CLINICAL STUDY
The prognostic value of creatine kinase elevations extends across the whole spectrum of acute coronary syndromes
Stefano Savonitto, MD*,*,
Christopher B. Granger, MD, FACC ,
Diego Ardissino, MD ,
Laura Gardner, BSPH ,
Claudio Cavallini, MD||,
Marcello Galvani, MD¶,
Filippo Ottani, MD#,
Harvey D. White, DSc, FACC**,
Paul W. Armstrong, MD, FACC,
E. Magnus Ohman, MD, FACC,
Karen S. Pieper, MSc,
Robert M. Califf, MD, FACC,
Eric J. Topol, MD, FACC GUSTO-IIb Investigators
* Department of Cardiology, Niguarda Hospital, Milan, Italy
Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
Division of Cardiology, Ospedali Riuniti di Parma, Parma, Italy
Duke Clinical Research Institute, Durham, North Carolina, USA
|| Division of Cardiology, Presidio Ospedaliero Ca’ Foncello, Treviso, Italy
¶ Division of Cardiology, Ospedale Morgagni-Pierantoni, Forlí, Italy
# Division of Cardiology, Ospedale Civile, Bentivoglio, Italy
** Cardiology Department, Green Lane Hospital, Auckland, New Zealand
Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
Department of Cardiology, Cleveland Clinic, Cleveland, Ohio, USA
Manuscript received April 18, 2001;
revised manuscript received August 29, 2001,
accepted September 7, 2001.
* Reprint requests and correspondence: Dr. Stefano Savonitto, Divisione di Cardiologia, Ospedale Niguarda Ca’ Granda, Piazza Ospedale Maggiore 3, 20162 Milan, Italy.
ssavoni{at}tin.it
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Abstract
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OBJECTIVES: The study investigated the relationship among creatine kinase (CK) elevations, clinical characteristics and cardiac events across the whole spectrum of acute coronary syndromes (ACS).
BACKGROUND: Elevated serum levels of cardiac enzymes have been shown to be a major prognostic determinant in acute myocardial ischemia. Yet prior to this report, the relation between cardiac enzyme levels and other prognostic determinants across the entire spectrum of ACS has not been explored by a large clinical study.
METHODS: We evaluated the relation between the maximum CK ratio (CK level/upper limit of normal) in the early hours following admission and cardiac events at six months in 11,725 patients enrolled in a large trial of ACS.
RESULTS: Patients with higher risk characteristics, such as older age, female gender, hypertension, diabetes, prior coronary events or heart failure, more frequently presented without ST-segment elevation on the electrocardiogram and tended to develop lesser enzyme elevations. After adjusting for significant baseline predictors of cardiac events, a continuous correlation was observed between the CK ratio and death (chi-square 63.04, p < 0.0001) and (re)infarction or death (chi-square 55.48, p < 0.0001). This correlation was similar for patients with and without ST-segment elevation. The adjusted incidence of cardiac events at follow-up began to rise even for CK levels within the normal range, the steepest part of the curve residing between one and three times the upper limit of normal. In patients with a CK ratio of >1 to 2 compared with those within the normal range, the adjusted odds ratio for death was 1.26 (95% confidence interval [CI] 0.98 to 1.63), and 1.59 (95% CI 1.38 to 1.90) for (re)infarction and death. For all CK levels, the event rate was higher among patients without ST-segment elevation.
CONCLUSIONS: Although high-risk patients with ACS often develop lesser CK elevations, this study demonstrated that even minor enzyme elevations appear to have important and independent prognostic implications.
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Abbreviations and Acronyms
| | ACS | | acute coronary syndromes | | CK | | creatine kinase | | CK-MB | | creatine kinase-myocardial band | | ECG | | electrocardiogram/electrocardiographic | | GUSTO-IIb | | Global Use of Strategies to Open Occluded Coronary Arteries-IIb trial | | MI | | myocardial infarction | | PTCA | | percutaneous transluminal coronary angioplasty |
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Elevated cardiac enzyme levels during an episode of acute myocardial ischemia have been shown to imply a worse prognosis (1). A number of experimental and clinical studies have illustrated the relation between the amount of myocardial damage estimated by serum levels of creatine kinase (CK) and infarct size and the incidence and severity of heart failure, ventricular arrhythmias, left ventricular dysfunction and, ultimately, clinical outcomes (2–10). This model has been particularly validated for patients with myocardial infarction (MI) and ST-segment elevation. More recently, the focus has shifted to the prognostic importance of enzyme elevations in non–ST-segment elevation acute coronary syndromes (ACS) (11). However, the prognostic significance of CK levels in a large population of patients encompassing the entire range of ACS, the relative importance of CK elevations in patients with or without ST-segment elevation and the relation between CK levels and other prognostically meaningful baseline characteristics have not been investigated. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)-IIb trial offers a unique opportunity to explore these issues because it is presently the only study to have enrolled the entire spectrum of patients with ACS, including those with recent or ongoing chest pain and electrocardiographic (ECG) signs of acute myocardial ischemia (12).
