Myonecrosis following isolated coronary artery bypass grafting is common and associated with an increased risk of long-term mortality
Steven P Marso*,
Brent D Bliven,
John A House,
Gregory F Muehlebach and
A.Michael Borkon
Mid America Heart Institute, Missouri 64111, Kansas City, USA
* Correspondence to: Steven P. Marso MD, FACC, Mid America Heart Institute, Saint Luke's Hospital, 4401 Wornall, Kansas City, Missouri 64111, USA. Tel: (816) 932-5773; fax: (816) 932-5798
E-mail address: smarso{at}saint-lukes.org
Received 14 November 2002;
revised 13 March 2003;
accepted 27 March 2003
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Abstract
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Aims We sought to evaluate the risk of long-term mortality with respect to post-operative elevation of the isoenzyme CK-MB following first-time isolated coronary artery bypass grafting (CABG) surgery.
Methods Patients undergoing first-time isolated CABG between September 1992 and December 2001, at the Mid America Heart Institute, were included in this registry analysis. A sole CK-MB measurement was obtained at an average of 15.2h following CABG. The main endpoint was long-term mortality.
Results There were 3667 patients included in this registry. The mean follow up was 5.1 years. The event-free survival rate was 80%, 78% and 73%, for the normal, 13 and >3 times by ULN groups respectively; log-rank p=0.0058. The event-free survival for the four CK-MB groups was 80%, 78%, 75% and 72% for the normal, 13 times, >35, and >5 times ULN groups respectively, log-rank p=0.0078. The CK-MB elevation following CABG remained a significant predictor following multivariate adjustment. With a point estimate of 1.04, 95% confidence limits 1.0091.062, p=0.007.
Conclusion Elevation of the isoenzyme CK-MB is an important predictor of longterm mortality following coronary bypass grafting. These data support routine use of creatinine kinase measurement following bypass surgery to further delineate long-term risk.
Key Words: Coronary artery bypass grafting Creatinine kinase Myocardial infarction Mortality
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1. Introduction
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Numerous studies have demonstrated an increased hazard for all-cause mortality for those patients with myonecrosis as determined by elevation of the isoenzyme creatine kinase MB following percutaneous coronary intervention (PCI).17However, both the underlying pathophysiology and the absolute value of CK-MB, thought to be associated with this risk, remain ill-defined and controversial. Although a recent consensus report suggests that a CK-MB elevation, following PCI of three times the upper limit of normal and five times the upper limit of normal following coronary artery bypass grafting (CABG) is associated with increased risk. There have been a scarce number of studies with relatively small numbers of patients characterizing CK-MB elevation following CABG with respect to cardiovascular events.812Therefore, we sought to evaluate the risk of long-term mortality withrespect to post-operative elevation of CK-MB following first-time isolated CABG.
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2. Methods
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2.1. Patient selection
Patients undergoing first-time isolated CABG between September 1992 and December 2001, at the Mid America Heart Institute, were included in this registry analysis. Thus, patients undergoing concomitant or isolated valve surgery were excluded. Patients with a prior CABG were also excluded. Patients who had undergone a prior PCI procedure or myocardial infarction (MI) within 7 days of undergoing CABG were also not included, given the potential for confounding the post-CABG CK-MB analysis. There were no other clinical or anatomic exclusions for this analysis.
2.2. Data collection
The methodology and details of data collection for patients undergoing CABG at the Mid America Heart Institute have been described previously.13Briefly, data concerning the clinical, operative and follow-up details were collected and recorded in a prospective fashion by personnel dedicated to the surgical registry. Data elements were collected via patient interviews and chart review at the time of CABG. Patient co-variate data were based upon patient-reported responses to questions and data elements. This data was populated into the surgical data-base by dedicated data coordinators.
2.3. CK-MB determination and stratification
A single blood draw was routinely performed for measurement of CK-MB, 1216h following completion of the surgical procedure. The upper limit of normal for CK-MB was 6ng/dl. The CK-MB data were stratified with respect to mortality in three ways. Firstly, the CK-MB data were stratified into three groups: within normal limits, >13 times upper limit of normal (ULN) and >3 times ULN. Secondly, the CK-MB data were stratified into four groups: within normal limits, >13 times ULN, >35 ULN and >5 times ULN. Lastly, we reported the individual relative risks for long-term all-cause mortality of CK-MB data stratified at individual increments.
