SPECIAL CONTRIBUTION/NATIONAL HEART ATTACK

ALERT PROGRAM

Accuracy of Biomarkers to Diagnose Acute

Cardiac Ischemia in the Emergency Department:
A Meta-Analysis

From the Evidence-based Practice Ethan M. Balk, MD, MPH See related articles, p. 450, p. 453, p. 461, and p. 471.
Center, Division of Clinical Care John P. A. Ioannidis, MD
Research, New England Medical Deeb Salem, MD
Center, Boston, MA. Study objective: We sought to evaluate quantitatively the
Priscilla W. Chew, MPH
Dr. Ioannidis is now at the Depart- evidence on the diagnostic performance of presentation and
Joseph Lau, MD
ment of Hygiene and Epidemiology, serial biochemical markers for emergency department diagnosis
University of Ioannina School of of acute cardiac ischemia (ACI), including acute myocardial in-
Medicine, Ioannina, Greece.
farction (AMI) and unstable angina.
Received for publication July 17, 2000.
Revision received December 29, 2000. Methods: We conducted a systematic review and meta-analy-
Accepted for publication
sis of the English-language literature published between 1966
February 1, 2001.
and December 1998. We examined the diagnostic performance
Presented in part at the Society of
General Internal Medicine of creatine kinase, creatine kinase-MB, myoglobin, and tro-
Conference, Boston, MA, May 2000, ponin I and T testing. Diagnostic performance was assessed by
and the American Association of using estimates of test sensitivity and specificity and was sum-
Clinical Chemists, Arlington, VA,
May 2000. marized by summary receiver-operating characteristic curves.
This study was conducted by the New Results: Only 4 studies were found that evaluated all patients
England Medical Center Evidence- with ACI; 73 were found that focused only on a diagnosis of
based Practice Center under contract
to the Agency for Healthcare Research AMI. To diagnose ACI, presentation biomarker tests had sensi-
and Quality (formerly, Agency for tivities of 16% to 19% and specificities of 96% to 100%; serial
Health Care Policy and Research),
biomarker tests had sensitivities of 31% to 45% and specifici-
contract No. 290-97-0019, Rockville,
MD. ties of 95% to 98%. Considering only the diagnosis of AMI,
Reprints not available from the presentation biomarker tests had summary sensitivities of 37%
authors. to 49% and summary specificities of 87% to 97%; serial bio-
Address for correspondence: Joseph marker tests had summary sensitivities of 79% to 93% and
Lau, MD, Division of Clinical Care summary specificities of 85% to 96%. Variation of test sensitiv-
Research, New England Medical
Center, Box 63, 750 Washington
ity was best explained by test timing. Longer symptom duration
Street, Boston, MA 02111; or time between serial tests yielded higher sensitivity.
617-636-7670, fax 617-636-8023;
E-mail jlau1@lifespan.org. Conclusion: The limited evidence available to evaluate the
Copyright © 2001 by the American
diagnostic accuracy of biomarkers for ACI suggests that bio-
College of Emergency Physicians. markers have very low sensitivity to diagnose ACI. Thus, bio-
0196-0644/2001/$35.00 + 0 markers alone will greatly underdiagnose ACI and will be
47/1/114905 inadequate to make triage decisions. For AMI diagnosis alone,
doi:10.1067/mem.2001.114905
multiple testing of individual biomarkers over time substantially
improves sensitivity, while retaining high specificity, at the
expense of additional time. Further high-quality studies are

4 7 8 ANNALS OF EMERGENCY MEDICINE 37:5 MAY 2001

BIOMARKERS AND ACUTE CARDIAC ISCHEMIA
Balk et al

needed on the clinical effect of using biomarkers for patients emergency department setting. However, the vast major-
with ACI in the ED and on optimal timing of serial testing and in ity of evidence found focused on AMI alone. Because there
combination with other tests. were few studies that addressed ACI in the ED and to pro-
vide a more complete picture of the diagnostic perfor-
[Balk EM, Ioannidis JPA, Salem D, Chew PW, Lau J. Accuracy of mance of biomarker tests, we also included studies that
biomarkers to diagnose acute cardiac ischemia in the assessed AMI diagnosis only. In addition, we included
emergency department: a meta-analysis. Ann Emerg Med. May studies that carried out testing in the ED; many of these,
2001;37:478-494.] however, analyzed only hospitalized patients. When pos-
sible, we restricted analysis to studies that included all ED
INTRODUCTION patients (including those discharged from the ED).
We included relevant articles found in MEDLINE
The original 1997 report of the National Heart Attack Alert through December 1998, with additional articles known
Program Working Group summarized data from studies to our domain experts. The methods for the systematic
on creatine kinase (CK) and CK-MB; however, there were review, meta-analysis, general study selection criteria,
few studies on other biomarkers.1 Many studies on CK, and characterization of population category and study
CK-MB, myoglobin, and troponins T and I have been quality assessments are presented in the accompanying
published since. synopsis of the evidence report on ACI.2
As noted in the original report, biomarkers were devel- We investigated the use of both presentation and serial
oped for the diagnosis of acute myocardial infarction testing (single and multiple serum samples, respectively)
(AMI) and were not intended for the overall diagnosis of for each of the biochemical tests reviewed (CK, CK-MB,
acute cardiac ischemia (ACI), which includes unstable myoglobin, and troponin I and T tests). For each test, we
angina. Biomarkers detect evidence of necrotic myocard- describe the excluded studies and the reasons for their
ium but not noninfarction ACI (unstable angina), which is exclusion. We summarize the eligible articles, including
an important reason for appropriate hospitalization and study eligibility criteria, ACI prevalence, outcome (AMI,
further diagnostic evaluation. For this reason, very few unstable angina, or both) definition, and thresholds used
biomarker studies report test performance data for ACI. to define positive test results. When meta-analysis was
The present systematic review and meta-analyses aimed feasible, we report combined estimates of the test perfor-
to characterize the test performance of these biomarkers mance for each of the tests. In our primary analysis, we
to diagnose ACI, both AMI and unstable angina, in the included all studies in which laboratory testing was per-

Table 1.
Study characteristics and performance of biomarker tests in the diagnosis of ACI.

Prevalence Prevalence Subjects Test Criteria

Biomarker Population of AMI of Unstable Evaluated (Timing of Sensitivity Specificity Study
Tested Study Category* (%) Angina (%) (Enrolled) Serial Testing) (%) (%) Quality†

CK-MB, presentation Hedges et al, 199624 III 6 14 1,042 (1,055) CK-MB >7 ng/mL 19 96 A
CK-MB, serial Hedges et al, 199624 III 6 14 1,042 (1,055) CK-MB >7 ng/mL 31 95 A
(presentation and 3 h)
Myoglobin, presentation Kennedy et al, 199752 III 23 52‡ 86 (91) Myoglobin >90 ng/mL 16 100 C
Troponin I, serial Hamm et al, 199756 III 6 41 773 (no data) Troponin I >0.1 ng/mL 44 98 A
(presentation and ≥4 h)
Troponin T, serial Mohler et al, 199860 IV 21 41 98 (no data) Troponin T >0.1 ng/mL 45 97 B
(presentation and ≥4 h)
Hamm et al, 199756 III 6 41 773 (no data) Troponin T >0.18 ng/mL 31 98 A
(presentation and ≥4 h)
*Category I studies included all patients seen in the ED with symptoms suggestive of ACI; category II studies included all patients seen in the ED with chest pain; category III studies included all

patients seen in the ED with chest pain but nondiagnostic ECGs; and category IV studies included hospitalized patients only or other inclusion criteria. See accompanying synopsis article.3
†
Study quality A articles are high-quality, well-documented, unbiased studies. Study quality B articles are fair quality and incompletely documented, with no evidence of significant bias. Study quality
C articles are poor quality, poorly documented, with possibly significant bias. See accompanying synopsis article.3
‡Subjects with “angina”; no definition provided.

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BIOMARKERS AND ACUTE CARDIAC ISCHEMIA
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formed in the ED setting; however, when possible, we ing diagnostic odds ratios (which allow direct compar-
also analyzed only those studies that included all eligible isons between diagnostic tests), are reported in the 2000
ED patients (ie, those in which patients discharged from updated National Heart Attack Alert Program report.3
the ED were also included). Figures 1 through 4 present summary receiver-operating
Table 1 presents the study characteristics and test per- characteristic curves for specific tests.
formance for studies of ACI. Tables 2 through 13 present Among studies in each of the biomarker groups, there
the characteristics and test performance for studies that was a large degree of heterogeneity in eligibility criteria.
evaluated each of the biomarkers for the diagnosis of AMI As discussed in greater detail in the accompanying
only. Tables 14 and 15 present summaries of AMI-only article,2 this resulted in a wide range of both ACI and AMI
studies; they include the total number of studies analyzed, prevalence. Across all studies, ACI prevalence ranged
the total number of patients included, and the diagnostic from 20% to 75%, and AMI prevalence ranged from 1% to
performance (test sensitivity and specificity) of each test. 78%. In addition, individual studies used many different
Results of analyses are presented for all included articles criteria to define test positivity and timing of serial testing
and, when feasible, for the subgroup of studies that in- (Tables 1-15). We examined all these factors to explain
cluded all ED patients. Further detailed analyses, includ- variability in study results.

