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OBJECTIVE: The accuracy of the troponin T and I test as a prognostic tool for patients with chest pain varies considerably depending on the patient population, the cutoff for an abnormal test result, and other factors. The goal of our systematic review was to synthesize the best available evidence on this topic.
SEARCH STRATEGY: We searched the MEDLINE database, bibliographies of identified articles, and articles identified from a previous meta-analysis of diagnosis.
SELECTION CRITERIA: We included cohort studies that had at least 80% follow-up and reported useful data.
DATA COLLECTION AND ANALYSIS: Data from each study were abstracted by 2 investigators. We calculated sensitivity and specificity for the prediction of death, fatal or nonfatal myocardial infarction (MI), or any cardiac event for each combination of patient population, troponin test, interval from admission to blood draw, and cutoff for an abnormal test result.
MAIN RESULTS: For patients with chest pain and a normal electrocardiogram, the peak troponin I level drawn 6 or more hours after the onset of chest pain is useful for identifying patients at low risk of death or nonfatal MI at 30 days (negative likelihood ratio=0.07; probability of outcome=0.3% with a negative test, given a pretest probability of 4.4%). For patients with unstable angina, the sensitivity of troponin I for the identification of patients who die or have a nonfatal MI in the next 30 days is only 59%, and the specificity is only 79%. The sensitivity and specificity varied widely for patients with unstable angina or non-Q-wave MI depending on the inclusion criteria, cutoff used, timing of the blood draw, duration of follow-up, and other factors.
CONCLUSIONS: If the peak troponin T or I level measured at least 6 hours after the onset of chest pain symptoms is in the normal range in a patient with a normal electrocardiogram, it is very unlikely that the patient will die or have a nonfatal MI in the next 30 days (1%). The initial troponin value is not as helpful as the peak value at least 6 hours after the onset of chest pain. An abnormal troponin test result for patients with unstable angina or non-Q-wave MI identifies a subset at greater risk of death.
Not all patients with acute chest pain can be monitored as inpatients. Some are sent home with instructions to follow up with their personal physician, while others have noninvasive cardiovascular testing scheduled as outpatients. Formal protocols that use the history, physical examination, laboratory tests, or noninvasive testing have been developed and shown to reduce costs and improve outcomes.1-4
Recently, it has been suggested that troponin T and I values may be useful for prognosis in patients with acute chest pain in the emergency department.5,6 These enzymes are released by damaged cardiac muscle. However, the accuracy of troponin levels for the diagnosis of acute myocardial infarction (MI) varies considerably, depending on the specific test used, cutoff to define an abnormal test result, and timing of the blood test in relation to the onset of chest pain.7 The usefulness of these tests for prognosis is likely to be affected by the same factors.
The authors of several previous meta-analyses have considered this question. However, all of these studies had significant limitations. Wu and colleagues5 published a meta-analysis in 1995 that obviously could not include the large number of studies published since that time. The meta-analysis by Ollatidoye and colleagues6 included more studies but did not distinguish between different cutoffs to define an abnormal test result, combined all intervals from 4 days to 1095 days into a single summary estimate, and did not consider the time at which the troponin test was drawn in relation to either emergency department arrival or the onset of chest pain. In our study, we systematically reviewed the evidence for the accuracy of troponin T and I values in determining the prognosis of patients presenting to the emergency department with chest pain, unstable angina, and other acute coronary syndromes.
Methods
Search Strategy
We conducted searches of the MEDLINE database in June 1999 and December 1999 (the second search was of 1999 only). We used the following search strategy: troponin [text word] or troponin [MeSH] and prognosis [MeSH]. Studies were limited to those that provided an abstract, were written in English or German, and used human subjects. The October through December 1999 issues of the American Journal of Cardiology, the Journal of the American College of Cardiology, the American Heart Journal, and Clinical Chemistry were hand-searched. We also reviewed the bibliographies of articles meeting the final inclusion criteria. The abstract of each article was reviewed by one of the investigators, and articles were evaluated in detail if troponin levels were used to predict the prognosis of patients with chest pain, unstable angina, or other acute coronary syndromes.
Inclusion Criteria and Assessment of Study Quality
Inclusion criteria were designed to identify only those studies meeting Level 1b criteria, as defined by the Centre for Evidence-Based Medicine (cebm.jr2.ox.ac.uk/docs/levels.html). These inclusion criteria are:
- Prospective cohort study
- Adult patients with acute chest pain or other acute coronary syndrome
- At least 80% follow-up of patients
- Death, fatal or nonfatal MI, or any cardiac event at some point following hospital discharge
We excluded studies reporting only in-hospital outcomes and those without sufficient data to calculate sensitivity or specificity for at least one outcome.
Data Abstraction
Two independent investigators (either ME and DW or ME and LW) reviewed each article and abstracted data related to study quality, inclusion criteria, and test characteristics. Any discrepancies were resolved by consensus decision. The following data were abstracted: reference, study design, percentage of follow-up, outcomes measured, inclusion criteria for patients in the study, and data needed to calculate sensitivity or specificity.
Statistical Analysis
The primary outcomes were the test characteristics (sensitivity, specificity, post-test probability positive and negative, and positive and negative likelihood ratios* [LR+ and LR-, respectively]) for each combination of inclusion criteria, diagnostic test, and patient outcome.
Where possible, summary estimates of sensitivity and specificity were made using a DerSimonian and Laird random effects model. Sensitivity and specificity were pooled independently and weighted by the inverse of the variance using MetaTest software (version 0.6, Joseph Lau, MD, used with permission). If a fixed effects model and a random effects model calculated similar estimates of sensitivity or specificity, the statistic was deemed homogenous, and the more conservative random effects model result was reported. If the fixed effects model and the random effects model gave estimates that were different in a clinically meaningful way, the statistic was deemed heterogeneous, and only a range was reported.
Results
Twenty-eight studies met the inclusion criteria and had usable data for our systematic review.6,8-34 Two studies used the research version of the Baxter Stratus enzyme-linked immunosorbent assay troponin I assay. A cutoff of 3.1 ng/mL corresponds to a cutoff of 0.6 in the commercial version of this assay.15,19 One study28 measured the troponin T level at 10 or more hours after the onset of chest pain. This was included with studies measuring the peak value within the first 24 hours. The study by Kerr and Dunt10 measured the troponin T value at 14 hours after the onset of chest pain. The study by Janorkar and colleagues31 followed patients for a variable length of time with a mean follow-up of 9 months and a standard deviation of 4 months.
In general, the studies used a wide variety of cutoffs, durations of follow-up, inclusion criteria, and outcomes. We have organized the results in 3 tables on the basis of the 3 populations studied in the available literature. [Table 1] shows data for patients with chest pain syndromes, [Table 2] for patients with unstable angina, and [Table 3] for patients with unstable angina or non-Q-wave MI. Unstable angina was generally defined as chest pain accompanied by electrocardiogram (ECG) changes but without evidence of MI, and non-Q-wave MI was defined on the basis of clinical and biochemical criteria for MI but without Q waves on the ECG.
Patients with Chest Pain
Troponin I. Only 1 study14 of patients with chest pain used the troponin I test, in this case a rapid bedside assay. It included 773 patients with chest pain and a normal ECG and used death or nonfatal MI as the outcome. The authors reported a sensitivity of 0.94, a specificity of 0.81, an LR+ of 5.0, and a very low LR- of 0.07.
