432 Original research

Carbohydrate antigen 125 levels and clinical outcomes after off-pump coronary artery bypass grafting Jing Lib, Shu-Jiang Songb, Fu-Lin Liua, Zhi-Qiang Loua, Zhe Hana, Yang Wanga, Xiao-Dong Zhoua, Cheng Zhoua and Ke-Ye Liua Objectives The present study aimed to evaluate the prognostic value of preoperative carbohydrate antigen 125 (CA125) levels for clinical outcomes after off-pump coronary artery bypass grafting (OPCAB). Methods A total of 314 consecutive patients who underwent OPCAB were enrolled in this study and divided into three groups corresponding to baseline CA125 level tertiles. Clinical outcomes of these patients were followed up after 1 year. The primary endpoint was the incidence of combined major adverse cardiac events (MACE). Results Event-free survival was significantly associated with the CA125 tertile (log-rank P = 0.021); specifically, hazard ratios (HRs) increased progressively from CA125 tertile 1 to tertile 3 [vs. tertile 1: tertile 2 h = 1.8; 95% confidence interval (CI): 1.1–2.8, P = 0.040; tertile 3 h = 2.9; 95% CI: 1.1–8.1, P = 0.018]. In the first multivariate Cox regression analytical model (all variables except EuroSCORE), CA125 was an independent predictor of MACE (HR = 1.1, 95% CI: 1.0–2.4, P = 0.016). In a second

model (CA125 levels and EuroSCORE only), CA125 remained an independent predictor of MACE (HR = 1.1, 95% CI: 1.0–1.3, P = 0.036). Conclusion An increased preoperative CA125 level is an independent predictor of worse clinical outcomes after OPCAB during a 1-year follow-up. Coron Artery Dis 26:432–436 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Coronary Artery Disease 2015, 26:432–436 Keywords: carbohydrate antigen 125, clinical outcomes, off-pump coronary artery bypass grafting Departments of aCardiac Surgery and bCardiology, Affiliated Hospital of Hebei University, Baoding, Hebei, China Correspondence to Ke-Ye Liu, MD, Department of Cardiac Surgery, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, China Tel/fax: + 86 312 5981196; e-mail: [email protected] Received 26 January 2015 Revised 24 March 2015 Accepted 14 April 2015

Introduction

Methods

Coronary artery bypass grafting (CABG) is an effective treatment method for multivessel coronary artery disease. However, CABG has been associated with morbidity and mortality, although the incidence rates are low, and widely used risk assessment methods such as EuroSCORE are imperfect [1]. Therefore, additional methods of risk stratification are needed.

Patients and study design

Carbohydrate antigen 125 (CA125) is a high-molecularweight glycoprotein produced by epithelial ovarian tumors and mesothelial cells and is therefore used as a marker of ovarian cancer. In addition, normal cells from different tissues derived from coelomic epithelium, including the pericardium, pleura, and peritoneum, can produce CA125 in response to mechanical stress and inflammatory stimuli [2–4]. Recent studies have shown that increased CA125 levels play a prognostic role in cardiopulmonary disorders such as coronary heart disease, chronic obstructive pulmonary disease, hypertrophic cardiomyopathy, cardiac angiosarcoma, infective perimyocarditis, and atrial fibrillation [5–9]. However, the relationship between elevated CA125 levels and clinical outcomes after off-pump coronary artery bypass grafting (OPCAB) has not been reported. Therefore, this study aimed to investigate the relationship between CA125 levels and the prognosis of patients following OPCAB. 0954-6928 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

