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Original Contribution |

Association Between Minor Elevations of Creatine Kinase-MB Level and Mortality in Patients With Acute Coronary Syndromes Without ST-Segment Elevation FREE

John H. Alexander, MD; Rodney A. Sparapani, BS; Kenneth W. Mahaffey, MD; Jaap W. Deckers, MD; L. Kristin Newby, MD; E. Magnus Ohman, MD; Ramòn Corbalàn, MD; Sergio L. Chierchia, MD; Jean B. Boland, MD; Maarten L. Simoons, MD; Robert M. Califf, MD; Eric J. Topol, MD; Robert A. Harrington, MD; for the PURSUIT Steering Committee
[+] Author Affiliations

Author Affiliations: Duke Clinical Research Institute, Durham, NC (Drs Alexander, Mahaffey, Newby, Ohman, Califf, and Harrington, and Mr Sparapani); Cardialysis, Rotterdam, the Netherlands (Drs Deckers and Simoons); Universidad Católica, Santiago, Chile (Dr Corbalán); Ospedale San Raffaele, Milan, Italy (Dr Chierchia); Hopital de la Citadelle, Liege, Belgium (Dr Boland); and the Cleveland Clinic Foundation, Cleveland, Ohio (Dr Topol). A list of the names of members of the PURSUIT Steering Committee has been published (N Engl J Med. 1998;338:436-443).


JAMA. 2000;283(3):347-353. doi:10.1001/jama.283.3.347.
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Context Controversy surrounds the diagnostic and prognostic importance of slightly elevated cardiac markers in patients with acute coronary syndromes without ST-segment elevation.

Objectives To investigate the relationship between peak creatine kinase (CK)-MB level and outcome and to determine whether a threshold CK-MB level exists below which risk is not increased.

Design and Setting Retrospective observational analysis of data from the international Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, conducted from November 1995 to January 1997.

Patients A total of 8250 patients with acute coronary sydromes without ST-segment elevation who had at least 1 CK-MB sample collected during their index hospitalization.

Main Outcome Measure Mortality at 30 days and 6 months, was assessed by category of index-hospitalization peak CK-MB level (0-1, >1-2, >2-3, >3-5, >5-10, or >10 times the upper limit of normal). Multivariable logistic regression was used to determine the independent prognostic significance of peak CK-MB level after adjustment for baseline predictors of 30-day and 6-month mortality.

Results Mortality at 30 days and 6 months increased from 1.8% and 4.0%, respectively, in patients with normal peak CK-MB levels, to 3.3% and 6.2% at peak CK-MB levels 1 to 2 times normal, to 5.1% and 7.5% at peak CK-MB levels 3 to 5 times normal, and to 8.3% and 11.0% at peak CK-MB levels greater than 10 times normal. Log-transformed peak CK-MB levels were predictive of adjusted 30-day and 6-month mortality (P<.001 for both).

Conclusions Our data show that elevation of CK-MB level is strongly related to mortality in patients with acute coronary syndromes without ST-segment elevation, and that the increased risk begins with CK-MB levels just above normal. In the appropriate clinical context, even minor CK-MB elevations should be considered indicative of myocardial infarction.

Figures in this Article

The criteria used to diagnose myocardial infarction (MI) are important both clinically and in clinical trials. The most widely accepted diagnostic criteria for MI are those of the World Health Organization, first proposed almost 20 years ago. These criteria require presence of at least 2 of the following 3 elements to diagnose MI: (1) a history of ischemic-type chest discomfort, (2) evolutionary changes on serial electrocardiograms, and (3) a rise and fall in serum cardiac enzymes.1

Today, the cornerstone of these diagnostic criteria is evaluation of serial cardiac markers. The most commonly used markers, both clinically and in clinical research, are creatine kinase (CK) and its more myocardium-specific MB isoenzyme, CK-MB.2,3 While many physicians consider even small elevations in CK-MB levels to represent evidence of MI, the diagnostic and prognostic importance of these small elevations remains controversial both in patients with acute coronary syndromes (ACSs) and in those who undergo coronary intervention.410 Due to evolving cardiac-marker technology and the vagueness of the World Health Organization criteria regarding what constitutes adequate evidence of "a rise and fall in serum enzymes," the definitions of MI used both clinically and in clinical trials have varied widely.

The large, multicenter Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial presents a unique opportunity to investigate the prognostic significance of CK-MB elevations in patients with ACSs without persistent ST-segment elevation.11 We evaluated the relationship between peak CK-MB level (as an estimate of infarct size) and outcome to determine whether a threshold of CK-MB elevation exists below which there is no increased risk. In addition, we examined the relationship between MI at the time of admission to the hospital (admission infarction) and after admission (postadmission infarction) and subsequent mortality.

Study Population

This study involved the 9461 patients included in the primary analysis of the PURSUIT trial. The PURSUIT trial has been described in detail.11 Briefly, patients with ACSs without persistent ST-elevation were randomly assigned to receive either a 180-µg/kg bolus and 2.0-µg/kg per minute infusion of the glycoprotein IIb/IIIa inhibitor eptifibatide (Integrilin, COR Therapeutics Inc, San Francisco, Calif) or placebo for up to 72 to 96 hours. Inclusion criteria were ischemic symptoms within 24 hours of randomization accompanied by (1) ST-segment depression, transient ST-segment elevation, or T-wave inversion, or (2) an elevated CK-MB level. Major exclusion criteria were persistent ST-segment elevation, history of bleeding diathesis, recent gastrointestinal tract or genitourinary bleeding, severe hypertension, recent major surgery, prior hemorrhagic stroke, stroke of any type in the past 30 days, pregnancy, renal failure (serum creatinine level ≥2.0 mg/dL), and planned or recent administration of a glycoprotein IIb/IIIa inhibitor or thrombolytic agent. Patients were followed up for a primary end point of death or nonfatal MI at 30 days.