Troponin T. Only 2 studies examined the accuracy of troponin T in patients with nontraumatic chest pain.11,20 However, neither reported the rates of death or nonfatal MI during follow-up in a way that allowed calculation of sensitivity and specificity. The range of sensitivity for any cardiac event was from 0.31 to 0.54, the specificity from 0.78 to 0.92, the LR+ from 2.4 to 3.8, and the LR- from 0.6 to 0.7. Among patients with chest pain and a normal ECG, Hamm and coworkers14 reported an LR+ of 6.1 and an LR- of 0.2. Three studies included patients with chest pain who were admitted to rule out MI and were followed for 180 days to 2 years.8-10 They reported a range of sensitivity of 0.52 to 0.67, specificity from 0.72 to 0.83, LR+ from 2.3 to 3.2, and LR- from 0.5 to 0.6.
Patients with Unstable Angina
Troponin I. Three studies of troponin I included patients with unstable angina and used the outcome of death during follow-up. The duration of follow-up ranged from 30 days to 9 months, and the cutoff for an abnormal test result was from 0.6 to 1.5 ng/mL.19,21,31 The sensitivity varied widely from 0.5 to 1.0; however, 2 of the studies were small, with only 2 deaths in each study. The largest study found a sensitivity of only 0.52 and specificity of 0.73.21 For studies of troponin I using death or nonfatal MI as an outcome, results from 3 studies15,18,22 could be combined, because the study designs were similar. They used a cutoff of 0.6 ng/mL, followed patients for 30 days, and used the peak troponin value in the first 8 to 72 hours. The summary test characteristics for these 3 studies were a sensitivity of 0.59, a specificity of 0.79, an LR+ of 2.8, and an LR- of 0.5.
Troponin T. Using unstable angina to determine inclusion and 30 days as the duration of follow-up, several studies found a low sensitivity of troponin T as a prognostic test. Three studies of unstable angina were quite similar in design and inclusion, using a cutoff of 0.1 ng/mL, blood drawn on admission to the emergency department, and an outcome of death at 30 days.16,21,24 The summary test characteristics for these studies were a sensitivity of 0.63, a specificity of 0.66, an LR+ of 1.9, and an LR- of 0.6.
Depending on the combination of cutoff, timing of the blood draw, and duration of follow-up, a positive troponin T had a range of sensitivity from 0.38 to 0.63 and of specificity from 0.77 to 0.95 for the outcome of death or nonfatal MI at 30 days.6,18,19,23,26,27 Two studies 18.19 were similar in design, and their test characteristics could be combined (sensitivity=0.44, specificity=0.81, LR+=2.3, and LR-=0.7).
Patients with Unstable Angina or Non-Q-Wave MI
Troponin I .A positive troponin I in patients with unstable angina or non-Q-wave MI produced sensitivities from 0.72 to 0.78 and specificities from 0.59 to 0.60 for the outcome of death at 30 to 42 days.18,34 For the outcome of death or nonfatal Ml using the same inclusion criteria, the range of sensitivity was from 0.59 to 1.00 and of specificity was from 0.60 to 0.74.18,32,33
Troponin T. For an outcome of death, the LR+ was 1.3 to 1.8, and the LR- was 0.0 to 0.3.18,29 The study29 with an LR- of 0.0 had no false-negatives and a sensitivity of 1.0; it used a very low cutoff of 0.06 for an abnormal test result. Using the same cohort with a cutoff of 0.2, the investigators found a sensitivity of 0.72 and a specificity of 0.45. As expected, a lower cutoff improved the sensitivity of the test.
Discussion
Although one goal of systemic reviews is to pool study data from multiple sources to calculate summary measures of test accuracy, not all reviews can achieve that goal. In our study, a lack of standardization in study parameters limited our ability to combine summary estimates effectively. However, we have identified several important guidelines for clinicians using the troponin test and for future research in this area.
Most studies of the troponin test have evaluated it in patients with unstable angina or unstable angina and non-Q-wave MI. Although the test has some value in the non-Q-wave MI patients for identifying higher-risk and lower-risk groups, all such patients would generally be admitted to the hospital and followed closely. For primary care and emergency physicians evaluating a patient with chest pain in the emergency department, an important goal is to identify patients for whom adverse cardiac events such as death or nonfatal MI are unlikely in the near future. These patients could be sent home to follow up with their primary care physician and possibly undergo noninvasive testing as outpatients.
Unfortunately, only a few studies have included patients with chest pain or patients with chest pain and a normal ECG. The most useful study is that of Hamm and colleagues.14 In their study of 773 patients with chest pain and no ST elevation, troponin T and I both had a low LR- for the identification of patients at low risk of death or nonfatal MI in the 30 days following their episode of chest pain. Only 1 in 300 patients with a normal ECG and normal troponin I 6 hours after the onset of chest pain had an adverse outcome in the 30 days after hospital discharge and only 1 in 100 of those with normal ECG and normal troponin T. Although the troponin T test actually had a lower LR- and was potentially more useful, this test is not widely available in the United States. More studies of both troponin T and I are needed among patients with chest pain or chest pain and normal ECG to validate the findings of Hamm and coworkers.
Using a lower cutoff for abnormal with troponin T improves the sensitivity of the test. Lindahl and colleagues29 found a sensitivity of 1.0 at a cutoff of 0.06 for the outcome of death in a study of patients with unstable angina or non-Q-wave MI; the sensitivity was only 0.86 for a cutoff of 0.2. Other pairs of studies had a similar pattern, which was expected. Future studies should report the sensitivity and specificity of the tests for several cutoffs, including lower values such as 0.05 ng/mL for troponin T.
Also, the sensitivity of troponin was improved when the peak value in the first 6 to 24 hours of admission was used instead of the value on admission to the emergency department. For example, among patients with unstable angina the sensitivity was 0.63 when blood was drawn on admission to the emergency department16,21,24 and 1.0 when the peak value in the first 16 hours was used.24 This makes physiologic sense, since patients presenting early in the course of their episode of unstable angina or MI may have undetectable levels of troponin which rise as the episode progresses.
Recommendations for future research
To facilitate future meta-analyses, we recommend the following parameters for the design of studies of troponin. First, studies should use larger populations and standardize their inclusion and testing criteria. We also recommend durations of follow-up of 7 days, 30 days, and 1 year. Although a longer duration is helpful in predicting the patient’s overall prognosis, shorter durations are more useful for identifying patients who can be discharged for close outpatient follow-up and noninvasive testing. Cutoffs of 0.05 ng/mL, 0.10 ng/mL, and 0.20 ng/mL for troponin T and cutoffs of 0.3 and 0.6 for troponin I should be used. Authors should report the test characteristics for several cutoffs and also for ranges of troponin, such as less than 0.05 ng/mL, 0.06 ng/mL to 0.10 ng/mL, and greater than 0.10 ng/mL. In addition, we recommend that sensitivity and specificity be reported both for the initial value on admission to the emergency department and for peak values after 12 and 24 hours. Finally, standard definitions for inclusion criteria and outcomes should be used, such as the Braunwald criteria* for unstable angina and the World Health Organization criteria for acute MI.
We also suggest that valuable information would be added if population demographics were reported in study results. Although most studies considered patient demographics carefully in determining study eligibility, they did not report those characteristics in their findings. It is not clear, for example, that the test performs similarly in younger and older patients, in men and women, or in different ethnic or racial groups.
Finally, we recommend that more studies evaluate the accuracy of troponin I in prognosis, particularly among patients with chest pain syndromes. Of the 28 studies we analyzed, only 11 measured troponin I and only 1 enrolled patients who had chest pain and a normal ECG.
Recommendations for practice
If the peak troponin T or I level measured at least 6 hours after the onset of chest pain symptoms is in the normal range and the ECG is normal, it is very unlikely that the patient will die or have a nonfatal MI in the next 30 days (1%).14 It is important to note that decisions about care should be made on the basis of the troponin value and ECG and in light of the patient’s clinical presentation and comorbidities, and that this finding is based on only 1 study, albeit a large one. The initial troponin value is not as helpful as the peak value at least 6 hours after the onset of chest pain. An abnormal troponin test in patients with unstable angina or non-Q-wave MI identifies a subset at greater risk of death; those patients should be closely monitored.