The study protocol was approved by an institutional ethical committee, and the study itself was carried out in accordance with the Declaration of Helsinki. A total of 343 consecutive patients who underwent OPCAB at our hospital from January 2010 to January 2013 were initially enrolled in this study. Written informed consent was obtained from all participants. After applying the exclusion criteria, which included active or chronic inflammatory or autoimmune disease, any other concomitant surgery, malignancies or gynecological diseases, cirrhotic hepatic disease, nephritic syndrome, acute (< 1 month) myocardial infarction (MI), or any increase in creatine kinase-MB isoenzyme (CK-MB) or cardiac troponin I (cTnI) levels, 314 eligible patients remained. Baseline clinical data were obtained prospectively and included cardiovascular risk factors, cardiac medication, medical history, laboratory values, left ventricular ejection fraction (LVEF; obtained from echocardiography reports), and operative risk estimates (EuroSCORE). In addition, blood samples were obtained from each patient immediately before surgery and serum CA125 levels were determined using an ARCHITECT Ci8200 automatic analyzer (Abbott Laboratories, Abbott Park, Illinois, DOI: 10.1097/MCA.0000000000000262

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CA125 and clinical outcomes after CABG Li et al. 433

USA). These levels were used to divide study participants into three groups in accordance with the following baseline CA125 tertiles: tertile 1, CA125 less than 30 U/ml (n = 106 patients); tertile 2, CA125 of 30–51 U/ml (n = 106 patients); and tertile 3, CA125 greater than 51 U/ml (n = 102 patients). Venous blood samples for the measurement of CK-MB and cTnI levels were obtained from all patients before surgery and at 8 and 24 h after surgery. High-sensitivity C-reactive protein (hs-CRP) levels were also assessed before surgery. Anesthetic procedures for all patients were supervised by a single anesthesiologist according to the same anesthetic protocol. All surgical procedures were performed by a single surgeon using the same surgical technique. After surgery, all patients were transferred to the ICU. Patients were discharged from the ICU to the general ward when they became stable and did not require further ICU monitoring and care. Endpoints and definitions

The primary endpoint was the occurrence of combined major adverse cardiac events (MACE), including cardiac death, MI, stroke, and repeated revascularization. MI was defined as the occurrence of ischemic syndrome and an elevation of cTnI to more than 10 times the normal limit within 48 h post OPCAB; beyond 48 h, MI was defined as an elevation of cTnI above the normal limit, in accordance with a universal definition [10]. A diagnosis of stroke was made if there was clinical and radiological evidence. Repeat revascularization was defined as an intervention of the grafts or grafted native vessels. The secondary endpoint was the difference in the mean peak CK-MB and cTnI values after the procedure. Follow-ups were performed through clinic visits or telephone interviews over a 12-month period after the procedure. Statistical analysis

All normally distributed data are expressed as means ± SD. Variables that were not normally distributed are expressed as medians (interquartile ranges). Categorical variables are presented as frequencies (%). Comparisons of continuous variables with normal distributions were performed using the Student t-test or an analysis of variance where appropriate, whereas non-normally distributed data were assessed using the Kruskal–Wallis test or the Mann–Whitney U-test. Comparisons of categorical variables were performed using the χ2-test or the Fisher exact test. The Pearson correlation test was used to analyze the relationships between CA125 tertiles and LVEF and hs-CRP levels. Event-free survival was analyzed by Kaplan–Meier estimations using the log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models. In the multivariate analysis, one model included all variables, except EuroSCORE, whereas a second model included only the CA125 levels and EuroSCORE. The risks associated with different CA125 tertiles were assessed by Cox

regression, with the lowest tertile set as the reference. Differences were considered significant at a P-value less than 0.05. All P-values were derived from two-sided significance tests. All statistical analyses were carried out using SPSS, version 13.0 (SPSS Inc., Chicago, Illinois, USA).