Table 2.
Study characteristics and diagnostic test performance of presentation CK in the diagnosis of AMI.

Prevalence Subjects
Population of AMI Evaluated Sensitivity Specificity Study
Study Category (%) (Enrolled) Test Criteria (%) (%) Quality

Eisenberg et al, 197910 II 16 80 (129) No data 54 82 C

Roxin et al, 198411 I 26 305 (no data) CK >326.5 U/L 28 96 C
Lee et al, 198712 II 16 639 (1,055) CK >180 U/L (men); CK >160 U/L (women) 38 80 C
Hedges et al,198713 II 7 732 (861) CK >120 U/L (men); CK >100 U/L (women) 55 65 B
Viskin et al, 198714 II 30 252 (300) CK >140 U/L (men); CK >100 U/L (women) 38 93 C
Mair et al, 199115 II 24 96 (no data) CK >80 U/L (men); CK >70 U/L (women) 35 89 C
Mair et al, 199116 II 40 126 (no data) CK >80 U/L (men); CK >70 U/L (women) 43 83 C
Tucker et al, 199420 IV 29 133 (193) No data 51 82 C
Thomson et al, 199517 II 18 383 (511) CK >336 U/L (men); CK >176 U/L (women) 42 93 C
Gornall and Roth, 199618 III 41 98 (no data) CK >170 U/L (men); CK >140 U/L (women) 28 86 B
Hetland and Dickstein, 199619 II 34 133 (no data) CK >200 U/L 7 93 C
Tucker et al, 199721 IV 15 177 (no data) CK >170 U/L (men); CK >135 U/L (women) 31 84 B
For definition of population category and study quality, see legend for Table 1.

Table 3.
Study characteristics and diagnostic test performance of serial CK in the diagnosis of AMI.

Prevalence Subjects
Population of AMI Evaluated Test Criteria Sensitivity Specificity Study
Study Category (%) (Enrolled) (Timing of Serial Testing) (%) (%) Quality

Gerhardt et al, 198223 I 43 481 (no data) CK >200 U/L (men); CK >150 U/L (women) 99 68 C
(10 h and 16 h of symptoms)
Roxin et al, 198411 I 26 305 (no data) CK >326.5 U/L (presentation, 2 h, and 4 h) 69 84 C
For definition of population category and study quality, see legend for Table 1.

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Table 4.
Study characteristics and diagnostic test performance of presentation CK-MB in the diagnosis of AMI.

Prevalence Subjects
Population of AMI Evaluated Sensitivity Specificity Study
Study Category (%) (Enrolled) Test Criteria (%) (%) Quality

Gibler et al, 198736 IV 36 59 (73) No data 14 97 C

Gibler et al, 199037 IV 17 183 (186) CK-MB >7.5 ng/mL 55 97 A
Mair et al, 199116 II 40 126 (no data) CK-MB >7 ng/mL 57 92 C
Marin and Teichman, 199238 IV 22 313 (400) CK-MB >7.5 ng/mL 41 95 C
Collins et al, 199332 II 42 195 (no data) CK-MB >7 ng/mL 52 97 B
Brogan et al, 199433 I 12 189 (no data) CK-MB >9 ng/mL and >2% 23 99 A
Castaldo et al, 199434 II 37 157 (no data) CK-MB >5% 22 98 C
Tucker et al, 199420 IV 29 133 (193) CK-MB >5 ng/mL 33 99 C
Apple et al, 199539 IV 6 98 (no data) CK-MB >5 ng/mL 100 86 C
Montague and Kircher, 199535 II 28 89 (132) CK-MB >5 ng/mL 36 98 C
Thomson et al, 199517 II 18 375 (511) CK-MB >4.7 ng/mL 56 93 C
Gornall and Roth, 199618 III 41 98 (no data) CK-MB >8 ng/mL 25 98 B
Hedges et al, 199624 III 6 1,042 (1,055) CK-MB >7 ng/mL 57 96 A
Hetland and Dickstein, 199619 II 34 133 (no data) CK-MB >5 ng/mL 44 98 C
Mair et al, 19965 II 39 101 (no data) CK-MB >5 ng/mL 59 89 B
Kontos et al, 199741 IV 20 101 (110) CK-MB >4.7 or 8 ng/mL dependent on analyzer 30 100 B
Tucker et al, 199721 IV 15 177 (no data) CK-MB >5 ng/mL 26 97 B
Fesmire et al, 199840 IV 20 764 (1,000) CK-MB >6 ng/mL 48 97 C
Kontos et al, 199942 IV 9 2,093 (2,784) CK-MB >8 ng/mL and >4% 46 99 C
For definition of population category and study quality, see legend for Table 1.

Table 5.
Study characteristics and diagnostic test performance of serial CK-MB in the diagnosis of AMI.

Prevalence Subjects
Population of AMI Evaluated Test Criteria Sensitivity Specificity Study
Study Category (%) (Enrolled) (Timing of Serial Testing) (%) (%) Quality

Gerhardt et al, 198223 I 43 481 (no data) CK-MB >12 U/L (10 h and 16 h of symptoms) 99.5 97 C
Gibler et al, 198736 IV 36 59 (73) No data (presentation, 3 h, and 6 h) 100 92 C
Gibler et al, 199243 IV 12 577 (629) CK-MB >8 ng/mL (presentation, 1 h, 2 h, and 3 h) 80 94 B
Hedges et al, 199248 III 11 261 (420) CK-MB >8 ng/mL (presentation, 1 h, 2 h, and 3 h) 68 95 C
Marin and Teichman, 199238 IV 20 313 (400) CK-MB >7.5 ng/mL (presentation, 1 h, 2 h, and 3 h) 90 93 C
Brogan et al, 199433 I 12 189 (no data) CK-MB >9 ng/mL and >2% (presentation and 1 h) 41 99 A
Castaldo et al, 199434 II* 37 157 (no data) CK-MB >5% (3 h and 6 h of symptoms) 62* 94* C
Hoekstra et al, 199450 IV 7 5,120 (no data) CK-MB >5.6–7.5 ng/mL dependent on analyzer 93 95 B
(presentation and 2 h)
Gibler et al, 199549 III 1 1,010 (no data) CK-MB >6 or 7 ng/mL dependent on analyzer 100 98 C
(presentation, 3 h, 6 h, and 9 h)
Montague and Kircher, 199535 II 28 89 (132) CK-MB >5 ng/mL (presentation and 2 h) 68 92 C
Hedges et al, 199624 III 6 1,042 (1,055) CK-MB >7 ng/mL (presentation and 3 h) 88 95 A
Levitt et al, 199651 IV 11 190 (no data) CK-MB >11.9 ng/mL (presentation and 3 h) 81 99 A
Kontos et al, 199741 IV 20 101 (110) CK-MB >4.7 or 8 ng/mL dependent on analyzer 90 100 B
(presentation and 4 h)
Kontos et al, 199942 IV 9 2,093 (2,784) CK-MB >8 ng/mL and >4% (presentation and 3 h) 78 99 C
For definition of population category and study quality, see legend for Table 1.
*
Not all subjects had 2 laboratory samples.

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Table 6.
Study characteristics and diagnostic test performance of presentation myoglobin in the diagnosis of AMI.

Prevalence Subjects
Population of AMI Evaluated Sensitivity Specificity Study
Study Category (%) (Enrolled) Test Criteria (%) (%) Quality

Gilkeson et al, 197853 I 18 71 (no data) Myoglobin >85 ng/mL 38 93 C

Roxin et al, 198411 I 26 305 (no data) Myoglobin >97 ng/mL 71 83 C
Gibler et al, 198736 IV 36 59 (73) No data 62 89 C
Ohman et al, 19907 IV 62 74 (82) Myoglobin >90 ng/mL 57 96 B
Mair et al, 19924 I 40 126 (no data) Myoglobin >80 ng/mL 45 91 B
Brogan et al, 199433 I 12 189 (no data) Myoglobin >110 ng/mL 55 98 A
Castaldo et al, 199434 II 37 157 (no data) Myoglobin >100 ng/mL 38 100 C
Tucker et al, 199420 IV 29 133 (193) Myoglobin >90 ng/mL 44 96 C
Apple et al, 199539 IV 6 98 (no data) Myoglobin >110 ng/mL 100 61 C
Montague and Kircher, 199535 I 28 89 (132) Myoglobin >70 ng/mL 56 81 B
Davis et al, 199654 IV 33 42 (no data) Myoglobin >100 ng/mL 21 93 C
Gornall and Roth, 199618 III 41 98 (no data) Myoglobin >100 ng/mL 43 98 B
Hetland and Dickstein, 199619 II 34 133 (no data) Myoglobin >70 ng/mL 51 94 C
Mair et al, 19965 II 39 101 (no data) Myoglobin >70 ng/mL 46 89 B
Kennedy et al, 199752 III 23 86 (91) Myoglobin >90 ng/mL 38 96 C
Kontos et al, 199741 IV 20 101 (110) Myoglobin >92 ng/mL 70 84 B
Tucker et al, 199721 IV 15 177 (no data) Myoglobin >110 ng/mL 33 93 B
Kontos et al, 199942 IV 9 2,093 (2,784) Myoglobin >92 ng/mL 46 90 B
For definition of population category and study quality, see legend for Table 1.

