Emergency room triage of patients with acute chest pain by means of rapid testing for cardiac troponin T or troponin I

Authors Hamm C, Goldmann B, Heeschen C, Kreymann G, Berger J, Meinertz T.
Source New England Journal of Medicine. 337:1648-53. December 4, 1997. 
Institutions University Hospital Eppendorf, Hamburg, Germany
Support None indicated

Background

Myocardial injury, commonly assessed by CPK-MB levels, can be detected with greater sensitivity by assaying blood levels of the cardiac contractile proteins troponin T and I. These have been shown to have prognostic significance in the setting of acute ischemic syndromes, such as unstable angina. With the development of rapid bedside assays for these proteins, their use in the evaluation of chest pain in the emergency room becomes feasible. This study was designed to investigate the diagnostic and prognostic value of rapid bedside troponin testing in emergency room patients with chest pain and without ST-segment elevation on EKG. 

Methods

Patients

Patients were eligible if they presented to the emergency room of the University Hospital with less than 12 hours of anterior or left-sided chest pain, not explained by trauma or obvious abnormality on chest x-ray. 

Patients with ST-segment elevation or recent MI were excluded. 

Protocol

Troponin assays

Blood was obtained for troponin T and I assays within 15 minutes of arrival at the ER and again four hours later. For those patients who had arrived less than two hours after the onset of pain, a third sample was drawn 6 hours after the onset of pain (so that all patients had one sample drawn at least 6 hours after the onset of pain). 

A rapid, qualitative bedside assay for troponin T was performed on all samples and the results were immediately available to the treating physicians. 

Serum was centrifuged and frozen for quantitative troponin T measurement as well as for rapid qualitative and quantitative troponin I measurements. 

Other clinical data

Patients also had EKG's performed, blood drawn for CPK and MB fractions and history and physical examination recorded according to a protocol. 

After excluding patients with ST-segment elevation, the admission EKG was classified as: 

  • ST segment depression (with or without T-wave inversions) 
  • T-wave inversion only 
  • Nondiagnostic (paced or bundle branch block) 
  • Normal 
Follow-up and endpoints

MI at the time of admission was judged to be present if the CPK within 24 hours of admission was greater than twice the upper limits of normal with an elevated MB fraction. 

Patients were followed during hospitalization and for 30 days after discharge. Endpoints were death from cardiac causes and nonfatal MI (more than 24 hours after admission). 

 

Results

Patients and clinical diagnoses

870 eligible patients were screened between June, 1994 and March, 1996. There were 97 with ST-segment elevation, which left 773 study patients with chest pain but no ST-segment elevation. 

The final diagnoses were: 

  • Acute MI (by CPK): 47 patients 
  • Unstable angina: 315 
  • Stable angina: 121 
  • Heart failure: 15 
  • Pulmonary embolus: 12 
  • Myocarditis: 5 
  • No specific cardiovascular diagnosis: 258 
487 patients were admitted to the hospital (63%), 224 to the ICU. 
 

Qualitative and quantitative troponin tests

There was good correspondence between the rapid bedside assays and the quantitative assays -- 94.8% for troponin T and 98.7% for troponin I. There was only one false negative for troponin T and 5 for troponin I. 
 

Troponins and clinical diagnoses

Of the 773 patients, 16% had at least one positive troponin T result; 22% had at least one positive troponin I. Approximately 40% of patients with a positive test had a negative first sample. 

CPK-documented MI within the first 24 hours (47 patients): 

  • On admission, troponin T was positive in 51%, troponin I in 66%, CPK-MB was elevated in 53%. 
  • Four hours later, troponin T was positive in 94%, troponin I in 100%, CPK-MB in 91%
Unstable angina (315 patients): 22% had at least one positive troponin T; 36% had at least one positive troponin I; 5% had elevation of CPK-MB (presumably the total CPK did not rise enough to qualify for acute MI). 

Other diagnoses:

  • CHF: 1 positive troponin T, 5 positive troponin I 
  • PE: 1 positive troponin T, 2 positive troponin I 
  • myocarditis: 1 positive troponin T, 2 positive troponin I 
  • unexplained chest pain: 1 positive troponin I 
False positives

Seven patients had an elevated troponin T but normal troponin I; these were considered to be false positives. Six of these patients also had renal failure. 
 

