The long-term prognostic value of elevated cardiac biomarkers after elective cardiac surgery is not clear. The recent guidelines for diagnosing perioperative infarcts have advocated the use of similar thresholds for creatine kinase-MB (CK-MB) mass and the cardiac troponins. However, few previous data are available comparing these biomarkers after cardiac surgery, and it is not clear whether postoperative elevations of the troponins can be treated the same as elevations of CK-MB. We sought to compare the prognostic value of the cardiac troponins versus the CK-MB mass after elective cardiac surgery in low-risk patients with stable symptoms. A total of 204 consecutive patients undergoing cardiac surgery were included in the final analysis. Blood samples were drawn just before and 1 to 3 and 4 to 8 hours after the procedure, and every morning for 3 days thereafter. Patients with elevated baseline values were excluded. Using a cutoff value of 5 times the reference, patients with high and low values (controls) of CK-MB mass, cardiac troponin T (cTnT) and cardiac troponin I (cTnI) were compared. The median follow-up time was 92 months. None developed new Q-waves on the electrocardiogram. The incidence of the composite end point of all-cause mortality, readmission for acute coronary syndrome, and target vessel revascularization in the high CK-MB group was 41.2% compared to 21.8% in the controls (p = 0.004). The corresponding values for cTnT were 33.3% and 20.4% (p = 0.075) and for cTnI were 27.0% and 34.6% (p = 0.237). The p value in the isolated coronary artery bypass grafting subgroup (n = 156) was p = 0.043 for CK-MB, p = 0.137 for cTnT, and p = 0.795 for cTnI. High CK-MB (p = 0.001), ejection fraction (p = 0.002), and body mass index (p = 0.010) were the only variables independently related to reduced event-free survival. No such relation was found for high cTnT and cTnI. In conclusion, CK-MB was superior to the cardiac troponins (values ≥5 times the reference) in predicting long-term event-free survival after elective cardiac surgery in low-risk patients with stable symptoms undergoing coronary artery bypass grafting and/or valve surgery.
Recently, we have shown that creatine kinase-MB (CK-MB) values ≥5 times the reference predict worse long-term survival after elective cardiac surgery in stable, low-risk patients during a median follow-up of 95 months. The recent guidelines for diagnosing perioperative infarcts have advocated the use of similar thresholds for CK-MB and the cardiac troponins. However, few previous data are available comparing these biomarkers after cardiac surgery, and it is not clear whether postoperative elevations of the troponins can be treated the same as elevations of CK-MB. In the present study, we compared the long-term (>5 years) prognostic value of both cardiac troponin T (cTnT) and cardiac troponin I (cTnI) versus the CK-MB mass (using a cutoff value of 5 times the reference for all biomarkers) in patients with stable symptoms for ≥1 month before elective coronary artery bypass grafting (CABG) and/or valve replacement.
Methods
In the present prospective study, 210 consecutive patients with coronary artery and/or valve disease and stable symptoms were screened for inclusion from 1997 to 1998. Six patients were excluded. The exclusion criteria were elevated or missing cardiac troponin or CK-MB values just before surgery, not available for follow-up evaluations, recent acute coronary syndrome (ACS) of <1 month, malignant disease, or creatinine >200 μmol/L (2.3 mg/dl). Patients were compared according to biomarker values <5 times the reference (controls) versus ≥5 times the reference (high biomarker group) at any point after surgery, in line with the recent guidelines.
A few patients with elevated baseline values were still included in the present study if the other cardiac biomarkers were within the reference limit. All patients underwent angiography before surgery, according to the established routines at our institution. Additional treatment strategies were determined by a consensus decision among the cardiologists and cardiac surgeons. Only patients with low risk were included in the present study. The decisions were determined by the clinical presentation, operability, and co-morbidity.
The regional ethics committee approved the study, and all patients provided written informed consent. Predefined major adverse clinical events included the composite end point of all-cause mortality (>24 hours after the procedure), readmission for ACS, and target vessel revascularization. ACS (unstable angina pectoris, ST-segment elevation myocardial infarction, and non–ST-segment elevation myocardial infarction) were defined according to the guidelines.
