5 indicate severe or fatal bleeding. BARC: Bleeding Academic Research Consortium; COPD: chronic obstructive pulmonary disease; TIMI: thrombolysis in myocardial infarction. Table 3: Periprocedural major adverse events (within 30 days) End points COPD, n (%) No COPD, n (%) P-value Periprocedural major adverse events (any) 28/135 (20.7) 103/675 (15.2) 0.11  Deatha 4/135 (3.0) 6/675 (0.9) 0.06  Myocardial infarctiona 14/135 (10.4) 29/675 (4.3) 0.005  Strokea 2/135 (1.5) 9/675 (1.3) 0.89  TIMI major or minor bleeding 12/135 (8.9) 41/675 (6.1) 0.24  Transfusion ≥2 units of blood 17/135 (12.6) 75/675 (11.1) 0.60  Major arrhythmiab 14/135 (10.4) 64/675 (9.5) 0.75  Ischaemia-driven revascularizationa 0/135 (0.0) 6/675 (0.9)  Any unplanned surgery or therapeutic radiological procedure 4/135 (3.0) 24/675 (3.4) 0.73  Renal failurec 4/135 (3.0) 15/675 (2.2) 0.61  Sternal wound dehiscence 0/135 (0.0) 11/675 (1.6)  Infection requiring antibiotics 10/135 (7.4) 77/675 (11.4) 0.17  Prolonged intubation (>48 h) 4/135 (3.0) 14/675 (2.1) 0.53  Post-pericardiotomy syndrome 1/135 (0.7) 1/675 (0.1) 0.26 End points COPD, n (%) No COPD, n (%) P-value Periprocedural major adverse events (any) 28/135 (20.7) 103/675 (15.2) 0.11  Deatha 4/135 (3.0) 6/675 (0.9) 0.06  Myocardial infarctiona 14/135 (10.4) 29/675 (4.3) 0.005  Strokea 2/135 (1.5) 9/675 (1.3) 0.89  TIMI major or minor bleeding 12/135 (8.9) 41/675 (6.1) 0.24  Transfusion ≥2 units of blood 17/135 (12.6) 75/675 (11.1) 0.60  Major arrhythmiab 14/135 (10.4) 64/675 (9.5) 0.75  Ischaemia-driven revascularizationa 0/135 (0.0) 6/675 (0.9)  Any unplanned surgery or therapeutic radiological procedure 4/135 (3.0) 24/675 (3.4) 0.73  Renal failurec 4/135 (3.0) 15/675 (2.2) 0.61  Sternal wound dehiscence 0/135 (0.0) 11/675 (1.6)  Infection requiring antibiotics 10/135 (7.4) 77/675 (11.4) 0.17  Prolonged intubation (>48 h) 4/135 (3.0) 14/675 (2.1) 0.53  Post-pericardiotomy syndrome 1/135 (0.7) 1/675 (0.1) 0.26 Data are expressed as binary event rates. P-values were derived using generalized estimating equation models. P-values were determined by the χ2 or the Fisher’s exact test and, thus, may vary slightly from those in Table 2 for the same events. a Adjudicated events; others are site reported. b Supraventricular tachycardia requiring cardioversion, ventricular tachycardia or fibrillation requiring treatment or bradyarrhythmia requiring temporary or permanent pacemaker. c Serum creatinine increased by ≥0.5 mg/dl from baseline or the need for dialysis. COPD: chronic obstructive pulmonary disease; TIMI: thrombolysis in myocardial infarction. Table 3: Periprocedural major adverse events (within 30 days) End points COPD, n (%) No COPD, n (%) P-value Periprocedural major adverse events (any) 28/135 (20.7) 103/675 (15.2) 0.11  Deatha 4/135 (3.0) 6/675 (0.9) 0.06  Myocardial infarctiona 14/135 (10.4) 29/675 (4.3) 0.005  Strokea 2/135 (1.5) 9/675 (1.3) 0.89  TIMI major or minor bleeding 12/135 (8.9) 41/675 (6.1) 0.24  Transfusion ≥2 units of blood 17/135 (12.6) 75/675 (11.1) 0.60  Major arrhythmiab 14/135 (10.4) 64/675 (9.5) 0.75  Ischaemia-driven revascularizationa 0/135 (0.0) 6/675 (0.9)  Any unplanned surgery or therapeutic radiological procedure 4/135 (3.0) 24/675 (3.4) 0.73  Renal failurec 4/135 (3.0) 15/675 (2.2) 0.61  Sternal wound dehiscence 0/135 (0.0) 11/675 (1.6)  Infection requiring antibiotics 10/135 (7.4) 77/675 (11.4) 0.17  Prolonged intubation (>48 h) 4/135 (3.0) 14/675 (2.1) 0.53  Post-pericardiotomy syndrome 1/135 (0.7) 1/675 (0.1) 0.26 End points COPD, n (%) No COPD, n (%) P-value Periprocedural major adverse events (any) 28/135 (20.7) 103/675 (15.2) 0.11  Deatha 4/135 (3.0) 6/675 (0.9) 0.06  Myocardial infarctiona 14/135 (10.4) 29/675 (4.3) 0.005  Strokea 2/135 (1.5) 9/675 (1.3) 0.89  TIMI major or minor