Special Contribution—National Heart Attack Alert Program ReportAccuracy of biomarkers to diagnose acute cardiac ischemia in the emergency department: A meta-analysis☆,☆☆,★
Introduction
The original 1997 report of the National Heart Attack Alert Program Working Group summarized data from studies on creatine kinase (CK) and CK-MB; however, there were few studies on other biomarkers.1 Many studies on CK, CK-MB, myoglobin, and troponins T and I have been published since.
As noted in the original report, biomarkers were developed for the diagnosis of acute myocardial infarction (AMI) and were not intended for the overall diagnosis of acute cardiac ischemia (ACI), which includes unstable angina. Biomarkers detect evidence of necrotic myocardium but not noninfarction ACI (unstable angina), which is an important reason for appropriate hospitalization and further diagnostic evaluation. For this reason, very few biomarker studies report test performance data for ACI.
The present systematic review and meta-analyses aimed to characterize the test performance of these biomarkers to diagnose ACI, both AMI and unstable angina, in the emergency department setting. However, the vast majority of evidence found focused on AMI alone. Because there were few studies that addressed ACI in the ED and to provide a more complete picture of the diagnostic performance of biomarker tests, we also included studies that assessed AMI diagnosis only. In addition, we included studies that carried out testing in the ED; many of these, however, analyzed only hospitalized patients. When possible, we restricted analysis to studies that included all ED patients (including those discharged from the ED).
We included relevant articles found in MEDLINE through December 1998, with additional articles known to our domain experts. The methods for the systematic review, meta-analysis, general study selection criteria, and characterization of population category and study quality assessments are presented in the accompanying synopsis of the evidence report on ACI.2
We investigated the use of both presentation and serial testing (single and multiple serum samples, respectively) for each of the biochemical tests reviewed (CK, CK-MB, myoglobin, and troponin I and T tests). For each test, we describe the excluded studies and the reasons for their exclusion. We summarize the eligible articles, including study eligibility criteria, ACI prevalence, outcome (AMI, unstable angina, or both) definition, and thresholds used to define positive test results. When meta-analysis was feasible, we report combined estimates of the test performance for each of the tests. In our primary analysis, we included all studies in which laboratory testing was performed in the ED setting; however, when possible, we also analyzed only those studies that included all eligible ED patients (ie, those in which patients discharged from the ED were also included).
Table 1 presents the study characteristics and test performance for studies of ACI. Tables 2 through 13 present the characteristics and test performance for studies that evaluated each of the biomarkers for the diagnosis of AMI only. Tables 14 and 15 present summaries of AMI-only studies; they include the total number of studies analyzed, the total number of patients included, and the diagnostic performance (test sensitivity and specificity) of each test. Results of analyses are presented for all included articles and, when feasible, for the subgroup of studies that included all ED patients. Further detailed analyses, including diagnostic odds ratios (which allow direct comparisons between diagnostic tests), are reported in the 2000 updated National Heart Attack Alert Program report.3Figures 1 through 4 present summary receiver-operating characteristic curves for specific tests.
Among studies in each of the biomarker groups, there was a large degree of heterogeneity in eligibility criteria. As discussed in greater detail in the accompanying article,2 this resulted in a wide range of both ACI and AMI prevalence. Across all studies, ACI prevalence ranged from 20% to 75%, and AMI prevalence ranged from 1% to 78%. In addition, individual studies used many different criteria to define test positivity and timing of serial testing (Table 1, Table 15). We examined all these factors to explain variability in study results.
Section snippets
CK and CK-MB
A total of 47 studies were assessed for the accuracy of either CK or CK-MB testing in the diagnosis of ACI or AMI in the ED. Of the eligible studies, 12 studies addressed CK measurement as a single test on admission to the ED, 2 addressed serial testing of CK levels, 19 studies addressed CK-MB measurement as a single test on admission to the ED, and 14 addressed serial testing of CK-MB levels. Only one study evaluated patients with ACI in the ED.
No studies evaluated CK measurement as a single
Myoglobin
A total of 27 reports were evaluated for the assessment of the diagnostic accuracy of myoglobin testing in the diagnosis of ACI or AMI in the ED. Of the eligible studies, 18 evaluated single myoglobin tests performed in the ED setting and 11 evaluated serial myoglobin tests. Only one study evaluated patients with ACI.
Only 1 study evaluated myoglobin measurement as a single test on presentation to the ED for the diagnosis of ACI.52 We found 23 studies that evaluated presentation myoglobin
Troponin I and troponin T
A total of 18 reports were evaluated for the assessment of the diagnostic accuracy of troponin I or T in the diagnosis of ACI or AMI in the ED. Of the eligible studies, 4 evaluated single troponin I tests performed in the ED setting, 2 evaluated serial troponin I tests, 6 evaluated single troponin T tests performed in the ED setting, and 3 evaluated serial troponin T tests. Two studies evaluated ACI.
No studies evaluated troponin I tests performed at presentation to the ED for the diagnosis of
Direct comparisons of biomarker tests
Most studies reported the diagnostic performance of multiple presentation or serial biomarker tests. Within given studies (thus, in the same patients following the same protocol), myoglobin measurement, either as a presentation or serial test, generally had a higher test sensitivity in the diagnosis of AMI than either CK or CK-MB measurement. In addition, the level of myoglobin peaked earlier. The few studies of either troponin I or T testing found varying relative sensitivity levels compared
Combination biomarker tests
Four studies reported on the combination of CK-MB and myoglobin testing. Three of these reported data on the 2 tests drawn in 1 serum sample, and 2 reported data on serial samples. No other combinations of biomarker tests were reported by other studies. No studies evaluated ACI.
No studies evaluated combination CK-MB and myoglobin testing at presentation to the ED for the diagnosis of ACI. Two studies reported data on combination CK-MB and myoglobin testing at presentation to diagnose AMI.41, 42
Clinical effect of biomarker tests
Only 1 study reported data on the clinical effect of using biomarker tests in the ED. The study evaluated serial CK-MB testing and changes in decisionmaking by ED physicians on whether patients required hospital or CCU admission.24 Patients had chest discomfort and a clinical suspicion of AMI but were excluded if they had diagnostic ECGs or chest radiographs, clinical instability, recent cardioversion, or chest trauma.
The analysis pertained primarily to rankings by the physicians of the
Comment
Biomarker tests have been developed primarily to diagnose AMI. Thus, very little evidence exists to describe the performance of these tests in the diagnosis of ACI. Limited evidence suggests that current biomarker tests have low sensitivity and high specificity for ACI. Many patients with unstable angina would therefore be missed by using biomarkers alone.
The evidence for AMI suggests that individual biochemical markers drawn at presentation have uniformly low test sensitivity (<50%) but high
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Cited by (0)
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Dr. Ioannidis is now at the Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
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This study was conducted by the New England Medical Center Evidence-based Practice Center under contract to the Agency for Healthcare Research and Quality (formerly, Agency for Health Care Policy and Research), contract No. 290-97-0019, Rockville, MD.
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Reprints not available from the authors.