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Methods
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Patient population.
The GUSTO-IIb trial enrolled 12,142 patients with symptoms of cardiac ischemia at rest within 12 h of admission and accompanying ECG signs of acute ischemia defined as either transient or persistent ST-segment elevation or depression (>0.05 mV), or persistent and definite T-wave inversion (>0.1 mV) (12). Patient enrollment was balanced to include two-thirds of patients without ST-segment elevation and one-third of patients with ST-segment elevation. All patients were treated with antithrombotic therapy including aspirin and either hirudin or heparin (for 48 to 72 h according to a randomized, double-blind schedule), fibrinolytic therapy when indicated and anti-ischemic drugs. Revascularization procedures were discouraged for the first 48 to 72 h unless there was evidence of recurrent ischemia.
CK measurements.
Enzymes were measured according to local hospital standards. During the pretrial phase, a specific form was sent to each of the participating centers in which the normal laboratory ranges for CK and creatine kinase-myocardial band (CK-MB) had to be reported, and the form was returned to the data coordinating center. The CK and, if available, CK-MB levels were determined at admission, 6 to 8 h after admission and 12 to 16 h after admission so as to reflect the enzyme elevation consequence of the event leading to enrollment. Overall, 98% of the patients had CK levels measured; CK-MB values were available for only 56% of patients. Therefore, only CK values were used in this analysis.
End points.
The primary end point of the GUSTO-IIb trial was the composite of death and (re)MI at 30 days, whereas the incidences of death and (re)MI at six months were secondary end points. However, the present study focused on mortality and the combined end point of death and (re)MI at six-month follow-up. Figure 1 shows the distribution of patients according to the availability of CK measurements and end point data for this study.
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Figure 1 Distribution of patients for each end point. CK = creatine kinase; MI = myocardial infarction.
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Patient’s vital status was derived from the 30-day and six-month follow-up forms completed by the investigators after a medical examination, a patient’s self-administered questionnaire or by telephone interview. The (re)MI was defined based on either cardiac enzyme or ECG evidence. Enzyme evidence was defined as a (re)elevation of CK-MB to above the upper limit of normal if the prior level was in the normal range, or >50% above the prior level if the prior level was above normal range. If CK-MB was not available, then the total CK elevation must have been greater than two times above the upper limit of normal and increased by at least 25% or 200 U/ml over the previous value. The ECG evidence of recurrent MI was defined as new, significant Q waves in at least two leads and discrete from the enrollment MI. All of the events were adjudicated by the clinical events committee at the coordinating center.
The events occurring during the initial hospital stay were adjudicated following a review of all source documents, whereas those occurring after hospital discharge were derived from the 30-day and six-month follow-up forms completed by the investigators. Because the present study examined the relation between the maximal CK level recorded during the episode leading to the index hospital admission and the incidences of subsequent events, the 95 patients who died within 16 h from admission were not included in the analysis, and MIs that occurred during the first 16 h of the index hospital admission were not considered as end points.
Statistical analysis.
The absolute CK values reported in each patient’s case record form were computer-transformed to CK ratios according to the following formula: CK ratio = CK level divided by the upper limit of normal in the local laboratory. As a continuous measure, the maximum CK ratio among the three measurements taken at admission, 6 to 8 h after admission and 12 to 16 h after admission was used. As a categorical measure, the maximum CK ratio was broken down into the following categories: 0 to 1 time, >1 to 2 times, >2 to 5 times and >5 times the upper limit of normal. The relation between these categories and baseline factors was described by using medians with 25th and 75th percentiles for continuous measures and percentages for categorical measures. Percentages of patients with and frequencies of events within each of these four categories of maximum CK ratio were also used in illustrating the association of increasing CK levels with death, (re)MI and death or (re)MI.