bleeding 12/135 (8.9) 41/675 (6.1) 0.24  Transfusion ≥2 units of blood 17/135 (12.6) 75/675 (11.1) 0.60  Major arrhythmiab 14/135 (10.4) 64/675 (9.5) 0.75  Ischaemia-driven revascularizationa 0/135 (0.0) 6/675 (0.9)  Any unplanned surgery or therapeutic radiological procedure 4/135 (3.0) 24/675 (3.4) 0.73  Renal failurec 4/135 (3.0) 15/675 (2.2) 0.61  Sternal wound dehiscence 0/135 (0.0) 11/675 (1.6)  Infection requiring antibiotics 10/135 (7.4) 77/675 (11.4) 0.17  Prolonged intubation (>48 h) 4/135 (3.0) 14/675 (2.1) 0.53  Post-pericardiotomy syndrome 1/135 (0.7) 1/675 (0.1) 0.26 Data are expressed as binary event rates. P-values were derived using generalized estimating equation models. P-values were determined by the χ2 or the Fisher’s exact test and, thus, may vary slightly from those in Table 2 for the same events. a Adjudicated events; others are site reported. b Supraventricular tachycardia requiring cardioversion, ventricular tachycardia or fibrillation requiring treatment or bradyarrhythmia requiring temporary or permanent pacemaker. c Serum creatinine increased by ≥0.5 mg/dl from baseline or the need for dialysis. COPD: chronic obstructive pulmonary disease; TIMI: thrombolysis in myocardial infarction. Figure 1: View largeDownload slide The Kaplan–Meier failure rates in the propensity score-matched cohort stratified according to the presence of COPD. (A) Primary composite end point of death, stroke or myocardial infarction; (B) all-cause death; (C) myocardial infarction and (D) stroke. P-values are derived from a marginal effects Cox proportional hazards model. COPD: chronic obstructive pulmonary disease; HR: hazard ratio. Figure 1: View largeDownload slide The Kaplan–Meier failure rates in the propensity score-matched cohort stratified according to the presence of COPD. (A) Primary composite end point of death, stroke or myocardial infarction; (B) all-cause death; (C) myocardial infarction and (D) stroke. P-values are derived from a marginal effects Cox proportional hazards model. COPD: chronic obstructive pulmonary disease; HR: hazard ratio. There was no significant interaction between COPD status and randomization to revascularization with PCI versus CABG in regard to primary composite end point at 30 days [6.6% vs 16.4%, respectively, in patients with COPD; hazard ratio (HR) 0.39, 95% confidence interval (CI) 0.12–1.21 and 4.4% vs 5.8%, respectively, in patients without COPD; HR 0.55, 95% CI 0.29–0.1.06] (Pinteraction = 0.61). Similarly, the risk of periprocedural MAE in patients randomized to PCI versus CABG was consistent in those with versus without COPD (Table 4). Lower respiratory tract infections within 30 days after randomization to PCI versus CABG in the PSM cohorts occurred in 4 of 61 (6.6%) vs 12 of 74 (16.2%) patients, respectively, with COPD [odds ratio (OR) 0.36, 95% CI 0.11–1.18] and in 31 of 314 (3.5%) vs 27 of 361 (7.5%) patients, respectively, without COPD (OR 0.44, 95% CI 0.22–0.90) (Pinteraction = 0.77). Finally, the 3-year risks of the primary composite end point and other adverse events after PCI versus CABG were consistent in patients with and without COPD, both in the PSM cohorts and the entire population after multivariable adjustment (Fig. 2, Supplementary Material, Table S7 and Fig. S1). Table 4: Periprocedural major adverse events according to revascularization modality and the presence of COPD End points COPD No COPD PCI, n (%) CABG, n (%) P-value PCI, n (%) CABG, n (%) P-value Pinteraction Periprocedural major adverse events (any) 6/61 (9.8) 22/74 (29.7) 0.007 26/314 (8.3) 77/361 (21.3) <0.0001 0.63  Deatha 1/61 (1.6) 3/74 (4.1) 0.43 1/314 (0.3) 5/361 (1.4) 0.18 0.74  Myocardial infarctiona 4/61 (6.6) 10/74 (13.5) 0.20 11/314 (3.5) 18/361 (5.0) 0.34 0.56  Strokea 1/61 (1.6) 1/74 (1.4) 0.89 2/314 (0.6) 7/361 (1.9) 0.17 0.42  TIMI major or minor bleeding 4/61 (6.6) 8/74 (10.8) 0.39 9/314 (2.9) 32/361 (8.9) 0.003 0.40  Transfusion ≥2 units of blood 3/61 (4.9) 14/74 (18.9) 0.02 16/314 (5.1) 59/361 (16.3) <0.0001 0.75  Major arrhythmiab 1/61 (1.6) 13/74 (17.6) 0.02 5/314 (1.6) 59/361 (16.3) <0.0001 0.99  Ischaemia-driven revascularizationa 0/61 (0.0) 0/74 (0.0) 2/314 (0.6) 4/361 (1.1) 0.53  Any unplanned surgery or therapeutic radiological procedure 0/61 (0.0) 4/74 (5.4) 0.13 3/314 (1.0) 21/361 (5.8) 0.003 0.97a  Renal failurec 3/61 (4.9) 1/74 (1.4) 0.26 2/314 (0.6) 13/361 (3.6) 0.02 0.04  Sternal wound dehiscence 0/61 (0.0) 0/74 (0.0) 0/314 (0.0) 11/361 (3.0)  Infection requiring antibiotics 2/61 (3.3) 8/74 (10.8) 0.12 9/314 (2.9) 68/361 (18.8) <0.0001 0.37  Prolonged intubation (>48 h) 2/61 (3.3) 2/74 (2.7) 0.84 0/314 (0.0) 14/361 (3.9) 0.93a  Post-pericardiotomy syndrome 0/61 (0.0) 1/74 (1.4) 0/314 (0.0) 1/361 (0.3) 1.00a End points COPD No COPD PCI, n (%) CABG, n (%) P-value PCI, n (%) CABG, n (%) P-value Pinteraction Periprocedural major adverse events (any) 6/61 (9.8) 22/74 (29.7) 0.007 26/314 (8.3) 77/361 (21.3) <0.0001 0.63  Deatha 1/61 (1.6) 3/74 (4.1) 0.43 1/314 (0.3) 5/361 (1.4) 0.18 0.74  Myocardial infarctiona 4/61 (6.6) 10/74 (13.5) 0.20 11/314 (3.5) 18/361 (5.0) 0.34 0.56  Strokea 1/61 (1.6) 1/74 (1.4) 0.89 2/314 (0.6) 7/361 (1.9) 0.17 0.42  TIMI major or minor bleeding 4/61 (6.6) 8/74 (10.8) 0.39 9/314 (2.9) 32/361 (8.9) 0.003 0.40  Transfusion ≥2 units of blood 3/61 (4.9) 14/74 (18.9) 0.02 16/314 (5.1) 59/361 (16.3) <0.0001 0.75  Major arrhythmiab 1/61 (1.6) 13/74 (17.6) 0.02 5/314 (1.6) 59/361 (16.3) <0.0001 0.99  Ischaemia-driven revascularizationa 0/61 (0.0) 0/74 (0.0) 2/314 (0.6) 4/361 (1.1) 0.53  Any unplanned surgery or therapeutic radiological procedure 0/61 (0.0) 4/74 (5.4) 0.13 3/314 (1.0) 21/361 (5.8) 0.003 0.97a  Renal failurec 3/61 (4.9) 1/74 (1.4) 0.26 2/314 (0.6) 13/361 (3.6) 0.02 0.04  Sternal wound dehiscence 0/61 (0.0) 0/74 (0.0) 0/314 (0.0) 11/361 (3.0)  Infection requiring antibiotics 2/61 (3.3) 8/74 (10.8) 0.12 9/314 (2.9) 68/361 (18.8) <0.0001 0.37  Prolonged intubation (>48 h) 2/61 (3.3) 2/74 (2.7) 0.84 0/314 (0.0) 14/361 (3.9) 0.93a  Post-pericardiotomy syndrome 0/61 (0.0) 1/74 (1.4) 0/314 (0.0) 1/361 (0.3) 1.00a Data are expressed as binary event rates. P-values were derived using generalized estimating equation models. a Adjudicated events; others are site reported. b Supraventricular tachycardia requiring cardioversion, ventricular tachycardia or fibrillation requiring treatment or bradyarrhythmia requiring temporary or permanent pacemaker. c Serum creatinine increased by ≥0.5 mg/dl from baseline or the need for dialysis. CABG: coronary artery bypass grafting; COPD: chronic obstructive pulmonary disease; PCI: percutaneous coronary intervention; TIMI: thrombolysis in myocardial infarction. Table 4: Periprocedural major adverse events according to revascularization modality and the presence of COPD End points COPD No COPD PCI, n (%) CABG, n (%) P-value PCI, n (%) CABG, n (%) P-value Pinteraction Periprocedural major adverse events (any) 6/61 (9.8) 22/74 (29.7) 0.007 26/314 (8.3) 77/361 (21.3) <0.0001 0.63  Deatha 1/61 (1.6) 3/74 (4.1) 0.43 1/314 (0.3) 5/361 (1.4) 0.18 0.74  Myocardial infarctiona 4/61 (6.6) 10/74 (13.5) 0.20 11/314 (3.5) 18/361 (5.0) 0.34 0.56  Strokea 1/61 (1.6) 1/74 (1.4) 0.89 2/314 (0.6) 7/361 (1.9) 0.17 0.42  TIMI major or minor bleeding 4/61 (6.6) 8/74 (10.8) 0.39 9/314 (2.9) 32/361 (8.9) 0.003 0.40  Transfusion ≥2 units of blood 3/61 (4.9) 14/74 (18.9) 0.02 16/314 (5.1) 59/361 (16.3) <0.0001 0.75  Major arrhythmiab 1/61 (1.6) 13/74 (17.6) 0.02 5/314 (1.6) 59/361 (16.3) <0.0001 0.99  Ischaemia-driven revascularizationa 0/61 (0.0) 0/74 (0.0) 2/314 (0.6) 4/361 (1.1) 