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CLINICAL STUDY: MYOCARDIAL INFARCTION

The prognostic value of serum myoglobin in patients with non–ST-segment elevation acute coronary syndromes

Results from the TIMI 11B and TACTICS-TIMI 18 studies

James A. de Lemos, MD^*,*, David A. Morrow, MD, MPH^*, C. Michael Gibson, MD, MS, FACC^*, Sabina A. Murphy, MPH^*, Marc S. Sabatine, MD^*, Nader Rifai, PhD^||, Carolyn H. McCabe, BS^*, Elliott M. Antman, MD, FACC^*, Christopher P. Cannon, MD, FACC^* and Eugene Braunwald, MD, FACC^*

^* Thrombolysis In Myocardial Infarction (TIMI) Study Group, Boston, Massachusetts, USA
Donald W. Reynolds Cardiovascular Clinical Research Center, University of Texas Southwestern Medical School, Dallas, Texas, USA
Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts, USA
Harvard Clinical Research Institute, Boston, Massachusetts, USA
^|| Children’s Hospital, Boston, Massachusetts, USA

Manuscript received December 17, 2001; revised manuscript received March 7, 2002, accepted April 18, 2002.

^* Reprint requests and correspondence: Dr. James A. de Lemos, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Room CS7.142, Dallas, Texas 75390-9047, USA.
james.delemos{at}utsouthwestern.edu

	Abstract

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OBJECTIVES: The goal of this study was to define the prognostic value of serum myoglobin in patients with non–ST-elevation acute coronary syndromes (ACS).

BACKGROUND: While myoglobin is useful for the early diagnosis of myocardial infarction (MI), its role in the early risk-stratification of patients with ACS has not been established.

METHODS: Myoglobin, creatine kinase-MB subfraction (CK-MB) and troponin I (cTnI) were measured at randomization in 616 patients from the Thrombolysis In Myocardial Ischemia/Infarction (TIMI) 11B study and 1,841 patients from the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Therapy-Thrombolysis In Myocardial Ischemia/Infarction (TACTICS-TIMI) 18 study. The risks for death and nonfatal MI through six months of follow-up were compared between patients with and without myoglobin elevation (>110 µg/l) in each study and in a dataset combining all eligible patients from both studies (n = 2,457).

RESULTS: In a multivariate model adjusting for baseline characteristics, ST changes and CK-MB and cTnI levels, an elevated baseline myoglobin was associated with increased six-month mortality in TIMI 11B (adjusted odds ratio [OR] 2.9 [95% confidence interval {CI} 1.2 to 7.1]), TACTICS-TIMI 18 (adjusted OR 3.0 [95% CI 1.5 to 5.9]) and the combined dataset (adjusted OR 3.0 [95% CI 1.8 to 5.0]). In contrast, there was no significant association between myoglobin elevation and nonfatal MI (combined dataset adjusted OR 1.55, 95% CI 0.9 to 2.6). In TACTICS-TIMI 18, patients with versus those without myoglobin elevation were more likely to have an occluded culprit artery (28% vs. 10%; p < 0.0001) and visible thrombus (49% vs. 34%; p = 0.006) and less likely to have TIMI 3 flow (53% vs. 68%; p = 0.009).

CONCLUSIONS: A serum concentration of myoglobin above the MI detection threshold (>110 µg/l) is associated with an increased risk of six-month mortality, independent of baseline clinical characteristics, electrocardiographic changes and elevation in CK-MB and cTnI. These findings suggest that myoglobin may be a useful addition to cardiac biomarker panels for early risk-stratification in ACS.

Abbreviations and Acronyms   ACS   acute coronary syndrome   CHECKMATE   Chest Pain Evaluation by Creatine Kinase-MB, Myoglobin and Troponin I study   CI   confidence interval   CK-MB   creatine kinase-MB subfraction   cTnI   cardiac troponin I   cTnT   cardiac troponin T   ECG   electrocardiogram/electrocardiographic   MI   myocardial infarction   OR   odds ratio   RR   relative risk   TACTICS-TIMI   Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Therapy-Thrombolysis In Myocardial Ischemia/Infarction   TIMI   Thrombolysis In Myocardial Ischemia/Infarction

Recent studies have demonstrated that, among patients with ST-elevation myocardial infarction (MI), those with myoglobin elevation before the initiation of fibrinolytic therapy are at high risk for death and heart failure (4). In this setting, the prognostic value of myoglobin is independent of baseline variables, time to initiation of reperfusion therapy, infarct location and measures of the efficacy of therapy such as ST-segment resolution (4). A later measurement of myoglobin, obtained 12 h after the administration therapy, was also shown to discriminate patients at high and low risk for mortality. For this purpose, myoglobin performed better than cTnI and creatine kinase-MB subfraction (CK-MB) (5).