Table 7.
Study characteristics and diagnostic test performance of serial myoglobin in the diagnosis of AMI.

Prevalence Subjects
Population of AMI Evaluated Test Criteria Sensitivity Specificity Study
Study Category (%) (Enrolled) (Timing of Serial Testing) (%) (%) Quality

Roxin et al, 198411 I 26 305 (no data) Myoglobin >97 ng/mL (presentation, 2 h, and 4 h) 98 83 C
Gibler et al, 198736 IV 36 59 (73) No data (presentation, 3 h, and 6 h) 100 82 C
Brogan et al, 199433 I 12 189 (no data) Myoglobin >110 ng/mL (presentation and 1 h) 73 96 A
Brogan et al, 199433 I 12 189 (no data) Myoglobin >110 ng/mL or increase of >40 ng/mL* 91* 96* A
(presentation and 1 h)
Castaldo et al, 199434 II† 37 157 (no data) Myoglobin >100 ng/mL (3 h and 6 h of symptoms) 90† 100† C
Montague and Kircher, 199535 I 28 89 (132) Myoglobin >70 ng/mL (presentation and 2 h) 100 77 B
Montague and Kircher, 199535 I 28 89 (132) Myoglobin level doubles* (presentation and 2 h) 64* 98* B
Davis et al, 199654 IV 33 42 (no data) Myoglobin >100 ng/mL (presentation and 1 h) 57 93 C
Davis et al, 199654 IV 33 42 (no data) Myoglobin >100 ng/mL or increase of >50%* 93* 79* C
(presentation and 1 h)
Gornall and Roth, 199618 II 41 98 (no data) Myoglobin >100 ng/mL or doubling* 93* 100* B
(presentation, 1 h, and 2 h)
Levitt et al, 199651 IV 11 190 (no data) Myoglobin >88.7 ng/mL (presentation and 3 h) 90 88 A
D’Costa et al, 199727 IV‡ 26 54 of 316‡ (no data) Myoglobin >110 ng/mL (presentation and 2 h) 100 72 C
Kennedy et al, 199752 III§ 23 91 (no data) Myoglobin >90 ng/mL (presentation and 3 h) 86 96§ C
Kontos et al, 199741 IV 20 101 (110) Myoglobin >90 ng/mL (presentation and 4 h) 90 75 B
For definition of population category and study quality, see legend for Table 1.
*
Not represented in Figure 2B.
†
Not all subjects had 2 laboratory samples.
‡
Selected subset of category II ED patients. Reason for only subset having laboratory test done not reported.
§
Text unclear; specificity not stated clearly for serial myoglobin. Value reported here may be overestimation of specificity.

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Table 8.
Study characteristics and diagnostic test performance of presentation troponin I in the diagnosis of AMI.

Prevalence Subjects
Population of AMI Evaluated Sensitivity Specificity Study
Study Category (%) (Enrolled) Test Criteria (%) (%) Quality

Apple et al, 199539 IV 6 98 (no data) Troponin I >3.1 ng/mL 100 91 C

Mair et al, 19965 II 39 101 (no data) Troponin I >0.1 ng/mL 23 95 C
D’Costa et al, 199727 II* 20 316 (no data) Troponin I >1.0 ng/mL 79 No data* C
Hamm et al, 199756 III 6 773 (no data) Troponin I >0.1 ng/mL 66 89 A
Laurino et al, 19979 I* 22 115 (no data) Troponin I >0.6 ng/mL 32 No data* C
Tucker et al, 199721 IV 15 177 (no data) Troponin I >0.6 ng/mL 4 98 B
Kontos et al, 199957 IV*† 9 620 (721) Troponin I >2.0 ng/mL 39 No data* C
For definition of population category and study quality, see legend for Table 1.
*Insufficient data. Not included in meta-analysis.
†Blood test drawn in CCU after perfusion imaging. All patients were initially evaluated in ED.

Table 9.
Study characteristics and diagnostic test performance of serial troponin I in the diagnosis of AMI.

Prevalence Subjects
Population of AMI Evaluated Test Criteria Sensitivity Specificity Study
Study Category (%) (Enrolled) (Timing of Serial Testing) (%) (%) Quality

Hamm et al, 199756 III 6 773 (no data) Troponin I >0.1 ng/mL (presentation and ≥4 h) 100 83 A
Kontos et al, 199957 IV* 9 620 (721) Troponin I >2.0 ng/mL (within 8 h) 90 96 B
For definition of population category and study quality, see legend for Table 1.
*Blood test drawn in CCU after perfusion imaging. All patients were initially evaluated in ED.

Table 10.
Study characteristics and diagnostic test performance of presentation troponin T in the diagnosis of AMI.

Prevalence Subjects
Population of AMI Evaluated Sensitivity Specificity Study
Study Category (%) (Enrolled) Test Criteria (%) (%) Quality

Mair et al, 199115 II 24 96 (no data) Troponin T >0.5 ng/mL 57 96 C

de Winter et al, 199528 II* 53 309* (317) Troponin T >0.1 ng/mL 34* 91* C
Mach et al, 199530 IV† 78 32 (no data) Troponin T >0.2 ng/mL 40† 80† C
Hetland and Dickstein, 199619 II 34 133 (no data) Troponin T >0.05 ng/mL 53 86 C
Mair et al, 19965 II 39 101 (no data) Troponin T >0.2 ng/mL 28 92 C
Hamm et al, 199756 III 6 773 (no data) Troponin T >0.18 ng/mL 51 94 A
Tucker et al, 199721 IV 15 177 (no data) Troponin T >0.1 ng/mL 15 97 B
Gust et al, 199859 II‡ 24 68 (no data) Troponin T >0.2 ng/mL 25 98 B
For definition of population category and study quality, see legend for Table 1.
*
Not included in meta-analysis. Test performance data refer to results of blood sample drawn at 3 hours from time of onset of chest pain. No data on numbers of subjects included in analysis of tro-
ponin T. Does not include all patients presenting to the ED.
†
Not included in meta-analysis. Highly selected ED patients. Study of bedside rapid analyzer. Reported specificity not consistent with 7 patients without AMI.
‡
Serum sample drawn before arrival in ED.

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CK AND CK-MB in the ED. Of the eligible studies, 12 studies addressed CK

measurement as a single test on admission to the ED, 2
A total of 47 studies were assessed for the accuracy of addressed serial testing of CK levels, 19 studies addressed
either CK or CK-MB testing in the diagnosis of ACI or AMI CK-MB measurement as a single test on admission to the

Table 11.
Study characteristics and diagnostic test performance of serial troponin T in the diagnosis of AMI.

Prevalence Subjects
Population of AMI Evaluated Test Criteria Sensitivity Specificity Study
Study Category (%) (Enrolled) (Timing of Serial Testing) (%) (%) Quality

Mach et al, 199530 IV* 78 32 (no data) Troponin T >0.2 ng/mL (presentation and 4 h) 100 86 C
Hamm et al, 199756 III 6 773 (no data) Troponin T >0.18 ng/mL (presentation and ≥4 h) 94 89 A
Mohler et al, 199860 IV 21 98 (no data) Troponin T >0.1 ng/mL (presentation and 4 h) 90 87 B
Sayre et al, 199847 I† 5 546† (700) Troponin T >0.2 ng/mL (presentation, 3 h, or both)† 65† 93† C
For definition of population category and study quality, see legend for Table 1.
*Highly selected ED patients. Study of bedside rapid analyzer.
†Five hundred forty-six of 667 patients had blood drawn within 3 hours of presentation to ED. Some had 1 sample drawn; the rest had 2 samples drawn. Data could not be extracted for use in meta-

analysis.

Table 12.
Study characteristics and diagnostic test performance of presentation combination CK-MB and myoglobin in the diagnosis of AMI.

Prevalence Subjects
Population of AMI Evaluated Sensitivity Specificity Study
Study Category (%) (Enrolled) Test Criteria (%) (%) Quality

Montague and Kircher, 199535 II* 28 89 (132) CK-MB >5 ng/mL or myoglobin >70 ng/mL 100* 72* C
Kontos et al, 199741 IV 20 101 (110) CK-MB >4.7 or 8 ng/mL or myoglobin >92 ng/mL 85 80 B
Kontos et al, 199942 IV 9 2,093 (2,784) CK-MB >8 ng/mL and >4% or myoglobin >92 ng/mL 62 89 C
For definition of population category and study quality, see legend for Table 1.
*
Results from sample drawn at 2 hours after presentation to ED.