The protocol specified that 3 CK-MB samples be collected from all patients every 8 hours after enrollment, with another 3 samples (at 8-hour intervals) after any suspected MI, percutaneous coronary intervention, or coronary artery bypass grafting. Additional samples were collected at the discretion of the treating physician. Sites that could not perform CK-MB assays performed total CK assays. The CK-MB and CK samples were analyzed in each hospital's clinical laboratory. The results, along with the upper limit of normal (ULN) for that laboratory, were collected on the case report form and verified against original source documents. Baseline characteristics, enrollment variables, and clinical outcomes also were collected on the case report form.

The primary use of the CK and CK-MB data was to diagnose MI. A diagnosis of MI on admission was made if there was elevation of CK-MB above the ULN prior to or within 16 hours of admission. Postadmission MI was diagnosed if there was new ischemic chest pain and new ST-segment elevation lasting at least 30 minutes within 18 hours of admission. After 18 hours, MI was diagnosed if there was a new or repeated elevation of CK-MB above the ULN or if there were new Q waves in 2 electrocardiographic leads. For patients undergoing percutaneous coronary intervention, an MI after the procedure was diagnosed if there was elevation of CK-MB to 3 or more times the ULN or new Q waves in 2 electrocardiographic leads. The diagnosis of MI following coronary artery bypass graft surgery required an elevation of CK-MB to 5 or more times the ULN or new Q waves in 2 electrocardiographic leads.11 A blinded clinical events committee adjudicated all suspected infarctions that occurred after admission to 30 days according to prespecified criteria.11

Comparison Groups

The 8250 patients (87.2%) who had at least 1 CK-MB sample collected during the index admission were stratified by the peak CK-MB level during this admission: 0 to 1 times ULN (or normal), greater than 1 to 2 times ULN, greater than 2 to 3 times ULN, greater than 3 to 5 times ULN, greater than 5 to 10 times ULN, or greater than 10 times ULN. Patients also were stratified into these categories after excluding enzymes associated with an admission infarction. To exclude these enzymes, patients who had either an admission infarction or an elevated CK-MB level within 12 hours of admission had CK-MB samples excluded for 48 hours or until they had a CK-MB level of less than the ULN. To eliminate the potentially confounding effect of percutaneous coronary intervention and coronary artery bypass surgery on CK-MB levels, analyses were repeated after excluding patients who had these procedures during their first admission. Patients also were stratified into the categories of admission infarction only, postadmission infarction only, neither, or both.

Statistical Methods

Continuous variables are expressed as medians, and categorical variables are expressed as percentages. Baseline variables, 30-day and 6-month mortality, and other clinical outcomes were determined by peak CK-MB category. The continuous relationships between peak CK-MB level and both 30-day and 6-month mortality also were determined. Hypothesis testing was performed using a logistic-proportional odds regression model for continuous variables and the Cochran-Mantel-Haenszel general association and correlation statistics for nominal and ordinal variables, respectively. Mortality rates were then determined for patients in each infarction category (admission infarction, postadmission infarction, neither, and both). Odds ratios and 95% confidence intervals were calculated for 30-day and 6-month mortality for each category vs the no infarction category.

A multivariable regression model that predicts 30-day mortality in the PURSUIT population has been developed.12 Variables in this model are age, sex, weight, weight squared, height, region of enrollment, prior hypertension, diabetes mellitus, smoking status, worst Canadian Heart Classification in the past 6 weeks, prior congestive heart failure, prior angioplasty, prior coronary artery bypass surgery, prior β-blocker use, prior calcium-antagonist use, prior nitrate use, admission MI, systolic blood pressure, heart rate, rales, ST-segment depression, time from onset of symptoms, eptifibatide use, and the interaction terms of age by admission infarction, heart rate by admission infarction, and eptifibatide by admission infarction.

For the purpose of our analyses, variables pertaining to admission infarction were removed from the model because of their confounding effect with CK-MB data. A single variable describing peak CK-MB level was then added to the model to determine whether overall peak CK-MB level had independent prognostic significance for 30-day and 6-month mortality, after adjustment. Log transformation was performed because of the nonlinear relationship between peak CK-MB level and mortality. This single-peak CK-MB variable was then removed and each individual peak CK-MB category was added to the model to determine its independent prognostic significance after adjusting for other baseline predictors of mortality.

Of 8250 patients with CK-MB data, 42% did not have CK-MB levels above the ULN, 18% had peak CK-MB levels of greater than 1 to 2 times the ULN, and approximately 10% had peak CK-MB levels in each of the other categories (Figure 1). Baseline patient characteristics by peak CK-MB category are shown in Table 1. Patients with higher peak CK-MB levels were older, and more often were male, white, and current smokers. These patients also had lower systolic blood pressure on admission, tended to weigh more and be taller, had more prior strokes and peripheral vascular disease, were less likely to have had prior angina, and were more likely to have ST-segment depression on their admission electrocardiogram.

