A Systematic Review of Troponin T and I for Diagnosing Acute Myocardial Infarction

Until recently, creatine kinase (CK) and creatine kinase, myocardial bound (CK-MB) fractions were used most often for evaluating patients with acute chest pain and suspected acute myocardial infarction (AMI). The World Health Organization (WHO) criteria for diagnosing AMI include elevation in this blood test result, along with typical electrocardiographic changes and a history compatible with ischemia.¹ Recently, elevations in the serum troponin T and troponin I levels have been used both to test for AMI and to predict adverse cardiac events.²

However, interpretation of the troponin test results can be problematic. The test characteristics vary considerably, depending on the cutoff used to define abnormal, the troponin fraction used (T or I), and the time from the onset of myocardial ischemia. For example, increases in the cutoff number will decrease sensitivity but improve specificity.³ Because the troponin tests rely on damage to myocardial cells and the release of troponins into the circulation, sensitivity initially increases with the number of hours from the onset of chest pain, then decreases as the enzyme is cleared from the circulation. However, many of the reports on which current estimates of sensitivity and specificity are based do not report the time from the onset of symptoms or only provide the worst value in the first 24 hours. Decision making in the emergency department (ED) is often based on earlier values, and it is therefore important to carefully describe the accuracy of the test at different times.²

One previous meta-analysis of the use of troponins for diagnosing AMI was published.⁴ Unfortunately, it had several limitations. The literature review was abbreviated, and numerous important articles have been published since the review was completed. There was no assessment of study quality, and the outcome used was adverse cardiac events rather than diagnosis of AMI. We report the results of a systematic review of the literature documenting use of troponins for diagnosing AMI, with assessment of the quality of the studies and synthesis of results when appropriate.

Methods

Search Strategy

We conducted a search of the MEDLINE database in June 1999 using the following strategy: troponin (text word) and diagnosis (medical subject heading [MeSH]) or troponin/diagnostic use (MeSH). This initial search identified approximately 800 articles. The abstract of each article was reviewed, and articles were evaluated in detail if: (1) troponins were used in the diagnosis of heart disease; (2) the study involved human subjects; and (3) the articles were written in English, German, French, or Spanish. A total of 114 articles met these basic criteria. A second search of the 1999 literature took place in December 1999, and 10 additional articles that met the basic criteria were identified.

Inclusion Criteria and Assessment of Study Quality

We included studies in the analysis if, after a review of the full article, they met the following inclusion criteria:

• The study design was prospective data collection, consecutive or nonconsecutive patient enrollment (but not case-control), and the physician determining whether the patient had an AMI was blinded to the troponin results.
• The study population was of adult patients with acute chest pain.
• The WHO reference standard or similar criteria was used to diagnose AMI.
• The authors reported data for calculating sensitivity or specificity for at least one point from the onset of pain or presentation to the ED for troponin T or I.

The WHO criteria for diagnosing AMI require 2 of the following: clinical history, typical electrocardiogram changes, and an increase of CK and CK-MB activity. Case-series studies of only patients with AMI were included for the calculation of sensitivity. We further classified studies meeting these basic criteria as level I or II depending on whether the patient enrollment was clearly stated as consecutive (level I), or nonconsecutive or unspecified (level II).

Data Abstraction

Two independent investigators (either ME and DF or CF and DF) reviewed each article for study quality and inclusion criteria. We resolved any discrepancies by consensus decision. Two articles were in French or German, and only one investigator reviewed each of these. Neither study met inclusion criteria.

We abstracted the following data from each article: setting, variables required for evaluation of study quality, time from onset of chest pain or admission to the ED, and cutoff value(s) for abnormal levels of troponin T or I. If a range of 4 hours or less was reported for the time from onset of pain or the time from arrival at the ED, the mean time was used as a point estimate. Ranges of greater than 4 hours were discarded. For example, if a study reported the specificity for blood drawn between 4 and 6 hours after presentation to the ED, this range was recorded as a point estimate of 5 hours. We compared the data abstracted by each of the 2 reviewers, and all discrepancies were resolved by consensus decision. If it appeared that additional data might have been collected but not reported, we contacted the authors of the articles by postal or electronic mail.

Statistical Analysis

The primary outcomes were the test characteristics (sensitivity, specificity, predictive values, and positive and negative likelihood ratios) for each test at different points in time. Sensitivity is the proportion of patients with AMI who have an abnormal troponin test result, and specificity is the proportion without AMI who have a normal troponin test result. The positive and negative likelihood ratios are calculated using the following equations:

Positive likelihood ratio=sensitivity/(100-specificity)

Negative likelihood ratio=(100-sensitivity)/specificity

The positive and negative likelihood ratios correspond to the clinical concepts of ruling in and ruling out disease. Thus, a higher positive likelihood ratio means that a test result is better for ruling in disease when positive, and a lower negative likelihood ratio means that a test result is better for ruling out disease when negative. When possible, we made summary estimates of sensitivity and specificity using a DerSimonian and Laird random effects model. Sensitivity and specificity were pooled independently and weighted by the inverse of the variance using the MetaTest software (Joseph Lau, MD, New England Medical Center, Boston, Mass). If a fixed effects model (Mantel-Haenszel, chi-square) and a random effects model (DerSimonian and Laird) calculated similar estimates of sensitivity or specificity the studies were homogenous, and we reported the more conservative random effects model result. If the fixed effects model and random effects model gave estimates that were different in a clinically meaningful way, the studies were heterogeneous, and only a range was reported.