All patients underwent standard CABG and/or valve surgery according to the established routines at our hospital. Left internal mammary artery bypass was used to the left anterior descending artery, and saphenous vein grafts were used to the other coronary arteries and/or valve surgery during cardiopulmonary bypass with moderate general hypothermia (32°C). Cardiac arrest was induced by infusion of cold (8°C) oxygenated blood cardioplegia administered every 20 minutes during the ischemic period. The vast majority of the patients were given cardioplegia using the anterograde route. The postoperative shed mediastinal blood was not retransfused. In >95% of the patients, the proximal anastomosis was made after declamping the aorta, with a side clamp on the aorta.
Venous blood samples were prospectively collected just before surgery from all patients. Blood samples were also taken at 1 to 3 and 4 to 8 hours after the procedure, and every morning thereafter for 3 days. The CK-MB mass (reference limit <5 μg/L) was assayed using an established immunoassay, the Technicon Immuno 1 System (Bayer Business Group Diagnostics, Tarrytown, New York) according to the manufacturer’s instructions. CTnI was analyzed using a one-step, immunoenzymometric assay (ERIA, Diagnostics Pasteur, Marnes-la-Coquette, France). The detection limit was <0.10 μg/L for healthy donors, and our reference was similar. CTnT was analyzed according to a revised procedure using microtiter plates, with which our laboratory was familiar, with a reference value of <0.15 μg/L. The reference values of the cardiac troponins were defined as the mean baseline values plus 3 times the SEM.
An electrocardiogram was taken before and at least once daily after the procedure until discharge, and any changes were assessed according to the Minnesota Code for defining myocardial infarction according to the presence of new Q-waves. During follow-up, all available medical records, as well as the Central Population Register and local patient administrative registries, were investigated in detail for the predefined end points and other adverse clinical events.
The data are presented as the mean ± SD, if not otherwise stated. Student’s t test was used when comparing continuous variables and the chi-square test (or Fisher’s exact test) for analysis of discrete variables (Statistical Package for Social Sciences, version 15, SPSS, Chicago, Illinois). The Kaplan-Meier method and log-rank test were used to evaluate differences in event-free survival. The independent ability of the cardiac markers to predict worse outcome was assessed using univariate and multivariate logistic regression analyses. All clinical relevant baseline and procedural variables were tested in the univariate analysis. Variables with a univariate p <0.10 were adjusted for in the logistic regression multivariate analysis. The differences were considered significant with a 2-sided p <0.05, if not otherwise stated.
Results
Tables 1 and 2 list the patient characteristics and procedural data. Of the 204 patients (mean age 71 years, range 31 to 92) enrolled in the final analysis, 38 patients underwent aortic valve surgery and 10 patients underwent mitral valve surgery; 13 patients underwent both CABG and valve surgery. One patient had a creatinine value >150 μg/L (1.7 mg/dl), and 2 patients (1.1%) had an ejection fraction of <30%. The number of patients with elevated biomarkers (≥5 times the reference) versus controls was 85 versus 119 for CK-MB, 150 versus 54 cTnT, and 126 versus 78 cTnI. The aortic cross-clamp time was significantly longer in the high value group of all biomarkers in both the total cohort and the isolated CABG subgroup. In the subgroup of patients (n = 156) who had undergone isolated CABG (mean age 69.8 years, range 41 to 89), no significant differences were found between the controls and the high CK-MB groups regarding patient characteristics comparing the same variables as listed in Table 1 . The left internal mammary artery was used in 94.2% of the isolated CABG patients, with no significant difference between the controls and the high biomarker groups.