Figure 1. Distribution of Peak Creatine Kinase (CK)-MB Levels by Category
Graphic Jump Location
Includes all enzymes and only enzymes associated with postadmission infarctions.
Table Graphic Jump LocationTable 1. Baseline Patient Characteristics by Peak Creatine Kinase (CK)-MB Category*

The relationship between peak CK-MB level and mortality at 30 days and 6 months is shown in Figure 2 and Figure 3. There was a statistically significant overall relationship between peak CK-MB level and both 30-day and 6-month mortality (P<.001 for both). This higher risk of 30-day mortality began with the peak CK-MB category just above the ULN (P<.001). The relationship between peak CK-MB level and other clinical outcomes is shown in Table 2. Patients with higher peak CK-MB levels had higher in-hospital rates of stroke, shock, congestive heart failure, ventricular tachycardia or fibrillation, atrioventricular block, moderate or severe bleeding, and coronary artery bypass surgery and percutaneous coronary artery intervention at 30 days, than patients with lower peak CK-MB levels.

Figure 2. Mortality at 30 Days and 6 Months by Peak Creatine Kinase (CK)-MB Category, All CK-MB Samples
Graphic Jump Location
Figure 3. Continuous Relationship Between Peak Creatine Kinase (CK)-MB as a Multiple of the Upper Limit of Normal and Mortality at 30 Days and 6 Months
Graphic Jump Location
Dotted lines represent 95% confidence intervals. Gray line represents the upper limit of the normal range.
Table Graphic Jump LocationTable 2. Clinical Outcomes by Peak Creatine Kinase (CK)-MB Category*

When only CK-MB samples not associated with admission infarctions were considered, 71% of patients did not have CK-MB levels above the ULN, 13% had peak CK-MB levels of greater than 1 to 2 times the ULN, and between 3% and 5% had peak CK-MB levels in each of the other categories (Figure 1). The relationship between postadmission infarction peak CK-MB level and mortality is shown in Figure 4. There was a statistically significant relationship overall between postadmission infarction peak CK-MB level and 30-day and 6-month mortality (P<.001 for each), similar to the relationship observed when all CK-MB samples were included. This higher risk of 30-day mortality began with the postadmission infarction peak CK-MB category just above the ULN (P<.001).

Figure 4. Mortality at 30 Days and 6 Months by Peak Creatine Kinase (CK)-MB Category, Postadmission Infarction CK-MB Samples Only
Graphic Jump Location

Patients receiving only medical treatment (no percutaneous or surgical revascularization) (n = 6512) showed the same significant relationship between peak CK-MB level and both 30-day and 6-month mortality (P<.001 for each). This higher risk of 30-day mortality also began with the peak CK-MB category just above the ULN (P<.001).

A total of 3545 patients had only an admission infarction, 529 had only a postadmission infarction, 681 had both, and 3791 patients had neither. Admission infarction was associated with modestly higher odds of death at 30 days and 6 months, whereas postadmission infarction was associated with markedly higher odds of death at both 30 days and 6 months compared with those with no infarction (Figure 5).

Figure 5. Odds Ratios and 95% Confidence Intervals for Risk of 30-Day and 6-Month Mortality
Graphic Jump Location
Values represent patients with admission infarction only, postadmission infarction only, and both compared with those with no infarction. MI indicates myocardial infarction. Gray line represents referent for 30-day and 6-month mortality for those patients with no infarction.

The log-transformed peak CK-MB level was highly predictive of both 30-day (Wald χ2, 80.57; P<.001) and 6-month mortality (Wald χ2, 74.46; P<.001) after adjustment for other baseline predictors. When the individual peak CK-MB categories were included in the model, a strong stepwise association was found between peak CK-MB level and 30-day mortality (Figure 6). The relationship between peak CK-MB level and mortality was similar between patients who received eptifibatide and those who did not.

Figure 6. Odds Ratios and 95% Confidence Intervals for 30-Day Mortality for Each Peak Creatine Kinase (CK)-MB Category Relative to the Normal Range After Adjustment for Other Baseline Predictors
Graphic Jump Location
Gray line represents referent for 30-day mortality for normal peak CK-MB level.

In this analysis of more than 8000 patients with ACSs, we found a strong relationship between a patient's peak CK-MB level during hospitalization and both 30-day and 6-month mortality. There was no threshold peak CK-MB elevation below which the risk of mortality was not increased. Even the peak CK-MB category of 1 to 2 times the ULN conferred a highly significant increase in the risk of death compared with a peak CK-MB level within the normal range. After adjustment for other baseline predictors of mortality, peak CK-MB level remained a strong independent predictor of mortality. Although the risk associated with a CK-MB level of just 1 to 2 times the ULN was not statistically significant after adjustment, there was a stepwise increase in risk with each higher peak CK-MB category. In addition to having higher mortality, patients with higher peak CK-MB levels also had higher rates of stroke, shock, congestive heart failure, ventricular arrhythmias, coronary procedures, and bleeding. This relationship between peak CK-MB level and mortality was observed both when all enzymes were included and when enzymes associated with admission infarctions were excluded. In addition, the same relationship between peak CK-MB level and mortality was observed when the potentially confounding effects of percutaneous intervention and bypass surgery were removed.