Acknowledgments
This project was supported by the Michigan Consortium for Family Practice Research, one of 3 research centers funded by the American Academy of Family Physicians. We wish to acknowledge the assistance of Dan Flewelling in the literature search and of Deb Richardson in the preparation of the manuscript.
1. TH, Juarez G, Cook EF, et al. Ruling out acute myocardial infarction: a prospective multicenter validation of a 12-hour strategy for patients at low risk. N Engl J Med 1991;324:1239-46.
2. TH, Cook EF, Weisberg M, Sargent RK, Wilson C, Goldman L. Acute chest pain in the emergency room: identification and examination of low risk patients. Arch Intern Med 1985;145:65-69.
3. RR, Zalenski RJ, Mensay EK, et al. Costs of an emergency department based accelerated diagnostic protocol vs hospitalization in patients with chest pain: a randomized controlled trial. JAMA 1997;278:1670-76.
4. ME, Smars PA, Reeder GS, et al. A clinical trial of a chest-pain observation unit for patients with unstable angina. N Engl J Med 1998;339:1882-88.
5. Software, version 0.6. Joseph Lau, MD, New England Medical Center. Used with permission.
6. AG, Wu AH, Feng YJ, Waters D. Prognostic role of troponin T versus troponin I in unstable angina pectoris for cardiac events with meta-analysis comparing published studies. Am J Cardiol 1998;81:1405-10.
7. MH, Flynn C, Fiewelling D. A systematic review of troponin T and I for diagnosing acute myocardial infarction. J Fam Pract 2000;49:550-56.
8. J, Horder M, Gerhardt W, et al. Diagnostic performance and prognostic value of serum troponin T in suspected acute myocardial infarction. Scand J Clin Lab Invest 1993;53:677-85.
9. J, Nissen H, Horder M, Thygesen K. Independent prognostic value of serum creatine kinase isoenzyme MB mass, cardiac troponin T and myosin light chain levels in suspected acute myocardial infarction. Am Coll Cardiol 1995;25:574-81.
10. GD, Dunt DR. Early prediction of risk in patients with suspected unstable angina using serum troponin T. Aust NZ J Med 1997;27:554-60.
11. GB, Beaudreau RW, Chan DW, DeLong D, Kelley CA, Kelen GD. Use of troponin T and creatine kinase-MB subunit levels for risk stratification of emergency department patients with possible myocardial ischemia. Ann Emerg Med 1998;31:19-29.
12. EM, Sacks DB, Rifai N, McCabe CH, Cannon CP, Braunwald E. Time to positivity of a rapid bedside assay for cardiac-specific troponin T predicts prognosis in acute coronary syndromes: a thrombolysis in myocardial infarction (TIMI) 11A substudy. J Am Coll Cardiol 1998;31:326-30.
13. ER, Ryan T, Segar D, et al. Clinical utility of troponin T levels and echocardiography in the emergency department. Am Heart J 1998;135:253-60.
14. CW, Goldmann B, Heeschen C, Kreymann G, Berger J, Meinertz T. Emergency room triage of patients with acute chest pain by means of rapid testing for cardiac troponin T or troponin 1. N Engi J Med 1997;337:1648-53.
15. M, Oftani F, Ferrini D, et al. Prognostic influence of elevated values of cardiac troponin I in patients with unstable angina. Circulation 1997;95:2053-59.
16. EM, Armstrong PW, Christenson RH, et al. Cardiac troponin T levels for risk stratification in acute myocardial ischemia. N Engl J Med 1996;335:1333-41.
17. Winter RJ, Koster RW, Schotveld JH, Sturk A, van Stallen JP, Sanders GT. Prognostic value of troponin T, myoglobin, and CK-MB mass in patients presenting with chest pain without acute myocardial infarction. Heart 1996;75:235-39.
18. MS, Thygesen K, Ravkilde J, Heickendorff L. Applicability of cardiac troponin T and I for early risk stratification in unstable coronary artery disease. Circulation 1997;96:2578-85.
19. F, Galvani M, Ferrini D, Ladenson JH, et al. Direct comparison of early elevations of cardiac troponin T and I in patients with clinical unstable angina. Am Heart J 1999;137:284-91.
20. 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;31:539-49.
21. RH, Duh SH, Newby LK, et al. Cardiac troponin T and cardiac troponin 1: relative values in short-term risk stratification of patients with acute coronary syndromes. Clin Chem 1998;44:494-501.
22. E, Chiappino I, Bergerone S, et al. Prognostic implications of detection of troponin I in patients with unstable angina pectoris. Am J Cardiol 1998;82:971-73.
23. AG, Quaranta G, Liuzzo G, et al. Incremental prognostic value of serum levels of troponin T and C-reactive protein on admission in patients with unstable angina pectoris. Am J Cardiol 1998;82:715-19.
24. LK, Christenson RH, Ohman EM, et al. Value of serial troponin T measures for early and late risk stratification in patients with acute coronary syndromes. Circulation 1998;98:1853-59.
25. L, Luscher MS, Clemmensen P, Thygesen K, Grande P. Very early risk stratification using combined ECG and biochemical assessment in patients with unstable coronary artery disease. TRIM substudy. Circulation 1998;98:2004-09.
26. P, Collinson P, Mosely D, et al. Prospective study of the role of cardiac troponin T in patients admitted with unstable angina. BMJ 1996;313:262-64.
27. BL, Andersen K, Dellborg M, et al. Admission risk assessment by cardiac troponin T in unstable coronary artery disease: additional prognostic information from continuous ST segment monitoring. J Am Coll Cardiol 1999;33:1519-27.
28. CR, et al. Diagnostic accuracy, angiographic correlates and long-term risk stratification with the troponin T ultra sensitive rapid assay in chest pain patients at low risk for acute myocardial infarction. Eur Heart J 1998;19 (suppl N):N42-47.
29. B, Andren B, Ohlsson J, Penge P, Wallentin L. Risk stratification in unstable coronary artery disease: additive value of troponin T determinations and pre-discharge exercise tests. Eur Heart J 1997;18:762-70.
30. VJ, Kumar DS, Baruah DK. Serum troponin T in unstable angina-a preliminary report. Indian Heart J 1994;46:89-90.
31. S, Koning R, Eitchaninoff H, et al. Relation between serum cardiac troponin I values and severity of clinical, electrocardiographic and quantitative angiographic features in unstable angina. Indian Heart J 1999;51:31-34.
32. Winter RJ, Bholasingh R, Lijmer JG, et al. Independent prognostic value of creactive protein and troponin I in patients with unstable angina or non-Q-wave myocardial infarction. Cardiovascular Res 1999;42:240-45.
33. S, Nishimura S, Tashiro Y, et al. Cardiac troponin-I in diagnosis and prognosis of unstable coronary artery disease. Clin Chem 1997;43:Sl 57.-
34. EM, Tanasijevic MJ, Thompson B, et al. Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med 1996;335:1342-9
OBJECTIVE: The accuracy of the troponin T and I test as a prognostic tool for patients with chest pain varies considerably depending on the patient population, the cutoff for an abnormal test result, and other factors. The goal of our systematic review was to synthesize the best available evidence on this topic.
SEARCH STRATEGY: We searched the MEDLINE database, bibliographies of identified articles, and articles identified from a previous meta-analysis of diagnosis.
SELECTION CRITERIA: We included cohort studies that had at least 80% follow-up and reported useful data.
DATA COLLECTION AND ANALYSIS: Data from each study were abstracted by 2 investigators. We calculated sensitivity and specificity for the prediction of death, fatal or nonfatal myocardial infarction (MI), or any cardiac event for each combination of patient population, troponin test, interval from admission to blood draw, and cutoff for an abnormal test result.