We drew summary receiver operating characteristic (ROC) curves, and calculated the weighted area under the curve by the method of Moses⁵ using the MetaTest software. The area under the ROC curve is a measure of the ability of a test to discriminate between healthy and diseased individuals, and it is equal to the proportion of patients correctly classified in a forced-choice comparison. Models for sensitivity and specificity versus hours from the onset of chest pain and models for sensitivity and specificity versus cutoff level were fitted using SPSS 9.0 software (SPSS, Chicago, Ill). The choice of linear or logarithmic model was based on inspection of the data.

Results

Eleven studies met level I criteria for quality,^6-16 and an additional 8 met level II criteria.^17-24 Study characteristics are summarized in Table 1. Most studies only reported data for the time from presentation to the ED, rather than the time from onset of chest pain.

Test Accuracy by Time from the Onset of Symptoms

Figure 1 shows the sensitivity for studies of troponin T using cutoffs of 0.1,7,8,14 0.2,6,14,19 and 0.519 plotted against the number of hours from the onset of chest pain. Specificity was similar for all 3 cutoffs and is plotted as a single line. The authors of most of these studies evaluated the widely used enzyme-linked immunoassay test from Boehringer-Mannheim. The following equations plot the logarithmic curves for sensitivity shown on the graph and allow for the calculation of the sensitivity and specificity of troponin T for any number of hours following the onset of chest pain (note that these equations are only valid over the range for which data are available; ie, 0-12 hours from the onset of chest pain):

Cutoff 0.1: sensitivity=(-0.0011 × hours2) + (0.0634 × hours) + 0.4036

Cutoff 0.2: sensitivity=(-0.0132 × hours2) + (0.2363 × hours) - 0.0862

Cutoff 0.5: sensitivity=(-0.0111 × hours2) + (0.223 × hours) - 0.0981

All cutoffs: specificity=(-.0084 × hours) + 0.8821

Data from high-quality studies were more limited for troponin I. Only 4 level I studies reported data for troponin I,^10,11,13,15 and only one of these reported results for sensitivity and specificity for different times from the onset of symptoms. The authors of that study¹³ only reported the sensitivity and specificity for ranges of 6, 12, 24, and 72 hours and used a cutoff of 2.5 ng/mL. Sensitivity was 17% in the 0 to 6-hour range, 92% in the 6 to 12-hour range, and 100% for the highest value in the 12 to 24-hour range. The specificity was 95% from 0 to 12 hours, and 98% from 12 to 24 hours. The corresponding positive and negative likelihood ratios are 3.4 and 0.9 for the 0 to 6-hour range, 18.4 and 0.08 for the 6 to 12-hour range, and 50 and 0.01 for the 12 to 24-hour range. A single level II study of a bedside troponin I test²⁴ measured the sensitivity as a function on the hours from the onset of chest pain, using a cutoff of 0.1 ng/mL. This graph is shown in Figure 2. The formula for sensitivity is:

Sensitivity=(-0.0128 × hours2) + (0.2438 × hours) - 0.0971

Sensitivity does not exceed 80% until 5 hours after the onset of chest pain. Specificity was not reported in this study.

Test Accuracy by Time After Admission

The authors of 5 studies reported the sensitivity and specificity measured from the time of arrival at the ED. Summary estimates of the sensitivity and specificity for troponin T, using a cutoff of 0.2 ng/mL at the time of admission, were 33% and 93% (values from the fixed effects model were 35% and 94%). The corresponding positive and negative likelihood ratios are 4.7 and 0.7, and the weighted area under the ROC curve is 0.77.^{14,18,19,22,23} Using the peak value of troponin T in the first 24 hours and a cutoff of 0.2, the sensitivity and specificity are 98% and 87% (values from the fixed effects model were 98% and 89%). The corresponding positive and negative likelihood ratios are 7.5 and 0.02, and the weighted area under the ROC curve is 0.99.^19,16,20

Discussion

We have summarized the existing data on the accuracy of troponin T and I values as diagnostic tests for AMI for patients with acute chest pain. These data are summarized for clinicians in Table 2. The sensitivities and specificities in Table 2 are estimated from the best-fit curves shown in Figure 2. Note that for troponin I, sensitivity data are from one study²⁴ and specificity from another.¹³ Nomograms can help physicians interpret the results of troponin T and troponin I at different times from the onset of chest pain and for different pretest probabilities of AMI.* Although troponin I appears to be better at ruling in MI than troponin T, these results are based on a single small study.

The most important take-home message for clinicians is that the sensitivity of the troponin tests, like that of any other cardiac enzyme, is highly dependent on the number of hours since the onset of chest pain. The test is insensitive (ie, will miss many cases of AMI) within the first 6 hours after the onset of chest pain, when patients often present to the ED. However, by 12 or more hours after pain onset the test is quite sensitive, and a negative troponin value is strong evidence against the presence of AMI.