For patients presenting to the emergency room with chest pain in the absence of ST-elevation, the addition of myoglobin to biomarker panels that include CK-MB and cTnI or cTnT improves sensitivity for the detection of MI, particularly in patients presenting early after symptom onset (2,6–11). Beyond the diagnosis of MI, it is important to consider whether myoglobin is useful for risk stratification in patients with non–ST-elevation acute coronary syndromes (ACS). Here, data are more limited: while one recent study has suggested that myoglobin provides incremental prognostic information to CK-MB and troponin (12), others have not reached the same conclusion (8,9,13,14). We performed the present analyses to evaluate the role of myoglobin for risk stratification in patients with non–ST-elevation ACS and to determine whether therapy with enoxaparin, or with an early invasive management strategy, might be of particular benefit in patients with myoglobin elevation.

	Methods

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Patient populations.   The present study was conducted in two distinct patient populations. The hypotheses were initially tested in a substudy of the Thrombolysis In Myocardial Ischemia/Infarction (TIMI) 11B trial and then prospectively validated in the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Therapy-Thrombolysis In Myocardial Ischemia/Infarction (TACTICS-TIMI) 18 trial. The TIMI 11B was a randomized double-blind trial comparing unfractionated heparin with the low molecular weight heparin enoxaparin in 3,910 patients with suspected non–ST-elevation ACS, conducted between 1996 to 1998 (15). TACTICS-TIMI 18 was a randomized trial comparing early invasive and early conservative management strategies in 2,220 patients with non–ST-elevation ACS treated with the glycoprotein IIb/IIIa receptor inhibitor tirofiban, unfractionated heparin and aspirin conducted between 1997 to 2000 (16). Both trials required that patients present with evidence of ischemic discomfort at rest and either dynamic electrocardiographic (ECG) changes, elevated cardiac markers or documented prior evidence of coronary artery disease. Patients in both trials provided written informed consent for participation (15,16).

Of 681 patients in the TIMI 11B trial and 1,851 patients in the TACTICS-TIMI 18 trial who provided baseline blood samples, specimens were suitable for myoglobin analysis in 616 and 1,841 patients, respectively. In both trials, serum was separated and immediately frozen at –20°C or colder at the study site; samples were subsequently shipped on dry ice to the TIMI Biomarker Core Laboratory at the Children’s Hospital in Boston, Massachusetts, where they were stored at –80°C until assays were performed.

Biochemical assays
All assays were performed on thawed sera using the ACS:180 automated chemiluminescence system (Bayer Diagnostics, Tarrytown, New York). Each of the assays (myoglobin, cTnI and CK-MB) are two-site sandwich immunoassays that use direct chemiluminescence technology. For myoglobin, the manufacturer’s recommended detection limit for MI is 110 µg/l, and this threshold was prospectively selected for the current studies. Previous studies using this cTnI assay have established a threshold of 0.1 µg/l for assessing prognosis in patients with non–ST-elevation ACS (17,18). The MI detection limit for CK-MB with the ACS:180 assay is 5 µg/l. Thus, a cTnI threshold of 0.1 µg/l and a CK-MB threshold of 5 µg/l were prospectively selected.

Clinical end points
The primary end point of the TIMI 11B trial was the composite of death, MI or severe ischemia requiring urgent revascularization eight days after randomization. End points were also collected at 43 days and six months (15). The primary end point of the TACTICS-TIMI 18 trial was the composite of death, MI or rehospitalization for ACS at six months (16). All primary end point events in both trials were adjudicated by clinical event committees. Because both trials reported end points at six months, the present analyses were based on six-month event rates. While new or recurrent MI was defined using the same criteria in both trials, recurrent ischemia was defined differently; thus, the present analyses focus on the end points of death and nonfatal MI at six months.

Statistical analyses
Analyses were performed in the TIMI 11B study population, the TACTICS-TIMI 18 study population and a combined dataset including all patients from both trials. Baseline variables were compared between patients with and without myoglobin elevation using the chi-square test for categorical variables and Student t test for continuous variables. The relation between myoglobin and six-month outcomes was evaluated considering myoglobin both as a continuous and a categorical variable. First, the concentration of myoglobin was compared between patients with and without adverse outcomes using the Wilcoxon rank-sum test. Next, unadjusted associations between myoglobin elevation and outcomes were assessed by calculating relative risks with 95% confidence intervals (CI). Stratified analyses were performed based on gender, index diagnosis (unstable angina vs. non–ST-elevation MI), cTnI level (>0.1 vs. 0.1 µg/l), CK-MB level (>5 vs. 5 µg/l), time to randomization (0 to 6 h, >6 to 12 h and >12 h; TIMI 11B only) and treatment assignment (enoxaparin vs. unfractionated heparin in TIMI 11B, early invasive vs. early conservative strategy in TACTICS-TIMI 18). Tests for interaction with treatment assignment were performed. Logistic regression modeling was performed for the end point of six-month mortality. The following variables were included: age, gender, diabetes, hypertension, prior aspirin use, current smoking, index diagnosis, ST-deviation >1 mm, CK-MB >5 µg/l, cTnI >0.1 µg/l and myoglobin >110 µg/l.