EKG and troponins

  • Normal EKG was present in 331 patients (43%). At least one positive troponin test (both T and I) was present in 10% of these. One of the 47 myocardial infarctions on admission was in this group. 
  • Non-diagnostic EKG (paced or bundle branch block) was present in 87 patients (11%). The percentage of positive troponin T and I tests in this group was 32% and 47%, respectively. Of the 47 myocardial infarctions, 23 were in this group. 
  • ST-segment depression was present in 158 patients (20%). The percentage of positive troponin T and I tests was 32% and 56%. There were 8 myocardial infarctions in this group. 
  • T-wave inversions only were present in 197 patients (25%). Positive troponin T and I tests were present in 6% and 5%. There were 15 myocardial infarctions in this group. 
Troponin and events during follow-up

There were 20 deaths from cardiac causes during the follow-up period (11 in hospital and 9 after discharge). The troponin T test was positive in 16 out of these 20 patients; troponin I was positive in all but one. 

Myocardial infarction after admission occurred in 14 patients (9 in hospital, 5 after discharge). Troponin T was positive in 11 and negative in 3. Troponin I was positive in 13 and negative in 1. 

For the 34 total events, troponin I was positive in 32 and negative in 2. Troponin T was positive in 27 and negative in 7. The EKG was normal in 5 and abnormal or nondiagnostic in 29. 

In the 331 patients with a normal EKG, there were 5 events. Four of these had an abnormal troponin T, all 5 had an abnormal troponin I. 

The overall event rate for patients with negative troponin T was 1.1%, and for negative troponin I 0.3%. Troponin T and troponin I provided additional prognostic information, after EKG status and CPK-MB were taken into account. 

Author's discussion

The authors state that "the primary aim of this study was to demonstrate that two negative test results on admission and four hours later (or at least six hours from the onset of chest pain) allow safe early discharge". Patients with two normal troponin measurements had a low rate of cardiac events within 30 days (1.1% for troponin T; 0.3% for troponin I). 

They note that patients with one positive result should be admitted and evaluated further, and that a single test on admission is not sufficient. They feel that the slightly higher sensitivity of the troponin I test "may be related to different release kinetics and different limits of detection of the versions of the test that are currently available". They also feel that the six false positives seen in patients with renal failure may reflect a true difference between the troponin T and I assays. 

Editorial

In an accompanying editorial, Dr. Mark Hlatky from Stanford University reviews the problem of the evaluation of chest pain in the emergency room. He makes several important points about this article: 
  • Patients with a positive troponin test who were classified as unstable angina could also be classified as "small myocardial infarctions". 
  • Since no details about the clinical history were given, it is not possible to determine the risk of events in clinically high-risk subsets with negative troponin tests. 
  • The results obtained here only apply when at least two samples are obtained, with one sample at least 6 hours after the onset of chest pain. 
  • Among patients with ST-segment depression, the event rates with negative troponin T and I were 2.8% and 1.4%, not negligeable numbers. 
 

Comment

This was a study of 773 patients evaluated in an emergency room for chest pain without ST-segment evaluation. Patients underwent troponin T and I determination; the troponin T results were immediately available and all patients with a positive test were admitted. Patients with negative troponin tests had a good prognosis -- the event rate (cardiac MI or death) within 30 days was 1.1% for patients with a negative troponin T test and 0.3% for patients with a negative troponin I test. 

In addition to the limitations noted in Dr. Hlatky's editorial, there is another problem with the study that greatly limits its applicability, in my opinion. Of the 773 patients, 487 were admitted to the hospital, the vast majority with a diagnosis of unstable or stable angina. Overall, 123 patients had at least one positive troponin T test and 171 had a positive troponin I test. This means that at least 364 patients were admitted to the hospital with negative troponin T tests and at least 316 with negative troponin I tests. 

Thus, a large number of patients with negative troponin tests were admitted to the hospital, mainly with the diagnoses of unstable and stable angina, and presumably received treatment for this. Their good prognosis could be in part related to in-hospital therapy (such as heparin), not only to their negative troponin tests. 

Although we can conclude that patients who are appropriately treated (including hospitalization) have a good prognosis with negative troponins, we cannot conclude from this study that it is safe to discharge patients from the emergency room, even with normal EKG's and negative troponin tests, since so many patients in this study were, in fact, hospitalized. We do not know how they would have fared had they been discharged from the emergency room. 