Diagnostic tests are symmetric if a positive test result as effectively rules in disease as a negative test result rules it out. For example, a test with a positive likelihood ratio of 5 and a negative likelihood ratio of 0.2 (1/5) would be symmetric. Examination of the likelihood ratios reveals that the troponin tests are asymmetric with respect to the positive and negative likelihood ratios. However, this relationship is not consistent. Troponin T and I are very useful at ruling out AMI when the value is negative at 10 or more hours from the onset of chest pain (negative likelihood ratio 0.1). However, a negative test value early in the course of the episode of chest pain does very little to reduce the likelihood of AMI. A positive troponin T value, however, is only moderately useful at ruling in AMI when blood was drawn 6 or more hours after the onset of pain (positive likelihood ratio=~5). Although a positive troponin I value from blood drawn 6 or more hours after the onset of pain appears to be very useful at ruling in AMI (positive likelihood ratio=~15), this is based on one relatively small study. While asymmetry is neither good nor bad, it is important to recognize when interpreting test results.

Limitations

An important limitation of any systematic review of this topic is the wide variety of cutoffs, manufacturers, processes, and reagents used in the studies. Ideally, each clinical site will identify for its physicians the optimal cutoffs for each test at each point in time. This is probably unrealistic, however, and we hope our results will guide physicians in the absence of such data. Although differences in the manufacturing of a particular test may affect the sensitivity and specificity, there was no clear pattern in these data, and other differences between study populations, settings, and inclusion criteria made it difficult to quantify the magnitude of this effect.

The diagnosis of AMI is only one use of troponin and other biochemical markers. Risk stratification is another important goal, and a future systematic review will evaluate the ability of troponin T and I to stratify patients into high-risk and low-risk groups for adverse cardiac events.

Recommendations for future research

Although an important goal of systematic reviews is to provide summary estimates of the accuracy of diagnostic tests, it is equally important to use these results to guide further research. Because the sensitivity of troponin T and I is so dependent on the number of hours from the onset of chest pain, future studies should always record this time when the blood is drawn. Using time from the admission to the ED is less useful, because pain could have begun any time before arrival. Also, the investigators of future studies should use the WHO criteria for AMI, ensure blinding of the diagnosing physicians to the results of the troponin test, and provide adequate data for future systematic reviews and meta-analyses. Finally, studies should measure troponin T and I, myoglobin, and CK so their accuracy can be compared for both diagnosis and prognosis.

Recommendations for clinical practice

Although troponin T and I are useful for the diagnosis of AMI, clinicians should interpret the results according to the number of hours from the onset of chest pain, whenever possible. Table 2 and the nomograms on the Journal’s Web site (www.jfampract.com) can assist in this task. A peak value of troponin T of less than 0.2 in the first 24 hours after arrival in the ED is strong evidence against the presence of AMI; a normal troponin T or I value from blood drawn 8 or more hours after the onset of chest pain is also strong evidence against its presence. However, a normal value of troponin T or I at the time of admission or within 4 or fewer hours of the onset of pain does not significantly reduce the likelihood of AMI. Abnormal values of troponin T or I from blood drawn 8 or more hours after the onset of chest pain are moderately strong evidence in favor of the presence of AMI, particularly for patients who are otherwise at high risk.

Acknowledgments

This work was supported by the Michigan Consortium for Family Practice Research, one of 3 research centers funded by the American Academy of Family Physicians and its members. The authors do not have any financial or professional connection to the manufacturer of any test kits. We wish to thank Ian Katz, MD; Alan Wu, MD; Johannes Mair, MD; Hugo Katus, MD; and Bernd Puschendorff, MD, for their willingness to share their original data for this systematic review. We also wish to thank Deb Richardson for her assistance with the preparation of this manuscript.

Until recently, creatine kinase (CK) and creatine kinase, myocardial bound (CK-MB) fractions were used most often for evaluating patients with acute chest pain and suspected acute myocardial infarction (AMI). The World Health Organization (WHO) criteria for diagnosing AMI include elevation in this blood test result, along with typical electrocardiographic changes and a history compatible with ischemia.¹ Recently, elevations in the serum troponin T and troponin I levels have been used both to test for AMI and to predict adverse cardiac events.²

However, interpretation of the troponin test results can be problematic. The test characteristics vary considerably, depending on the cutoff used to define abnormal, the troponin fraction used (T or I), and the time from the onset of myocardial ischemia. For example, increases in the cutoff number will decrease sensitivity but improve specificity.³ Because the troponin tests rely on damage to myocardial cells and the release of troponins into the circulation, sensitivity initially increases with the number of hours from the onset of chest pain, then decreases as the enzyme is cleared from the circulation. However, many of the reports on which current estimates of sensitivity and specificity are based do not report the time from the onset of symptoms or only provide the worst value in the first 24 hours. Decision making in the emergency department (ED) is often based on earlier values, and it is therefore important to carefully describe the accuracy of the test at different times.²

One previous meta-analysis of the use of troponins for diagnosing AMI was published.⁴ Unfortunately, it had several limitations. The literature review was abbreviated, and numerous important articles have been published since the review was completed. There was no assessment of study quality, and the outcome used was adverse cardiac events rather than diagnosis of AMI. We report the results of a systematic review of the literature documenting use of troponins for diagnosing AMI, with assessment of the quality of the studies and synthesis of results when appropriate.