Table 13.
Study characteristics and diagnostic test performance of serial combination CK-MB and myoglobin in the diagnosis of AMI.

Prevalence Subjects
Population of AMI Evaluated Test Criteria Sensitivity Specificity Study
Study Category (%) (Enrolled) (Timing of Serial Testing) (%) (%) Quality

Levitt et al, 199651 IV 11 190 (no data) CK-MB >11.9 ng/mL or myoglobin >88.7 ng/mL 100 91 A
(presentation and 3 h)
Kontos et al, 199741 IV 20 101 (110) CK-MB >4.7 or 8 ng/mL or myoglobin >92 ng/mL 100 75 B
(presentation and 4 h)
For definition of population category and study quality, see legend for Table 1.

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ED, and 14 addressed serial testing of CK-MB levels. Only thresholds (definition of test positivity), reported differ-
one study evaluated patients with ACI in the ED. ences in eligibility criteria, study setting, or prevalence of
No studies evaluated CK measurement as a single test AMI. Across studies, there were insufficient data to allow
on presentation to the ED for the diagnosis of ACI. We full analysis of symptom duration before testing; how-
found 18 studies that evaluated presentation CK testing ever, those studies that analyzed test performance by
for the diagnosis of AMI in the ED. Six articles were ex- symptom duration all found increased sensitivity of pre-
cluded for being duplicate publications4 or for not meeting sentation CK testing in patients with longer duration of
the criteria for analysis.5-9 Thus, 12 data sets were available symptoms.9,12,14,16,19,20
for meta-analysis. Of these, 10 included all eligible ED No studies evaluated CK levels in serial testing in the
patients,10-19 and 2 included only patients admitted to ED setting for the diagnosis of ACI. We found 4 studies
the hospital.20,21 that evaluated serial CK testing in the diagnosis of AMI.
Few of the 12 evaluable studies reported detailed de- Two studies were excluded because data could not be
scriptions of eligibility criteria. In general, included patients extracted for meta-analysis.6,21 Meta-analysis was not
had chest pain. Most studies excluded patients with clear performed on the remaining 2 studies because of the
noncardiac explanations for their symptoms. small sample size.
In general, AMI was defined by using World Health Both remaining studies reported broad eligibility crite-
Organization (WHO) criteria22 or variations thereof. Only ria; however, these 2 studies varied significantly in their
one11 explicitly did not use CK levels to define AMI but
instead used serial AST levels.
Eligible studies using presentation CK testing in the
diagnosis of AMI are described in Table 2; summaries of Table 15.
diagnostic performance are presented in Table 14. Summary of evidence of diagnostic test performance of serial
Heterogeneity among studies (primarily differences in biomarker in the diagnosis of AMI.
test sensitivity levels) was not explained by different CK
No. of No. of Sensitivity, Specificity,
Test Studies Subjects % (95% CI) % (95% CI)

Table 14. CK
Summary of evidence of diagnostic test performance of All studies 2 786 69–99* 68–84*
biomarker at presentation in the diagnosis of AMI. CK-MB
All studies 14 11,625 79 (71–86) 96 (95–97)
All ED patients† 7 3,229 80 (61–91) 96 (94–98)
Myoglobin, numerical‡
No. of No. of Sensitivity, Specificity, All studies 10 1,277 89 (80–94) 87 (80–92)
Test Studies Subjects % (95% CI) % (95% CI) All ED patients 5 831 90 (78–96) 92 (82–97)
Myoglobin, doubling§
CK All ED patients 1 89 64II 98II
All studies 12 3,195 37 (31–44) 87 (80–91) Myoglobin, increase¶
All ED patients* 10 2,885 36 (29–44) 88 (80–93) All studies 3 329 92 (83–96) 94 (75–99)
CK-MB Troponin I
All studies 19 6,425 42 (36–48) 97 (95–98) All studies 2 1,393 90–100* 83–96*
All ED patients 10 2,504 44 (35–53) 96 (94–97) Troponin T
Myoglobin All studies 3 904 93 (85–97) 85 (76–91)
All studies 18 4,172 49 (43–55) 91 (87–94) CK-MB and myo-
All ED patients 10 1,395 49 (41–57) 93 (88–96) globin combination#
Troponin I All studies 2 291 100* 75–91*
All studies 4 1,149 39 (10–78) 93 (88–97) *Range of values.
Troponin T †Studies that included all ED patients (including those discharged). Biomarker tests without this
All studies 6 1,348 39 (26–53) 93 (90–96)
row had too few studies for analysis.
All ED patients 5 1,171 44 (32–56) 92 (88–95) ‡Positive test result defined by one or more samples with value greater than threshold.
CK-MB and myo- §
Positive test result defined by doubling of value of test over time. Not represented in Figure 2 B.
globin combination† II
Single study.
All studies 3 2,283 83 (51–96) 82 (68–90) ¶Positive test result defined by either one or more sample with value greater than threshold or
*
Studies that included all ED patients (including those discharged). Biomarker tests without this given increase in value of test. Not represented in Figure 2 B.
row had too few studies for analysis. #Positive test result defined as either CK-MB or myoglobin level above threshold in either pre-
†
Positive test result defined as either CK-MB or myoglobin level above threshold at presentation. sentation or subsequent test.

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methods.11,23 One23 based timing of serial testing on toms consistent with ACI.33 Most studies excluded
symptom duration, and the other11 based timing of serial patients with clear noncardiac explanations for their
testing on time since arrival to the ED. symptoms. Others excluded patients with diagnostic
Eligible studies using serial CK testing in the diagnosis ECGs or with prolonged symptoms.
of AMI are described in Table 3; summaries of diagnostic Most studies defined AMI by using WHO criteria or
performance are presented in Table 15. variations thereof. The study of ACI did not define unsta-
Only 1 study evaluated CK-MB measurement as a sin- ble angina.24 Only 2 studies explicitly did not use CK-MB
gle test on presentation to the ED for diagnosis of ACI.24 levels to define AMI (apparently using CK levels only).16,33
We found 31 studies that evaluated presentation CK-MB The study of test performance of presentation CK-MB
testing for the diagnosis of AMI. Twelve studies were testing in the diagnosis of ACI is described in Table 1.
excluded for being duplicate publications4,25,26 or for Eligible studies for presentation CK-MB testing in the
not meeting criteria for analysis.6-9,27-31 Therefore, 19 diagnosis of AMI are described in Table 4; summaries of
data sets were available for analysis of CK-MB testing in diagnostic performance are presented in Table 14 and
the diagnosis of AMI. Of these, 10 studies included all eli- Figure 1A. The limited data suggest that presentation CK-
gible patients seen in the ED,5,16-19,24,32-35 7 included MB testing has substantially lower sensitivity for ACI than
only patients who were admitted to the hospital after ED for AMI, with similar specificity.
evaluation,20,21,36-40 and 2 included only patients admit- As with presentation CK testing, heterogeneity among
ted to the cardiac care unit (CCU) after ED evaluation.41,42 AMI studies could not be explained by means of CK-MB
In general, subjects were patients who presented to the thresholds, reported differences in eligibility criteria, study
ED with chest pain; one included all patients with symp- setting, or prevalence of AMI. There was not a clear corre-

Figure 1.
A, Presentation CK-MB testing summary receiver-operating characteristic curve analysis (n=19) for AMI. Individual studies are depicted as
ellipses. The x- and y-dimensions of the ellipses are proportional to the square root of the number of patients available to study the speci-
ficity and sensitivity, respectively, within the analysis. Also shown is the unweighted summary receiver-operating characteristic curve limited
to the range where data are available. The cross (x) represents the independent random-effects pooling of sensitivity and specificity values of
the studies. The x- and y-dimensions of the shaded rectangle represent the 95% CIs of the combined specificity and sensitivity, respectively.
B, Serial CK-MB testing summary receiver-operating characteristic curve analysis (n=14). Each ellipse is labeled with the duration of time
in hours between presentation and final test, except the 2 studies marked with an asterisk (*), which are labeled with the duration of time
from onset of symptoms to final test.