The objective of this study, according to the authors, was to demonstrate that "two negative test results on admission and four hours later (or at least six hours from the onset of chest pain) allow safe early discharge". This has not yet been persuasively accomplished, in my opinion. 

December 20, 1997 


References

References related to this article from the NLM's PubMed database. 


Reader Comments

Date: Sun, 21 Dec 1997
From: "Mark Leber" <besterdoc@email.msn.com> 

I feel that the paper contributes to improving accuracy in ruling out cardiac chest pain in the emergency room. If serial troponin I can predict greater than 99% of cardiac events within 30 days, then we could discharge patients more quickly from the emergency room, especially patients who are weak rule outs. 

I agree that a prospective trial is needed to determine what combination of tests should be done (serial cpk mbs, serial troponins and serial ekgs) to best r/o cardiac events, since the troponin study was done in isolation of the other modalities ordinarily used. Also, it would be interesting to know how often troponins agreed with serial cpk mbs and ekgs. 

Mark Leber,M.D. 
 
 

    If the troponin I test should turn out to perform with a sensitivity of 99% for subsequent events, then it will be useful for the ER evaluation of "soft rule-outs". I don't believe this has been proven, yet. 

    The troponin tests are more sensitive than CPK-MB's, and more specific than the EKG. In multivariate analysis (table 4 in the article), troponins did add a significant amount of prognostic information to that derived from CPKs and from the EKG, separately and in combination. -- mj 


January 11, 1998 

I received the following letter from Dr. Christian Hamm, corresponding author of this study. 
 

Dear Dr. Jacobson, 

Thank you for considering our paper on troponins for your internet journal club. 

I appreciate your comments and agree that discharge of patients based on 2 biochemical tests requires further validation. However, you may have overlooked that troponins are much better parameters than CK, ECG or the clinical evaluation (see table 4). Please read our position which is clearly stated in the discussion: "bedside tests for troponin T and troponin I result in more accurate diagnoses than do previous more time-consuming methods and allow safer and more rapid decision making for most patients with acute chest pain." 

I share your concerns with respect to a possible influence of hospital admissions of troponin negative patients on the prognosis. However, there is no evidence at all that any therapy today has influence on the inhospital outcome even of troponin positive patients. Moreover, if you refer to table 1 you may appreciate that most events occurred after discharge in troponin positive patients. Therefore, your point is well taken but plays very likely no major role. The answer could only be given, if you randomize patients with negative tests to hospitalization and discharge. In my view, this is, however, a very unrealistic study design. Again, I like to refer to our discussion which states: "The troponin test cannot replace the clinical evaluation of the patient with chest pain." 

Thanks again for interesting comments. 

With kind regards, 

Christian W. Hamm, M.D. FACC 
Associate Professor of Internal Medicine and Cardiology 
 
 

    I am grateful to Dr. Hamm for these clarifying comments. I agree that this study supports the notion that troponin tests provide useful prognostic information, over and above the EKG and traditional cardiac enzymes. 

    My main concern is that negative troponin tests should not be used to justify discharging patients from the ER who have a good history for unstable angina. We seem to agree on this point as well. 

    -- mj 


Date: Thu, 29 Jan 1998
From: johann steurer <polstf@usz.unizh.ch> 

I don`t understand why the patients with a myocardial infarction within 24 hours after hospitalisation were excluded from the final analysis of the results?? 

J.Steurer MD, Zürich
www.evimed.ch 
 
 

    Patients with a myocardial infarction within the first 24 hours were excluded from analysis for the endpoint of recurrent MI only. This makes sense, since they are not recurrent infarctions but, rather, presented initially with an infarction. -- mj 


In the April 30, 1998 New England Journal of Medicine are several letters to the editor about this study, two of which raise the same points that were raised here.


Date: Wed, 10 Mar 1999
From: TOPFL54@aol.com

Dr. Jacobson,

At first I was quite skeptical about the use of troponins in determining who can safely go home from the ER. However over the past several months I have routinely ordered  troponin I in all of my chest pain patients and it is quite good in discriminating acute coronary syndromes from non cardiac causes. It is always elevated in my non q wave MI' s, frequently in my people with unstable angina with or without ecg changes (who subsequently have coronary disease on invasive studies) and never in those who subsequently do not have coronary disease.

