European Journal of Cardio-Thoracic Surgery 43 (2013) 697 703 doi:10.1093/ejcts/ezs454 Advance Access publication 24 October 2012 ORIGINAL ARTICLE Long-term survival of patients with pulmonary disease undergoing coronary artery bypass surgery Francesca O Boyle, Neeraj Mediratta, John Chalmers, Omar Al-Rawi, Kamlesh Mohan, Matthew Shaw and Michael Poullis* Department of Cardiac Surgery, Liverpool Heart and Chest Hospital, Liverpool, UK *Corresponding author. Department of Cardiac Surgery, Liverpool Heart and Chest Hospital, Thomas Drive, Liverpool L14 3PE, UK. Tel: +44-151-2281616; fax: +44-151-2932254; e-mail: mike.poullis@lhch.nhs.uk (M. Poullis). Received 7 May 2012; received in revised form 16 June 2012; accepted 25 June 2012 Abstract OBJECTIVES: We sought to investigate the long-term survival of patients with obstructive, restrictive and chronic obstructive pulmonary disease (COPD) as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). METHODS: A prospective database was retrospectively analysed and cross-correlated with the UK strategic tracking service to evaluate survival after primary coronary artery bypass grafts (CABG). Univariate and multivariate Cox regression analyses were performed. Three separate multivariate analyses were performed: COPD GOLD criteria for obstructive and/or restrictive lung disease, forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and the FEV1/FVC ratio to investigate the effect of FEV1 and FVC individually. RESULTS: We analysed 13 337 primary CABG procedures. The median follow-up was 7 years. Univariate analysis demonstrated that obstructive (P < 0.0001), restrictive (P < 0.0001) and mixed obstructive and restrictive pulmonary disease (P < 0.0001), and COPD as defined by the GOLD criteria (P < 0.0001), are all significant factors determining long-term survival. Cox regression analysis identified age, diabetes, moderate LV, poor LV, peripheral vascular disease, dialysis, left internal mammary artery (LIMA) usage, EuroSCORE, cardiopulmonary bypass and creatinine kinase muscle-brain isoenzyme as significant factors in addition to pulmonary disease that determine long-term survival. Moderate and severe COPD defined by GOLD criteria were significant factors determining long-term survival, but mild COPD had no significant effect. Obstructive and restrictive lung disease were both significant factors determining long-term survival. Restrictive lung disease, however, carried a greater prognostic significance (higher hazard ratio 2.2 vs 1.6) than obstructive. LIMA utilization in patients with COPD was not associated with an increased intensive care unit stay, re-intubation rate or in-hospital mortality rate. CONCLUSIONS: Pulmonary disease is a significant factor determining long-term survival. Patients with severe COPD still have a relatively good long-term survival and should not be denied surgery. LIMA utilization in patients with COPD results in a significantly increased long-term survival, without an increased intensive care unit stay, re-intubation rate or in-hospital mortality rate. Keywords: Coronary Survival Chronic obstructive pulmonary disease INTRODUCTION Pulmonary disease is known to be a risk factor for in-hospital mortality, hence its inclusion in the EuroSCORE and Southern Thoracic Society (STS) risk models. A number of the risk factors in the EuroSCORE have previously been identified by Cox regression analysis as possible significant factors [1] with regard to long-term survival, leading to a number of authors [2, 3], utilizing EuroSCORE as a possible predictor of long-term survival despite its derivation being based on in-hospital operative mortality. This concept has been recently extended, via the addition of diabetes, left internal mammary artery (LIMA) usage, body mass index (BMI) and postoperative creatinine kinase (muscle brain; CKMB) in its calculation [4]. Little consensus existed in the diagnosis of chronic obstructive pulmonary disease (COPD) until the publication of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria, which are based on spirometric findings [5]. We sought to investigate the role of pulmonary disease as a prognostic factor with regard to long-term survival after primary coronary artery bypass surgery. MATERIALS AND METHODS Local institutional review board approval was granted for this study. Database A prospective institutional cardiac surgery database, validated by the hospital data analysis department and accredited by the The Author 2012. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