0.53  Any unplanned surgery or therapeutic radiological procedure 0/61 (0.0) 4/74 (5.4) 0.13 3/314 (1.0) 21/361 (5.8) 0.003 0.97a  Renal failurec 3/61 (4.9) 1/74 (1.4) 0.26 2/314 (0.6) 13/361 (3.6) 0.02 0.04  Sternal wound dehiscence 0/61 (0.0) 0/74 (0.0) 0/314 (0.0) 11/361 (3.0)  Infection requiring antibiotics 2/61 (3.3) 8/74 (10.8) 0.12 9/314 (2.9) 68/361 (18.8) <0.0001 0.37  Prolonged intubation (>48 h) 2/61 (3.3) 2/74 (2.7) 0.84 0/314 (0.0) 14/361 (3.9) 0.93a  Post-pericardiotomy syndrome 0/61 (0.0) 1/74 (1.4) 0/314 (0.0) 1/361 (0.3) 1.00a End points COPD No COPD PCI, n (%) CABG, n (%) P-value PCI, n (%) CABG, n (%) P-value Pinteraction Periprocedural major adverse events (any) 6/61 (9.8) 22/74 (29.7) 0.007 26/314 (8.3) 77/361 (21.3) <0.0001 0.63  Deatha 1/61 (1.6) 3/74 (4.1) 0.43 1/314 (0.3) 5/361 (1.4) 0.18 0.74  Myocardial infarctiona 4/61 (6.6) 10/74 (13.5) 0.20 11/314 (3.5) 18/361 (5.0) 0.34 0.56  Strokea 1/61 (1.6) 1/74 (1.4) 0.89 2/314 (0.6) 7/361 (1.9) 0.17 0.42  TIMI major or minor bleeding 4/61 (6.6) 8/74 (10.8) 0.39 9/314 (2.9) 32/361 (8.9) 0.003 0.40  Transfusion ≥2 units of blood 3/61 (4.9) 14/74 (18.9) 0.02 16/314 (5.1) 59/361 (16.3) <0.0001 0.75  Major arrhythmiab 1/61 (1.6) 13/74 (17.6) 0.02 5/314 (1.6) 59/361 (16.3) <0.0001 0.99  Ischaemia-driven revascularizationa 0/61 (0.0) 0/74 (0.0) 2/314 (0.6) 4/361 (1.1) 0.53  Any unplanned surgery or therapeutic radiological procedure 0/61 (0.0) 4/74 (5.4) 0.13 3/314 (1.0) 21/361 (5.8) 0.003 0.97a  Renal failurec 3/61 (4.9) 1/74 (1.4) 0.26 2/314 (0.6) 13/361 (3.6) 0.02 0.04  Sternal wound dehiscence 0/61 (0.0) 0/74 (0.0) 0/314 (0.0) 11/361 (3.0)  Infection requiring antibiotics 2/61 (3.3) 8/74 (10.8) 0.12 9/314 (2.9) 68/361 (18.8) <0.0001 0.37  Prolonged intubation (>48 h) 2/61 (3.3) 2/74 (2.7) 0.84 0/314 (0.0) 14/361 (3.9) 0.93a  Post-pericardiotomy syndrome 0/61 (0.0) 1/74 (1.4) 0/314 (0.0) 1/361 (0.3) 1.00a Data are expressed as binary event rates. P-values were derived using generalized estimating equation models. a Adjudicated events; others are site reported. b Supraventricular tachycardia requiring cardioversion, ventricular tachycardia or fibrillation requiring treatment or bradyarrhythmia requiring temporary or permanent pacemaker. c Serum creatinine increased by ≥0.5 mg/dl from baseline or the need for dialysis. CABG: coronary artery bypass grafting; COPD: chronic obstructive pulmonary disease; PCI: percutaneous coronary intervention; TIMI: thrombolysis in myocardial infarction. Figure 2: View largeDownload slide The association between COPD, randomized revascularization modality and 3-year adverse clinical events in the propensity score-matched groups. Marginal effects Cox proportional hazards regression. BARC: Bleeding Academic Research Consortium; CI: confidence interval; COPD: chronic obstructive pulmonary disease; HR: hazard ratio; PCI: percutaneous coronary intervention. Figure 2: View largeDownload slide The association between COPD, randomized revascularization modality and 3-year adverse clinical events in the propensity score-matched groups. Marginal effects Cox proportional hazards regression. BARC: Bleeding Academic Research Consortium; CI: confidence interval; COPD: chronic obstructive pulmonary disease; HR: hazard ratio; PCI: percutaneous coronary intervention. DISCUSSION The major finding of this analysis from the randomized, multicentre EXCEL trial is that patients with LMCAD undergoing revascularization in whom COPD was present had higher 30-day and 3-year rates of mortality and MAE compared with those without COPD, regardless of whether they were treated with PCI or CABG. Similar to prior studies in patients without LMCAD [4, 8–13], in the EXCEL trial, the hazard curves for patients with COPD compared with those without COPD diverged early after