2.4. Statistical analysis and depiction of data
Statistical tests were performed using SAS version 8.2 (SAS Institute, Inc). Continuous data were depicted as mean±SD. A chi-square or independent t-test was used to determine statistical significance of categorical and continuous data, respectively. The long-term mortality data for the study groups were depicted as KaplanMeier survival curves and statistical significance was determined utilizing the log-rank test. A multi-variable logistical regression analysis was developed for the primary endpoint of all-cause mortality. Baseline co-variates that were identified as significantly different (p<0.25) in univariate analysis between the three CK-MB groups (within normal limits, >13 times ULN and >3 times ULN) were included in the multi-variate modelling selection process. The multivariable model was then obtained with stepwise entry significance of p<0.15 and stayed in the model with p<0.10. Furthermore, available clinical co-variates that were shown to be predictive of long-term mortality by Sergeant et al., were also included in the model.14Co-variates utilized from this model included overweight, renal failure, ejection fraction, number of diseased vessels, history of cerebral vascular accident (CVA) and grafting to left anterior descending (LAD).
The survival analyses for this study cohort were depicted as KaplanMeier survival curves and significance was determined by log-rank testing. The relative risk for long-term mortality was depicted with respect to CK-MB elevation cut points, in order to determine the association between risk and level of isoenzyme elevation. Significance was determined by the slope of the weighted linear regression line compared with zero slope line.
2.5. Definition of terms
Overweight was defined as more than 10kg above the calculated ideal body weight. The ideal weight for men is height (cm) minus 100 and for women height (cm) minus 110. Its predictive nature, following CABG, has been previously described.14Renal failure existed if the patient was on dialysis before CABG or if the creatinine >2.0mg/dl before or during the procedure. Neurologic complications were defined as an episode of transient ischaemic attack, stroke, coma or seizure, following CABG. Cross-clamp time was defined as the time the aorta was clamped. Perfusion time was defined as time on a bypass machine.
2.6. End-point determination
The primary end-point for this analysis was all-cause mortality. Mortality was determined utilizing the Social Security Death master file, as previously described.15
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3. Results
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3.1. Clinical characteristics
There were 3667 patients who underwent isolated first-time CABG between September 1992 through December 2001 at The Mid America Heart Institute. The mean follow-up for this cohort was 5.1 years. The mean length of stay for the entire cohort was 5.1±2.5 days. A sole blood sample was obtained for CK-MB determination at 15.1±2.6h following CABG, for the entire cohort. There were differences in the baseline clinical demographics among the study groups, as shown in Table 1. Patients with >3 times ULN elevation of CK-MB were more frequently older, had a smaller BMI, a greater number of diseased vessels and more likely to receive an arterial conduit. The frequency of diabetes mellitus was lower in the >3 times ULN CK-MB elevation group. The procedural characteristics and short-term outcomes of the depicted CK-MB groups are shown in Table 2. Patients with an elevation of CK-MB had significantly longer cross-clamp times compared with the normal CK-MB group. They were also more likely to receive blood products during the peri-operative period. The in-hospital complications were similar, including the rate of re-operation, neurologic complications, dialysis, or in-hospital mortality. The difference in mortality is noted early, following CABG.
3.2. Concomitant medications
The utilization of concomitant medications among the study groups was similar. The incidence of immediate pre-operative use of beta-blockers was 40%, 47% and 47% for the normal, >13 and >3 times ULN groups respectively, p=0.2. The incidence of immediate pre-operative use of angiotensin converting enzyme inhibitors was 31%, 28% and 28% for the normal, >13 and >3 times ULN groups respectively, p=0.5. The incidence of immediate pre-operative use of aspirin was 11%, 10% and 11% for the normal, >13 and >3 times ULN groups respectively, p=0.6. The incidence of immediate pre-operative use of lipid-lowering agents was 43%, 42% and 41% for the normal, >13 and >3 times ULN groups respectively, p=0.8. The incidence of immediate pre-operative use of calcium antagonists was 39%, 37% and 39% for the normal, >13 and >3 times ULN groups respectively, p=0.6.
3.3. Survival
The difference in mortality is noted early, following CABG. The 30-day mortality rate was 0.6%, 1.1% and 2.2% for the normal, >13 times and >3 times the ULN groups respectively, p=0.03. The unadjusted event-free survival for the study groups are depicted in the KaplanMeier curves in Fig. 1and Fig. 2. Fig. 1stratifies this cohort into three CK-MB groups: normal, >13 and >3 times the ULN. Fig. 2stratifies this cohort into four CK-MB groups: normal, >13, >35 and >5 times the ULN. Additionally, the risk of long-term mortality is stratified for each incremental CK-MB elevation as shown in Fig. 3. This figure demonstrates the relative risk and 95% confidence limits for long-term mortality for the depicted cut points of CK-MB. There appears to be a threshold for an increased risk of mortality associated with increased CK-MB elevation. Based upon this figure, that threshold is approximately four times the upper limit of normal. Further clarifying the risk of mortality with CK-MB elevation, the slope of the weighted linear regression also demonstrates a significant incremental increase in mortality (compared with a zero slope line) for an increasing level of CK-MB, following first time isolated CABG.