698 F. O Boyle et al. / European Journal of Cardio-Thoracic Surgery Society of Cardiothoracic Surgeons of Great Britain and Ireland (SCTS) was utilized in conjunction with the national strategic tracking service for long-term follow-up that exists in the UK, as has been described previously [6 10]. All patients have their forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) measured prior to surgery. Patients Patients who had undergone isolated coronary artery bypass grafts (CABG) only were included, N = 13 337, between 1st April 1997 and 31st March 2010. Benchmarking We benchmarked our in-hospital mortality figures against the UK national results (http://www.scts.org). Methodology The characteristics of the patients in this study are shown in Table 1. Definitions Chronic lung disease can be classified as chronic obstructive lung disease (COPD, GOLD criteria [5]), or obstructive and/or restrictive ( physiological criteria [11]), as defined below. GOLD criteria Normal spirometry: FEV1/FVC ratio > 70%, and FEV1 80% Mild COPD: FEV1/FVC ratio < 70%, and FEV1 80% Moderate COPD: FEV1/FVC ratio < 70%, and 50% FEV1 < 80% Severe COPD: FEV1/FVC ratio < 70%, and FEV1 < 50% Physiological criteria Obstructive lung disease: relative FEV1 < 70%, and FVC > 70% Restrictive lung disease: FVC < 70%, and relative FEV1 > 70% Mixed obstructive and restrictive lung disease: FVC < 70%, and relative FEV1 < 70% The differences in GOLD criteria and physiological criteria are diagrammatically shown in Fig. 1. Long-term survival Univariate analysis. Kaplan Meier survival curves were constructed, for patients with restrictive, obstructive and mixed obstructive and restrictive pulmonary disease, and for patients with COPD as defined by the GOLD criteria (Fig. 2). Table 1: Pre-, peri- and postoperative characteristics of patients in the study group Data (N = 13 337) Preoperative Age (years) 64.911 (47 82.6) Female (%) 19.6 BMI (kg/m 2 ) 28.4 (19.8 37.0) Heart failure (%) 0.14 Critical preoperative state (%) 0.13 Previous CVA (%) 0.1 Diabetes (%) 36.7 Preoperative dialysis (%) 0.4 Previous MI (%) 48.9 PVD (%) 13.6 Hypertension (%) 60.1 COPD (%) a None 79.49 Mild 7.66 Moderate 11 Severe 1.85 Type of lung disease (%) None 85.0 Obstructive 13.2 Restrictive 1.01 Mixed 0.83 FEV1 (%) 71.7 (62 97) Preoperative IABP (%) 1.3 Ejection Good (%) 59.7 Fraction Moderate (%) 31.4 Poor (%) 8.9 Previous PCI (%) 6.4 Status Elective (%) 80.5 Urgent (%) 18.2 Emergency (%) 1.3 Log EuroSCORE 4.7 (0 17.7) Operative LIMA (%) 91.9 No. of grafts 3.3 (1.5 5.2) CPB time (min) 109 (46 173) Postoperative CKMB 30.3 (0 139) ITU LOS (days) 2.161 (0 9.7) Hospital LOS (days) 9.5 (0 32) Mortality (%) 2.1 Median follow-up (years) 7.02 Continuous variables are shown as mean with 95% confidence intervals shown in brackets. Categorical variables are shown as a percentage. a As defined by the GOLD criteria. BMI: body mass index; CVA: cerebral vascular accident; MI: myocardial infarction; PVD: peripheral vascular disease; IABP: intra-aortic balloon pump; PCI: percutaneous coronary intervention; LIMA: left internal mammary artery; CPB: cardiopulmonary bypass; CKMB: creatinine kinase myocardial isoenzyme; ITU LOS: intensive care length of stay. The discrimination abilities of FEV1, FVC, FEV1/FVC ratio and GOLD criteria were assessed by the Somers Dxy test. Multivariate analysis. Stepwise Cox proportional hazards regression analysis was utilized to identify potential significant determining factors with regard to long-term survival. Entry criteria had a significance at P < 0.05, and removal criteria had a significance at P > 0.1 (Table 2). The effect of the COPD GOLD