Methods

Search Strategy

We conducted a search of the MEDLINE database in June 1999 using the following strategy: troponin (text word) and diagnosis (medical subject heading [MeSH]) or troponin/diagnostic use (MeSH). This initial search identified approximately 800 articles. The abstract of each article was reviewed, and articles were evaluated in detail if: (1) troponins were used in the diagnosis of heart disease; (2) the study involved human subjects; and (3) the articles were written in English, German, French, or Spanish. A total of 114 articles met these basic criteria. A second search of the 1999 literature took place in December 1999, and 10 additional articles that met the basic criteria were identified.

Inclusion Criteria and Assessment of Study Quality

We included studies in the analysis if, after a review of the full article, they met the following inclusion criteria:

• The study design was prospective data collection, consecutive or nonconsecutive patient enrollment (but not case-control), and the physician determining whether the patient had an AMI was blinded to the troponin results.
• The study population was of adult patients with acute chest pain.
• The WHO reference standard or similar criteria was used to diagnose AMI.
• The authors reported data for calculating sensitivity or specificity for at least one point from the onset of pain or presentation to the ED for troponin T or I.

The WHO criteria for diagnosing AMI require 2 of the following: clinical history, typical electrocardiogram changes, and an increase of CK and CK-MB activity. Case-series studies of only patients with AMI were included for the calculation of sensitivity. We further classified studies meeting these basic criteria as level I or II depending on whether the patient enrollment was clearly stated as consecutive (level I), or nonconsecutive or unspecified (level II).

Data Abstraction

Two independent investigators (either ME and DF or CF and DF) reviewed each article for study quality and inclusion criteria. We resolved any discrepancies by consensus decision. Two articles were in French or German, and only one investigator reviewed each of these. Neither study met inclusion criteria.

We abstracted the following data from each article: setting, variables required for evaluation of study quality, time from onset of chest pain or admission to the ED, and cutoff value(s) for abnormal levels of troponin T or I. If a range of 4 hours or less was reported for the time from onset of pain or the time from arrival at the ED, the mean time was used as a point estimate. Ranges of greater than 4 hours were discarded. For example, if a study reported the specificity for blood drawn between 4 and 6 hours after presentation to the ED, this range was recorded as a point estimate of 5 hours. We compared the data abstracted by each of the 2 reviewers, and all discrepancies were resolved by consensus decision. If it appeared that additional data might have been collected but not reported, we contacted the authors of the articles by postal or electronic mail.

Statistical Analysis

The primary outcomes were the test characteristics (sensitivity, specificity, predictive values, and positive and negative likelihood ratios) for each test at different points in time. Sensitivity is the proportion of patients with AMI who have an abnormal troponin test result, and specificity is the proportion without AMI who have a normal troponin test result. The positive and negative likelihood ratios are calculated using the following equations:

Positive likelihood ratio=sensitivity/(100-specificity)

Negative likelihood ratio=(100-sensitivity)/specificity

The positive and negative likelihood ratios correspond to the clinical concepts of ruling in and ruling out disease. Thus, a higher positive likelihood ratio means that a test result is better for ruling in disease when positive, and a lower negative likelihood ratio means that a test result is better for ruling out disease when negative. When possible, we made summary estimates of sensitivity and specificity using a DerSimonian and Laird random effects model. Sensitivity and specificity were pooled independently and weighted by the inverse of the variance using the MetaTest software (Joseph Lau, MD, New England Medical Center, Boston, Mass). If a fixed effects model (Mantel-Haenszel, chi-square) and a random effects model (DerSimonian and Laird) calculated similar estimates of sensitivity or specificity the studies were homogenous, and we reported the more conservative random effects model result. If the fixed effects model and random effects model gave estimates that were different in a clinically meaningful way, the studies were heterogeneous, and only a range was reported.

We drew summary receiver operating characteristic (ROC) curves, and calculated the weighted area under the curve by the method of Moses⁵ using the MetaTest software. The area under the ROC curve is a measure of the ability of a test to discriminate between healthy and diseased individuals, and it is equal to the proportion of patients correctly classified in a forced-choice comparison. Models for sensitivity and specificity versus hours from the onset of chest pain and models for sensitivity and specificity versus cutoff level were fitted using SPSS 9.0 software (SPSS, Chicago, Ill). The choice of linear or logarithmic model was based on inspection of the data.

Results

Eleven studies met level I criteria for quality,^6-16 and an additional 8 met level II criteria.^17-24 Study characteristics are summarized in Table 1. Most studies only reported data for the time from presentation to the ED, rather than the time from onset of chest pain.