	Results

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Baseline characteristics were similar between patients participating in the TIMI 11B and TACTICS-TIMI 18 substudies (Table 1). The percentage of patients with myoglobin elevation (>110 µg/l) at the time of randomization was 22% in TIMI 11B, 18% in TACTICS-TIMI 18 and 19% in the combined data set (Table 1). Patients with myoglobin elevation were older, disproportionately male and more likely to present with suspected MI, ST changes on the ECG and elevation of cTnI and CK-MB (Table 1).

Stratified analyses
A consistent association between myoglobin elevation and increased six-month mortality was observed among men and women; patients with unstable angina and those with non–ST-elevation MI; patients with CK-MB >5 µg/l and 5 µg/l; patients with a cTnI >0.1 µg/l and 0.1 µg/l (Fig. 1) and those presenting 0 to 6 h, >6 to 12 h and >12 h after the onset of ischemic symptoms (Table 4). In addition, in the TIMI 11B trial, there was no interaction between time to randomization, myoglobin elevation and six-month mortality (p interaction >0.48). In TIMI 11B, myoglobin elevation was associated with increased six-month mortality both among patients randomized to enoxaparin and those randomized to unfractionated heparin; in TACTICS-TIMI 18, myoglobin elevation was associated with increased mortality both among patients randomized to an early invasive strategy and those randomized to an early conservative strategy (Table 4). There was no interaction between treatment assignment, myoglobin elevation and six-month mortality (p interaction = 0.47 in TIMI 11B and p interaction = 0.79 in TACTICS-TIMI 18).

View larger version (15K): [in this window] [in a new window]   Figure 1 Comparison of myoglobin and troponin I for predicting death and nonfatal myocardial infarction (MI) in the combined TIMI 11B/TACTICS-TIMI 18 dataset. Open bar = normal myoglobin (110 µg/l); solid bar = elevated myoglobin (>110 µg/l). cTnI = cardiac troponin I. For acronym definition, see Abbreviation box.

	Discussion

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In two separate contemporary cohorts of patients with non–ST-elevation ACS, a serum concentration of myoglobin above the MI detection threshold (>110 µg/l) was associated with an increased risk of six-month mortality, independent of baseline clinical variables, ECG changes and elevation in CK-MB and cTnI. In contrast, after adjustment for the same baseline variables, myoglobin elevation was not significantly associated with the occurrence of nonfatal MI. No interaction with treatment assignment was detected; myoglobin elevation was associated with increased mortality whether patients received enoxaparin or unfractionated heparin in TIMI 11B or whether they were treated with an early invasive or early conservative strategy in TACTICS-TIMI 18.

Comparison with prior studies.   Previous studies have demonstrated that measuring myoglobin in addition to CKMB and troponin I or T improves the early detection of MI (6–11), but results have been inconsistent with regard to the prognostic implications of myoglobin elevation in patients with non–ST-elevation ACS. Several studies have suggested that myoglobin adds little prognostic information to CK-MB and troponins (8,9,13,14); however, these studies have been small and have included few mortality end points. Because myoglobin appears to predict mortality to a greater extent than it does MI, large sample sizes would be required to provide sufficient statistical power to evaluate the prognostic value of myoglobin independent of other risk predictors. In the Chest Pain Evaluation by Creatine Kinase-MB, Myoglobin and Troponin I (CHECKMATE) study, which included 1,005 patients, a diagnostic strategy that included myoglobin, CK-MB and cTnI measurement identified more patients at risk for death by 30 days than did a strategy employing only CK-MB and cTnI. In contrast, the addition of myoglobin to CK-MB and cTnI did not improve the prediction of recurrent MI (12).

Clinical implications
Our findings in 2,457 patients with non–ST-elevation ACS are consistent with the results of the CHECKMATE study. Taken together, these studies suggest that different cardiac biomarkers may have greater relative predictive value for different cardiovascular end points. For example, the cardiac troponins appear to provide excellent discrimination of the risk for recurrent ischemic events (MI and recurrent ischemia) but may not provide comparable mortality prediction to myoglobin, particularly when one considers low-level troponin elevation, that is, in the 0.1 to 1.5 µg/l range (Fig. 1). The relative specificity of low-level troponin elevation for nonfatal end points may help to explain why troponin elevation identifies patients likely to benefit from potent antiplatelet and antithrombotic agents and an early invasive treatment strategy (16,18–20). These therapies appear to reduce nonfatal ischemia events to a greater extent than mortality (15,16,21). In contrast with cTnI, myoglobin appears to be more predictive of mortality than of nonfatal ischemic end points. Studies are needed in which specific therapies are targeted to patients with myoglobin elevation in an attempt to reduce mortality.