A Sensitivity B Sensitivity
16h* 6h
100 100
9h
4h 3h
90 90
3h
3h
80 80 3h
3h
70 70 3h 2h
2h
60 60 6h*

50 50
1h
40 40

30 30
20 20

10 10

0 0
0 10 20 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 70 80 90 100
100–Specificity 100–Specificity

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lation between mean or median symptom duration and included patients who presented to the ED with chest
test sensitivity in the 9 studies that reported this informa- pain. Three studies included all patients with symptoms
tion; however, the one study with 100% sensitivity had an consistent with ACI.23,33,51 Some studies excluded
average patient symptom duration of 14 hours39 com- patients with prolonged symptoms who were unstable,
pared with 2 to 6 hours in other studies. The 10 studies had diagnostic ECGs, or had a cardiac history. Most stud-
that analyzed test performance by means of symptom ies excluded patients with clear noncardiac explanations
duration all found increased sensitivity of presentation for their symptoms.
CK-MB measurement in patients with longer durations of In general, AMI was defined by using WHO criteria.
symptoms.5,9,16,19,20,28,29,32,33,43 One study used primarily AST and lactate dehydrogenase
Only 1 study evaluated serial CK-MB testing in the ED to define AMI.23 Others also used elevated serial troponin
for the diagnosis of ACI.24 We found 23 studies that eval- I testing or angiography in the diagnosis of AMI.
uated serial CK-MB testing in the ED for the diagnosis of Two studies drew laboratory samples according to
AMI in the ED. Nine articles were excluded from analysis symptom duration at either 10 and 16 hours after onset of
for being duplicate publications25,26 or for not meeting symptoms23 or at 3 and 6 hours after onset of symptoms.34
criteria for analysis.6,28,30,44-47 Thus, 14 studies were The rest of the studies drew samples at ED presentation
included in the meta-analysis. Of these, 7 evaluated all and at various times from 1 to 9 hours after presentation.
eligible patients seen in the ED23,24,33-35,48 or a “heart The study of performance of serial CK-MB testing in the
emergency room,”49 5 included only patients subse- diagnosis of ACI is described in Table 1. Eligible studies for
quently admitted to the hospital,36,38,43,50,51 and 2 serial CK-MB testing in the diagnosis of AMI are described
included only patients subsequently admitted to the in Table 5; summaries of diagnostic performance are pre-
CCU.41,42 sented in Table 15 and Figure 1B. The limited data suggest
The only ACI study is the same as that discussed with that serial CK-MB testing has substantially lower sensitivity
regard to presentation CK-MB testing.24 Most studies for ACI than for AMI, with similar specificity.

Figure 2.
A, Presentation myoglobin testing summary receiver-operating characteristic curve analysis (n=18) for AMI. Graph described in legend for
Figure 1. B, Serial myoglobin testing summary receiver-operating characteristic curve analysis (n=10). Only studies that used simple
numeric thresholds for myoglobin level are represented. Each ellipse is labeled with the duration of time in hours between presentation and
final test, except the study marked with an asterisk (*), which is labeled with the duration of time from onset of symptoms to final test.

A Sensitivity B Sensitivity
6h 2h 2h
100 100 4h
6h*3h
90 90 4h
3h
80 80
1h
70 70

60 60 1h

50 50

40 40

30 30
20 20

10 10

0 0
0 10 20 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 70 80 90 100
100–Specificity 100–Specificity

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Heterogeneity among AMI studies was best explained Five articles were excluded from analysis for being a
by timing of serial testing (Figure 1B). Studies that per- duplicate publication4 or for failing to meet criteria for
formed serial testing within 2 hours of presentation had analysis.27-29,45 Thus, 18 studies were included in the
test sensitivity levels below 70%. Those that drew serum meta-analysis for AMI. Of these, 10 evaluated all eligible
samples at presentation and 3 or 4 hours had sensitivities patients seen in the ED,4,5,11,18,19,33-35,52,53 5 included
from 68% to 90%. Test sensitivity was 100% in the 2 stud- only patients subsequently admitted to the hospi-
ies in which serial testing was performed at 6 or more tal,20,21,36,39,54 and 3 included only patients subse-
hours after presentation.36,49 Likewise, the study in quently admitted to the CCU.7,41,42
which serial testing was performed up to 16 hours after One study evaluated the diagnostic performance of
onset of symptoms23 had substantially higher sensitivity presentation myoglobin testing for ACI (defined as AMI
than the study in which serial testing was performed up to and angina); however, no definition of angina was
6 hours after symptom onset.34 given.52 In general, subjects of presentation myoglobin
studies were patients who presented to the ED with chest
MYOGLOBIN pain. Some studies included patients with other symp-
toms consistent with ACI. Some excluded patients with
A total of 27 reports were evaluated for the assessment of prolonged symptoms, diagnostic ECGs or chest radio-
the diagnostic accuracy of myoglobin testing in the diag- graphs, trauma or cardiopulmonary resuscitation, or kid-
nosis of ACI or AMI in the ED. Of the eligible studies, 18 ney failure or muscular dystrophy. Three studies did not
evaluated single myoglobin tests performed in the ED set- define how AMI was diagnosed20,53,54; the remainder
ting and 11 evaluated serial myoglobin tests. Only one used variations of the WHO criteria to define AMI.
study evaluated patients with ACI. The study of test performance of presentation myo-
Only 1 study evaluated myoglobin measurement as a globin measurement for ACI is described in Table 1.
single test on presentation to the ED for the diagnosis of Eligible studies for presentation myoglobin testing in the
ACI.52 We found 23 studies that evaluated presentation diagnosis of AMI are described in Table 6; summaries of
myoglobin testing for the diagnosis of AMI in the ED. diagnostic performance are presented in Table 14 and

Figure 3.
A, Presentation troponin I testing summary receiver-operating characteristic curve analysis (n=4) for AMI. Graph described in legend for
Figure 1. B, Serial troponin I studies in summary receiver-operating characteristic space (n=2).

A Sensitivity B Sensitivity
100 100
90 90

80 80

70 70

60 60

50 50

40 40

30 30
20 20

10 10

0 0
0 10 20 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 70 80 90 100
100–Specificity 100–Specificity

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Figure 2A. The limited data suggest that presentation was included, even though data on specificity was not
myoglobin testing has substantially lower sensitivity for explicitly reported52; the specificity of the presentation
ACI than for AMI, with similar, although possibly higher, myoglobin testing is included. Thus, 11 studies were
specificity. available for meta-analysis. Seven included eligible ED
As with presentation CK and CK-MB testing, hetero- patients11,18,27,33-35,52 (however, 1 study27 included
geneity among studies on the diagnosis of AMI could not only a subset of eligible subjects), 3 included only patients
be explained by myoglobin thresholds, reported differ- admitted to the hospital,36,51,54 and 1 included only
ences in eligibility criteria, study setting, or prevalence of patients admitted to the CCU.41
AMI. There was again not a clear correlation between In general, eligible patients were those who presented
mean or median symptom duration and test sensitivity in with chest pain or with other symptoms of ACI. Some
the 9 studies that reported this information. As was the studies restricted duration of symptoms, excluded
case with CK-MB testing, the one study with 100% sensi- patients with diagnostic ECGs or chest radiographs, or
tivity had an average patient symptom duration of 14 excluded patients with either trauma, kidney failure, or
hours39; however, the study with the lowest sensitivity muscular dystrophy.
(21%)54 had a median symptom duration of 8 hours. The One study did not define how AMI was diagnosed.54
6 studies that analyzed test performance by means of The remainder used variations of WHO criteria. To define
symptom duration all found increased sensitivity of pre- a positive test result, 10 studies used simple thresholds
sentation myoglobin testing in patients with longer for myoglobin levels,11,27,33-36,41,51,52,54 3 used a com-
symptom duration.5,9,19,20,28,33 bination of a simple threshold and an increase over time
No studies evaluated serial myoglobin testing in the in the myoglobin level,18,33,54 and 1 used a doubling of
ED for the diagnosis of ACI. We found 14 articles that myoglobin level alone.35 For meta-analysis, we included
evaluated serial myoglobin testing in the diagnosis of AMI data from serial testing done within 6 hours of presenta-
in the ED. Three were excluded for failing to meet the cri- tion. In addition, we included 1 study that drew labora-
teria for analysis.20,45,55 Because of the relatively small tory samples at 3 hours, 6 hours, or both from onset of
number of studies on serial myoglobin testing, 1 study symptoms.34 One study performed serial testing within 1

Figure 4.
A, Presentation of troponin T testing summary receiver-operating characteristic curve analysis (n=6) for AMI. Graph described in legend
for Figure 1. B, Serial troponin T summary receiver-operating characteristic curve analysis (n=3).

