Troponin has become the preferred cardiac biomarker with respect to the diagnosis of acute myocardial infarction (AMI) [
The American College of Emergency Physicians (ACEP) has published a clinical policy that supports the use of a single negative TnI obtained 8 to 12 hours after symptom onset for the exclusion of non-ST-segment elevation myocardial infarction (NSTEMI). There are, however, relatively few published reports substantiating the safety of this approach. Furthermore, a review of the use of troponin T in this setting was unable to confirm the safety of this approach [
We sought to define the frequency and clinical characteristics of ED patients with an initial nondiagnostic, but subsequent positive TnI. In addition, we sought to determine what percentage of the aforementioned patients presented with a symptom duration greater than 8 hours. These patients reflect a population that the ACEP guidelines for the diagnosis of NSTEMI would have failed to recognize.
All data for this study was obtained through a systematic review of the electronic and paper medical record (when available) for patients evaluated in the emergency department of a single urban county teaching hospital with an annual census of approximately 80,000 visits. Two authors (J. S. Lynn and A. Singh) conducted the data abstraction using a standardized data abstraction worksheet. Approval for this study was granted by the institutional review board at our institution, prior to the commencement of data acquisition.
Patients were included in this study if they presented to the emergency department (ED) between January 2004 and December 2005 and fulfilled all of the following criteria: (1) had at least two TnI laboratory values obtained, (2) the first TnI value was ≤0.6 ng/mL, and (3) any subsequent troponin I value in the ED was >0.6 ng/mL. There were no exclusion criteria. A laboratory database of all TnI results obtained during the study period was used to identify participants.
From January 2004 through September 2005 the Stratus stat-fluorometric analyzer (Dade-Behring) was used to measure troponin values. The analytical lower threshold for detection for this method was 0.03 ng/mL, the laboratory reference range extended to 0.06 ng/mL, and the threshold for suspecting acute myocardial infarction was ≥0.6 ng/mL [
Data was collected directly onto a standardized secure computerized database. Source documents included all parts of the ED electronic medical record, including triage notes, nursing notes, any physician notes, and laboratory data. In addition, the paper record was reviewed for each subject including the ED physician’s history and physical (H&P), admitting resident’s H&P, consulting specialist’s H&P, and both the written and dictated discharge summary (when available).
Discrepancies among the medical records for a given subject were reconciled according to the following predefined rules. If one or more source listed a given condition in the patient’s past medical history, it was recorded as present; otherwise, it was recorded as absent. When determining the duration of symptoms, the most specific time of onset recorded by any provider was used (i.e., 9 AM instead of “this morning”). If two sources had equal specificity, then the later time was recorded. When nonspecific times of the day were all that was available, preassigned times were used as follows—“last night” = 8 PM, “this morning” = 8 AM, or “this afternoon” = 2 PM.
The duration of symptoms was defined as the duration of time between the onset of symptoms for which the patient presented to the ED and arrival in the ED. For example, if the patient had worsening chest pain for 2 days, and eventually came to the ED, the duration of symptoms was defined as 2 days. However, if a patient had shortness of breath for one week and developed chest pain 3 h prior to arrival, the duration of symptoms was recorded as 3 h.
ECGs were recorded as either diagnostic or non-diagnostic of ischemia. ECGs were considered diagnostic of ischemia if they were recorded by the treating physicians as having any one of the following, not known to be old: >0.2 mV ST depression in 2 or more contiguous leads, >0.1 mV ST elevation in 2 or more contiguous leads, or a left bundle branch block.
Data was analyzed using descriptive statistical analysis.
Five thousand five hundred and ninety-six patients presenting to the ED during the study period that had at least one TnI obtained. One thousand and eighty-six patients did not have a second TnI obtained and were therefore excluded. Of the remaining 4,510 patients, 4,208 (93.3%) did not have any TnI levels greater than 0.6 ng/mL. This left a total of 302 (6.7%) patients that had at least one TnI value ≥0.6 ng/mL. Of these 302 patients, 187 (61.9%) had an initial troponin I value that was ≥0.6 ng/mL and were therefore excluded from analysis. The remaining 115 patients were the group of patients who had at least two TnI values obtained, with the first value <0.6 ng/mL and at least one subsequent value ≥0.6 ng/mL. These patients comprised the study population (Figure
Ninety (78.2%) patients had their positive troponin drawn within 8 hours of the first sample. Of the remaining 25 patients that required >8 hours, 11 were not positive until three or more TnI values were obtained.