Test Accuracy by Time from the Onset of Symptoms

Figure 1 shows the sensitivity for studies of troponin T using cutoffs of 0.1,7,8,14 0.2,6,14,19 and 0.519 plotted against the number of hours from the onset of chest pain. Specificity was similar for all 3 cutoffs and is plotted as a single line. The authors of most of these studies evaluated the widely used enzyme-linked immunoassay test from Boehringer-Mannheim. The following equations plot the logarithmic curves for sensitivity shown on the graph and allow for the calculation of the sensitivity and specificity of troponin T for any number of hours following the onset of chest pain (note that these equations are only valid over the range for which data are available; ie, 0-12 hours from the onset of chest pain):

Cutoff 0.1: sensitivity=(-0.0011 × hours2) + (0.0634 × hours) + 0.4036

Cutoff 0.2: sensitivity=(-0.0132 × hours2) + (0.2363 × hours) - 0.0862

Cutoff 0.5: sensitivity=(-0.0111 × hours2) + (0.223 × hours) - 0.0981

All cutoffs: specificity=(-.0084 × hours) + 0.8821

Data from high-quality studies were more limited for troponin I. Only 4 level I studies reported data for troponin I,^10,11,13,15 and only one of these reported results for sensitivity and specificity for different times from the onset of symptoms. The authors of that study¹³ only reported the sensitivity and specificity for ranges of 6, 12, 24, and 72 hours and used a cutoff of 2.5 ng/mL. Sensitivity was 17% in the 0 to 6-hour range, 92% in the 6 to 12-hour range, and 100% for the highest value in the 12 to 24-hour range. The specificity was 95% from 0 to 12 hours, and 98% from 12 to 24 hours. The corresponding positive and negative likelihood ratios are 3.4 and 0.9 for the 0 to 6-hour range, 18.4 and 0.08 for the 6 to 12-hour range, and 50 and 0.01 for the 12 to 24-hour range. A single level II study of a bedside troponin I test²⁴ measured the sensitivity as a function on the hours from the onset of chest pain, using a cutoff of 0.1 ng/mL. This graph is shown in Figure 2. The formula for sensitivity is:

Sensitivity=(-0.0128 × hours2) + (0.2438 × hours) - 0.0971

Sensitivity does not exceed 80% until 5 hours after the onset of chest pain. Specificity was not reported in this study.

Test Accuracy by Time After Admission

The authors of 5 studies reported the sensitivity and specificity measured from the time of arrival at the ED. Summary estimates of the sensitivity and specificity for troponin T, using a cutoff of 0.2 ng/mL at the time of admission, were 33% and 93% (values from the fixed effects model were 35% and 94%). The corresponding positive and negative likelihood ratios are 4.7 and 0.7, and the weighted area under the ROC curve is 0.77.^{14,18,19,22,23} Using the peak value of troponin T in the first 24 hours and a cutoff of 0.2, the sensitivity and specificity are 98% and 87% (values from the fixed effects model were 98% and 89%). The corresponding positive and negative likelihood ratios are 7.5 and 0.02, and the weighted area under the ROC curve is 0.99.^19,16,20

Discussion

We have summarized the existing data on the accuracy of troponin T and I values as diagnostic tests for AMI for patients with acute chest pain. These data are summarized for clinicians in Table 2. The sensitivities and specificities in Table 2 are estimated from the best-fit curves shown in Figure 2. Note that for troponin I, sensitivity data are from one study²⁴ and specificity from another.¹³ Nomograms can help physicians interpret the results of troponin T and troponin I at different times from the onset of chest pain and for different pretest probabilities of AMI.* Although troponin I appears to be better at ruling in MI than troponin T, these results are based on a single small study.

The most important take-home message for clinicians is that the sensitivity of the troponin tests, like that of any other cardiac enzyme, is highly dependent on the number of hours since the onset of chest pain. The test is insensitive (ie, will miss many cases of AMI) within the first 6 hours after the onset of chest pain, when patients often present to the ED. However, by 12 or more hours after pain onset the test is quite sensitive, and a negative troponin value is strong evidence against the presence of AMI.

Diagnostic tests are symmetric if a positive test result as effectively rules in disease as a negative test result rules it out. For example, a test with a positive likelihood ratio of 5 and a negative likelihood ratio of 0.2 (1/5) would be symmetric. Examination of the likelihood ratios reveals that the troponin tests are asymmetric with respect to the positive and negative likelihood ratios. However, this relationship is not consistent. Troponin T and I are very useful at ruling out AMI when the value is negative at 10 or more hours from the onset of chest pain (negative likelihood ratio 0.1). However, a negative test value early in the course of the episode of chest pain does very little to reduce the likelihood of AMI. A positive troponin T value, however, is only moderately useful at ruling in AMI when blood was drawn 6 or more hours after the onset of pain (positive likelihood ratio=~5). Although a positive troponin I value from blood drawn 6 or more hours after the onset of pain appears to be very useful at ruling in AMI (positive likelihood ratio=~15), this is based on one relatively small study. While asymmetry is neither good nor bad, it is important to recognize when interpreting test results.

Limitations

An important limitation of any systematic review of this topic is the wide variety of cutoffs, manufacturers, processes, and reagents used in the studies. Ideally, each clinical site will identify for its physicians the optimal cutoffs for each test at each point in time. This is probably unrealistic, however, and we hope our results will guide physicians in the absence of such data. Although differences in the manufacturing of a particular test may affect the sensitivity and specificity, there was no clear pattern in these data, and other differences between study populations, settings, and inclusion criteria made it difficult to quantify the magnitude of this effect.

The diagnosis of AMI is only one use of troponin and other biochemical markers. Risk stratification is another important goal, and a future systematic review will evaluate the ability of troponin T and I to stratify patients into high-risk and low-risk groups for adverse cardiac events.