Results Baseline characteristics

The patients’ clinical, laboratory, and procedural data are summarized in Table 1. Patient characteristics at baseline, including sex, age, cardiovascular risk factors, clinical presentation, left ventricular function, renal function, leukocyte counts, and medical therapy, were similar among the three tertile groups. However, a significant association was observed between an increased tertile ranking and hs-CRP concentration. No difference was observed among the three groups in terms of the EuroSCORE, use of the internal mammary artery, use of an intra-aortic balloon pump, number of bypass grafts, number of intracoronary shunts, and coronary bypass time. In the Pearson correlation analysis, the CA125 level was not associated with LVEF (P = 0.057), but did correlate positively with the hs-CRP concentration (r = 0.378, P < 0.001). Postprocedural elevation of CK-MB and cTnI

The preprocedural levels of both CK-MB and cTnI were similar among the three groups. However, the postprocedural peak CK-MB values of patients in tertile 3 [2.1 (1.2–13.0) ng/ml] were significantly higher than those of patients in tertile 2 [2.0 (1.0–7.3) ng/ml, P = 0.047] and tertile 1 [1.1 (0.9–1.6) ng/ml, P < 0.001]. The postprocedural cTnI levels in tertile 3 patients [0.075 (0.010–0.185) ng/ml] were also significantly higher than those of patients in tertile 2 [0.020 (0.000–0.103) ng/ml, P = 0.011] and tertile 1 [0.010 (0.000–0.030) ng/ml, P < 0.001] (Fig. 1). Relationship of CA125 with 12-month MACE

At the 12-month follow-up (median, 12 months, interquartile range, 3.5–18 months), the endpoint of MACE occurred in 17 (16.7%), 13 (12.2%), and five (4.7%) patients in tertiles 3, 2, and 1, respectively. Cardiac death occurred in four patients in tertile 3 and two patients each in tertiles 2 and 1. MI was observed in seven, eight, and one patient in tertiles 3, 2, and 1, respectively. Revascularization was required in six, three, and two patients in tertiles 3, 2, and 1, respectively. No cases of stroke were identified during follow-up. Event-free survival was found to be associated significantly with the CA125 tertile (log-rank, P = 0.021) (Fig. 2). HRs increased progressively from CA125 tertile 1 to tertile 3 [vs. tertile 1: tertile 2 = 1.8 (95% CI: 1.1–2.8), P = 0.040; tertile 3 = 2.9 (95% CI: 1.1–8.1), P = 0.018].

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434 Coronary Artery Disease 2015, Vol 26 No 5

Table 1

Patient baseline characteristics

Characteristics Age( years) Male sex [n (%)] Diabetes mellitus [n (%)] Hypertension [n (%)] Hypercholesterolemia [n (%)] Current smokers [n (%)] Family history [n (%)] BMI MI [n (%)] History of PCI [n (%)] LVEF (%) CCS I or II [n (%)] NYHA I or II [n (%)] Statins [n (%)] β-Blockers [n (%)] ACEI [n (%)] hs-CRP (mg/l) GFR (ml/min/1.73 m2) Leukocyte count (×109/l) EuroSCORE IABP used [n (%)] IMA used [n (%)] Number of intracoronary shunt Number of bypass grafts Coronary bypass time (min)

Tertile 1

Tertile 2

Tertile 3

CA125 < 30 U/ml (n = 106)

30 U/ml ≤ CA125 ≤ 51 U/ml (n = 106)

CA125 > 51 U/ml (n = 102)

P-value

61.0 ± 5.9 67 (63.2) 36 (34.0) 41 (38.7) 58 (54.7) 26 (24.5) 15 (14.2) 25.4 ± 4.1 16 (15.1) 8 (7.5) 52.5 ± 7.5 46 (43.7) 71 (67.0) 92 (86.8) 74 (69.8) 85 (80.2) 3.7 ± 1.3 61.9 ± 9.9 7.1 ± 1.2 3.0 (1.0–6.3) 10 (9.4) 90 (84.9) 3 (2–3) 3 (2–3) 66.9 ± 10.7