The characteristics of the study population including age, gender, race, and significant past medical history are listed in Table
Characteristics of patients in the study group.
Age, y (%) | |
---|---|
20–29 | 4 (3.5) |
30–39 | 5 (4.3) |
40–49 | 17 (14.8) |
50–59 | 22 (19.1) |
60–69 | 25 (21.7) |
70–79 | 20 (17.4) |
80–89 | 17 (14.8) |
90–99 | 5 (4.3) |
Gender (%) | |
Male | 62 (53.9) |
Female | 53 (46.1) |
Race (%) | |
African American | 55 (47.8) |
Hispanic | 26 (22.6) |
Caucasian | 18 (15.7) |
Asian | 9 (7.8) |
Other | 7 (6.1) |
Past Medical History (%) | |
Hypertension | 81 (70.4) |
Diabetes | 41 (35.7) |
Prior myocardial infarction | 41 (35.7) |
Hyperlipidemia | 33 (28.7) |
Congestive heart failure | 30 (26.1) |
Prior stroke | 16 (13.9) |
Prior cardiac catheterization | 12 (10.4) |
Chronic kidney disease | 9 (7.8) |
Prior CABG | 6 (5.2) |
Family history of early myocardial infarction | 6 (5.2) |
Substance abuse (%) | |
Tobacco | 38 (33.0) |
Cocaine | 19 (16.5) |
Alcohol | 14 (12.2) |
Injection drug use | 1 (0.9) |
CABG: coronary artery bypass graft.
Table
Presenting characteristics of the study population.
Arrival (%) | |
---|---|
Medical code | 47 (40.9) |
Trauma activation | 9 (7.8) |
Presenting symptom (%) | |
Chest pain | 50 (43.5) |
Shortness of breath | 35 (30.4) |
Altered mental status | 10 (8.7) |
Cardiac/respiratory arrest | 8 (7.0) |
Syncope | 4 (3.5) |
Other | 12 (10.4) |
Duration of symptoms, h (%) | |
≤1 hr | 61 (53.0) |
>1 hr–≤4 hr | 22 (19.1) |
>4 hr–≤8 hr | 7 (6.1) |
>8 hr–24 hr | 10 (8.7) |
>24 hr | 15 (13.0) |
ECG diagnostic of ischemia (%) | |
Yes | 38 (33.0) |
No | 77 (67.0) |
Ongoing symptoms (%) | |
Yes | 109 (94.8) |
No | 6 (5.2) |
ACLS (%) | |
Cardioversion | 8 (7.0) |
Chest compression | 8 (7.0) |
Code drugs | 9 (7.8) |
ACLS: advanced cardiac life support.
Selected details regarding the hospital course of these 25 patients are presented in Tables
Outcomes of the study population.
Workup/treatment (%) | |
---|---|
Cardiac Catheterization | 21 (18.3) |
Stress test | 17 (14.8) |
Thrombolysis | 12 (10.4) |
Primary diagnosis (%) | |
NSTEMI | 39 (33.9) |
STEMI | 16 (13.9) |
CHF exacerbation | 9 (7.8) |
Arrest | 8 (7.0) |
Tachydysrhythmia | 5 (4.3) |
Pulmonary embolism | 5 (4.3) |
Pneumonia | 3 (2.6) |
Pulmonary edema | 3 (2.6) |
Intracranial hemorrhage | 3 (2.6) |
Sepsis | 3 (2.6) |
Gastrointestinal bleed | 3 (2.6) |
Syncope | 3 (2.6) |
Hypertensive emergency | 2 (1.7) |
Stroke | 2 (1.7) |
Other | 9 (7.8) |
Death (%) | |
Yes | 14 (12.2) |
STEMI: ST segment elevation myocardial infarction, NSTEMI: non-ST segment elevation myocardial infarction, CHF: congestive heart failure.
Selected details of 25 patients with an initial troponin value <0.6 ng/mL, any subsequent troponin value ≥0.6 ng/mL, and ≥8 hours of symptoms.