A Sensitivity B Sensitivity
100 100
90 90

80 80

70 70

60 60

50 50

40 40

30 30
20 20

10 10

0 0
0 10 20 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 70 80 90 100
100–Specificity 100–Specificity

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BIOMARKERS AND ACUTE CARDIAC ISCHEMIA
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hour33 and another within 6 hours36; the rest performed geneity was not explained by eligibility criteria, AMI
serial testing within 2 to 4 hours. prevalence, or test threshold.
Eligible studies for serial myoglobin testing in the diag- We found 3 articles that evaluated serial troponin I
nosis of AMI are described in Table 7; summaries of diag- testing performed in the ED. One was excluded because
nostic performance are presented in Table 15 and Figure serial testing was performed over a 24-hour period.27
2B. As with serial CK-MB testing, heterogeneity was best One study included all ED patients.56 The other study
explained by timing of serial testing. Overall, as the time included only patients admitted to the CCU.57
between serial tests was increased, the sensitivity of the The ED study included patients with less than 6 hours
test also increased. However, 2 small studies that per- of chest pain who did not have diagnostic ECGs or chest
formed serial testing at 2 hours after presentation re- radiographs, trauma, or recent AMI.56 Unstable angina
ported test sensitivity of 100%.27,35 was defined as type IIIB in the Braunwald classification.58
AMI was defined by elevation of CK levels. The CCU
TROPONIN I AND TROPONIN T study included only patients with moderate risk of AMI
who had blood drawn for troponin I testing in the CCU
A total of 18 reports were evaluated for the assessment of after perfusion imaging.57 Patients with diagnostic ECGs
the diagnostic accuracy of troponin I or T in the diagnosis or at high risk of AMI were excluded. AMI was defined by
of ACI or AMI in the ED. Of the eligible studies, 4 evalu- using WHO criteria.
ated single troponin I tests performed in the ED setting, 2 The study of performance of serial troponin I testing in
evaluated serial troponin I tests, 6 evaluated single tro- the diagnosis of ACI is described in Table 1. Eligible stud-
ponin T tests performed in the ED setting, and 3 evalu- ies for serial troponin I testing in the diagnosis of AMI are
ated serial troponin T tests. Two studies evaluated ACI. described in Table 9; summaries of diagnostic perfor-
No studies evaluated troponin I tests performed at pre- mance are presented in Table 15 and Figure 3B. The lim-
sentation to the ED for the diagnosis of ACI. We found 8 ited data suggest that serial troponin I testing has substan-
articles that evaluated presentation troponin I testing in tially lower sensitivity for ACI than for AMI, with similar,
the diagnosis of AMI in the ED. Only 4 articles reported although possibly higher, specificity.
sufficient data to allow meta-analysis; 2 studies included No studies evaluated troponin T measurement as a sin-
all eligible ED patients,5,56 and 2 included only patients gle test at presentation to the ED for the diagnosis of ACI.
admitted to the hospital from the ED.21,39 Three studies We found 9 studies that evaluated presentation troponin T
did not report test specificity.9,27,57 However, because of testing in the diagnosis of AMI in the ED. One study was
the small number of studies, these studies are included in excluded because it did not report test performance data.6
Table 8. One study was excluded because performance Two studies are presented in Table 10 but are not included
data on presentation testing could not be extracted.46 in the meta-analysis: one did not report sufficient informa-
All studies included patients who presented to the ED tion to be able to extract data for meta-analysis,28 and the
with chest pain or with symptoms suggestive of ACI or other studied a highly selected sample of patients and
AMI. Some studies excluded patients with diagnostic reported test performance data inconsistent with the num-
ECGs or chest radiographs or those who received throm- ber of patients analyzed.30 Four of the eligible studies
bolysis, cardiopulmonary resuscitation, or had trauma. included all ED patients,5,15,19,56 1 enrolled subjects and
Most studies defined AMI by using WHO criteria. drew blood samples before arrival in the ED,59 and 1
Eligible studies for presentation troponin I testing in included only patients admitted to the hospital.21
the diagnosis of AMI are described in Table 8; summaries In general, subjects were those with chest pain or
of diagnostic performance are presented in Table 14 and symptoms suggestive of AMI not caused by trauma. Most
Figure 3A. There was a large degree of heterogeneity studies excluded patients with prolonged symptoms.
among the test sensitivity values: they ranged between Other reasons for exclusion included diagnostic ECGs or
4% and 100%. The heterogeneity is best explained by chest radiographs, cardiopulmonary resuscitation, recent
duration of symptoms. The study with a test sensitivity of AMI, angioplasty, or thrombolysis. The study with the
4%21 reported an average duration of pain for all patients highest AMI prevalence included only patients who met
of 4 hours. However, a study with an average of 2 hours of the criteria of the Imminent Myocardial Infarction
patient symptoms reported a test sensitivity of 23%.5 In Rotterdam Study.30 AMI was defined by using WHO cri-
the study with a test sensitivity of 100%, subjects with teria, except in one study, which used elevation of CK lev-
AMI had an average of 7 hours of symptoms.39 Hetero- els only.56

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Eligible studies for presentation troponin T testing in tests drawn in 1 serum sample, and 2 reported data on
the diagnosis of AMI are described in Table 10; sum- serial samples. No other combinations of biomarker tests
maries of diagnostic performance are presented in Table were reported by other studies. No studies evaluated ACI.
14 and Figure 4A. There is some indication that the stud- No studies evaluated combination CK-MB and myo-
ies with smaller test sensitivity values included patients globin testing at presentation to the ED for the diagnosis
with shorter durations of symptoms; however, this is not of ACI. Two studies reported data on combination CK-MB
as clear as for troponin I. and myoglobin testing at presentation to diagnose
We found 6 articles that evaluated serial troponin T AMI.41,42 A third study on AMI reported combination
testing in the ED; however, 2 were excluded from analysis data only from the serum sample drawn 2 hours after pre-
because data on test performance were not presented.6,29 sentation.35 Eligibility criteria and test thresholds were
One study is presented in Table 11 but not in the meta- the same as for evaluation of the individual tests. Two
analysis because data were not available for extraction.47 studies included only patients admitted to the CCU,41,42
One of the eligible studies included all ED patients,56 1 and the third included all eligible ED patients.35 A posi-
was a highly selected ED population,30 and 1 included tive combination test result was defined as either a posi-
only patients admitted to the hospital.60 tive CK-MB or a positive myoglobin level.
The studies represent a diverse set of patient samples. Eligible studies for presentation combination CK-MB
In general, subjects presented with chest pain; however, a and myoglobin testing in the diagnosis of AMI are de-
variety of exclusion criteria were used. Two of the studies scribed in Table 2; summaries of diagnostic performance
reported diagnostic performance for ACI.56,60 Both diag- are presented in Table 14. Although the performance of
nosed unstable angina by using the Braunwald classifica- the combination test appears better than that for each of
tion. In general, AMI was defined by using WHO criteria. the individual tests, it should be noted that it is likely
The studies of performance of serial troponin T testing that the decision to report the combination result was
in the diagnosis of ACI are described in Table 1. Eligible made a posteriori. It is unclear whether the small number
studies for serial troponin T testing in the diagnosis of of studies that actually reported the combination data are
AMI are described in Table 11; summaries of diagnostic a biased sample (in that studies with better combination
performance are presented in Table 15 and Figure 4B. The than individual test performance may be more likely to
limited data suggest that serial troponin T testing has sub- report the data). In addition, the study that reported only
stantially lower sensitivity for ACI than for AMI, possibly 2-hour data35 had a substantially higher test sensitivity of
with higher specificity. 100%.
No studies evaluated combination CK-MB and myo-
DIRECT COMPARISONS OF BIOMARKER TESTS globin testing in serial serum samples in the diagnosis of
ACI. Only 2 studies reported on serial testing of combina-
Most studies reported the diagnostic performance of mul- tion CK-MB and myoglobin levels in the diagnosis of
tiple presentation or serial biomarker tests. Within given AMI.41,51 Eligibility criteria and test thresholds were the
studies (thus, in the same patients following the same same as for evaluation of the individual tests. The studies
protocol), myoglobin measurement, either as a presenta- included only patients admitted to either the hospital51 or
tion or serial test, generally had a higher test sensitivity in the CCU.41 A positive combination test result was defined
the diagnosis of AMI than either CK or CK-MB measure- as either a positive CK-MB or a positive myoglobin level in
ment. In addition, the level of myoglobin peaked earlier. either of the serum samples drawn. However, at least 1 of
The few studies of either troponin I or T testing found the 2 studies used test thresholds that were chosen post
varying relative sensitivity levels compared with CK, CK- hoc after examination of receiver-operating characteristic
MB, and myoglobin testing, and therefore, no conclusion curves for individual and combination tests.51
could be reached. No study directly compared biomark- Eligible studies for serial combination CK-MB and
ers for ACI. myoglobin testing in the diagnosis of AMI are described
in Table 13; summaries of diagnostic performance are
C O M B I N AT I O N B I O M A R K E R T E S T S presented in Table 15. With such a small sample, it is diffi-
cult to compare individual and combination serial test-
Four studies reported on the combination of CK-MB and ing, although the test performance appears to be at least
myoglobin testing. Three of these reported data on the 2 similar.