Patients who had an admission infarction (vs those with unstable angina) had a modestly increased risk of death at both 30 days and 6 months. In contrast, patients who had a postadmission infarction had a markedly increased risk of death, whether the patient was admitted with unstable angina or MI. Previous studies have shown that patients with positive cardiac markers at admission, whether CK-MB or troponin, have an increased risk of reinfarction1215 and that recurrent events are associated with an increased risk of death.1620 The reasons that recurrent coronary events carry such prognostic importance are not clear. These events may represent evidence of a refractory pathophysiological process that progresses despite ongoing medical therapy. Regardless of the mechanism, our findings reinforce the clinical importance of preventing, detecting, and treating even small reinfarctions in patients admitted with ACSs.

The relationship between the magnitude of CK increase and infarct size has been shown in patients with ST-segment elevation and acute MI.21,22 In addition, prethrombolytic-era studies, primarily of patients with ST-segment elevation infarction, have reported associations between infarct size (as measured by CK or CK-MB) and prognosis, the incidence and severity of congestive heart failure, left ventricular dysfunction, the frequency and severity of ventricular arrhythmias, infarct size at autopsy, and angiographic estimates of infarct size.2230 Several studies in small numbers of patients with suspected infarction have shown that even mildly elevated CK-MB levels are associated with worse clinical outcomes.5,7,8,31,32 Long-term mortality in these patients was found to be similar to that of patients without CK-MB elevation in one study6 but was significantly higher in another.8 Our analysis confirms, in a contemporary patient population presenting with ACSs without ST-segment elevation, that any elevation of CK-MB is associated with worse outcomes.

The most extensive work on the relationship between small-to-moderate CK-MB elevations and outcome has been done in patients undergoing coronary intervention.9,10 After percutaneous intervention, CK-MB elevation occurs in 10% to 40% of patients, and in most studies has been associated with an increased risk of adverse outcomes.9,10,3339 Similar to our findings, the increased risk associated with CK-MB elevation in these studies began just above the ULN and was proportional to the degree of elevation.9,37

The exact mechanism of minor CK-MB elevation in patients with ACSs or in patients undergoing coronary intervention is not known. Most studies support that myocardial CK-MB is not released in the absence of irreversible myocardial necrosis; however, controversy does still exist.9,4042 Whether associated with pathologically demonstrable myocardial necrosis, however, even minor elevation of CK-MB is prognostically important. There is increasing evidence, predominantly from the interventional literature, that minor CK-MB elevation may be a marker of ongoing vascular instability resulting in recurrent platelet microemboli and microscopic infarction.9,10,37,43 This vascular instability associated with recurrent platelet emboli may represent the refractory pathophysiology behind the worse outcomes observed in patients with ACSs who have evidence of recurrent myocardial necrosis. This hypothesis is supported by the effect of glycoprotein IIb/IIIa inhibitors on CK-MB elevations both after percutaneous intervention and in patients with ACSs, as well as the particularly robust effects of these agents in patients who present with evidence of myocardial necrosis.44,45

Almost 30% of the patients enrolled in the PURSUIT trial had an elevated CK-MB level after their admission event had resolved. This event rate is high compared with the 12.9% rate of MI reported in PURSUIT and the 6.0% rate in a similar subgroup within the Global Use of Strategies to Open Occluded Coronary Arteries-IIb (GUSTO-IIb) trial.11,46 The difference between the rates of infarction and CK-MB elevation in PURSUIT probably reflects the application by the clinical events committee of protocol-specified criteria to define infarction.11 Conversely, since GUSTO-IIb used the same definition of infarction, the difference in the infarction rates between PURSUIT and GUSTO-IIb likely results from a greater number of enzyme samples collected per patient in PURSUIT than in GUSTO-IIb (medians [25th, 75th percentiles], 3 [1, 4] vs 4.5 [3, 7]), respectively. Both the criteria for MI and the frequency of CK-MB sampling can have a profound effect on observed event rates. The accurate interpretation of trial results requires that these factors be reported in trial publications.

This analysis has several limitations. The study was retrospective and observational, and there may be unaccounted factors that could explain the observed differences in mortality. Although the PURSUIT inclusion criteria were broad, there are some patients with chest pain for whom these data do not apply. The 6-month follow-up period was relatively short; however, this should, if anything, reduce our ability to detect differences between groups. The CK-MB samples were analyzed in multiple laboratories using different assays. This variability also would reduce the ability to detect differences and we attempted to adjust for it by expressing the values as multiples of the laboratory's ULN. We used each patient's highest CK-MB level as an estimate of infarct size and did not take into account multiple infarctions. Finally, early deaths, which occurred before patients could reach their true peak CK-MB level, would be counted in a lower peak CK-MB category. This categorization would tend to bias the results in the direction of lower CK-MB categories being associated with worse outcomes, however, our primary findings were in the opposite direction.

In conclusion, this study demonstrates that in patients with ACSs without ST-segment elevation, a strong relationship exists between the magnitude of CK-MB elevation and mortality, and the risk begins just above the ULN. Small CK-MB elevations represent clinically important evidence of myocardial necrosis and, we believe, should be considered sufficient cardiac-marker criteria for a diagnosis of MI in patients with ACSs. Elevation of CK-MB above the ULN identifies a group of patients at higher risk of death. Whether these patients will benefit from aggressive medical or interventional therapy will require further study. Therapies that reduce the incidence or magnitude of CK-MB elevation may be clinically beneficial.