Biologic rationale
Both principal observations of this study, first, that myoglobin is associated with mortality independent of cTnI and CK-MB and, second, that it is not associated with the risk for nonfatal MI, are somewhat surprising because myoglobin, CK-MB and cTnI have all been classified together as markers of tissue necrosis. Indeed, the present findings raise the possibility that release of each of these markers into the circulation may not result from identical pathologic processes. Although the mechanisms underlying our observations require further study, we speculate below on several factors that may play a role.

In the present study, the extent of coronary atherosclerosis was similar in patients with and without myoglobin elevation. In contrast, patients with myoglobin elevation were more likely to have an occluded coronary artery (TIMI 0 or 1 flow) and visible intracoronary thrombus and less likely to have TIMI flow grade 3 than those without myoglobin elevation. These observations remained significant even in patients with cTnI elevation. Patients with complete occlusion of an infarct artery are at higher risk for mortality, but lower risk for reocclusion and recurrent MI, than those with a patent infarct artery (22). Myoglobin elevation may help to identify patients with infarct artery occlusion who do not manifest ST elevation on the presenting ECG, such as those with complete thrombotic occlusion of the circumflex artery. Due to the lower tissue-specificity of myoglobin, the clinical cut-point is set relatively high; thus, elevated levels of myoglobin may indicate larger areas of infarction than detected by low-level elevations of troponins.

Myoglobin differs from cTnI in that it is smaller and remains free in the cytoplasm of the cell, unbound to contractile proteins (1). As a result, the kinetics for myoglobin release differ from that for other cardiac proteins. In experimental acute MI, myoglobin release is best described by a one-compartment model: the amount of myoglobin released into the circulation is equal to the amount of myoglobin depleted from infarcted tissue (23). In contrast, low-level troponin release may be more complex and occurs frequently in patients with no detectable rise in other cardiac biomarkers (20). The mechanism of "microinfarction" in such patients is postulated to be embolization from complex coronary plaque with obstruction of the coronary microcirculation (24). However, it remains possible that isolated low-level troponin elevation is a manifestation of a pathologically distinct process, such as reversible myocyte injury during reduced coronary blood flow. Such patients may be at lower relative risk for death than patients with large infarction but remain at increased risk for recurrent ischemic events.

Finally, in some patients at risk for mortality, the source of myoglobin elevation may be skeletal muscle rather than the heart. Hypotension and reduced renal perfusion both may result in skeletal muscle release of myoglobin (25) and could contribute to mortality after ACS.

Study limitations
Time from symptom onset to randomization was not collected in the TACTICS-TIMI 18 trial. In the TIMI 11B study, however, myoglobin elevation was associated with a trend towards increased six-month mortality in patients randomized 0 to 6 h, 6 to 12 h and >12 h after symptom onset, and no interaction was found between time to treatment, myoglobin elevation and six-month mortality. Serial measurements of cardiac markers were not performed, so the peak cardiac marker values cannot be determined. It should be emphasized that the patients evaluated in these studies may differ from the broader group of patients who present to an emergency department with chest discomfort. Entry into the TIMI 11B and TACTICS-TIMI 18 studies required prior coronary disease, ST changes or cardiac marker elevation. Finally, though commercially available and in common clinical use, the assays in the present study were performed in a central research laboratory rather than by local investigators. Therefore, caution is warranted before generalizing findings from the present study to clinical practice, where different assays (with differing thresholds) may be used and where patients may be at lower risk for mortality.

Conclusions
Myoglobin elevation identifies patients with non–ST-elevation ACS who are at significantly increased risk for six-month mortality, independent of baseline clinical variables, ECG changes and elevation of other biomarkers such as cTnI and CK-MB. Although the mechanisms underlying these observations are not known, we observed that patients with myoglobin elevation have a greater burden of intracoronary thrombus and are more likely to present with an occluded coronary artery than those without myoglobin elevation. In contrast with cTnI, myoglobin does not discriminate the risk for nonfatal MI. These findings suggest that different cardiac biomarkers may be predictive of different cardiovascular end points and highlights the need for future trials in which the relationship between cardiac markers and individual cardiac end points is evaluated.

	Footnotes

 
Supported by grants from Aventis Pharmaceuticals (TIMI 11B) and Merck and Co. (TACTICS-TIMI 18). Assay reagents were provided by Bayer Diagnostics, Inc.

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