LMCAD revascularization (signifying increased periprocedural risk) and continued to spread throughout the 3-year duration of follow-up. The significantly higher 30-day rates of periprocedural MI, lower respiratory tract infections and cardiovascular and all-cause mortality in patients with COPD compared to those without COPD in the EXCEL trial are consistent with previous reports of an increased risk of in-hospital complications, cardiogenic shock and death in non-LMCAD patients with COPD with medical or surgical management [10, 11]. Our finding of a long-term COPD-associated risk of adverse outcomes is also consistent with previous studies reporting a greater long-term risk of recurrent MI and death in patients with COPD versus patients without COPD after PCI [9] and CABG [4, 11, 12]. The mechanisms underlying the increased rates of periprocedural and spontaneous MI associated with COPD are unknown and may be multifactorial. COPD is associated with other cardiovascular risk factors, which may in part explain its association with MI. Previous studies have also suggested that more severe coronary calcification and a higher prevalence of high-risk plaque features are present in patients with COPD which may contribute to an increased risk of MI [14, 15]. However, COPD in the EXCEL trial was not associated with the extent of CAD as assessed by the SYNTAX score. In addition to higher rates of MI, the greater risk of in-hospital infections [16] and difficulties in weaning patients with COPD from mechanical ventilation [16] may contribute to increased mortality in patients with COPD, especially after CABG. Of note, however, in the EXCEL trial, COPD was not associated with prolonged intubation after CABG (although lower respiratory tract infections were increased). Our findings are consistent with recent nationwide data from Sweden reporting a significantly increased adjusted risk of pneumonia but not of prolonged mechanical ventilation after CABG in patients with COPD versus without COPD [13]. COPD is considered by many to be a greater risk factor for patients undergoing CABG compared to PCI. COPD portends worse outcomes after CABG [17] and is an independent predictor of operative mortality in the Society of Thoracic Surgeons (STS) and the European System for Cardiac Operative Risk Evaluation (EuroSCORE) risk scores [17–20]. COPD is, therefore, incorporated in both these scores, which are used to assess the surgical risk of patients who are candidates for CABG as noted in the 2018 ESC/EACTS guidelines on myocardial revascularization [21]. In the SYNTAX trial, COPD was independently associated with 4-year mortality after CABG but not after PCI [22, 23]. Conversely, the outcomes of PCI versus CABG were consistent in patients with and without COPD in the DELTA [23, 24] and SWEDEHEART registries [13]. In this large-scale randomized trial, no significant interactions were present between revascularization strategy and COPD status regarding the risk of periprocedural MAE or lower respiratory tract infections; however, treatment with PCI compared with CABG resulted in greater absolute reductions in lower respiratory tract infections in patients with COPD versus without COPD. Nonetheless, no significant interactions between COPD and treatment modality (PCI versus CABG) were present for the 3-year primary composite end point or any of its components. Thus, the principal finding from the EXCEL trial is that PCI and CABG result in comparable 3-year outcomes after revascularization of patients with LMCAD, and low or intermediate SYNTAX scores apply to patients with and without COPD who are acceptable candidates for both procedures. Study strengths and limitations As the largest randomized trial to date of patients with LMCAD undergoing revascularization, the