MAIN RESULTS: For patients with chest pain and a normal electrocardiogram, the peak troponin I level drawn 6 or more hours after the onset of chest pain is useful for identifying patients at low risk of death or nonfatal MI at 30 days (negative likelihood ratio=0.07; probability of outcome=0.3% with a negative test, given a pretest probability of 4.4%). For patients with unstable angina, the sensitivity of troponin I for the identification of patients who die or have a nonfatal MI in the next 30 days is only 59%, and the specificity is only 79%. The sensitivity and specificity varied widely for patients with unstable angina or non-Q-wave MI depending on the inclusion criteria, cutoff used, timing of the blood draw, duration of follow-up, and other factors.
CONCLUSIONS: If the peak troponin T or I level measured at least 6 hours after the onset of chest pain symptoms is in the normal range in a patient with a normal electrocardiogram, it is very unlikely that the patient will die or have a nonfatal MI in the next 30 days (1%). The initial troponin value is not as helpful as the peak value at least 6 hours after the onset of chest pain. An abnormal troponin test result for patients with unstable angina or non-Q-wave MI identifies a subset at greater risk of death.
Not all patients with acute chest pain can be monitored as inpatients. Some are sent home with instructions to follow up with their personal physician, while others have noninvasive cardiovascular testing scheduled as outpatients. Formal protocols that use the history, physical examination, laboratory tests, or noninvasive testing have been developed and shown to reduce costs and improve outcomes.1-4
Recently, it has been suggested that troponin T and I values may be useful for prognosis in patients with acute chest pain in the emergency department.5,6 These enzymes are released by damaged cardiac muscle. However, the accuracy of troponin levels for the diagnosis of acute myocardial infarction (MI) varies considerably, depending on the specific test used, cutoff to define an abnormal test result, and timing of the blood test in relation to the onset of chest pain.7 The usefulness of these tests for prognosis is likely to be affected by the same factors.
The authors of several previous meta-analyses have considered this question. However, all of these studies had significant limitations. Wu and colleagues5 published a meta-analysis in 1995 that obviously could not include the large number of studies published since that time. The meta-analysis by Ollatidoye and colleagues6 included more studies but did not distinguish between different cutoffs to define an abnormal test result, combined all intervals from 4 days to 1095 days into a single summary estimate, and did not consider the time at which the troponin test was drawn in relation to either emergency department arrival or the onset of chest pain. In our study, we systematically reviewed the evidence for the accuracy of troponin T and I values in determining the prognosis of patients presenting to the emergency department with chest pain, unstable angina, and other acute coronary syndromes.
Methods
Search Strategy
We conducted searches of the MEDLINE database in June 1999 and December 1999 (the second search was of 1999 only). We used the following search strategy: troponin [text word] or troponin [MeSH] and prognosis [MeSH]. Studies were limited to those that provided an abstract, were written in English or German, and used human subjects. The October through December 1999 issues of the American Journal of Cardiology, the Journal of the American College of Cardiology, the American Heart Journal, and Clinical Chemistry were hand-searched. We also reviewed the bibliographies of articles meeting the final inclusion criteria. The abstract of each article was reviewed by one of the investigators, and articles were evaluated in detail if troponin levels were used to predict the prognosis of patients with chest pain, unstable angina, or other acute coronary syndromes.
Inclusion Criteria and Assessment of Study Quality
Inclusion criteria were designed to identify only those studies meeting Level 1b criteria, as defined by the Centre for Evidence-Based Medicine (cebm.jr2.ox.ac.uk/docs/levels.html). These inclusion criteria are:
- Prospective cohort study
- Adult patients with acute chest pain or other acute coronary syndrome
- At least 80% follow-up of patients
- Death, fatal or nonfatal MI, or any cardiac event at some point following hospital discharge
We excluded studies reporting only in-hospital outcomes and those without sufficient data to calculate sensitivity or specificity for at least one outcome.
Data Abstraction
Two independent investigators (either ME and DW or ME and LW) reviewed each article and abstracted data related to study quality, inclusion criteria, and test characteristics. Any discrepancies were resolved by consensus decision. The following data were abstracted: reference, study design, percentage of follow-up, outcomes measured, inclusion criteria for patients in the study, and data needed to calculate sensitivity or specificity.
Statistical Analysis
The primary outcomes were the test characteristics (sensitivity, specificity, post-test probability positive and negative, and positive and negative likelihood ratios* [LR+ and LR-, respectively]) for each combination of inclusion criteria, diagnostic test, and patient outcome.
Where possible, summary estimates of sensitivity and specificity were made using a DerSimonian and Laird random effects model. Sensitivity and specificity were pooled independently and weighted by the inverse of the variance using MetaTest software (version 0.6, Joseph Lau, MD, used with permission). If a fixed effects model and a random effects model calculated similar estimates of sensitivity or specificity, the statistic was deemed homogenous, and the more conservative random effects model result was reported. If the fixed effects model and the random effects model gave estimates that were different in a clinically meaningful way, the statistic was deemed heterogeneous, and only a range was reported.
Results
Twenty-eight studies met the inclusion criteria and had usable data for our systematic review.6,8-34 Two studies used the research version of the Baxter Stratus enzyme-linked immunosorbent assay troponin I assay. A cutoff of 3.1 ng/mL corresponds to a cutoff of 0.6 in the commercial version of this assay.15,19 One study28 measured the troponin T level at 10 or more hours after the onset of chest pain. This was included with studies measuring the peak value within the first 24 hours. The study by Kerr and Dunt10 measured the troponin T value at 14 hours after the onset of chest pain. The study by Janorkar and colleagues31 followed patients for a variable length of time with a mean follow-up of 9 months and a standard deviation of 4 months.
In general, the studies used a wide variety of cutoffs, durations of follow-up, inclusion criteria, and outcomes. We have organized the results in 3 tables on the basis of the 3 populations studied in the available literature. [Table 1] shows data for patients with chest pain syndromes, [Table 2] for patients with unstable angina, and [Table 3] for patients with unstable angina or non-Q-wave MI. Unstable angina was generally defined as chest pain accompanied by electrocardiogram (ECG) changes but without evidence of MI, and non-Q-wave MI was defined on the basis of clinical and biochemical criteria for MI but without Q waves on the ECG.
Patients with Chest Pain
Troponin I. Only 1 study14 of patients with chest pain used the troponin I test, in this case a rapid bedside assay. It included 773 patients with chest pain and a normal ECG and used death or nonfatal MI as the outcome. The authors reported a sensitivity of 0.94, a specificity of 0.81, an LR+ of 5.0, and a very low LR- of 0.07.
Troponin T. Only 2 studies examined the accuracy of troponin T in patients with nontraumatic chest pain.11,20 However, neither reported the rates of death or nonfatal MI during follow-up in a way that allowed calculation of sensitivity and specificity. The range of sensitivity for any cardiac event was from 0.31 to 0.54, the specificity from 0.78 to 0.92, the LR+ from 2.4 to 3.8, and the LR- from 0.6 to 0.7. Among patients with chest pain and a normal ECG, Hamm and coworkers14 reported an LR+ of 6.1 and an LR- of 0.2. Three studies included patients with chest pain who were admitted to rule out MI and were followed for 180 days to 2 years.8-10 They reported a range of sensitivity of 0.52 to 0.67, specificity from 0.72 to 0.83, LR+ from 2.3 to 3.2, and LR- from 0.5 to 0.6.