Recommendations for future research

Although an important goal of systematic reviews is to provide summary estimates of the accuracy of diagnostic tests, it is equally important to use these results to guide further research. Because the sensitivity of troponin T and I is so dependent on the number of hours from the onset of chest pain, future studies should always record this time when the blood is drawn. Using time from the admission to the ED is less useful, because pain could have begun any time before arrival. Also, the investigators of future studies should use the WHO criteria for AMI, ensure blinding of the diagnosing physicians to the results of the troponin test, and provide adequate data for future systematic reviews and meta-analyses. Finally, studies should measure troponin T and I, myoglobin, and CK so their accuracy can be compared for both diagnosis and prognosis.

Recommendations for clinical practice

Although troponin T and I are useful for the diagnosis of AMI, clinicians should interpret the results according to the number of hours from the onset of chest pain, whenever possible. Table 2 and the nomograms on the Journal’s Web site (www.jfampract.com) can assist in this task. A peak value of troponin T of less than 0.2 in the first 24 hours after arrival in the ED is strong evidence against the presence of AMI; a normal troponin T or I value from blood drawn 8 or more hours after the onset of chest pain is also strong evidence against its presence. However, a normal value of troponin T or I at the time of admission or within 4 or fewer hours of the onset of pain does not significantly reduce the likelihood of AMI. Abnormal values of troponin T or I from blood drawn 8 or more hours after the onset of chest pain are moderately strong evidence in favor of the presence of AMI, particularly for patients who are otherwise at high risk.

Acknowledgments

This work was supported by the Michigan Consortium for Family Practice Research, one of 3 research centers funded by the American Academy of Family Physicians and its members. The authors do not have any financial or professional connection to the manufacturer of any test kits. We wish to thank Ian Katz, MD; Alan Wu, MD; Johannes Mair, MD; Hugo Katus, MD; and Bernd Puschendorff, MD, for their willingness to share their original data for this systematic review. We also wish to thank Deb Richardson for her assistance with the preparation of this manuscript.

Until recently, creatine kinase (CK) and creatine kinase, myocardial bound (CK-MB) fractions were used most often for evaluating patients with acute chest pain and suspected acute myocardial infarction (AMI). The World Health Organization (WHO) criteria for diagnosing AMI include elevation in this blood test result, along with typical electrocardiographic changes and a history compatible with ischemia.¹ Recently, elevations in the serum troponin T and troponin I levels have been used both to test for AMI and to predict adverse cardiac events.²

However, interpretation of the troponin test results can be problematic. The test characteristics vary considerably, depending on the cutoff used to define abnormal, the troponin fraction used (T or I), and the time from the onset of myocardial ischemia. For example, increases in the cutoff number will decrease sensitivity but improve specificity.³ Because the troponin tests rely on damage to myocardial cells and the release of troponins into the circulation, sensitivity initially increases with the number of hours from the onset of chest pain, then decreases as the enzyme is cleared from the circulation. However, many of the reports on which current estimates of sensitivity and specificity are based do not report the time from the onset of symptoms or only provide the worst value in the first 24 hours. Decision making in the emergency department (ED) is often based on earlier values, and it is therefore important to carefully describe the accuracy of the test at different times.²

One previous meta-analysis of the use of troponins for diagnosing AMI was published.⁴ Unfortunately, it had several limitations. The literature review was abbreviated, and numerous important articles have been published since the review was completed. There was no assessment of study quality, and the outcome used was adverse cardiac events rather than diagnosis of AMI. We report the results of a systematic review of the literature documenting use of troponins for diagnosing AMI, with assessment of the quality of the studies and synthesis of results when appropriate.

Methods

Search Strategy

We conducted a search of the MEDLINE database in June 1999 using the following strategy: troponin (text word) and diagnosis (medical subject heading [MeSH]) or troponin/diagnostic use (MeSH). This initial search identified approximately 800 articles. The abstract of each article was reviewed, and articles were evaluated in detail if: (1) troponins were used in the diagnosis of heart disease; (2) the study involved human subjects; and (3) the articles were written in English, German, French, or Spanish. A total of 114 articles met these basic criteria. A second search of the 1999 literature took place in December 1999, and 10 additional articles that met the basic criteria were identified.

Inclusion Criteria and Assessment of Study Quality

We included studies in the analysis if, after a review of the full article, they met the following inclusion criteria:

• The study design was prospective data collection, consecutive or nonconsecutive patient enrollment (but not case-control), and the physician determining whether the patient had an AMI was blinded to the troponin results.
• The study population was of adult patients with acute chest pain.
• The WHO reference standard or similar criteria was used to diagnose AMI.
• The authors reported data for calculating sensitivity or specificity for at least one point from the onset of pain or presentation to the ED for troponin T or I.

The WHO criteria for diagnosing AMI require 2 of the following: clinical history, typical electrocardiogram changes, and an increase of CK and CK-MB activity. Case-series studies of only patients with AMI were included for the calculation of sensitivity. We further classified studies meeting these basic criteria as level I or II depending on whether the patient enrollment was clearly stated as consecutive (level I), or nonconsecutive or unspecified (level II).

Data Abstraction

Two independent investigators (either ME and DF or CF and DF) reviewed each article for study quality and inclusion criteria. We resolved any discrepancies by consensus decision. Two articles were in French or German, and only one investigator reviewed each of these. Neither study met inclusion criteria.