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Fig. 1 KaplanMeier survival curves depicting the risk of all-cause mortality for this cohort stratified into three CK-MB groups: Normal, 13 times, >3 times the upper limit of normal.
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Fig. 2 KaplanMeier survival curves depicting the risk of all-cause mortality for this cohort stratified into four CK-MB groups: Normal, 13 times, >35 times and >5 times the upper limit of normal.
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Fig. 3 This figure demonstrates the relative risk and 95% confidence limits for long-term mortality for each elevation of CK-MB. The weighted linear regression line (and slope) is also depicted in this figure.
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A multi-variate analysis was performed in order to determine if CK-MB elevation following coronary surgery remained associated with mortality after controlling for known predictors of long-term mortality and after adjusting for the imbalances in the clinical demographics associated with CK-MB elevation. The results of this multi-variate analysis are depicted in Table 3. Significant predictors of mortality following this modeling process included age, creatinine, no arterial conduit, NYHA, ejection fraction, history of peripheral arterial disease, CK-MB elevation and diabetes mellitus. Thus, CK-MB level following CABG remained a significant predictor of long-term mortality, following adjustment for these depicted co-variates.
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4. Discussion
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These data suggest that any CK-MB elevation following CABG is common, occurring in 95% of patients within this registry. There were 57% of patients with a CK-MB value >3 times the upper limit of normal. CK-MB elevation is associated with an increased risk of both early and late mortality, following isolated CABG. This risk becomes apparent at approximately four times the upper limit of normal and persists following multi-variate adjustment. This work is consistent with two other recently published studies linking post-operative CK-MB elevation with an increased hazard for long-term mortality, following CABG and numerous other reports published demonstrating a similar association following PCI.
A sub-study from the Arterial Revascularization Study (ARTS) evaluated the risk of 1-year death or non-fatal MI associated with a CK-MB rise, among the 496 patients randomized to the CABG arm of this trial. In this series, nearly 62% of patients had CK-MB elevation following CABG. Furthermore, there appeared to be an increased risk of either 1-year death or MI in the >5ULN of normal. Additionally, there was a trend for an increased risk of death for the >35ULN group in this analysis. In further support of this link are data from a sub-set of 2394 patients enrolled in the GUARDIAN trial. In this analysis there was an increasing risk of 6-month mortality with each incremental increase in the CK-MB isoenzyme elevation <5ULN 3.4%, =5 and <10ULN 5.8%, =10 and <20ULN 7.8% and =20ULN 20.2%, p<0.001. In all three analyses, CK-MB elevation, following isolated CABG, remained a predictor of death (death or MI in the ARTS analysis) following multi-variate adjustment for imbalances in the study cohort and known predictors of mortality, following CABG.
Similar to the finding in ARTS, patients with diabetes mellitus were more likely to be in the normal or >13 ULN group in this analysis. Yet, patients with diabetes remain at heightened risk for long-term mortality, following CABG. The mechanism for this remains unexplained but may be related to the negative arterial remodelling process among patients with diabetes mellitus. Patients with diabetes mellitus have been shown to have a maladaptive arterial remodelling process resulting in small reference vessel size and greater luminal stenosis with lower plaque area.16Thus, for any given stenosis among it is thought there is less plaque mass. Recent intravascular serial ultrasound data suggest the post-PCI elevation of CK-MB may be related to plaque area.17If, in fact, these observations are correct, it is plausible that patients with diabetes may have a lower incidence of post-procedural CK-MB elevation than patients without diabetes, based solely upon plaque area.
4.1. Limitations
There are numerous limitations in this type of analysis. Firstly, this is a post hoc analysis from registry data with the resultant accompanying biases. Although it should be remembered that this type of analysis also results in consecutive series of patients undergoing CABG without the referral bias of a randomized controlled trial. The time to peak CK-MB level, following CABG, has been ill-defined but likely occurs relatively early within 612h following CABG.18The major limitation to this study is that a sole CK-MB value was obtained approximately 15h following CABG. This limitation very likely bias our CK-MB data, with respect to the risk associated with an absolute level of CK-MB elevation, given it is likely that the level peaked prior to obtaining this sample. Fortunately, there was little variation with respect to obtaining the CK-MB sample across the study participants, as evidenced by the relatively narrow standard deviation. This lack of serial CK-MB determination does not, however, detract from the predictive nature of CK-MB elevation for mortality, following CABG. The lack of serial collection of CK-MB results in identification of mortality risk for a 12-h CK-MB elevation rather than identification of risk for peak value of CK-MB.