| Characteristic | All patients † | Controls vs High Biomarker Group ⁎ | ||
|---|---|---|---|---|
| CK-MB ‡ | cTnT § | cTnI ¶ | ||
| Age (y) (range) | 70.9 (31-92) | 70.7 vs 71.3 | 69.1 vs 71.6 | 70.9 vs 70.9 |
| Men | 157 (77.0%) | 96 vs 61 | 42 vs 115 | 64 vs 93 |
| Ejection fraction ∥ | 62.3 ± 13.2 | 61.5 vs 63.5 | 62.6 vs 62.2 | 60.9 vs 63.2 |
| Surgery | ||||
| Bypass only | 156 (77.6%) | 97 vs 59 ⧣ | 49 vs 107 ⁎⁎ | 68 vs 88 ⁎⁎ |
| Aortic valve | 38 (18.0%) | 15 vs 23 ⁎⁎ | 4 vs 34 ⁎⁎ | 8 vs 30 ⁎⁎ |
| Mitral valve | 10 (4.9%) | 3 vs 7 | 1 vs 9 | 3 vs 7 |
| Body mass index (kg/m 2 ) | 25.2 (3.5) | 25.2 vs 25.3 | 25.3 vs 25.2 | 25.3 vs 25.2 |
| Smoking status | ||||
| Never | 88 (43.1%) | 45 vs 43 | 21 vs 67 | 25 vs 63 ⁎⁎ |
| Ever | 116 (56.9%) | 72 vs 42 | 34 vs 82 | 53 vs 63 ⁎⁎ |
| Current smoker | 49 (24.1%) | 32 vs 17 | 16 vs 33 | 18 vs 31 |
| Exsmoker | 67 (32.8%) | 42 vs 25 | 18 vs 49 | 35 vs 32 ⁎⁎ |
| Hypercholesterolemia †† | 154 (76.2%) | 96 vs 58 ⁎⁎ | 45 vs 109 | 58 vs 96 |
| Diabetes mellitus | 13 (6.4%) | 8 vs 5 | 2 vs 11 | 7 vs 6 |
| Hypertension | 57 (28.1%) | 31 vs 26 | 11 vs 46 | 18 vs 39 |
| Current use of aspirin | 152 (74.5%) | 94 vs 58 | 48 vs 104 ⁎⁎ | 64 vs 88 |
| Previous myocardial infarction | 83 (40.7%) | 55 vs 28 | 26 vs 57 | 34 vs 49 |
| Anterior | 34 (16.7%) | 25 vs 9 | 12 vs 22 | 14 vs 20 |
| Inferior | 40 (19.6%) | 23 vs 17 | 11 vs 29 | 13 vs 27 |
| Bypass + valve | 9 (4.4%) | 7 vs 2 | 3 vs 6 | 7 vs 2 |
| New York Heart Association class | ||||
| 0–1 | 19 (9.3%) | 9 vs 10 | 3 vs 16 | 10 vs 11 |
| 2 | 123 (60.3%) | 70 vs 53 | 35 vs 88 | 4 vs 79 |
| 3 | 60 (29.4%) | 39 vs 21 | 15 vs 45 | 24 vs 36 |
| Not known | 2 (1.0%) | |||
| Previous bypass surgery | 9 (4.4%) | 2 vs 7 | 4 vs 5 | 2 vs 7 |
| Previous coronary angioplasty | 18 (8.8%) | 12 vs 6 | 10 vs 8 | 9 vs 9 |
| Creatinine | ||||
| μmol/L | 95.4 ± 36.6 | 96.0 vs 94.5 | 91.1 vs 97.0 | 98.6 vs 93.4 |
| mg/dl | 1.1 ± 0.4 | 1.1 vs 1.1 | 1.0 vs 1.1 | 1.1 vs 1.1 |
| Hospital stay (d) | 10.4 ± 4.1 | 10.4 vs 10.5 | 10.3 vs 10.5 | 10.6 vs 10.3 |
⁎ Data are presented as absolute number of patients.
† Data are presented as n (%) or mean ± SD.
‡ CK-MB <25 μg/L (n =119) versus ≥25 μg/L (n = 85).
§ cTnT <0.75 μg/L (n = 54) versus ≥0.75 μg/L (n = 150).