Patients with Unstable Angina
Troponin I. Three studies of troponin I included patients with unstable angina and used the outcome of death during follow-up. The duration of follow-up ranged from 30 days to 9 months, and the cutoff for an abnormal test result was from 0.6 to 1.5 ng/mL.19,21,31 The sensitivity varied widely from 0.5 to 1.0; however, 2 of the studies were small, with only 2 deaths in each study. The largest study found a sensitivity of only 0.52 and specificity of 0.73.21 For studies of troponin I using death or nonfatal MI as an outcome, results from 3 studies15,18,22 could be combined, because the study designs were similar. They used a cutoff of 0.6 ng/mL, followed patients for 30 days, and used the peak troponin value in the first 8 to 72 hours. The summary test characteristics for these 3 studies were a sensitivity of 0.59, a specificity of 0.79, an LR+ of 2.8, and an LR- of 0.5.
Troponin T. Using unstable angina to determine inclusion and 30 days as the duration of follow-up, several studies found a low sensitivity of troponin T as a prognostic test. Three studies of unstable angina were quite similar in design and inclusion, using a cutoff of 0.1 ng/mL, blood drawn on admission to the emergency department, and an outcome of death at 30 days.16,21,24 The summary test characteristics for these studies were a sensitivity of 0.63, a specificity of 0.66, an LR+ of 1.9, and an LR- of 0.6.
Depending on the combination of cutoff, timing of the blood draw, and duration of follow-up, a positive troponin T had a range of sensitivity from 0.38 to 0.63 and of specificity from 0.77 to 0.95 for the outcome of death or nonfatal MI at 30 days.6,18,19,23,26,27 Two studies 18.19 were similar in design, and their test characteristics could be combined (sensitivity=0.44, specificity=0.81, LR+=2.3, and LR-=0.7).
Patients with Unstable Angina or Non-Q-Wave MI
Troponin I .A positive troponin I in patients with unstable angina or non-Q-wave MI produced sensitivities from 0.72 to 0.78 and specificities from 0.59 to 0.60 for the outcome of death at 30 to 42 days.18,34 For the outcome of death or nonfatal Ml using the same inclusion criteria, the range of sensitivity was from 0.59 to 1.00 and of specificity was from 0.60 to 0.74.18,32,33
Troponin T. For an outcome of death, the LR+ was 1.3 to 1.8, and the LR- was 0.0 to 0.3.18,29 The study29 with an LR- of 0.0 had no false-negatives and a sensitivity of 1.0; it used a very low cutoff of 0.06 for an abnormal test result. Using the same cohort with a cutoff of 0.2, the investigators found a sensitivity of 0.72 and a specificity of 0.45. As expected, a lower cutoff improved the sensitivity of the test.
Discussion
Although one goal of systemic reviews is to pool study data from multiple sources to calculate summary measures of test accuracy, not all reviews can achieve that goal. In our study, a lack of standardization in study parameters limited our ability to combine summary estimates effectively. However, we have identified several important guidelines for clinicians using the troponin test and for future research in this area.
Most studies of the troponin test have evaluated it in patients with unstable angina or unstable angina and non-Q-wave MI. Although the test has some value in the non-Q-wave MI patients for identifying higher-risk and lower-risk groups, all such patients would generally be admitted to the hospital and followed closely. For primary care and emergency physicians evaluating a patient with chest pain in the emergency department, an important goal is to identify patients for whom adverse cardiac events such as death or nonfatal MI are unlikely in the near future. These patients could be sent home to follow up with their primary care physician and possibly undergo noninvasive testing as outpatients.
Unfortunately, only a few studies have included patients with chest pain or patients with chest pain and a normal ECG. The most useful study is that of Hamm and colleagues.14 In their study of 773 patients with chest pain and no ST elevation, troponin T and I both had a low LR- for the identification of patients at low risk of death or nonfatal MI in the 30 days following their episode of chest pain. Only 1 in 300 patients with a normal ECG and normal troponin I 6 hours after the onset of chest pain had an adverse outcome in the 30 days after hospital discharge and only 1 in 100 of those with normal ECG and normal troponin T. Although the troponin T test actually had a lower LR- and was potentially more useful, this test is not widely available in the United States. More studies of both troponin T and I are needed among patients with chest pain or chest pain and normal ECG to validate the findings of Hamm and coworkers.
Using a lower cutoff for abnormal with troponin T improves the sensitivity of the test. Lindahl and colleagues29 found a sensitivity of 1.0 at a cutoff of 0.06 for the outcome of death in a study of patients with unstable angina or non-Q-wave MI; the sensitivity was only 0.86 for a cutoff of 0.2. Other pairs of studies had a similar pattern, which was expected. Future studies should report the sensitivity and specificity of the tests for several cutoffs, including lower values such as 0.05 ng/mL for troponin T.
Also, the sensitivity of troponin was improved when the peak value in the first 6 to 24 hours of admission was used instead of the value on admission to the emergency department. For example, among patients with unstable angina the sensitivity was 0.63 when blood was drawn on admission to the emergency department16,21,24 and 1.0 when the peak value in the first 16 hours was used.24 This makes physiologic sense, since patients presenting early in the course of their episode of unstable angina or MI may have undetectable levels of troponin which rise as the episode progresses.
Recommendations for future research
To facilitate future meta-analyses, we recommend the following parameters for the design of studies of troponin. First, studies should use larger populations and standardize their inclusion and testing criteria. We also recommend durations of follow-up of 7 days, 30 days, and 1 year. Although a longer duration is helpful in predicting the patient’s overall prognosis, shorter durations are more useful for identifying patients who can be discharged for close outpatient follow-up and noninvasive testing. Cutoffs of 0.05 ng/mL, 0.10 ng/mL, and 0.20 ng/mL for troponin T and cutoffs of 0.3 and 0.6 for troponin I should be used. Authors should report the test characteristics for several cutoffs and also for ranges of troponin, such as less than 0.05 ng/mL, 0.06 ng/mL to 0.10 ng/mL, and greater than 0.10 ng/mL. In addition, we recommend that sensitivity and specificity be reported both for the initial value on admission to the emergency department and for peak values after 12 and 24 hours. Finally, standard definitions for inclusion criteria and outcomes should be used, such as the Braunwald criteria* for unstable angina and the World Health Organization criteria for acute MI.
We also suggest that valuable information would be added if population demographics were reported in study results. Although most studies considered patient demographics carefully in determining study eligibility, they did not report those characteristics in their findings. It is not clear, for example, that the test performs similarly in younger and older patients, in men and women, or in different ethnic or racial groups.
Finally, we recommend that more studies evaluate the accuracy of troponin I in prognosis, particularly among patients with chest pain syndromes. Of the 28 studies we analyzed, only 11 measured troponin I and only 1 enrolled patients who had chest pain and a normal ECG.
Recommendations for practice
If the peak troponin T or I level measured at least 6 hours after the onset of chest pain symptoms is in the normal range and the ECG is normal, it is very unlikely that the patient will die or have a nonfatal MI in the next 30 days (1%).14 It is important to note that decisions about care should be made on the basis of the troponin value and ECG and in light of the patient’s clinical presentation and comorbidities, and that this finding is based on only 1 study, albeit a large one. The initial troponin value is not as helpful as the peak value at least 6 hours after the onset of chest pain. An abnormal troponin test in patients with unstable angina or non-Q-wave MI identifies a subset at greater risk of death; those patients should be closely monitored.
Acknowledgments
This project was supported by the Michigan Consortium for Family Practice Research, one of 3 research centers funded by the American Academy of Family Physicians. We wish to acknowledge the assistance of Dan Flewelling in the literature search and of Deb Richardson in the preparation of the manuscript.
OBJECTIVE: The accuracy of the troponin T and I test as a prognostic tool for patients with chest pain varies considerably depending on the patient population, the cutoff for an abnormal test result, and other factors. The goal of our systematic review was to synthesize the best available evidence on this topic.
SEARCH STRATEGY: We searched the MEDLINE database, bibliographies of identified articles, and articles identified from a previous meta-analysis of diagnosis.