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CLINICAL EFFECT OF BIOMARKER TESTS tom duration on test performance, but studies that did
examine symptom duration found increasing test sensi-
Only 1 study reported data on the clinical effect of using tivity with increasing symptom duration.
biomarker tests in the ED. The study evaluated serial CK- Multiple measurements over several hours greatly
MB testing and changes in decisionmaking by ED physi- increase test sensitivity for AMI (>79%) while retaining
cians on whether patients required hospital or CCU ad- high specificity (generally >85%). However, the im-
mission.24 Patients had chest discomfort and a clinical proved test performance comes at the expense of a con-
suspicion of AMI but were excluded if they had diagnostic siderable amount of additional time that may be neces-
ECGs or chest radiographs, clinical instability, recent car- sary. To achieve high sensitivity for AMI with serial
dioversion, or chest trauma. CK-MB testing, 4 hours between tests appears to be
The analysis pertained primarily to rankings by the required. For serial myoglobin testing, the duration
physicians of the importance attributed to CK-MB levels required between tests to achieve high sensitivity is less
(and other factors) to clinical decisionmaking for individ- clear, although a minimum of 2 to 4 hours appears neces-
ual patients. Overall, among 67 patients with AMI, the sary. As for presentation biomarker tests, within studies,
decision to admit to the hospital was changed from “no” to serial myoglobin testing generally had higher sensitivity
“yes” after reviewing the CK-MB results in 3 (4.5%) patients. than CK or CK-MB testing.
No patients with AMI were discharged after review of the The few studies available for analysis on troponin I and
CK-MB levels. Likewise, among the patients with AMI, T testing yielded similar findings of diagnostic perfor-
the decision to admit to the CCU was changed from “no” mance for AMI for both presentation and serial testing.
to “yes” in 13 (19.4%) patients. The decision was changed Too few studies were available to analyze optimal timing
to not admit to the CCU in 2 (3.0%) patients. of serial testing. Direct comparisons between the troponin
Among the 146 patients with unstable angina, the testing and other biomarker tests were also inconclusive.
decision to admit to the hospital was changed from “no” The few studies available for analysis of combination CK-
to “yes” in 1 (0.7%) patient. No patients with unstable MB and myoglobin testing found moderately high sensi-
angina were discharged from the ED. Among the 829 tivity while maintaining moderate specificity; however,
patients without ACI, 5 (0.6%) additional patients were these analyses were likely performed a posteriori, may be
admitted to the hospital after review of the test results; 27 selectively reported, and thus may overestimate test per-
(3.3%) additional patients were discharged. formance.
The methodologic quality of the studies was generally
COMMENT poor. Very few studies adequately reported on blinding of
either test results or diagnosis. This was especially true
Biomarker tests have been developed primarily to diag- with studies of CK and CK-MB testing, in which the
nose AMI. Thus, very little evidence exists to describe the biomarkers were frequently used to make the diagnosis.
performance of these tests in the diagnosis of ACI. In general, study eligibility criteria, sample population
Limited evidence suggests that current biomarker tests description, or description of follow-up were incomplete.
have low sensitivity and high specificity for ACI. Many Complete numbers and descriptions of patient with-
patients with unstable angina would therefore be missed drawals were rare. This made analysis of the differences
by using biomarkers alone. between study findings difficult. In addition, too few
The evidence for AMI suggests that individual bio- studies gave sufficient information for us to properly ana-
chemical markers drawn at presentation have uniformly lyze the effect of symptom duration on diagnostic perfor-
low test sensitivity (<50%) but high specificity (>85%) mance.
for AMI in the ED setting. Presentation myoglobin testing Of note, almost no research has been performed on the
appears to have slightly higher sensitivity than the other effect on actual clinical care or the cost-effectiveness of
presentation biomarkers, although few studies published using various biomarkers as a diagnostic aid for ACI. Only
by the date of this evidence report have reported on diag- 1 article examined the clinical effect of serial CK-MB test-
nostic performance of troponin testing. Within studies, ing. It showed a small but important effect on triage deci-
presentation myoglobin testing also generally had higher sions. More research is necessary on the clinical effect of
sensitivity than CK or CK-MB testing in the diagnosis of biomarker use in the ED for diagnosis of ACI. Because of
AMI. We were unable to fully analyze the effect of symp- the importance of providing a diagnosis for all patients at

4 9 2 ANNALS OF EMERGENCY MEDICINE 37:5 MAY 2001

BIOMARKERS AND ACUTE CARDIAC ISCHEMIA
Balk et al

risk of ACI, future research should include evaluation of 18. Gornall DA, Roth SN. Serial myoglobin quantitation in the early assessment of myocardial
damage: a clinical study. Clin Biochem. 1996;29:379-384.
patients with unstable angina, as well as patients with
19. Hetland O, Dickstein K. Cardiac markers in the early hours of acute myocardial infarction:
AMI. In addition, more research is necessary to determine clinical performance of creatine kinase, creatine kinase MB isoenzyme (activity and mass con-
the optimal timing of serial testing, especially for myo- centration), creatine kinase MM and MB subform ratios, myoglobin and cardiac troponin T.
globin and troponin I and T testing, to test a priori combi- Scand J Clin Lab Invest. 1996;56:701-713.