We abstracted the following data from each article: setting, variables required for evaluation of study quality, time from onset of chest pain or admission to the ED, and cutoff value(s) for abnormal levels of troponin T or I. If a range of 4 hours or less was reported for the time from onset of pain or the time from arrival at the ED, the mean time was used as a point estimate. Ranges of greater than 4 hours were discarded. For example, if a study reported the specificity for blood drawn between 4 and 6 hours after presentation to the ED, this range was recorded as a point estimate of 5 hours. We compared the data abstracted by each of the 2 reviewers, and all discrepancies were resolved by consensus decision. If it appeared that additional data might have been collected but not reported, we contacted the authors of the articles by postal or electronic mail.

Statistical Analysis

The primary outcomes were the test characteristics (sensitivity, specificity, predictive values, and positive and negative likelihood ratios) for each test at different points in time. Sensitivity is the proportion of patients with AMI who have an abnormal troponin test result, and specificity is the proportion without AMI who have a normal troponin test result. The positive and negative likelihood ratios are calculated using the following equations:

Positive likelihood ratio=sensitivity/(100-specificity)

Negative likelihood ratio=(100-sensitivity)/specificity

The positive and negative likelihood ratios correspond to the clinical concepts of ruling in and ruling out disease. Thus, a higher positive likelihood ratio means that a test result is better for ruling in disease when positive, and a lower negative likelihood ratio means that a test result is better for ruling out disease when negative. When possible, we made summary estimates of sensitivity and specificity using a DerSimonian and Laird random effects model. Sensitivity and specificity were pooled independently and weighted by the inverse of the variance using the MetaTest software (Joseph Lau, MD, New England Medical Center, Boston, Mass). If a fixed effects model (Mantel-Haenszel, chi-square) and a random effects model (DerSimonian and Laird) calculated similar estimates of sensitivity or specificity the studies were homogenous, and we reported the more conservative random effects model result. If the fixed effects model and random effects model gave estimates that were different in a clinically meaningful way, the studies were heterogeneous, and only a range was reported.

We drew summary receiver operating characteristic (ROC) curves, and calculated the weighted area under the curve by the method of Moses⁵ using the MetaTest software. The area under the ROC curve is a measure of the ability of a test to discriminate between healthy and diseased individuals, and it is equal to the proportion of patients correctly classified in a forced-choice comparison. Models for sensitivity and specificity versus hours from the onset of chest pain and models for sensitivity and specificity versus cutoff level were fitted using SPSS 9.0 software (SPSS, Chicago, Ill). The choice of linear or logarithmic model was based on inspection of the data.

Results

Eleven studies met level I criteria for quality,^6-16 and an additional 8 met level II criteria.^17-24 Study characteristics are summarized in Table 1. Most studies only reported data for the time from presentation to the ED, rather than the time from onset of chest pain.

Test Accuracy by Time from the Onset of Symptoms

Figure 1 shows the sensitivity for studies of troponin T using cutoffs of 0.1,7,8,14 0.2,6,14,19 and 0.519 plotted against the number of hours from the onset of chest pain. Specificity was similar for all 3 cutoffs and is plotted as a single line. The authors of most of these studies evaluated the widely used enzyme-linked immunoassay test from Boehringer-Mannheim. The following equations plot the logarithmic curves for sensitivity shown on the graph and allow for the calculation of the sensitivity and specificity of troponin T for any number of hours following the onset of chest pain (note that these equations are only valid over the range for which data are available; ie, 0-12 hours from the onset of chest pain):

Cutoff 0.1: sensitivity=(-0.0011 × hours2) + (0.0634 × hours) + 0.4036

Cutoff 0.2: sensitivity=(-0.0132 × hours2) + (0.2363 × hours) - 0.0862

Cutoff 0.5: sensitivity=(-0.0111 × hours2) + (0.223 × hours) - 0.0981

All cutoffs: specificity=(-.0084 × hours) + 0.8821

Data from high-quality studies were more limited for troponin I. Only 4 level I studies reported data for troponin I,^10,11,13,15 and only one of these reported results for sensitivity and specificity for different times from the onset of symptoms. The authors of that study¹³ only reported the sensitivity and specificity for ranges of 6, 12, 24, and 72 hours and used a cutoff of 2.5 ng/mL. Sensitivity was 17% in the 0 to 6-hour range, 92% in the 6 to 12-hour range, and 100% for the highest value in the 12 to 24-hour range. The specificity was 95% from 0 to 12 hours, and 98% from 12 to 24 hours. The corresponding positive and negative likelihood ratios are 3.4 and 0.9 for the 0 to 6-hour range, 18.4 and 0.08 for the 6 to 12-hour range, and 50 and 0.01 for the 12 to 24-hour range. A single level II study of a bedside troponin I test²⁴ measured the sensitivity as a function on the hours from the onset of chest pain, using a cutoff of 0.1 ng/mL. This graph is shown in Figure 2. The formula for sensitivity is:

Sensitivity=(-0.0128 × hours2) + (0.2438 × hours) - 0.0971

Sensitivity does not exceed 80% until 5 hours after the onset of chest pain. Specificity was not reported in this study.