SELECTION CRITERIA: We included cohort studies that had at least 80% follow-up and reported useful data.
DATA COLLECTION AND ANALYSIS: Data from each study were abstracted by 2 investigators. We calculated sensitivity and specificity for the prediction of death, fatal or nonfatal myocardial infarction (MI), or any cardiac event for each combination of patient population, troponin test, interval from admission to blood draw, and cutoff for an abnormal test result.
MAIN RESULTS: For patients with chest pain and a normal electrocardiogram, the peak troponin I level drawn 6 or more hours after the onset of chest pain is useful for identifying patients at low risk of death or nonfatal MI at 30 days (negative likelihood ratio=0.07; probability of outcome=0.3% with a negative test, given a pretest probability of 4.4%). For patients with unstable angina, the sensitivity of troponin I for the identification of patients who die or have a nonfatal MI in the next 30 days is only 59%, and the specificity is only 79%. The sensitivity and specificity varied widely for patients with unstable angina or non-Q-wave MI depending on the inclusion criteria, cutoff used, timing of the blood draw, duration of follow-up, and other factors.
CONCLUSIONS: If the peak troponin T or I level measured at least 6 hours after the onset of chest pain symptoms is in the normal range in a patient with a normal electrocardiogram, it is very unlikely that the patient will die or have a nonfatal MI in the next 30 days (1%). The initial troponin value is not as helpful as the peak value at least 6 hours after the onset of chest pain. An abnormal troponin test result for patients with unstable angina or non-Q-wave MI identifies a subset at greater risk of death.
Not all patients with acute chest pain can be monitored as inpatients. Some are sent home with instructions to follow up with their personal physician, while others have noninvasive cardiovascular testing scheduled as outpatients. Formal protocols that use the history, physical examination, laboratory tests, or noninvasive testing have been developed and shown to reduce costs and improve outcomes.1-4
Recently, it has been suggested that troponin T and I values may be useful for prognosis in patients with acute chest pain in the emergency department.5,6 These enzymes are released by damaged cardiac muscle. However, the accuracy of troponin levels for the diagnosis of acute myocardial infarction (MI) varies considerably, depending on the specific test used, cutoff to define an abnormal test result, and timing of the blood test in relation to the onset of chest pain.7 The usefulness of these tests for prognosis is likely to be affected by the same factors.
The authors of several previous meta-analyses have considered this question. However, all of these studies had significant limitations. Wu and colleagues5 published a meta-analysis in 1995 that obviously could not include the large number of studies published since that time. The meta-analysis by Ollatidoye and colleagues6 included more studies but did not distinguish between different cutoffs to define an abnormal test result, combined all intervals from 4 days to 1095 days into a single summary estimate, and did not consider the time at which the troponin test was drawn in relation to either emergency department arrival or the onset of chest pain. In our study, we systematically reviewed the evidence for the accuracy of troponin T and I values in determining the prognosis of patients presenting to the emergency department with chest pain, unstable angina, and other acute coronary syndromes.
Methods
Search Strategy
We conducted searches of the MEDLINE database in June 1999 and December 1999 (the second search was of 1999 only). We used the following search strategy: troponin [text word] or troponin [MeSH] and prognosis [MeSH]. Studies were limited to those that provided an abstract, were written in English or German, and used human subjects. The October through December 1999 issues of the American Journal of Cardiology, the Journal of the American College of Cardiology, the American Heart Journal, and Clinical Chemistry were hand-searched. We also reviewed the bibliographies of articles meeting the final inclusion criteria. The abstract of each article was reviewed by one of the investigators, and articles were evaluated in detail if troponin levels were used to predict the prognosis of patients with chest pain, unstable angina, or other acute coronary syndromes.
Inclusion Criteria and Assessment of Study Quality
Inclusion criteria were designed to identify only those studies meeting Level 1b criteria, as defined by the Centre for Evidence-Based Medicine (cebm.jr2.ox.ac.uk/docs/levels.html). These inclusion criteria are:
- Prospective cohort study
- Adult patients with acute chest pain or other acute coronary syndrome
- At least 80% follow-up of patients
- Death, fatal or nonfatal MI, or any cardiac event at some point following hospital discharge
We excluded studies reporting only in-hospital outcomes and those without sufficient data to calculate sensitivity or specificity for at least one outcome.
Data Abstraction
Two independent investigators (either ME and DW or ME and LW) reviewed each article and abstracted data related to study quality, inclusion criteria, and test characteristics. Any discrepancies were resolved by consensus decision. The following data were abstracted: reference, study design, percentage of follow-up, outcomes measured, inclusion criteria for patients in the study, and data needed to calculate sensitivity or specificity.
Statistical Analysis
The primary outcomes were the test characteristics (sensitivity, specificity, post-test probability positive and negative, and positive and negative likelihood ratios* [LR+ and LR-, respectively]) for each combination of inclusion criteria, diagnostic test, and patient outcome.
Where possible, summary estimates of sensitivity and specificity were made using a DerSimonian and Laird random effects model. Sensitivity and specificity were pooled independently and weighted by the inverse of the variance using MetaTest software (version 0.6, Joseph Lau, MD, used with permission). If a fixed effects model and a random effects model calculated similar estimates of sensitivity or specificity, the statistic was deemed homogenous, and the more conservative random effects model result was reported. If the fixed effects model and the random effects model gave estimates that were different in a clinically meaningful way, the statistic was deemed heterogeneous, and only a range was reported.
Results
Twenty-eight studies met the inclusion criteria and had usable data for our systematic review.6,8-34 Two studies used the research version of the Baxter Stratus enzyme-linked immunosorbent assay troponin I assay. A cutoff of 3.1 ng/mL corresponds to a cutoff of 0.6 in the commercial version of this assay.15,19 One study28 measured the troponin T level at 10 or more hours after the onset of chest pain. This was included with studies measuring the peak value within the first 24 hours. The study by Kerr and Dunt10 measured the troponin T value at 14 hours after the onset of chest pain. The study by Janorkar and colleagues31 followed patients for a variable length of time with a mean follow-up of 9 months and a standard deviation of 4 months.
In general, the studies used a wide variety of cutoffs, durations of follow-up, inclusion criteria, and outcomes. We have organized the results in 3 tables on the basis of the 3 populations studied in the available literature. [Table 1] shows data for patients with chest pain syndromes, [Table 2] for patients with unstable angina, and [Table 3] for patients with unstable angina or non-Q-wave MI. Unstable angina was generally defined as chest pain accompanied by electrocardiogram (ECG) changes but without evidence of MI, and non-Q-wave MI was defined on the basis of clinical and biochemical criteria for MI but without Q waves on the ECG.
Patients with Chest Pain
Troponin I. Only 1 study14 of patients with chest pain used the troponin I test, in this case a rapid bedside assay. It included 773 patients with chest pain and a normal ECG and used death or nonfatal MI as the outcome. The authors reported a sensitivity of 0.94, a specificity of 0.81, an LR+ of 5.0, and a very low LR- of 0.07.
Troponin T. Only 2 studies examined the accuracy of troponin T in patients with nontraumatic chest pain.11,20 However, neither reported the rates of death or nonfatal MI during follow-up in a way that allowed calculation of sensitivity and specificity. The range of sensitivity for any cardiac event was from 0.31 to 0.54, the specificity from 0.78 to 0.92, the LR+ from 2.4 to 3.8, and the LR- from 0.6 to 0.7. Among patients with chest pain and a normal ECG, Hamm and coworkers14 reported an LR+ of 6.1 and an LR- of 0.2. Three studies included patients with chest pain who were admitted to rule out MI and were followed for 180 days to 2 years.8-10 They reported a range of sensitivity of 0.52 to 0.67, specificity from 0.72 to 0.83, LR+ from 2.3 to 3.2, and LR- from 0.5 to 0.6.