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5. Conclusion
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Data from this consecutive series of patients, undergoing first time isolated CABG, suggest that post-operative CK-MB elevation is common and associated with a heightened risk of mortality. This difference in event-free survival is evident at 30-days, persists through 5-year follow-up and is maintained following multi-variate adjustment for known predictors of mortality and imbalances among the baseline demographics.
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References
|
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- Kornowski R et al. Prognostic value of recurrent episodes of creatine kinase-MB elevation following repeated catheter-based coronary interventions. Catheter Cardiovasc Interv. 2000;51(2):131137.[CrossRef][Medline]
- Stone GW et al. Differential impact on survival of electrocardiographic Q-wave versus enzymatic myocardial infarction after percutaneous intervention: a device-specific analysis of 7147 patients. Circulation. 2001;104(6):642647.[Abstract/Free Full Text]
- Dangas G et al. Postprocedure creatine kinase-MB elevation and baseline left ventricular dysfunction predict one-year mortality after percutaneous coronary intervention. Am J Cardiol. 2002;89(5):586589.[CrossRef][Medline]
- Gruberg L et al. Creatine kinase-MB fraction elevation after percutaneous coronary intervention in patients with chronic renal failure. Am J Cardiol. 2001;87(12):13561360.[CrossRef][Medline]
- Fuchs S et al. Prognostic value of cardiac troponin-I levels following catheter-based coronary interventions. Am J Cardiol. 2000;85(9):10771082.[CrossRef][ISI][Medline]
- Saucedo JF et al. Long-term clinical events following creatine kinase myocardial band isoenzyme elevation after successful coronary stenting. J Am Coll Cardiol. 2000;35(5):11341141.[CrossRef][ISI][Medline]
- Hong MK et al. Creatine kinase-MB enzyme elevation following successful saphenous vein graft intervention is associated with late mortality. Circulation. 1999;100(24):24002405.[Abstract/Free Full Text]
- Costa MA et al. Incidence, predictors, and significance of abnormal cardiac enzyme rise in patients treated with bypass surgery in the arterial revascularization therapies study (ARTS). Circulation. 2001;104(22):26892693.[Abstract/Free Full Text]
- Warren SG et al. Diagnostic and prognostic significance of electrocardiographic and CPK isoenzyme changes following coronary bypass surgery: correlation with findings at one year. Am Heart J. 1977;93(2):189196.[Medline]
- Machler H et al. Preoperative myocardial cell damage in patients with unstable angina undergoing coronary artery bypass graft surgery. Anesthesiology. 1994;81(6):13241331.[Medline]
- Codd JE et al. Myocardial injury following myocardial revascularization. Detection by isoenzyme analysis. Circulation. 1977;56(Suppl 3):II49II53.[Medline]
- Klatte K et al. Increased mortality after coronary artery bypass graft surgery is associated with increased levels of postoperative creatine kinase-myocardial band isoenzyme release: results from the GUARDIAN trial. J Am Coll Cardiol. 2001;38(4):10701077.[CrossRef][ISI][Medline]
- Gum PA et al. Bypass surgery versus coronary angioplasty for revascularization of treated diabetic patients. Circulation. 1997;96(Suppl II):II7II10.
- Sergeant P, Blackstone E, Meyns B. Validation and interdependence with patient-variables of the influence of procedural variables on early and late survival after CABG. K.U. Leuven Coronary Surgery Program. Eur J Cardiothorac Surg. 1997;12(1):119.[Abstract]
- Suero JA et al. Procedural outcomes and long-term survival among patients undergoing percutaneous coronary intervention of a chronic total occlusion in native coronary arteries: a 20-year experience. J Am Coll Cardiol. 2001;38(2):409414.[CrossRef][Medline]
- Kornowski R et al. Paradoxic decreases in atherosclerotic plaque mass in insulin-treated diabetic patients. Am J Cardiol. 1998;81(11):12981304.[CrossRef][ISI][Medline]
- Mehran R et al. Atherosclerotic plaque burden and CK-MB enzyme elevation after coronary interventions: intravascular ultrasound study of 2256 patients. Circulation. 2000;101(6):604610.[Abstract/Free Full Text]
- Bonnefoy E et al. Troponin I, troponin T, or creatine kinase-MB to detect perioperative myocardial damage after coronary artery bypass surgery. Chest. 1998;114(2):482486.[Abstract/Free Full Text]