Joint International Society and Federation of Cardiology/World Health Organization Task Force.  Nomenclature and criteria for diagnosis of ischemic heart disease.  Circulation.1979;59:707-709.
Adams JE, Abendschein DR, Jaffe AS. Biochemical markers of myocardial injury: is MB creatine kinase the choice for the 1990's?  Circulation.1993;88:750-763.
Wagner GS. Optimal use of serum enzyme levels in the diagnosis of acute myocardial infarction.  Arch Intern Med.1980;140:317-319.
Mercer DW, Varat MA. Detection of cardiac-specific creatine kinase isoenzyme in sera with normal or slightly increased total creatine kinase activity.  Clin Chem.1975;21:1088-1092.
Marmor A, Alpan G, Keidar S, Grendaier E, Palant A. The MB isoenzyme of creatine kinase as an indicator of severity of myocardial ischemia.  Lancet.1978;2:812-814.
White RD, Grande P, Califf L, Palmeri ST, Califf RM, Wagner GS. Diagnostic and prognostic significance of minimally elevated creatine kinase-MB in suspected acute myocardial infarction.  Am J Cardiol.1985;55:1478-1484.
Hong RA, Licht JD, Wei JY, Heller GV, Blaustein AS, Pasternak RC. Elevated CK-MB with normal total creatine kinase in suspected myocardial infarction: associated clinical findings and early prognosis.  Am Heart J.1986;111:1041-1047.
Yusuf S, Collins R, Lin L, Sterry H, Pearson M, Sleight P. Significance of elevated MB isoenzyme with normal creatine kinase in acute myocardial infarction.  Am J Cardiol.1987;59:245-250.
Califf RM, Abdelmeguid AE, Kuntz RE.  et al.  Myonecrosis after revascularization procedures.  J Am Coll Cardiol.1998;31:241-251.
Adgey AAJ, Mathew TP, Harbinson MT. Periprocedural creatine kinase-MB elevations: long-term impact and clinical implications.  Clin Cardiol.1999;22:257-265.
The PURSUIT Trial Investigators.  Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes without persistent ST-segment elevation.  N Engl J Med.1998;339:436-443.
Boersma E, Pieper KS, Steyerberg EW.  et al. for the PURSUIT Investigators.  Predictors of outcome in patients with acute coronary syndromes without persistent ST-segment elevation: results from an international trial of 9461 patients.  J Am Coll Cardiol.1999;33:359A.
Ohman EM, Armstrong PW, Christenson RH.  et al.  Cardiac troponin T levels for risk stratification in acute myocardial ischemia.  N Engl J Med.1996;335:1333-1341.
Antman EM, Tanasijevic MJ, Thompson B.  et al.  Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes.  N Engl J Med.1996;335:1342-1349.
Hamm CW, Godmann BU, Heeschen C, Kreymann G, Berger J, Meinertz T. Emergency room triage of patients with acute chest pain by means of rapid testing for cardiac troponin T or troponin I.  N Engl J Med.1997;337:1648-1653.
Benhorin J, Moss AJ, Oakes D. Prognostic significance of nonfatal myocardial reinfarction.  J Am Coll Cardiol.1990;15:253-258.
Mueller HS, Forman SA, Menegus MA, Cohen LS, Knatterud GL, Braunwald E. Prognostic significance of nonfatal reinfarction during 3-year follow-up: results of the Thrombolysis in Myocardial Infarction (TIMI) phase II clinical trial.  J Am Coll Cardiol.1995;26:900-907.
Kornowski R, Goldbourt U, Zion M.  et al.  Predictors and long-term prognostic significance of recurrent infarction in the year after a first myocardial infarction.  Am J Cardiol.1993;72:883-888.
Hudson MP, Granger CB, Pieper KS.  et al.  Reinfarction after thrombolytic therapy: experience from the GUSTO-I and -III trials.  J Am Coll Cardiol.1999;33:325A.
van Domberg RT, Deckers JW, Azar AJ.  et al.  Prognostic significance of nonfatal myocardial reinfarction in survivors of a first infarct.  Eur Heart J.1998;19:166.
Norris RM, Whitlock RM, Barratt-Boyes C, Small CW. Clinical measurement of myocardial infarct size: modification of a method for the estimation of total creatine phosphokinase release after myocardial infarction.  Circulation.1975;51:614-620.
Shell WE, Sobel BE. Biochemical markers of ischemic injury.  Circulation.1976;53(3 Suppl):I98-106.
Fioretti P, Sclavo M, Brower RW, Simoons ML, Hugenholtz PG. Prognosis of patients with different peak serum creatine kinase levels after first myocardial infarction.  Eur Heart J.1985;6:473-478.
Geltman EM, Ehsani AA, Campbell MK, Roberts R, Sobel BE. Determinants of prognosis after initial subendocardial compared to transmural myocardial infarction: the importance of infarct size.  Am J Cardiol.1979;43:370.
Sobel BE, Bresnahan GF, Shell WE, Yoder RD. Estimation of infarct size in man and its relation to prognosis.  Circulation.1972;46:640-648.
Mathey D, Bleifeld W, Hanrath P, Effert S. Attempt to quantitate relation between cardiac function and infarct size in acute myocardial infarction.  Br Heart J.1974;36:271-279.
Cox JR, Roberts R, Ambos HD, Oliver GC, Sobel BE. Relations between enzymatically estimated myocardial infarct size and early ventricular dysrhythmia.  Circulation.1976;53(3 suppl):I150-I155.
Roberts R, Husain A, Ambos HD, Oliver GC, Cox JR, Sobel BE. Relations between infarct size and ventricular arrhythmia.  Br Heart J.1975;37:1169-1175.
Bleifeld W, Mathey D, Hanrath P, Buss H, Effert S. Infarct size estimated from serial serum creatine phosphokinase in relation to left ventricular hemodynamics.  Circulation.1977;55:303-311.
Rogers WJ, McDaniel HG, Smith LR, Mantle JA, Russell RO, Rackley CE. Correlation of angiographic estimates of infarct size and accumulated release of creatine kinase MB isoenzyme in man.  Circulation.1977;56:199-204.
Clyne CA, Mederiros JL, Marton KI. The prognostic significance of immunoradiometric CK-MB assay (IRMA) diagnosis of myocardial infarction in patients with low total CK and elevated MB isoenzymes.  Am Heart J.1989;118:901-906.
Savonitto S, Granger CB, Ardissino D.  et al.  Even minor elevations of creatine kinase predict increased risk of cardiac events in acute coronary syndromes without ST-segment elevation.  J Am Coll Cardiol.1999;33:346A.
Harrington RA, Lincoff AM, Califf RM.  et al.  Characteristics and consequences of myocardial infarction after percutaneous coronary intervention.  J Am Coll Cardiol.1995;25:1693-1699.
Abdelmeguid AE, Topol EJ, Whitlow PL, Sapp SK, Ellis SG. Significance of mild transient release of creatine kinase-MB fraction after percutaneous coronary interventions.  Circulation.1996;94:1528-1536.
Kong TQ, Davidson CJ, Meyers SN, Tauke JT, Parker MA, Bonow RO. Prognostic implications of creatine kinase elevation following elective coronary interventions.  JAMA.1997;277:461-466.
Tardiff BE, Califf RM, Tcheng JE.  et al. for the IMPACT-II Investigators.  Clinical outcomes after detection of elevated cardiac enzymes in patients undergoing percutaneous intervention.  J Am Coll Cardiol.1999;33:88-96.
Simoons ML, van Den Brand M, Lincoff M.  et al.  Minimal myocardial damage during coronary intervention is associated with impaired outcome.  Eur Heart J.1999;20:1112-1119.
Cutlip DE, Baim DS, Senerchia C.  et al.  Clinical consequences of myocardial infarction following balloon angioplasty or directional coronary atherectomy: acute and one year results of the Balloon vs Optimal Atherectomy Trial (BOAT).  J Am Coll Cardiol.1997;29:187A.
Stone GW, Mehran R, Lansky AJ.  et al.  Long-term influence of CPK-MB elevation on mortality after percutaneous intervention: analysis of 7359 patients.  J Am Coll Cardiol.1999;33:80A.
Ahmed SA, Williamson JR, Roberts R.  et al.  The association of increased plasma MB CPK activity and irreversible ischemic myocardial injury in dog.  Circulation.1976;54:187-193.
Cohen L, Morgan J, Gustafson G. Enzyme and isoenzyme analysis in the coronary care unit. In: Gupta DS, ed. Principles and Practice of Acute Cardiac Care. Chicago, Ill: Year Book; 1984:383-403.
Bittl JA, Weisfeldt ML, Jacobus WE.  et al.  Creatine kinase of heart mitochondria: the progressive loss of enzyme activity during in vivo ischemia and its correlation to depressed myocardial function.  J Biol Chem.1985;260:208-214.
Koch K, von Dahl J, Dleinhans E.  et al.  Influence of a platelet GP IIb/IIIa receptor antagonist on myocardial hypoperfusion during rotational atherectomy as assessed by myocardial Tc-99m sestamibi scintigraphy.  J Am Coll Cardiol.1999;33:998-1004.
Kong DF, Califf RM, Miller DP.  et al.  Clinical outcomes of therapeutic agents that block the platelet glycoprotein IIb/IIIa integrin in ischemic heart disease.  Circulation.1998;98:2829-2835.
Hamm CW, Heeschen C, Goldmann B.  et al. and the CAPTURE Study Investigators.  Benefit of abciximab in patients with refractory unstable angina according to the troponin T status.  N Engl J Med.1999;340:1623-1629.
The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb Investigators.  A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes: The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb Investigators.  N Engl J Med.1996;335(11):775-782.