Patients with Unstable Angina
Troponin I. Three studies of troponin I included patients with unstable angina and used the outcome of death during follow-up. The duration of follow-up ranged from 30 days to 9 months, and the cutoff for an abnormal test result was from 0.6 to 1.5 ng/mL.19,21,31 The sensitivity varied widely from 0.5 to 1.0; however, 2 of the studies were small, with only 2 deaths in each study. The largest study found a sensitivity of only 0.52 and specificity of 0.73.21 For studies of troponin I using death or nonfatal MI as an outcome, results from 3 studies15,18,22 could be combined, because the study designs were similar. They used a cutoff of 0.6 ng/mL, followed patients for 30 days, and used the peak troponin value in the first 8 to 72 hours. The summary test characteristics for these 3 studies were a sensitivity of 0.59, a specificity of 0.79, an LR+ of 2.8, and an LR- of 0.5.
Troponin T. Using unstable angina to determine inclusion and 30 days as the duration of follow-up, several studies found a low sensitivity of troponin T as a prognostic test. Three studies of unstable angina were quite similar in design and inclusion, using a cutoff of 0.1 ng/mL, blood drawn on admission to the emergency department, and an outcome of death at 30 days.16,21,24 The summary test characteristics for these studies were a sensitivity of 0.63, a specificity of 0.66, an LR+ of 1.9, and an LR- of 0.6.
Depending on the combination of cutoff, timing of the blood draw, and duration of follow-up, a positive troponin T had a range of sensitivity from 0.38 to 0.63 and of specificity from 0.77 to 0.95 for the outcome of death or nonfatal MI at 30 days.6,18,19,23,26,27 Two studies 18.19 were similar in design, and their test characteristics could be combined (sensitivity=0.44, specificity=0.81, LR+=2.3, and LR-=0.7).
Patients with Unstable Angina or Non-Q-Wave MI
Troponin I .A positive troponin I in patients with unstable angina or non-Q-wave MI produced sensitivities from 0.72 to 0.78 and specificities from 0.59 to 0.60 for the outcome of death at 30 to 42 days.18,34 For the outcome of death or nonfatal Ml using the same inclusion criteria, the range of sensitivity was from 0.59 to 1.00 and of specificity was from 0.60 to 0.74.18,32,33
Troponin T. For an outcome of death, the LR+ was 1.3 to 1.8, and the LR- was 0.0 to 0.3.18,29 The study29 with an LR- of 0.0 had no false-negatives and a sensitivity of 1.0; it used a very low cutoff of 0.06 for an abnormal test result. Using the same cohort with a cutoff of 0.2, the investigators found a sensitivity of 0.72 and a specificity of 0.45. As expected, a lower cutoff improved the sensitivity of the test.
Discussion
Although one goal of systemic reviews is to pool study data from multiple sources to calculate summary measures of test accuracy, not all reviews can achieve that goal. In our study, a lack of standardization in study parameters limited our ability to combine summary estimates effectively. However, we have identified several important guidelines for clinicians using the troponin test and for future research in this area.
Most studies of the troponin test have evaluated it in patients with unstable angina or unstable angina and non-Q-wave MI. Although the test has some value in the non-Q-wave MI patients for identifying higher-risk and lower-risk groups, all such patients would generally be admitted to the hospital and followed closely. For primary care and emergency physicians evaluating a patient with chest pain in the emergency department, an important goal is to identify patients for whom adverse cardiac events such as death or nonfatal MI are unlikely in the near future. These patients could be sent home to follow up with their primary care physician and possibly undergo noninvasive testing as outpatients.
Unfortunately, only a few studies have included patients with chest pain or patients with chest pain and a normal ECG. The most useful study is that of Hamm and colleagues.14 In their study of 773 patients with chest pain and no ST elevation, troponin T and I both had a low LR- for the identification of patients at low risk of death or nonfatal MI in the 30 days following their episode of chest pain. Only 1 in 300 patients with a normal ECG and normal troponin I 6 hours after the onset of chest pain had an adverse outcome in the 30 days after hospital discharge and only 1 in 100 of those with normal ECG and normal troponin T. Although the troponin T test actually had a lower LR- and was potentially more useful, this test is not widely available in the United States. More studies of both troponin T and I are needed among patients with chest pain or chest pain and normal ECG to validate the findings of Hamm and coworkers.
Using a lower cutoff for abnormal with troponin T improves the sensitivity of the test. Lindahl and colleagues29 found a sensitivity of 1.0 at a cutoff of 0.06 for the outcome of death in a study of patients with unstable angina or non-Q-wave MI; the sensitivity was only 0.86 for a cutoff of 0.2. Other pairs of studies had a similar pattern, which was expected. Future studies should report the sensitivity and specificity of the tests for several cutoffs, including lower values such as 0.05 ng/mL for troponin T.
Also, the sensitivity of troponin was improved when the peak value in the first 6 to 24 hours of admission was used instead of the value on admission to the emergency department. For example, among patients with unstable angina the sensitivity was 0.63 when blood was drawn on admission to the emergency department16,21,24 and 1.0 when the peak value in the first 16 hours was used.24 This makes physiologic sense, since patients presenting early in the course of their episode of unstable angina or MI may have undetectable levels of troponin which rise as the episode progresses.
Recommendations for future research
To facilitate future meta-analyses, we recommend the following parameters for the design of studies of troponin. First, studies should use larger populations and standardize their inclusion and testing criteria. We also recommend durations of follow-up of 7 days, 30 days, and 1 year. Although a longer duration is helpful in predicting the patient’s overall prognosis, shorter durations are more useful for identifying patients who can be discharged for close outpatient follow-up and noninvasive testing. Cutoffs of 0.05 ng/mL, 0.10 ng/mL, and 0.20 ng/mL for troponin T and cutoffs of 0.3 and 0.6 for troponin I should be used. Authors should report the test characteristics for several cutoffs and also for ranges of troponin, such as less than 0.05 ng/mL, 0.06 ng/mL to 0.10 ng/mL, and greater than 0.10 ng/mL. In addition, we recommend that sensitivity and specificity be reported both for the initial value on admission to the emergency department and for peak values after 12 and 24 hours. Finally, standard definitions for inclusion criteria and outcomes should be used, such as the Braunwald criteria* for unstable angina and the World Health Organization criteria for acute MI.
We also suggest that valuable information would be added if population demographics were reported in study results. Although most studies considered patient demographics carefully in determining study eligibility, they did not report those characteristics in their findings. It is not clear, for example, that the test performs similarly in younger and older patients, in men and women, or in different ethnic or racial groups.
Finally, we recommend that more studies evaluate the accuracy of troponin I in prognosis, particularly among patients with chest pain syndromes. Of the 28 studies we analyzed, only 11 measured troponin I and only 1 enrolled patients who had chest pain and a normal ECG.
Recommendations for practice
If the peak troponin T or I level measured at least 6 hours after the onset of chest pain symptoms is in the normal range and the ECG is normal, it is very unlikely that the patient will die or have a nonfatal MI in the next 30 days (1%).14 It is important to note that decisions about care should be made on the basis of the troponin value and ECG and in light of the patient’s clinical presentation and comorbidities, and that this finding is based on only 1 study, albeit a large one. The initial troponin value is not as helpful as the peak value at least 6 hours after the onset of chest pain. An abnormal troponin test in patients with unstable angina or non-Q-wave MI identifies a subset at greater risk of death; those patients should be closely monitored.
Acknowledgments
This project was supported by the Michigan Consortium for Family Practice Research, one of 3 research centers funded by the American Academy of Family Physicians. We wish to acknowledge the assistance of Dan Flewelling in the literature search and of Deb Richardson in the preparation of the manuscript.