¶ cTnI <0.50 μg/L (n = 78) versus ≥0.50 (n = 126).
†† Treated hypercholesterolemia or cholesterol level ≥6.5mmol/L in untreated patients.
| Characteristic | All Patients † | Controls vs High Biomarker Group ⁎ | ||
|---|---|---|---|---|
| CK-MB ‡ | cTnT § | cTnI ¶ | ||
| Procedural time (min) | ||||
| All patients (n = 204) | 163 (85–318) | 154 vs 175 ∥ | 148 vs 168 ⧣ | 149 vs 171 ⧣ |
| Bypass surgery (n=156) | 157 (85–318) | 151 vs 169 ⧣ | 147 vs 162 ⧣ | 144 vs 167 ⧣ |
| Valve surgery (n = 35) | 176 (110–247) | 166 vs 183 | 162 vs 178 | 174 vs 177 |
| Bypass + valve (n = 13) | 193 (120–253) | 183 vs 197 | 156 vs 196 | 195 vs 192 |
| Bypass time (min) | ||||
| All patients | 82 (28–163) | 72 vs 96 ∥ | 68 vs 88 ∥ | 70 vs 90 ∥ |
| Bypass surgery | 74 (28–158) | 68 vs 86 ∥ | 65 vs 79 ∥ | 65 vs 81 ∥ |
| Valve surgery | 104 (50–163) | 93 vs 111 | 91 vs 106 | 96 vs 106 |
| Bypass + valve | 119 (72–144) | 110 vs 122 | 106 vs 120 | 120 vs 118 |
| Aortic cross clamp time (min) | ||||
| All patients | 50 (15–119) | 43 vs 61 ∥ | 39 vs 54 ⧣ | 41 vs 56 ∥ |
| Bypass surgery | 43 (15–106) | 39 vs 51 ∥ | 37 vs 46 ⧣ | 37 vs 47 ∥ |
| Valve surgery | 72 (40–119) | 62 vs 79 ⧣ | 58 vs 74 ⧣ | 65 vs 74 |
| Bypass + valve | 82 (51–108) | 76 vs 84 | 63 vs 83 | 73 vs 84 |
| Site of coronary artery stenosis ⁎⁎ | ||||
| Left main stem | 25 (16.0%) | 18 vs 7 | 9 vs 16 | 12 vs 13 |
| Left anterior descendant | 147 (94.2%) | 97 vs 50 | 48 vs 99 | 63 vs 84 |
| Circumflex/marginal | 137 (87.8%) | 88 vs 52 | 39 vs 98 | 53 vs 84 ⧣ |
| Right coronary artery | 132 (84.6%) | 86 vs 46 | 37 vs 95 | 55 vs 77 |
| No. of grafts ⁎⁎ | ||||
| 1 | 1 (0.6%) | 1 vs 0 | 1 vs 0 | 1 vs 0 |
| 2 | 16 (10.3%) | 14 vs 2 | 9 vs 7 ⧣ | 6 vs 10 |
| 3 | 114 (73.1%) | 71 vs 43 | 34 vs 80 | 51 vs 63 |
| 4 | 77 (49.4%) | 44 vs 33 ⧣ | 19 vs 58 | 34 vs 43 |
| 5 | 15 (9.6%) | 11 vs 4 | 3 vs 12 | 4 vs 11 |
| Left internal mammary artery graft ⁎⁎ | 147 (94.2%) | 96 vs 51 | 47 vs 100 | 67 vs 80 |
| Coronary artery disease ⁎⁎ | ||||
| One vessel | 2 (1.3%) | 2 vs 0 | 2 vs 0 | 1 vs 1 |
| Two vessel | 30 (19.2%) | 22 vs 8 | 14 vs 16 | 18 vs 12 ⧣ |
| Three vessel | 124 (79.5%) | 78 vs 46 | 33 vs 91 ⧣ | 49 vs 75 ⧣ |
⁎ Data are presented as absolute number of patients.
† Data are presented as minutes (range) or n (%).