Age gender | Chief complaint | Duration of symptoms | Initial troponin ng/mL | Peak troponin ng/mL | ECG diagnostic | Diagnosis primary, secondary |
---|---|---|---|---|---|---|
61 F | SOB | 2 weeks | <0.06 | 0.74 | No | Asthma exacerbation |
69 M | SOB | 3 days | <0.06 | 0.9 | No | Pleural effusion |
75 F | Chest Pain | 1 day | <0.06 | 6.49 | No | ACS-NSTEMI, pneumonia |
49 M | Rib Pain | 2 weeks | <0.06 | 1.92 | No | Pneumonia, cocaine abuse, and atrial Fibrillation |
22 M | Abdominal Pain | 1 week | 0.06 | 0.79 | No | Hypertensive emergency, renal failure, and cocaine abuse |
82 F | SOB | 3 days | 0.06 | 2.38 | Yes (LBBB) | ACS-NSTEMI, CHF exacerbation |
81 M | “feeling lousy” | 10 hours | 0.06 | 8.24 | Yes (STD) | Bacteremia, pneumonia, and ACS-NSTEMI |
73 F | SOB | 1 day | 0.08 | 0.87 | No | CHF exacerbation and ESRD |
70 F | Abdominal Pain | 3 days | 0.14 | 1.64 | No | Acute cholecystitis |
60 M | SOB | 3 days | 0.17 | 1.34 | No | CHF exacerbation and Pneumonia |
38 M | Chest Pain | 2 days | 0.17 | 2.32 | No | ACS-NSTEMI |
38 F | SOB | 1 day | 0.19 | 1.47 | No | CHF exacerbation and cocaine abuse |
74 M | Chest Pain | 10 hours | 0.22 | 1.24 | Yes (STE) | ACS-NSTEMI |
64 F | Chest Pain | 12 hours | 0.22 | 16.39 | Yes (LBBB) | ACS-NSTEMI |
48 M | Chest Pain | 8.5 hours | 0.24 | 3.99 | No | ACS-NSTEMI |
60 M | Chest Pain | 4 days | 0.25 | 3.30 | No | Gastrointestinal bleed |
54 M | SOB | 1 day | 0.31 | 0.89 | No | Pulmonary embolism and cocaine abuse |
70 F | SOB | 1 week | 0.31 | 0.7 | Yes (LBBB) | CHF exacerbation |
73 F | SOB | 18 hours | 0.35 | 1.13 | No | Pulmonary embolism |
50 M | SOB | 2 weeks | 0.43 | 0.76 | No | CHF exacerbation, cocaine abuse, emphysema |
75 F | Chest Pain | 1 day | 0.45 | 0.91 | No | ACS-NSTEMI |
67 F | Chest Pain | 4 days | 0.48 | 1.12 | No | ACS-NSTEMI |
64 M | Chest Pain | 2 days | 0.48 | 3.56 | No | ACS-NSTEMI |
49 F | Found Down | 22 hours | 0.56 | 0.94 | No | Mechanical fall, closed head injury |
83 F | SOB | 2 days | 0.58 | 0.66 | No | Pneumonia |
ACS: acute coronary syndrome, NSTEMI: non-ST segment elevation myocardial infarction, CHF: congestive heart failure.
Although 0.6 ng/mL is considered the “cutoff” for the diagnosis of acute MI, the 99th percentile of the upper limit of the TnI reference range for a healthy population is 0.06 ng/mL—an order of magnitude lower than the cutoff for AMI. Forty-eight (41.7%) patients of the 115 in the study had an initial troponin that was <0.06 ng/mL. Of those 48 patients with a true negative first troponin, only 7 patients had ≥8 hours of symptoms at the time of presentation.
Of all 4,510 patients that had more than one TnI value obtained, only 7 (0.16%) had ≥8 h of symptoms, an initial troponin <0.06 ng/mL and any subsequent troponin ≥0.6 ng/mL. Two of these 7 patients had an ultimate primary final diagnosis of acute coronary syndrome.