61.5 ± 5.6 68 (64.2) 28 (26.4) 51 (48.1) 56 (52.8) 28 (26.4) 19 (17.9) 25.6 ± 4.2 13 (12.3) 5 (4.7) 53.0 ± 7.4 45 (42.5) 74 (69.8) 89 (84.0) 76 (71.7) 80 (75.5) 4.2 ± 1.4 58.9 ± 8.9 7.1 ± 1.3 4.0 (1.0–8.3) 12 (11.3) 94 (88.7) 3 (2–3) 3 (2–3) 65.2 ± 9.4

61.1 ± 6.3 72 (70.6) 23 (22.5) 45 (44.1) 48 (47.1) 28 (27.5) 14 (13.7) 24.5 ± 4.5 11 (10.8) 5 (4.9) 51.4 ± 7.7 43 (42.2) 78 (76.5) 80 (83.1) 70 (70.1) 86 (84,.3) 5.4 ± 1.7 60.0 ± 9.7 7.2 ± 1.8 4.0 (2.0–9.0) 10 (9.8) 88 (86.3) 3 (2–3) 3 (2–3) 66.6 ± 11.5

0.803 0.476 0.173 0.381 0.517 0.888 0.648 0.158 0.637 0.613 0.309 0.982 0.303 0.263 0.888 0.281 < 0.001 0.074 0.917 0.127 0.891 0.716 0.876 0.787 0.461

ACEI, angiotensin-converting enzyme inhibitor; CA125, carbohydrate antigen 125; CCS, Canadian Cardiovascular Society; GFR, glomerular filtration rate; hs-CRP, highsensitivity C-reactive protein; IABP, intra-aortic balloon pump; IMA, internal mammary artery; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NYHA, New York Heart Association; PCI, percutaneous coronary intervention.

Fig. 1

Postprocedural peak values of CK-MB (ng/ml)

Postprocedural peak values of cTnl (ng/ml) 0.5

P < 0.001

30

P < 0.001

P = 0.047

P = 0.011

0.4

0.3

20

0.2 10 0.1

0.0

0 Tertile 1

Tertile 2

Tertile 3

Tertile 1

Tertile 2

Tertile 3

Postprocedural peak values of CK-MB and cTnI. CK-MB, creatine kinase-MB isoenzyme; cTnI, cardiac troponin I.

In the multivariate Cox regression analytical model, which included all variables shown in Table 1 except the EuroSCORE, CA125 was an independent predictor of

MACE (HR = 1.1, 95% CI: 1.0–2.4, P = 0.016). Other independent predictors included the hs-CRP concentration, LVEF less than 50%, and glomerular filtration rate

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CA125 and clinical outcomes after CABG Li et al. 435

Fig. 2

100

Freedom for MACE (%)

90

Log-rank P = 0.021

80

70

60

Tertile 1 Tertile 2 Tertile 3

0

0 27 0 30 0 33 0 36 0

24

21

0

0

18

15

90 12 0

60

0 30

50

Days after procedure Kaplan–Meier curves of event-free survival among the CA125 tertiles. CA125, carbohydrate antigen 125; MACE, major adverse cardiac events.

less than 60 ml/min/1.73 m2 (Table 2). In a second model that included only CA125 levels and EuroSCOREs, both CA125 (HR = 1.1, 95% CI: 1.0–1.3, P = 0.036) and EuroSCORE (HR = 1.3, 95% CI: 1.1–1.4, P < 0.001) were found to be independent predictors of the clinical outcome.

Discussion The key finding of the present study is that in patients undergoing OPCAB, preoperative CA125 levels provide useful prognostic information independent of other risk factors. To date, increases in serum CA125 levels have been observed predominantly in women with ovarian cancer, particularly in cases with peritoneal involvement [4,11]. CA125 levels have also been reported to increase, albeit less frequently, with other types of cancer and with some benign diseases characterized by serosal effusions. Multivariate analysis with combined major adverse cardiac events

Table 2

Variable

HR (95% CI)

P-value

CA125 hs-CRP concentration LVEF < 50% GFR