‡ CK-MB <25 μg/L (n =119) versus ≥25 μg/L (n = 85).
§ cTnT <0.75 μg/L (n = 54) versus ≥0.75 μg/L (n = 150).
¶ cTnI <0.50 μg/L (n = 78) versus ≥0.50 (n = 126).
In the total study cohort, both CK-MB and the cardiac troponins peaked rapidly within 4 to 8 hours after surgery ( Table 3 ). The mean peak CK-MB was 16.0 μg/L in the controls versus 46.0 μg/L in the high CK-MB group (p <0.001). The corresponding values for cTnT and cTnI were 0.38 and 2.31 μg/L (p <0.001) and 0.28 and 1.37 μg/L (p <0.001). One patient had a peak CK-MB value less than the reference limit, and 3 and 4 patients had a cTnT and cTnI value less than the reference limit, respectively. A typical increase and decrease of all 3 markers was seen, but only CK-MB returned to baseline levels within 3 days after surgery. The mean peak values of the biomarkers were greatest in the combined group ( Table 3 ) and lowest in the isolated CABG group, with the valve group in between.
| Marker | Before | 1–3 h | 4–8 h | 16–20 h | 40–44 h | 64–68 h | High Value ⁎ (%) |
|---|---|---|---|---|---|---|---|
| CK-MB (<5 μg/L) | |||||||
| All (n = 204) | 2.0 (1.2) | 23.6 (15.6) | 22.8 (17.0) | 17.4 (19.5) | 5.1 (6.5) | 3.0 (6.8) | 42.0 |
| Bypass (n = 156) | 1.9 (1.2) | 21.4 (14.6) | 20.4 (16.0) | 15.1 (20.8) | 4.6 (6.5) | 1.7 (20.8) | 35.0 |
| Valve (n = 35) | 2.2 (1.3) | 31.0 (17.8) | 32.2 (19.9) | 22.4 (15.7) | 6.9 (6.4) | 3.2 (2.9) | 66.9 |
| Bypass + valve (n = 13) | 1.7 (0.9) | 29.2 (15.0) | 26.2 (9.5) | 18.2 (6.2) | 6.5 (4.2) | 11.2 (26.7) | 69.2 |
| cTnI (<0.10 μg/L) | |||||||
| All (n = 204) | 0.03 (0.04) | 0.62 (0.60) | 0.85 (0.90) | 0.61 (0.85) | 0.40 (1.05) | 0.40 (0.45) | 60.5 |
| Bypass (n = 156) | 0.04 (0.04) | 0.54 (0.54) | 0.79 (0.96) | 0.55 (0.90) | 0.38 (1.18) | 0.22 (0.45) | 54.8 |
| Valve (n = 35) | 0.07 (0.04) | 0.84 (0.68) | 1.00 (0.67) | 0.74 (0.64) | 0.46 (0.44) | 0.27 (0.21) | 80.0 |
| Bypass + valve (n = 13) | 0.04 (0.03) | 1.04 (0.73) | 1.15 (0.59) | 0.88 (0.63) | 0.49 (0.34) | 0.63 (0.85) | 76.9 |
| cTnT (<0.15 μg/L) | |||||||
| All (n = 204) | 0.12 (0.05) | 1.01 (1.08) | 1.63 (1.60) | 0.79 (0.92) | 0.59 (0.90) | 0.46 (0.80) | 70.7 |
| Bypass (n = 156) | 0.12 (0.05) | 0.96 (1.13) | 1.66 (1.68) | 0.74 (0.98) | 0.52 (0.94) | 0.40 (0.86) | 66.2 |
| Valve (n = 35) | 0.12 (0.06) | 1.15 (0.84) | 1.56 (1.28) | 0.96 (0.70) | 0.85 (0.67) | 0.66 (0.56) | 82.9 |
| Bypass + valve (n = 13) | 0.11 (0.05) | 1.28 (1.13) | 1.62 (1.20) | 0.92 (0.57) | 0.77 (0.71) | 0.70 (0.63) | 92.3 |
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