nations of presentation biomarkers and of biomarkers 20. Tucker JF, Collins RA, Anderson AJ, et al. Value of serial myoglobin levels in the early diag-
nosis of patients admitted for acute myocardial infarction. Ann Emerg Med. 1994;24:704-708.
and other diagnostic methods for the diagnosis of ACI,
21. Tucker JF, Collins RA, Anderson AJ, et al. Early diagnostic efficiency of cardiac troponin I
and to determine the clinical effectiveness of using and troponin T for acute myocardial infarction. Acad Emerg Med. 1997;4:13-21.
biomarkers through prospective interventional trials. 22. Gillum RF, Fortmann SP, Prineas RJ, et al. International diagnostic criteria for acute myocar-
dial infarction and acute stroke. Am Heart J. 1984;108:150-158.
23. Gerhardt W, Waldenstrom J, Horder M, et al. Creatine kinase and creatine kinase B-subunit
REFERENCES
activity in serum in cases of suspected myocardial infarction. Clin Chem. 1982;28:277-283.
1. Selker HP, Zalenski RJ, Antman EM, et al. An evaluation of technologies for identifying
24. Hedges JR, Gibler WB, Young GP, et al. Multicenter study of creatine kinase-MB use: effect
acute cardiac ischemia in the emergency department: a report from the National Heart Attack
on chest pain clinical decision making. Acad Emerg Med. 1996;3:7-15.
Alert Program Working Group. Ann Emerg Med. 1997;29:13-87.
25. Hedges JR, Young GP, Henkel GF, et al. Early CK-MB elevations predict ischemic events in
2. Lau J, Ioannidis JPA, Balk EM, et al. Diagnosing acute cardiac ischemia in the emergency
stable chest pain patients. Acad Emerg Med. 1994;1:9-16.
department: a systematic review of the accuracy and clinical effect of current technologies. Ann
Emerg Med. 2001;37:453-460. 26. Young GP, Gibler WB, Hedges JR, et al. Serial creatine kinase-MB results are a sensitive
indicator of acute myocardial infarction in chest pain patients with nondiagnostic electrocardio-
3. New England Medical Center. Evaluation of Technologies for Identifying Acute Cardiac
grams: the second Emergency Medicine Cardiac Research Group Study. Acad Emerg Med.
Ischemia in Emergency Departments. Evidence Report/Technology Assessment No. 26 (prepared
1997;4:869-877.
under Contract No. 290-97-0019.) Rockville, MD: Agency for Healthcare Research and Quality;
2000. AHRQ Publication No. 01-E006. 27. D’Costa M, Fleming E, Patterson MC. Cardiac troponin I for the diagnosis of acute myocar-
dial infarction in the emergency department. Am J Clin Pathol. 1997;108:550-555.
4. Mair J, Artner-Dworzak E, Lechleitner P, et al. Early diagnosis of acute myocardial infarc-
tion by a newly developed rapid immunoturbidimetric assay for myoglobin. Br Heart J. 28. de Winter RJ, Koster RW, Sturk A, et al. Value of myoglobin, troponin T, and CK-MB mass
1992;68:462-468. in ruling out an acute myocardial infarction in the emergency room. Circulation. 1995;92:3401-
3407.
5. Mair J, Genser N, Morandell D, et al. Cardiac troponin I in the diagnosis of myocardial
injury and infarction. Clin Chim Acta. 1996;245:19-38. 29. Laurino JP, Bender EW, Kessimian N, et al. Comparative sensitivities and specificities of
the mass measurements of CK-MB2, CK-MB, and myoglobin for diagnosing acute myocardial
6. Katz IA, Irwig L, Vinen JD, et al. Biochemical markers of acute myocardial infarction: strate-
infarction. Clin Chem. 1996;42:1454-1459.
gies for improving their clinical usefulness. Ann Clin Biochem. 1998;35(Suppl):393-399.
30. Mach F, Lovis C, Chevrolet JC, et al. Rapid bedside whole blood cardiospecific troponin T
7. Ohman EM, Casey C, Bengtson JR, et al. Early detection of acute myocardial infarction:
immunoassay for the diagnosis of acute myocardial infarction. Am J Cardiol. 1995;75:842-845.
additional diagnostic information from serum concentrations of myoglobin in patients without
ST elevation. Br Heart J. 1990;63:335-338. 31. Zalenski RJ, McCarren M, Roberts R, et al. An evaluation of a chest pain diagnostic proto-
col to exclude acute cardiac ischemia in the emergency department. Arch Intern Med.
8. Young GP, Green TR. The role of single ECG, creatinine kinase, and CKMB in diagnosing 1997;157:1085-1091.
patients with acute chest pain. Am J Emerg Med. 1993;11:444-449.
32. Collins DR, Wright DJ, Rinsler MG, et al. Early diagnosis of acute myocardial infarction
9. Laurino JP, Pelletier TE, Eadry R, et al. Thrombus precursor protein and the measurement of with use of a rapid immunochemical assay of creatine kinase MB isoenzyme. Clin Chem.
thrombosis in patients with acute chest pain syndrome. Ann Clin Lab Sci. 1997;27:338-345. 1993;39:1725-1728.
10. Eisenberg JM, Horowitz LN, Busch R, et al. Diagnosis of acute myocardial infarction in the 33. Brogan GX Jr, Friedman S, McCuskey C, et al. Evaluation of a new rapid quantitative
emergency room: a prospective assessment of clinical decision making and the usefulness of immunoassay for serum myoglobin versus CK-MB for ruling out acute myocardial infarction in
immediate cardiac enzyme determination. J Community Health. 1979;4:190-198. the emergency department. Ann Emerg Med. 1994;24:665-671.
11. Roxin LE, Cullhed I, Groth T, et al. The value of serum myoglobin determinations in the early 34. Castaldo AM, Ercolini P, Forino F, et al. Plasma myoglobin in the early diagnosis of acute
diagnosis of acute myocardial infarction. Acta Med Scand. 1984;215:417-425. myocardial infarction. Eur J Clin Chem Clin Biochem. 1994;32:349-353.
12. Lee TH, Weisberg MC, Cook EF, et al. Evaluation of creatine kinase and creatine kinase-MB 35. Montague C, Kircher T. Myoglobin in the early evaluation of acute chest pain. Am J Clin
for diagnosing myocardial infarction. Clinical impact in the emergency room. Arch Intern Med. Pathol. 1995;104:472-476.
1987;147:115-121.
36. Gibler WB, Gibler CD, Weinshenker E, et al. Myoglobin as an early indicator of acute myo-
13. Hedges JR, Rouan GW, Toltzis R, et al. Use of cardiac enzymes identifies patients with cardial infarction. Ann Emerg Med. 1987;16:851-856.
acute myocardial infarction otherwise unrecognized in the emergency department. Ann Emerg
37. Gibler WB, Lewis LM, Erb RE, et al. Early detection of acute myocardial infarction in patients
Med. 1987;16:248-252.
presenting with chest pain and nondiagnostic ECGs: serial CK-MB sampling in the emergency
14. Viskin S, Heller K, Gheva D, et al. The importance of creatine kinase determination in iden- department. Ann Emerg Med. 1990;19:1359-1366.
tifying acute myocardial infarction among patients complaining of chest pain in an emergency
38. Marin MM, Teichman SL. Use of rapid serial sampling of creatine kinase MB for very early
room. Cardiology. 1987;74:100-110.
detection of myocardial infarction in patients with acute chest pain. Am Heart J. 1992;123:354-
15. Mair J, Artner-Dworzak E, Lechleitner P, et al. Cardiac troponin T in diagnosis of acute 361.
myocardial infarction. Clin Chem. 1991;37:845-852.
39. Apple FS, Voss E, Lund L, et al. Cardiac troponin, CK-MB and myoglobin for the early detec-
16. Mair J, Artner-Dworzak E, Dienstl A, et al. Early detection of acute myocardial infarction by tion of acute myocardial infarction and monitoring of reperfusion following thrombolytic therapy.
measurement of mass concentration of creatine kinase-MB. Am J Cardiol. 1991;68:1545-1550. Clin Chim Acta. 1995;237:59-66.
17. Thomson SP, Gibbons RJ, Smars PA, et al. Incremental value of the leukocyte differential 40. Fesmire FM, Percy RF, Bardoner JB, et al. Serial creatinine kinase (CK) MB testing during
and the rapid creatine kinase-MB isoenzyme for the early diagnosis of myocardial infarction. the emergency department evaluation of chest pain: utility of a 2-hour δCK-MB of +1.6 ng/ml.
Ann Intern Med. 1995;122:335-341. Am Heart J. 1998;136:237-244.

MAY 2001 37:5 ANNALS OF EMERGENCY MEDICINE 4 9 3

BIOMARKERS AND ACUTE CARDIAC ISCHEMIA
Balk et al

41. Kontos MC, Anderson FP, Hanbury CM, et al. Use of the combination of myoglobin and CK-
MB mass for the rapid diagnosis of acute myocardial infarction. Am J Emerg Med. 1997;15:14-19.
42. Kontos MC, Anderson FP, Schmidt KA, et al. Early diagnosis of acute myocardial infarction
in patients without ST-segment elevation. Am J Cardiol. 1999;83:155-158.
43. Gibler WB, Young GP, Hedges JR, et al. Acute myocardial infarction in chest pain patients
with nondiagnostic ECGs: serial CK-MB sampling in the emergency department. The Emergency
Medicine Cardiac Research Group. Ann Emerg Med. 1992;21:504-512.
44. Puleo PR, Meyer D, Wathen C, et al. Use of a rapid assay of subforms of creatine kinase-
MB to diagnose or rule out acute myocardial infarction. N Engl J Med. 1994;331:561-566.
45. Brogan GX Jr, Vuori J, Friedman S, et al. Improved specificity of myoglobin plus carbonic
anhydrase assay versus that of creatine kinase-MB for early diagnosis of acute myocardial
infarction. Ann Emerg Med. 1996;27:22-28.
46. Brogan GX Jr, Bock JL, McCuskey CF, et al. Evaluation of cardiac STATus CK-MB/myo-
globin device for rapidly ruling out acute myocardial infarction. Clin Lab Med. 1997;17:655-668.
47. Sayre MR, Kaufmann KH, Chen IW, et al. Measurement of cardiac troponin T is an effective
method for predicting complications among emergency department patients with chest pain.
Ann Emerg Med. 1998;31:539-549.
48. Hedges JR, Young GP, Henkel GF, et al. Serial ECGs are less accurate than serial CK-MB results
for emergency department diagnosis of myocardial infarction. Ann Emerg Med. 1992;21:1445-1450.
49. Gibler WB, Runyon JP, Levy RC, et al. A rapid diagnostic and treatment center for patients
with chest pain in the emergency department. Ann Emerg Med. 1995;25:1-8.
50. Hoekstra JW, Hedges JR, Gibler WB, et al. Emergency department CK-MB: a predictor of
ischemic complications. National cooperative CK-MB project group. Acad Emerg Med.
1994;1:17-27.
51. Levitt MA, Promes SB, Bullock S, et al. Combined cardiac marker approach with adjunct
two-dimensional echocardiography to diagnose acute myocardial infarction in the emergency
department. Ann Emerg Med. 1996;27:1-7.
52. Kennedy RL, Harrison RF, Burton AM, et al. An artificial neural network system for diagno-
sis of acute myocardial infarction (AMI) in the accident and emergency department: evaluation
and comparison with serum myoglobin measurements. Comput Methods Programs Biomed.
1997;52:93-103.
53. Gilkeson G, Stone MJ, Waterman M, et al. Detection of myoglobin by radioimmmunoassay
in human sera: its usefulness and limitations as an emergency room screening test for acute
myocardial infarction. Am Heart J. 1978;95:70-77.
54. Davis CP, Barrett K, Torre P, et al. Serial myoglobin levels for patients with possible myo-
cardial infarction. Acad Emerg Med. 1996;3:590-597.
55. Woo J, Lacbawan FL, Sunheimer R, et al. Is myoglobin useful in the diagnosis of acute
myocardial infarction in the emergency department setting? Am J Clin Pathol. 1995;103:725-
729.
56. Hamm CW, Goldmann BU, Heeschen C, et al. 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.
57. Kontos MC, Jesse RL, Anderson FP, et al. Comparison of myocardial perfusion imaging and
cardiac troponin I in patients admitted to the emergency department with chest pain.
Circulation. 1999;99:2073-2078.
58. Braunwald E. Unstable angina: a classification. Circulation. 1989;80:410-414.
59. Gust R, Gust A, Bottiger BW, et al. Bedside troponin T testing is not useful for early out-of-
hospital diagnosis of myocardial infarction. Acta Anaesthesiol Scand. 1998;42:414-417.
60. Mohler ER, Ryan T, Segar DS, et al. Clinical utility of troponin T levels and echocardiogra-
phy in the emergency department. Am Heart J. 1998;135:253-260.

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