In 2006, the ACEP Clinical Policies Subcommittee published guidelines for the evaluation and management of patients with potential NSTEMI [
Although the new ACEP guidelines endorse a single negative troponin I or T for the exclusion of NSTEMI when measured 8 to 12 hours after symptom onset, there are only a few trials that have directly addressed this issue. In 1997, Hamm et al. evaluated 773 consecutive patients who presented with chest pain of <12 h duration and an absence of acute ST-elevation myocardial infarction (STEMI). Among all patients with a negative troponin I, obtained at least 6 hours after the onset of symptoms, the event (death or MI at 30 days) rate was 0.3% [
The first study to evaluate a single troponin in relation to symptom duration was a small prospective study of 267 patients presenting to an ED with suspected myocardial ischemia [
Although providers may be wary to discharge patients home after a single troponin I, there has been at least one retrospective chart review that looked at the results of 588 patients who were discharged home from the ED after a single normal cTnI was obtained 6–9 hours after symptom onset [
The appropriate diagnostic cutoff to use for a single
In our study, we identified 115 patients with an initial negative, but subsequent positive, TnI out of population of 4510 ED patients undergoing serial cTnI testing. Within this group, 25 patients (21.7%) presented with >8 h of symptoms. At first glance, this percentage seems to be unacceptably high to exclude myocardial infarction on the basis of initial troponin and symptom duration. However, one must take a closer look at the details of these 25 patients (Table
First, the new ECS-ACC recommended cutoff for the diagnosis of cardiac injury would have us use a much lower value of troponin than the ROC cutoff for AMI (i.e., 0.06 ng/mL instead of the current 0.6 ng/mL). 18 of our 25 patients who presented to the ED >8 hours after symptom onset had an initial TnI that was >0.06 ng/mL. In other words, those 18 patients had biochemical evidence of cardiac injury at the time of arrival, requiring at least one additional TnI level to further define their disease process. Many of these patients had nonischemic etiologies responsible for TnI elevation (Table
Elevations of troponin in the absence of acute myocardial ischemia.
Cardiac trauma—for example, contusion and post-surgical trauma |
Congestive heart failure |
Pulmonary embolism |
Chronic kidney disease |
Severe sepsis |
Large burns with or without rhabdomyolysis |
Acute stroke or subarachnoid hemorrhage |
Cardiac infiltrative disease (e.g., amyloidosis, hemochromatosis, and sarcoidosis) |
Cardiac inflammatory disease (e.g., myocarditis and pericarditis) |
Aortic dissection of valve disease |
Hypertrophic cardiomyopathy |
Cardiac dysrhythmia |
Of the remaining 7 patients with no biochemical evidence of cardiac injury on the initial troponin, two had a final primary diagnosis of ACS. The first was a 75-year-old woman with a history of diabetes, hypertension, and prior MI, who presented with a week of worsening chest pain, much worse “for one day” who presented with 10/10 pain. Her duration of symptoms was recorded as 24 hours, because no more specific mention of an onset was made. The other patient with an ultimate primary diagnosis of ACS was an 82-year-old female with a history of hypertension and heart failure who presented with 3 days of worsening shortness of breath. She had an LBBB on her initial ECG and an elevated initial myoglobin value. Both of these patients were high-risk patients who presented in extremis—neither of which would have been “occult” NSTEMIs missed by the new guidelines. It should be further noted that of these 7 patients, 5 of them were >60 years old with at least one other cardiac risk factor and the other 2 had recently used cocaine—risk factors or practices that would have declared them as high-risk patients who would typically be either admitted or at least subjected to serial serum cardiac testing to exclude AMI.
This study has several potential limitations that are typical of a retrospective study design. Although the study population itself was identified using a laboratory database, the remainder of the information was obtained from a medical record review. Two authors did the entirety of the data abstraction, which could call in to question both the quality and the reliability of the data. In addition, the abstractors were not blinded to the objective of the study during the data abstraction. We feel that although this is a potential source of significant bias, we took steps to limit this. For example, we queried our troponin database using a broad definition of “initially negative, subsequently positive” troponin. By using the 0.6 ng/mL cutoff for normal rather than 0.06 ng/mL, we were certain to catch all possible cases that could have been missed with a single troponin. In addition, when determining the duration of symptoms, we required a specific mention to be made of a time of onset, or else we accepted the much longer time that is implicated by statements such as “one day”, even if it was clear that the patient had continuing or progressively worsening symptoms upon arrival to the ED. This maximizes the number of possible patients with >8 hours of symptoms upon arrival, so that we would not miss any potential cases.
Another potential limitation to this study is the fact that 187 patients had a first positive troponin upon arrival. Given the possibility that these patients may have been seen in the 7 days prior and discharged home after a single troponin, we queried our ED tracking system and found that 18 of these patients had been seen in the week prior. Two of these 18 patients had been discharged home after a single negative troponin.
The use of a negative initial TnI together with a symptom onset of ≥8 hours prior to serum marker testing defines a population at very low risk for a near-term diagnosis of ACS. Although we believe that our data considered in conjunction with all of the prior studies addressing this topic suggest, it is safe to exclude MI on the basis of symptom duration and initial TnI, and further research is needed to better define the population to which this strategy can be applied. The next step will be a prospective observational study assessing the ability of the combination of duration of symptoms, single TnI with the new lower cutoff, and ECG to exclude the diagnosis of acute myocardial infarction. Patients will be subclassified using the new grading system for myocardial infarction whenever possible [