Figures

Figure 1. Distribution of Peak Creatine Kinase (CK)-MB Levels by Category
Graphic Jump Location
Includes all enzymes and only enzymes associated with postadmission infarctions.
Figure 2. Mortality at 30 Days and 6 Months by Peak Creatine Kinase (CK)-MB Category, All CK-MB Samples
Graphic Jump Location
Figure 3. Continuous Relationship Between Peak Creatine Kinase (CK)-MB as a Multiple of the Upper Limit of Normal and Mortality at 30 Days and 6 Months
Graphic Jump Location
Dotted lines represent 95% confidence intervals. Gray line represents the upper limit of the normal range.
Figure 4. Mortality at 30 Days and 6 Months by Peak Creatine Kinase (CK)-MB Category, Postadmission Infarction CK-MB Samples Only
Graphic Jump Location
Figure 5. Odds Ratios and 95% Confidence Intervals for Risk of 30-Day and 6-Month Mortality
Graphic Jump Location
Values represent patients with admission infarction only, postadmission infarction only, and both compared with those with no infarction. MI indicates myocardial infarction. Gray line represents referent for 30-day and 6-month mortality for those patients with no infarction.
Figure 6. Odds Ratios and 95% Confidence Intervals for 30-Day Mortality for Each Peak Creatine Kinase (CK)-MB Category Relative to the Normal Range After Adjustment for Other Baseline Predictors
Graphic Jump Location
Gray line represents referent for 30-day mortality for normal peak CK-MB level.