1. TH, Juarez G, Cook EF, et al. Ruling out acute myocardial infarction: a prospective multicenter validation of a 12-hour strategy for patients at low risk. N Engl J Med 1991;324:1239-46.
2. TH, Cook EF, Weisberg M, Sargent RK, Wilson C, Goldman L. Acute chest pain in the emergency room: identification and examination of low risk patients. Arch Intern Med 1985;145:65-69.
3. RR, Zalenski RJ, Mensay EK, et al. Costs of an emergency department based accelerated diagnostic protocol vs hospitalization in patients with chest pain: a randomized controlled trial. JAMA 1997;278:1670-76.
4. ME, Smars PA, Reeder GS, et al. A clinical trial of a chest-pain observation unit for patients with unstable angina. N Engl J Med 1998;339:1882-88.
5. Software, version 0.6. Joseph Lau, MD, New England Medical Center. Used with permission.
6. AG, Wu AH, Feng YJ, Waters D. Prognostic role of troponin T versus troponin I in unstable angina pectoris for cardiac events with meta-analysis comparing published studies. Am J Cardiol 1998;81:1405-10.
7. MH, Flynn C, Fiewelling D. A systematic review of troponin T and I for diagnosing acute myocardial infarction. J Fam Pract 2000;49:550-56.
8. J, Horder M, Gerhardt W, et al. Diagnostic performance and prognostic value of serum troponin T in suspected acute myocardial infarction. Scand J Clin Lab Invest 1993;53:677-85.
9. J, Nissen H, Horder M, Thygesen K. Independent prognostic value of serum creatine kinase isoenzyme MB mass, cardiac troponin T and myosin light chain levels in suspected acute myocardial infarction. Am Coll Cardiol 1995;25:574-81.
10. GD, Dunt DR. Early prediction of risk in patients with suspected unstable angina using serum troponin T. Aust NZ J Med 1997;27:554-60.
11. GB, Beaudreau RW, Chan DW, DeLong D, Kelley CA, Kelen GD. Use of troponin T and creatine kinase-MB subunit levels for risk stratification of emergency department patients with possible myocardial ischemia. Ann Emerg Med 1998;31:19-29.
12. EM, Sacks DB, Rifai N, McCabe CH, Cannon CP, Braunwald E. Time to positivity of a rapid bedside assay for cardiac-specific troponin T predicts prognosis in acute coronary syndromes: a thrombolysis in myocardial infarction (TIMI) 11A substudy. J Am Coll Cardiol 1998;31:326-30.
13. ER, Ryan T, Segar D, et al. Clinical utility of troponin T levels and echocardiography in the emergency department. Am Heart J 1998;135:253-60.
14. CW, Goldmann B, Heeschen C, Kreymann G, Berger J, Meinertz T. Emergency room triage of patients with acute chest pain by means of rapid testing for cardiac troponin T or troponin 1. N Engi J Med 1997;337:1648-53.
15. M, Oftani F, Ferrini D, et al. Prognostic influence of elevated values of cardiac troponin I in patients with unstable angina. Circulation 1997;95:2053-59.
16. EM, Armstrong PW, Christenson RH, et al. Cardiac troponin T levels for risk stratification in acute myocardial ischemia. N Engl J Med 1996;335:1333-41.
17. Winter RJ, Koster RW, Schotveld JH, Sturk A, van Stallen JP, Sanders GT. Prognostic value of troponin T, myoglobin, and CK-MB mass in patients presenting with chest pain without acute myocardial infarction. Heart 1996;75:235-39.
18. MS, Thygesen K, Ravkilde J, Heickendorff L. Applicability of cardiac troponin T and I for early risk stratification in unstable coronary artery disease. Circulation 1997;96:2578-85.
19. F, Galvani M, Ferrini D, Ladenson JH, et al. Direct comparison of early elevations of cardiac troponin T and I in patients with clinical unstable angina. Am Heart J 1999;137:284-91.
20. 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;31:539-49.
21. RH, Duh SH, Newby LK, et al. Cardiac troponin T and cardiac troponin 1: relative values in short-term risk stratification of patients with acute coronary syndromes. Clin Chem 1998;44:494-501.
22. E, Chiappino I, Bergerone S, et al. Prognostic implications of detection of troponin I in patients with unstable angina pectoris. Am J Cardiol 1998;82:971-73.
23. AG, Quaranta G, Liuzzo G, et al. Incremental prognostic value of serum levels of troponin T and C-reactive protein on admission in patients with unstable angina pectoris. Am J Cardiol 1998;82:715-19.
24. LK, Christenson RH, Ohman EM, et al. Value of serial troponin T measures for early and late risk stratification in patients with acute coronary syndromes. Circulation 1998;98:1853-59.
25. L, Luscher MS, Clemmensen P, Thygesen K, Grande P. Very early risk stratification using combined ECG and biochemical assessment in patients with unstable coronary artery disease. TRIM substudy. Circulation 1998;98:2004-09.
26. P, Collinson P, Mosely D, et al. Prospective study of the role of cardiac troponin T in patients admitted with unstable angina. BMJ 1996;313:262-64.
27. BL, Andersen K, Dellborg M, et al. Admission risk assessment by cardiac troponin T in unstable coronary artery disease: additional prognostic information from continuous ST segment monitoring. J Am Coll Cardiol 1999;33:1519-27.
28. CR, et al. Diagnostic accuracy, angiographic correlates and long-term risk stratification with the troponin T ultra sensitive rapid assay in chest pain patients at low risk for acute myocardial infarction. Eur Heart J 1998;19 (suppl N):N42-47.
29. B, Andren B, Ohlsson J, Penge P, Wallentin L. Risk stratification in unstable coronary artery disease: additive value of troponin T determinations and pre-discharge exercise tests. Eur Heart J 1997;18:762-70.
30. VJ, Kumar DS, Baruah DK. Serum troponin T in unstable angina-a preliminary report. Indian Heart J 1994;46:89-90.
31. S, Koning R, Eitchaninoff H, et al. Relation between serum cardiac troponin I values and severity of clinical, electrocardiographic and quantitative angiographic features in unstable angina. Indian Heart J 1999;51:31-34.
32. Winter RJ, Bholasingh R, Lijmer JG, et al. Independent prognostic value of creactive protein and troponin I in patients with unstable angina or non-Q-wave myocardial infarction. Cardiovascular Res 1999;42:240-45.
33. S, Nishimura S, Tashiro Y, et al. Cardiac troponin-I in diagnosis and prognosis of unstable coronary artery disease. Clin Chem 1997;43:Sl 57.-
34. EM, Tanasijevic MJ, Thompson B, et al. Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med 1996;335:1342-9
1. TH, Juarez G, Cook EF, et al. Ruling out acute myocardial infarction: a prospective multicenter validation of a 12-hour strategy for patients at low risk. N Engl J Med 1991;324:1239-46.
2. TH, Cook EF, Weisberg M, Sargent RK, Wilson C, Goldman L. Acute chest pain in the emergency room: identification and examination of low risk patients. Arch Intern Med 1985;145:65-69.
3. RR, Zalenski RJ, Mensay EK, et al. Costs of an emergency department based accelerated diagnostic protocol vs hospitalization in patients with chest pain: a randomized controlled trial. JAMA 1997;278:1670-76.
4. ME, Smars PA, Reeder GS, et al. A clinical trial of a chest-pain observation unit for patients with unstable angina. N Engl J Med 1998;339:1882-88.
5. Software, version 0.6. Joseph Lau, MD, New England Medical Center. Used with permission.
6. AG, Wu AH, Feng YJ, Waters D. Prognostic role of troponin T versus troponin I in unstable angina pectoris for cardiac events with meta-analysis comparing published studies. Am J Cardiol 1998;81:1405-10.
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