To explore the relationship of CK ratio with cardiac events within six months, logistic regression analysis was used. The CK ratio was considered both as a continuous and as a categorical measure. For both outcomes of death and death or (re)MI in six months, the continuous measure of the maximum CK ratio was modeled using a three-knot cubic spline transformation. Graphs of the average predicted probability of the outcome by the maximum CK ratio were used to demonstrate the shape of the effect. By using the patient’s baseline characteristics in the models, predicted probabilities were calculated for each patient for values of CK ratio from 0 to 20. The average predicted value for each CK ratio was then plotted. Odds ratios (ORs) with 95% confidence intervals were used to demonstrate the effect of maximum CK ratio as a categorical measure on outcome. Interactions between maximum CK ratio and strata (ST-segment elevation, non–ST-segment elevation) were explored for both outcomes for maximum CK ratio as a continuous and categorical measure.
To provide an adjusted effect of maximum CK ratio on outcome, baseline characteristics that were determined to be predictive of 30-day death and 30-day death and (re)MI in the GUSTO-IIb model (13) were used as adjustment factors in the models of six-month outcomes. The variables found to be predictive of death were age, heart rate, Killip class, systolic and diastolic blood pressure, previous MI, gender, peripheral vascular disease, hypertension, height, chronic renal insufficiency, hyperlipidemia, smoking status, family history of coronary disease, previous percutaneous transluminal coronary angioplasty (PTCA), weight and diabetes. The variables found to be predictive of death or (re)MI were age, heart rate, Killip class, systolic and diastolic blood pressure, previous MI, gender (and interaction with strata), peripheral vascular disease, hypertension, height, chronic renal insufficiency (and interaction with strata), ECG strata and previous angina. These variables, excluding those highly nonsignificant in predicting events within six months (namely, smoking status and family history of coronary disease did not predict death, and ECG strata did not predict death or [re]MI), were used to provide an adjusted effect of maximum CK ratio on six-month mortality and death or (re)MI.
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Results
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CK levels and baseline characteristics.
Of the 11,725 patients with recorded CK ratio who survived the first 16 h after admission and had six-month survival data, 4,814 (41%) had a maximum CK ratio of <1; 1,546 (13%) >1 to 2; 1,985 (17%) >2 to 5; and 3,380 (29%) >5. As shown in Figure 2, the majority of patients in the higher CK categories were in the ST-segment elevation cohort, and patients in the normal or lower CK categories were in the non–ST-segment elevation cohort. Compared with the ST-segment elevation group on hospital admission, patients without ST-segment elevation were older, more frequently women, and had a higher prevalence of risk factors for coronary disease and of previous coronary events (Table 1). However, the distribution of baseline characteristics among levels of CK ratio was similar in the ST-segment elevation and non–ST-segment elevation strata. Patients with normal or minimally elevated enzyme levels tended to be older. Patients with lower enzyme levels also tended to have higher risk characteristics such as hypertension, diabetes, previous MIs, angina, congestive heart failure, PTCA or bypass operations.
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Figure 2 Percentages of patients with creatine kinase (CK) ratios of 0 to 1, >1 to 2, >2 to 5 and >5 within 16 h from hospital admission in the total study population and in the cohorts with ST-segment elevation and non–ST-segment elevation on the admission electrocardiogram.
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CK levels and cardiac events.
The incidence of cardiac events at six months is shown in Table 2, and the total patient population examined (11,725) included those who survived the first 16 h after hospital admission and provided follow-up data. In this population, an increase in CK ratio was associated with an increase in mortality in the highest CK category, and the incidence of death or (re)MI appeared to increase for all CK values above normal levels (Table 2). In patients without ST-segment elevation, a higher mortality was observed most strongly with a CK ratio of >5, whereas the incidence of (re)MI increased with even minimal CK elevations. These trends were rather flat in the ST-segment elevation cohort. In comparison with the ST-elevation cohort, patients without ST-segment elevation and elevated CK levels had a slightly higher incidence of (re)MI. As shown in Figure 3, (re)infarctions occurred mostly during the first two weeks after index admission and slightly but significantly earlier in patients with no ST-segment elevation.
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Figure 3 Time course of (re)myocardial infarction (MI) after the index hospital admission in the ST-segment elevation and non–ST-segment elevation cohorts.