Tables

Table Graphic Jump LocationTable 1. Baseline Patient Characteristics by Peak Creatine Kinase (CK)-MB Category*
Table Graphic Jump LocationTable 2. Clinical Outcomes by Peak Creatine Kinase (CK)-MB Category*

References

Joint International Society and Federation of Cardiology/World Health Organization Task Force.  Nomenclature and criteria for diagnosis of ischemic heart disease.  Circulation.1979;59:707-709.
Adams JE, Abendschein DR, Jaffe AS. Biochemical markers of myocardial injury: is MB creatine kinase the choice for the 1990's?  Circulation.1993;88:750-763.
Wagner GS. Optimal use of serum enzyme levels in the diagnosis of acute myocardial infarction.  Arch Intern Med.1980;140:317-319.
Mercer DW, Varat MA. Detection of cardiac-specific creatine kinase isoenzyme in sera with normal or slightly increased total creatine kinase activity.  Clin Chem.1975;21:1088-1092.
Marmor A, Alpan G, Keidar S, Grendaier E, Palant A. The MB isoenzyme of creatine kinase as an indicator of severity of myocardial ischemia.  Lancet.1978;2:812-814.
White RD, Grande P, Califf L, Palmeri ST, Califf RM, Wagner GS. Diagnostic and prognostic significance of minimally elevated creatine kinase-MB in suspected acute myocardial infarction.  Am J Cardiol.1985;55:1478-1484.
Hong RA, Licht JD, Wei JY, Heller GV, Blaustein AS, Pasternak RC. Elevated CK-MB with normal total creatine kinase in suspected myocardial infarction: associated clinical findings and early prognosis.  Am Heart J.1986;111:1041-1047.
Yusuf S, Collins R, Lin L, Sterry H, Pearson M, Sleight P. Significance of elevated MB isoenzyme with normal creatine kinase in acute myocardial infarction.  Am J Cardiol.1987;59:245-250.
Califf RM, Abdelmeguid AE, Kuntz RE.  et al.  Myonecrosis after revascularization procedures.  J Am Coll Cardiol.1998;31:241-251.
Adgey AAJ, Mathew TP, Harbinson MT. Periprocedural creatine kinase-MB elevations: long-term impact and clinical implications.  Clin Cardiol.1999;22:257-265.
The PURSUIT Trial Investigators.  Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes without persistent ST-segment elevation.  N Engl J Med.1998;339:436-443.
Boersma E, Pieper KS, Steyerberg EW.  et al. for the PURSUIT Investigators.  Predictors of outcome in patients with acute coronary syndromes without persistent ST-segment elevation: results from an international trial of 9461 patients.  J Am Coll Cardiol.1999;33:359A.
Ohman EM, Armstrong PW, Christenson RH.  et al.  Cardiac troponin T levels for risk stratification in acute myocardial ischemia.  N Engl J Med.1996;335:1333-1341.
Antman EM, Tanasijevic MJ, Thompson B.  et al.  Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes.  N Engl J Med.1996;335:1342-1349.
Hamm CW, Godmann BU, Heeschen C, Kreymann G, Berger J, Meinertz T. Emergency room triage of patients with acute chest pain by means of rapid testing for cardiac troponin T or troponin I.  N Engl J Med.1997;337:1648-1653.
Benhorin J, Moss AJ, Oakes D. Prognostic significance of nonfatal myocardial reinfarction.  J Am Coll Cardiol.1990;15:253-258.
Mueller HS, Forman SA, Menegus MA, Cohen LS, Knatterud GL, Braunwald E. Prognostic significance of nonfatal reinfarction during 3-year follow-up: results of the Thrombolysis in Myocardial Infarction (TIMI) phase II clinical trial.  J Am Coll Cardiol.1995;26:900-907.
Kornowski R, Goldbourt U, Zion M.  et al.  Predictors and long-term prognostic significance of recurrent infarction in the year after a first myocardial infarction.  Am J Cardiol.1993;72:883-888.
Hudson MP, Granger CB, Pieper KS.  et al.  Reinfarction after thrombolytic therapy: experience from the GUSTO-I and -III trials.  J Am Coll Cardiol.1999;33:325A.
van Domberg RT, Deckers JW, Azar AJ.  et al.  Prognostic significance of nonfatal myocardial reinfarction in survivors of a first infarct.  Eur Heart J.1998;19:166.
Norris RM, Whitlock RM, Barratt-Boyes C, Small CW. Clinical measurement of myocardial infarct size: modification of a method for the estimation of total creatine phosphokinase release after myocardial infarction.  Circulation.1975;51:614-620.
Shell WE, Sobel BE. Biochemical markers of ischemic injury.  Circulation.1976;53(3 Suppl):I98-106.
Fioretti P, Sclavo M, Brower RW, Simoons ML, Hugenholtz PG. Prognosis of patients with different peak serum creatine kinase levels after first myocardial infarction.  Eur Heart J.1985;6:473-478.
Geltman EM, Ehsani AA, Campbell MK, Roberts R, Sobel BE. Determinants of prognosis after initial subendocardial compared to transmural myocardial infarction: the importance of infarct size.  Am J Cardiol.1979;43:370.