EXCEL trial provides relevant insights into the association between medically treated COPD and the risk of adverse outcomes after contemporary LMCAD therapies; however, several limitations should be considered. First, this analysis was post hoc and should thus be considered as hypothesis generating. Second, the number of subjects with COPD was modest, and not all confounders in the described relationships may have been identified. Third, some of the outcomes were uncommon, resulting in imprecise effect sizes. The reported differences in the relative risk of PCI versus CABG for these infrequent events are inconclusive. Fourth, we do not have detailed data available on pulmonary function tests or other parameters reflecting the severity of COPD that might have provided greater insights as to whether certain COPD patients might selectively benefit from treatment with PCI versus CABG. Finally, equipoise for randomization may not have been present in patients with severe COPD including those with markedly reduced lung volumes or requiring continuous oxygen therapy. A review of the EXCEL screening registry demonstrates that COPD was present in only a slightly greater proportion of patients who were excluded compared to those who were randomized in the trial (9.8% vs 7.1%, P = 0.05) [6]; unfortunately, the severity of COPD in excluded versus randomized patients was not collected nor were clinical outcomes in registry patients. It is likely that patients with very severe COPD were not randomized, and thus, these results apply to patients with less severe COPD in whom the risk of general anaesthesia is acceptable. The results of the present study, thus, do not inform the optimal treatments or outcomes of the most severely impaired COPD patients. Nevertheless, our study confirms that patients with COPD are at increased risk of early mortality and late mortality irrespective of the revascularization therapy. CONCLUSIONS Patients with LMCAD undergoing PCI or CABG in whom medically treated COPD is present are at increased risk of periprocedural and long-term adverse events, including death and MI, irrespective of revascularization modality. In the EXCEL trial, the relative early and late risk: the benefit profile of PCI versus CABG was consistent in patients with and without COPD who were candidates for both procedures. Further studies are required to determine which COPD patients requiring revascularization, if any, might have a relatively improved prognosis with PCI compared with CABG. Funding The EXCEL trial was supported by Abbott Vascular (Santa Clara, CA, USA). Conflict of interest: David E. Kandzari: grant support—Abbott Vascular, Boston Scientific and Medtronic; consultant—Boston Scientific, Medtronic and Micell Technologies. Bela Merkely: lecture fees and grant support (to institution)—Abbott. Joseph F. Sabik III: consultant—Medtronic, Edwards and Sorin; advisory board—Medtronic (cardiac surgery). Patrick W. Serruys: consultant—Abbott, Biosensors, Cardialysis, Micell Technologies, Medtronic, Sinomed Science Technologies, Stentys France, Svelte Medical Systems, Philips/Volcano, St. Jude Medical and Xeltis. Arie Pieter Kappetein: employee—Medtronic. Gregg W. Stone: Columbia University (employer) receives royalties from Abbott Vascular for the sale of the MitraClip. 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The DELTA registry: a multicenter registry evaluating percutaneous coronary intervention versus coronary artery bypass grafting for left main treatment . JACC Cardiovasc Interv 2012 ; 5 : 718 – 27 . Google Scholar Crossref Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Journal

European Journal of Cardio-Thoracic SurgeryOxford University Press

Published: Dec 27, 2018

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