Test Accuracy by Time After Admission

The authors of 5 studies reported the sensitivity and specificity measured from the time of arrival at the ED. Summary estimates of the sensitivity and specificity for troponin T, using a cutoff of 0.2 ng/mL at the time of admission, were 33% and 93% (values from the fixed effects model were 35% and 94%). The corresponding positive and negative likelihood ratios are 4.7 and 0.7, and the weighted area under the ROC curve is 0.77.^{14,18,19,22,23} Using the peak value of troponin T in the first 24 hours and a cutoff of 0.2, the sensitivity and specificity are 98% and 87% (values from the fixed effects model were 98% and 89%). The corresponding positive and negative likelihood ratios are 7.5 and 0.02, and the weighted area under the ROC curve is 0.99.^19,16,20

Discussion

We have summarized the existing data on the accuracy of troponin T and I values as diagnostic tests for AMI for patients with acute chest pain. These data are summarized for clinicians in Table 2. The sensitivities and specificities in Table 2 are estimated from the best-fit curves shown in Figure 2. Note that for troponin I, sensitivity data are from one study²⁴ and specificity from another.¹³ Nomograms can help physicians interpret the results of troponin T and troponin I at different times from the onset of chest pain and for different pretest probabilities of AMI.* Although troponin I appears to be better at ruling in MI than troponin T, these results are based on a single small study.

The most important take-home message for clinicians is that the sensitivity of the troponin tests, like that of any other cardiac enzyme, is highly dependent on the number of hours since the onset of chest pain. The test is insensitive (ie, will miss many cases of AMI) within the first 6 hours after the onset of chest pain, when patients often present to the ED. However, by 12 or more hours after pain onset the test is quite sensitive, and a negative troponin value is strong evidence against the presence of AMI.

Diagnostic tests are symmetric if a positive test result as effectively rules in disease as a negative test result rules it out. For example, a test with a positive likelihood ratio of 5 and a negative likelihood ratio of 0.2 (1/5) would be symmetric. Examination of the likelihood ratios reveals that the troponin tests are asymmetric with respect to the positive and negative likelihood ratios. However, this relationship is not consistent. Troponin T and I are very useful at ruling out AMI when the value is negative at 10 or more hours from the onset of chest pain (negative likelihood ratio 0.1). However, a negative test value early in the course of the episode of chest pain does very little to reduce the likelihood of AMI. A positive troponin T value, however, is only moderately useful at ruling in AMI when blood was drawn 6 or more hours after the onset of pain (positive likelihood ratio=~5). Although a positive troponin I value from blood drawn 6 or more hours after the onset of pain appears to be very useful at ruling in AMI (positive likelihood ratio=~15), this is based on one relatively small study. While asymmetry is neither good nor bad, it is important to recognize when interpreting test results.

Limitations

An important limitation of any systematic review of this topic is the wide variety of cutoffs, manufacturers, processes, and reagents used in the studies. Ideally, each clinical site will identify for its physicians the optimal cutoffs for each test at each point in time. This is probably unrealistic, however, and we hope our results will guide physicians in the absence of such data. Although differences in the manufacturing of a particular test may affect the sensitivity and specificity, there was no clear pattern in these data, and other differences between study populations, settings, and inclusion criteria made it difficult to quantify the magnitude of this effect.

The diagnosis of AMI is only one use of troponin and other biochemical markers. Risk stratification is another important goal, and a future systematic review will evaluate the ability of troponin T and I to stratify patients into high-risk and low-risk groups for adverse cardiac events.

Recommendations for future research

Although an important goal of systematic reviews is to provide summary estimates of the accuracy of diagnostic tests, it is equally important to use these results to guide further research. Because the sensitivity of troponin T and I is so dependent on the number of hours from the onset of chest pain, future studies should always record this time when the blood is drawn. Using time from the admission to the ED is less useful, because pain could have begun any time before arrival. Also, the investigators of future studies should use the WHO criteria for AMI, ensure blinding of the diagnosing physicians to the results of the troponin test, and provide adequate data for future systematic reviews and meta-analyses. Finally, studies should measure troponin T and I, myoglobin, and CK so their accuracy can be compared for both diagnosis and prognosis.

Recommendations for clinical practice

Although troponin T and I are useful for the diagnosis of AMI, clinicians should interpret the results according to the number of hours from the onset of chest pain, whenever possible. Table 2 and the nomograms on the Journal’s Web site (www.jfampract.com) can assist in this task. A peak value of troponin T of less than 0.2 in the first 24 hours after arrival in the ED is strong evidence against the presence of AMI; a normal troponin T or I value from blood drawn 8 or more hours after the onset of chest pain is also strong evidence against its presence. However, a normal value of troponin T or I at the time of admission or within 4 or fewer hours of the onset of pain does not significantly reduce the likelihood of AMI. Abnormal values of troponin T or I from blood drawn 8 or more hours after the onset of chest pain are moderately strong evidence in favor of the presence of AMI, particularly for patients who are otherwise at high risk.

Acknowledgments

This work was supported by the Michigan Consortium for Family Practice Research, one of 3 research centers funded by the American Academy of Family Physicians and its members. The authors do not have any financial or professional connection to the manufacturer of any test kits. We wish to thank Ian Katz, MD; Alan Wu, MD; Johannes Mair, MD; Hugo Katus, MD; and Bernd Puschendorff, MD, for their willingness to share their original data for this systematic review. We also wish to thank Deb Richardson for her assistance with the preparation of this manuscript.