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Figures 4 and 5 show the relation between peak CK levels and the probability of cardiac events, after adjusting for the baseline predictors of mortality or the combined end point. In the total patient population, highly significant correlations were observed between the continuous measure of CK ratio and mortality (chi-square 65.49, p < 0.0001) and death or (re)MI (chi-square 51.00, p < 0.0001), and nonsignificant interactions were found with the ST-segment strata (Fig. 4A and 4B). The slope of the hazard curve for the relation between CK ratio and both end points tended to be steeper for non–ST-segment elevation, and for any given CK ratio the risk was higher in patients without ST-segment elevation (Fig. 4C and 4D). Also, no significant interaction with ST-segment strata was observed in the categorical analysis (overall chi-square 63.04 for death and 55.48 for death or (re)MI, both p < 0.0001). The adjusted OR for death in the total population showed an increase in the odds of mortality of 26% for a CK ratio as little as >1 to 2, increasing to 131% for CK ratios >5 (Fig. 5A). The OR for death or (re)MI showed a 59% increase already existing for a CK ratio >1 to 2 (Fig. 5B).
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Figure 4 Curves of the predicted probabilities averaged across all patients and adjusted for previously determined baseline covariates. Curves show the relationships between creatine kinase (CK) ratio and adjusted probability of death or death and (re)myocardial infarction (MI) at six months. A and B refer to the entire study population, which is split according to ST-segment presentation on the admission electrocardiogram (ECG) in C and D. No statistically significant interaction with ECG strata was observed after correcting for the significant prognostic predictors.
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Figure 5 (A) Adjusted odds ratios for six-month death in the total study population (11,725). No statistically significant interaction with electrocardiographic (ECG) strata was observed after correcting for the significant prognostic predictors (chi-square 63.04, p < 0.0001). (B) Adjusted odds ratio for six-month death and (re)myocardial infarction (MI) in the total study population (11,667). No statistically significant interaction with ECG strata was observed after correcting for the significant prognostic predictors (chi-square 55.48, p < 0.0001). CK = creatine kinase.
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Discussion
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The definition of an MI has been recently revised by the Joint Ad Hoc Committee of the European Society of Cardiology and the American College of Cardiology (14), and it is no longer based on the classical dichotomous partition between normal and abnormal levels of traditional cardiac enzymes. The revised definition now recognizes that any elevation in the biochemical markers of myocardial necrosis should be labeled as an MI, primarily because this elevation is associated with a worsened prognosis and a continuous relation starting from minimal myocardial damage up to large infarcts. The new definition emanated in large part from two recent sources: the large experience of studies of non–ST-segment elevation ACS (mostly characterized by undetectable or modest cell damage, as in the case of the non–ST-segment elevation cohort of the present study), and the recent availability of more sensitive and specific biochemical markers of myocardial necrosis, such as CK-MB mass and the troponins. The large population of patients enrolled in trials of ACS has encouraged the development of multivariable prognostic models based on clinical, ECG and biochemical data (1,11,13,15,16), and has refined the definition of the independent prognostic value of markers of acute myocardial damage (11,13,17–22).
The prognostic impact of CK elevations in patients with and without ST-segment elevation.
Taking advantage of the GUSTO-IIb database, the present study sought to determine the relation between CK elevations and cardiac events at follow-up and to compare the cohorts with and without ST-segment elevation on the admission ECG. This distinction between ST-segment elevation and non–ST-segment elevation presentations, beside having immediate therapeutic implications, implies important differences in terms of severity of coronary artery disease, prior cardiovascular events and long-term prognosis, all of which are worse in patients without ST-segment elevation (1,13). We found that patients in both ST-segment strata with higher risk characteristics (such as older age, prior cardiac events or heart failure) develop smaller enzyme elevations. This factor must be taken into account when looking at the unadjusted relation between CK ratio and event rates as the negative impact of CK elevations may be partially obscured by the high-risk characteristics of patients with lower enzyme levels.
Adjustment for the significant prognostic predictors revealed a highly significant correlation between CK levels and cardiac events, without significant interactions in the ST-segment strata. The higher risk characteristics of the non–ST-segment elevation cohort were reflected by higher event rates associated with any CK level. An explanation for why those with a longer history of coronary disease develop lesser enzyme elevations during an acute ischemic episode remains to be established. These patients may have a more developed collateral circulation or perhaps myocardial preconditioning. Reduced muscle mass might also explain smaller enzyme release in the elderly as well as in women.
According to the present study, the risk of (re)MI is maximal in the first few days or weeks after an ACS and appears to increase with even minimal CK elevations (particularly in the non–ST-segment elevation cohort), whereas the mortality risk increases more gradually, at least within the medium-term follow-up of the present study. Patients without ST-elevation reveal greater instability, as shown by a slightly higher and earlier incidence of (re)MI in comparison with those with ST-segment elevations. Previous studies have indicated that patients with positive cardiac markers on admission have an increased risk of (re)MI (21–23). In the multivariate model of the Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) study, CK-MB elevation was second only to old age in predicting the composite end point of death or (re)MI at 30 days. When predicting the risk of death only, CK-MB ranked after age, tachycardia, hypotension, ST-depression, and rales (16).