F. O Boyle et al. / European Journal of Cardio-Thoracic Surgery 699 Table 2: Cox regression analysis of survival using (A) COPD GOLD criteria, (B) Obstructive and/or restrictive analysis disease and (C) FEV1, FVC and FEV1/FVC analysis Covariate HR 95% CI of HR P-value Figure 1: (A) Pulmonary function classified by physiological criteria or (B) GOLD criteria. FEV1 cannot be higher than FVC, by definition, and hence no patients will be above the line FEV1/FVC = 1. criteria stage and obstructive and/or restrictive lung disease was analysed separately with regard to long-tem survival, and their effects were plotted at the mean of the covariates (Fig. 3). The effect of on- or off-pump is shown in Fig. 4. Statistical software All statistical analyses other than the neuronal network and Somers Dxy tests were performed with MedCalc for Windows, version 12.2.1 (MedCalc Software, Mariakerke, Belgium). Somers C statistic and Dxy was performed with R (http://www.r-project.org). (A) COPD GOLD criteria Age 1.053 1.047 1.060 <0.0001 Diabetes 1.197 1.142 1.254 <0.0001 Moderate LV 1.396 1.269 1.537 <0.0001 Poor LV 2.308 2.016 2.643 <0.0001 PVD 1.233 1.077 1.412 0.003 Dialysis 5.292 3.609 7.760 <0.0001 LIMA 0.696 0.615 0.788 <0.0001 EuroSCORE 1.024 1.019 1.030 <0.0001 CKMB 1.002 1.002 1.003 <0.0001 CPB 0.133 0.790 0.969 0.01 Moderate COPD 1.293 1.141 1.466 0.0001 Severe COPD 1.924 1.535 2.412 <0.0001 (B) Obstructive and/or restrictive analysis Age 1.057 1.050 1.063 <0.0001 Diabetes 1.199 1.144 1.257 <0.0001 Moderate LV 1.383 1.256 1.522 <0.0001 Poor LV 2.350 2.054 2.688 <0.0001 PVD 1.274 1.113 1.459 0.0005 Dialysis 5.568 3.793 8.172 <0.0001 LIMA 0.754 0.665 0.854 <0.0001 EuroSCORE 1.020 1.014 1.025 <0.0001 CKMB 1.002 1.002 1.003 <0.0001 Restrictive 2.154 1.601 2.898 <0.0001 Obstructive 1.616 1.434 1.821 <0.0001 (C) FEV1, FVC and FEV1/FVC analysis Age 1.055 1.047 1.062 <0.0001 Diabetes 1.171 1.108 1.237 <0.0001 Moderate LV 1.393 1.241 1.565 <0.0001 Poor LV 2.456 2.085 2.893 <0.0001 PVD 1.134 1.016 1.265 0.03 Dialysis 5.801 3.826 8.796 <0.0001 LIMA 0.696 0.592 0.818 <0.0001 EuroSCORE 1.028 1.020 1.035 <0.0001 CKMB 1.004 1.003 1.004 <0.0001 FEV1 0.178 0.110 0.289 <0.0001 FEV1/FVC ratio 0.395 0.209 0.748 0.005 LV: left ventricular function; PVD: peripheral vascular disease; LIMA: left internal mammary artery; CKMB: creatinine kinase muscle-brain type; CPB: cardiopulmonary bypass; HR: hazard ratio; CI: confidence interval; COPD: chronic obstructive pulmonary disease. RESULTS One hundred percent long-term follow-up via the national strategic tracing service was achieved. Benchmarking of our institutional mortality rates compared with the UK did not reveal any differences ( part of the continuous UK cardiac surgery quality assessment programme by the society of cardiothoracic surgeons). The logistic EuroSCORE ranged from 0.881 to 80.411, mean 4.743, 95% confidence interval: 4.632 4.855 and 90% were 10. Long-term follow-up was from 6 months to 12 years, mean 6.6 years and median 7 years. Figure 1 demonstrates that the GOLD criteria and the physiological criteria for the classification of respiratory function are different, and hence analysis was done in multiple different ways. A total of 2742 patients had mild, moderate or severe COPD, of which the majority, 1766 were purely obstructive in nature. Long-term survival Univariate. Kaplan Meier survival curves demonstrate that obstructive (P < 0.0001), restrictive (P < 0.0001) and mixed obstructive and restrictive pulmonary disease (P < 0.0001), and COPD as defined by the GOLD criteria (P < 0.0001), are all significant factors determining long-term survival (Fig. 2). The overall sensitivity and specificity of FEV1 for predicting long-term survival were 61.1 and 62.8%, respectively, with a C statistic of 0.381, and a Dxy of 0.24. The overall sensitivity and specificity of FVC for predicting long-term survival were 43.5 and 70.8%, respectively, with a C statistic of 0.41, and a Dxy of 0.18. The overall sensitivity and specificity of FEV1/FVC ratio for predicting long-term survival were 42.5 and 76.8%, respectively, with a C statistic of 0.43, and a Dxy of 0.15.