Sobel BE, Bresnahan GF, Shell WE, Yoder RD. Estimation of infarct size in man and its relation to prognosis.  Circulation.1972;46:640-648.
Mathey D, Bleifeld W, Hanrath P, Effert S. Attempt to quantitate relation between cardiac function and infarct size in acute myocardial infarction.  Br Heart J.1974;36:271-279.
Cox JR, Roberts R, Ambos HD, Oliver GC, Sobel BE. Relations between enzymatically estimated myocardial infarct size and early ventricular dysrhythmia.  Circulation.1976;53(3 suppl):I150-I155.
Roberts R, Husain A, Ambos HD, Oliver GC, Cox JR, Sobel BE. Relations between infarct size and ventricular arrhythmia.  Br Heart J.1975;37:1169-1175.
Bleifeld W, Mathey D, Hanrath P, Buss H, Effert S. Infarct size estimated from serial serum creatine phosphokinase in relation to left ventricular hemodynamics.  Circulation.1977;55:303-311.
Rogers WJ, McDaniel HG, Smith LR, Mantle JA, Russell RO, Rackley CE. Correlation of angiographic estimates of infarct size and accumulated release of creatine kinase MB isoenzyme in man.  Circulation.1977;56:199-204.
Clyne CA, Mederiros JL, Marton KI. The prognostic significance of immunoradiometric CK-MB assay (IRMA) diagnosis of myocardial infarction in patients with low total CK and elevated MB isoenzymes.  Am Heart J.1989;118:901-906.
Savonitto S, Granger CB, Ardissino D.  et al.  Even minor elevations of creatine kinase predict increased risk of cardiac events in acute coronary syndromes without ST-segment elevation.  J Am Coll Cardiol.1999;33:346A.
Harrington RA, Lincoff AM, Califf RM.  et al.  Characteristics and consequences of myocardial infarction after percutaneous coronary intervention.  J Am Coll Cardiol.1995;25:1693-1699.
Abdelmeguid AE, Topol EJ, Whitlow PL, Sapp SK, Ellis SG. Significance of mild transient release of creatine kinase-MB fraction after percutaneous coronary interventions.  Circulation.1996;94:1528-1536.
Kong TQ, Davidson CJ, Meyers SN, Tauke JT, Parker MA, Bonow RO. Prognostic implications of creatine kinase elevation following elective coronary interventions.  JAMA.1997;277:461-466.
Tardiff BE, Califf RM, Tcheng JE.  et al. for the IMPACT-II Investigators.  Clinical outcomes after detection of elevated cardiac enzymes in patients undergoing percutaneous intervention.  J Am Coll Cardiol.1999;33:88-96.
Simoons ML, van Den Brand M, Lincoff M.  et al.  Minimal myocardial damage during coronary intervention is associated with impaired outcome.  Eur Heart J.1999;20:1112-1119.
Cutlip DE, Baim DS, Senerchia C.  et al.  Clinical consequences of myocardial infarction following balloon angioplasty or directional coronary atherectomy: acute and one year results of the Balloon vs Optimal Atherectomy Trial (BOAT).  J Am Coll Cardiol.1997;29:187A.
Stone GW, Mehran R, Lansky AJ.  et al.  Long-term influence of CPK-MB elevation on mortality after percutaneous intervention: analysis of 7359 patients.  J Am Coll Cardiol.1999;33:80A.
Ahmed SA, Williamson JR, Roberts R.  et al.  The association of increased plasma MB CPK activity and irreversible ischemic myocardial injury in dog.  Circulation.1976;54:187-193.
Cohen L, Morgan J, Gustafson G. Enzyme and isoenzyme analysis in the coronary care unit. In: Gupta DS, ed. Principles and Practice of Acute Cardiac Care. Chicago, Ill: Year Book; 1984:383-403.
Bittl JA, Weisfeldt ML, Jacobus WE.  et al.  Creatine kinase of heart mitochondria: the progressive loss of enzyme activity during in vivo ischemia and its correlation to depressed myocardial function.  J Biol Chem.1985;260:208-214.
Koch K, von Dahl J, Dleinhans E.  et al.  Influence of a platelet GP IIb/IIIa receptor antagonist on myocardial hypoperfusion during rotational atherectomy as assessed by myocardial Tc-99m sestamibi scintigraphy.  J Am Coll Cardiol.1999;33:998-1004.
Kong DF, Califf RM, Miller DP.  et al.  Clinical outcomes of therapeutic agents that block the platelet glycoprotein IIb/IIIa integrin in ischemic heart disease.  Circulation.1998;98:2829-2835.
Hamm CW, Heeschen C, Goldmann B.  et al. and the CAPTURE Study Investigators.  Benefit of abciximab in patients with refractory unstable angina according to the troponin T status.  N Engl J Med.1999;340:1623-1629.
The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb Investigators.  A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes: The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb Investigators.  N Engl J Med.1996;335(11):775-782.
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