As hypothesized for elevated troponin levels, minimal enzyme elevations in patients with ACS may result from distal embolization of platelet and fibrin thrombi, emanating from an unstable coronary plaque (24,25), which may take months to stabilize fully after the index episode (26,27), and therefore identify patients at higher risk of (re)MI. Conversely, a large amount of myocardial necrosis or a history of repeated smaller infarcts puts the patient at high risk of death in the short-term period. These findings are consistent with those of smaller studies evaluating the risk of CK rises not exceeding the upper normal limit or that of CK-MB elevations with normal CK levels in patients with suspected acute MI (27,28). As in the present study, minimally elevated enzyme levels have been associated with severe medical problems (cardiac or respiratory failure) in which case these levels predicted a higher risk of death (29).
Study limitations.
The use of CK for detecting myocardial damage, which has largely been replaced by more sensitive biochemical markers (CK-MB and troponins), may be considered as a limitation of the present study. However, when assessed in patients with recent, typical ischemic symptoms and ECG signs of acute myocardial ischemia (such as those enrolled in the GUSTO-IIb trial), the prognostic value of CK elevations found in the present study is entirely consistent with the data derived from the above-mentioned smaller studies with CK-MB and troponins. The higher sensitivity of these latter markers might have resulted in an even steeper slope of the relation between minor myocardial damage and cardiac events. The relationship between peak CK or CK-MB levels and outcome might be less evident in patients with ST-elevation infarction achieving early reperfusion by either pharmacological or mechanical therapy. In fact, when reperfusion therapy is effective, cardiac enzyme levels tend to peak higher, due to a more rapid washout from the reperfused myocardium (30,31), though not implying worse prognosis. In the present study, 65% of the patients presenting with ST-segment elevation underwent fibrinolytic therapy (13), and an additional 14% underwent primary angioplasty (32); however, an objective distinction between those achieving and those not achieving reperfusion was not made, thus precluding this important analysis.
Clinical implications.
The most important clinical implication of our findings is that, for patients with an ACS, any enzyme elevation must be considered a predictor of worse outcome at follow-up, irrespective of the ECG presentation. Being aware of this increased risk is particularly important in the light of recent trials showing that antithrombotic therapies (such as the low-molecular-weight heparins [33] and glycoprotein IIb/IIIa receptor blockers [34]) and revascularization procedures [35] may be particularly effective in reducing the risk of cardiac events in patients with elevated biochemical markers. Results of the present study support, across the entire spectrum of the ACS, the revised definition of MI as a continuum of risk whose gradient is defined by the amount of myocardial damage (14). The prevention or the reduction of the amount of cell damage should be regarded as one of the main therapeutic goals in patients with ACS.
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Footnotes
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The GUSTO-IIb study was supported by Ciba Geigy (Summit, New Jersey), Boehringer Mannheim (Indianapolis, Indiana) and Guidant (Redwood City, California). The present analysis did not receive any financial support.
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O. Bazzino, J. J Fuselli, F. Botto, D. Perez de Arenaza, C. Bahit, J. Dadone, and for the PACS group of investigators
Relative value of N-terminal probrain natriuretic peptide, TIMI risk score, ACC/AHA prognostic classification and other risk markers in patients with non-ST-elevation acute coronary syndromes
Eur. Heart J.,
May 2, 2004;
25(10):
859 - 866.
[Abstract]
[Full Text]
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U. N. Khot, G. Jia, D. J. Moliterno, A. M. Lincoff, M. B. Khot, R. A. Harrington, and E. J. Topol
Prognostic Importance of Physical Examination for Heart Failure in Non-ST-Elevation Acute Coronary Syndromes: The Enduring Value of Killip Classification
JAMA,
October 22, 2003;
290(16):
2174 - 2181.
[Abstract]
[Full Text]
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K Foo, J Cooper, A Deaner, C Knight, A Suliman, K Ranjadayalan, and A D Timmis
A single serum glucose measurement predicts adverse outcomes across the whole range of acute coronary syndromes
Heart,
May 1, 2003;
89(5):
512 - 516.
[Abstract]
[Full Text]
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J. A. Goldstein
Angiographic plaque complexity: the tip of the unstable plaque iceberg
J. Am. Coll. Cardiol.,
May 1, 2002;
39(9):
1464 - 1467.
[Full Text]
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Abstract
Methods