700 F. O Boyle et al. / European Journal of Cardio-Thoracic Surgery Figure 2: Kaplan Meier survival curves for (A) restrictive, (B) obstructive, (C) mixed obstructive and restrictive pulmonary disease and (D) COPD as defined by the GOLD criteria. The overall sensitivity and specificity of moderate or severe GOLD criteria for predicting long-term survival were 17.4 and 88.8%, respectively, with a C statistic of 0.52. The above analysis implies that the GOLD criteria have a high specificity for predicting poor long-term survival, and the FEV1 has poor sensitivity and specificity for predicting long-term survival. Cox regression analysis. Cox regression analysis to determine the importance of respiratory function with regard to long-term survival is shown in Table 2. Three separate analyses were performed: COPD GOLD criteria, obstructive and/or restrictive lung disease, and FEV1, FVC and the FEV1/FVC ratio to investigate the effect of FEV1 and FVC individually. All three analyses identified age, diabetes, moderate LV, poor LV, PVD, dialysis, LIMA usage, EuroSCORE and CKMB as significant factors, in addition to pulmonary disease, influence longterm survival. Stepwise regression excluded female sex, BMI and hypertension were excluded from the models. Moderate and severe COPD defined by GOLD criteria were significant factors determining long-term survival, and mild COPD had no significant effect (Table 2A and Fig. 3A). Obstructive and restrictive lung disease were both significant factors determining long-terms survival (Fig. 3B D). Restrictive lung disease, however, carried a greater prognostic significance (higher hazard ratio) than obstructive lung disease (Table 2). FEV1 and FEV1/FVC ratio were significant factors determining long-term survival; however, a significant interaction existed between FVC and FEV1 as demonstrated by the ratio FEV1/FVC being of more significance than FVC by itself (Table 2C). The effect of on- or off-pump was only shown to be a significant factor when respiratory function was analysed with the use of the GOLD criteria (Table 2 and Fig. 4A). Subset analysis with patients classified as having COPD defined by GOLD criteria or not revealed that off-pump surgery was a significantly beneficial factor with regard to long-term survival in patients with no COPD (Fig. 4B), but had no impact in patients with COPD. LIMA usage was shown to be a significant factor determining of long-term survival regardless of the classification of respiratory disease utilized in the analysis. Subset analysis with patients classified as having or not having COPD defined by GOLD criteria revealed LIMA usage to be prognostically significantly beneficial regardless of the pulmonary status (data not shown). DISCUSSION COPD as defined by the GOLD criteria is a significant determinant of long-term survival, when moderate or severe in nature. Restrictive lung disease is of more prognostic importance than obstructive lung disease. Quantification of pulmonary dysfunction can be done in a number of ways, and hence our analysis by GOLD criteria for obstructive and/poor restrictive and on raw spirometric data (FEV1 and FVC). All three analyses identified the same non-respiratory factors determining long-term survival. Patients with severe
F. O Boyle et al. / European Journal of Cardio-Thoracic Surgery 701 Figure 3: The effect of (A) COPD GOLD criteria stage, (B) obstructive, (C) restrictive and (D) mixed obstructive and restrictive lung disease on long-tem survival plotted at the mean of the covariates. COPD as defined by the GOLD criteria had a 10-year survival of 50%, and patients with obstructive and restrictive lung disease had a 10-year survival rate of 70%. This implies that despite their having higher in-hospital predicted mortality, patients with pulmonary disease should not be denied surgery as their long-term outcomes are relatively good, despite pulmonary function being a significant factor determining survival. Previous large studies have failed to use quantifiable definitions and frequently relied on a clinical label of COPD [12], as no internationally agreed criteria existed until recently, resulting in different definitions of COPD depending on the author [13] and/ or have been underpowered due to the sample size [14]. COPD has been shown to be a significant factor determining long-term survival in patients with ischaemic heart disease patients [15], but no publications exist with regard to the prognostic importance in CABG patients of the GOLD criteria and obstructive and/or restrictive lung disease. Obstructive and restrictive lung disease represent different pathological processes. Analysis of the restrictive and obstructive components separately, as the GOLD classification system combined them, identifies that restrictive lung disease implies a worse long-term survival due to a higher hazard ratio on Cox analysis. It should be noted that FEV1 and FVC are continuous variables and using an arbitrary cut of values, as used in the GOLD and obstructive and/or restrictive classification systems, may introduce errors in risk prediction for individuals who fall near the artificial cut-off levels. The use of the internal mammary artery is known to be associated with increased survival post-cabg; however, it has not been included in a number of previous long-term prediction studies [16 18]. Concerns about LIMA usage in patients with COPD exist due to the concerns about pulmonary dysfunction. Multivariate analysis revealed that LIMA usage is not a risk factor in patients with COPD with regard to in-hospital mortality (data not shown), but is a significant factor determining long-term survival regardless of the COPD status. The number of patients with bilateral internal mammary arteries (BIMAs) was too small in our data set to analyse. Intraoperative myocardial damage is the main cause of cardiac dysfunction post-cardiac surgery, be it myocardial stunning, inadequate cardioplegia or coronary graft dysfunction. The finding that CKMB was a significant factor affecting the longterm outcome demonstrates the importance of intraoperative myocardial protection and the coronary anastomosis technique, and has been previously identified as a significant factor affecting long-term survival [19]. Concerns about postoperative morbidity, mainly respiratory complications and mortality in patients with COPD having their
702 F. O Boyle et al. / European Journal of Cardio-Thoracic Surgery pulmonary dysfunction makes comparison between different publications difficult. Pulmonary disease is a significant factor determining longterm survival. Patients with severe COPD still have a relatively good long-term survival and should not be denied surgery. LIMA utilization in patients with COPD results in a significantly increased long-term survival, without an increased intensive care unit stay, re-intubation rate or in-hospital mortality rate. LIMITATIONS We do not have the cause of death of the patients, a frequent limitation of retrospective analysis; however, our series is large, prospective, consecutive and features 100% long-term follow-up. Diffusion studies were not available for any of the patients. Very few patients received BIMA grafts, and so this factor could not be analysed without introducing a statistical error to a lack of power. We are unable to account for the patient selection bias, a limitation of all retrospective analyses. We made no attempt to break down the follow-up period into time intervals as have been done previously [1, 16, 20]. The 13-year time period that the patients in this study were recruited from may introduce a time factor error. This is a common confounding factor of any large study over a prolonged period of time. Conflict of interest: none declared. REFERENCES Figure 4: The effect of cardiopulmonary bypass on long-tem survival plotted at the mean of the covariates in (A) all patients and (B) those with COPD, as classified by the GOLD criteria. LIMA artery harvested exist. Multivariate analysis regarding re-intubation the rate of length of intensive care stay and in-hospital mortality failed to revealed LIMA usage as a risk factor. Subset analysis of just patients with COPD concurred (data not shown). Debate continues with regard to the use of off-pump techniques. Multivariate analysis demonstrated that off-pump is not associated with a significant difference in the hospital mortality; however, the technique is associated with significantly improved long-term survival in our cohort. Subanalysis reveals that off-pump is significantly beneficial with regard to longterm survival in patients who do not have COPD, but was of no benefit in patients with COPD. We speculate that the significantly reduced long-term survival of patients with COPD overshadows the relatively smaller benefits offered by off-pump surgery. Smoking cessation, oral and inhalational bronchodilator therapy can allow patients to move from one GOLD criteria to another. We speculate, but have no supporting evidence, that pulmonary risk factor assessment and modification may improve the long-term survival. Previous publications frequently classify pulmonary disease using qualitative criteria, usually clinical opinion. 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