I am aware that my experience is limited and anecdotal but when I combine a negative spect technetium sestamibi and a normal troponin in a patient with a normal or non diagnostic EKG I can comfortably send them home in 12-24 hrs with further followup. The insurance companies are rapidly putting pressure on us to "fast track" these patients who do not have acute ischemic syndromes and while I abhor this intrusion I dont think it will abate. However in patients where my clinical suspicion is not high, the EKG is not overtly ischemic and the troponins plus the spect technetium is non-ischemic I can usually get them home if not from the ER then in 6-12 hrs from our observation bed and feel comfortable albeit not arrogant that they will not have a life threatening event.

John D. Vance MD
 
 

This brings up a point that applies to many, if not most, studies: their frequent use for supporting an "agenda", in addition to their official purpose of furthering medical knowledge.  The ability to improve our diagnostic efficiency with regard to cardiac ischemia will certainly be used (and misused) to cut costs in the ER.  -- mj


Date: April 28, 1999
From: Kareena, ED Nursing [ED_Nursing.Kareena@hcoa.maynick.com.au]

Dear Dr Jacobson, 

As commentary on letter by Dr Vance. There is no logic in using a one off troponin test as back-up support to discharge a patient with non-diagnostic EKG if the troponin is done too early. My reading of recent literature suggests you must wait at least 6 hours from onset of pain. 

I wonder if Dr Vance is drawing the troponin level at the beginning or at the end of his period of observation.

Additionally I am seeing a number of articles in the last 12 months that seem to indicate troponin is not superior to CK-MB, especially CK-MB sub forms. Although we have switched to troponin at my hospital I feel the jury is still out.
 

Dr Paul Cunningham FACEM
Concord Hospital, Sydney Australia
 

Clearly, the troponin can't be used to send home a patient if drawn too soon after the onset of chest pain.  It is easier to perform at the bedside and may be somewhat more sensitive than the CK, however, and thus could be used to justify admitting a patient whose story is otherwise not very convincing.  -- mj



Date: June 6, 1999
From: John Vance [jdvmd54@worldnet.att.net]

Dr. Jacobson,

In response to Dr. Cunninghams letter. First I perform a Troponin I at least 6 hours after the onset of chest pain. Secondly I never discharge a patient based solely on a normal troponin. They are usually in an observation unit undergoing clinical assesment, further ekgs, serum markers and usually a technetium sestamibi scan. They are then discharged usually in 12 hrs if the troponins AND the nuclear scan are BOTH normal. My comments were related to my impression that so far troponins have been an excellent predictor of cardiac events. However I am not using a normal level to justify discharging a patient from the ER. I do think that if a clinician combines a good history with the ekg, serum troponins, nuclear scans and clinical judgement he/she can safely discharge those patients with a negative workup. However if my "gut" says otherwise I will keep them in house longer regardless of the initial workup. Nonetheless for most of my chest pain patients with an "atypical" history and normal or near normal ekgs the above protocol has been very useful and so far successful. 

John D. Vance MD
 
 


January 24, 2000
John Guiang [iqguiang@egis.net]

Greetings!

I have recently come across this issue of using Troponin assays to screen patients at the ER. In our hospital, the Troponin T assay is available, however it takes some time before the results come out. This, along with CPKs and EKGs are all done at the ER. The parameters we use to decide whether to admit a patient for observation or not are only the ECG and the patient's clinical history. Convincing history seems to carry the greatest weight of all the available diagnostics. What I mean is, we will always admit a patient with a very clearcut history and profile even if the ECG, enzymes, and Troponins turn out to be negative at the ER. We may not even proceed to do the assays if the history was not convincing enough, and that's the time we send someone home from the ER. Moroever, we also have to consider cost as another factor that carries a lot of weight.

Isauro Q. Guiang, Jr. MD
Internal Medicine
Philippines


January 24, 2000
makeitso [makeitso@gateway.net]


While doing some research online, I came across your interesting article. My area of concern is false positive troponin I tests. In our laboratory we use two instruments for troponins, the Bayer Immuno 1 and the Abbott Axsym. Recently our pathologist and cardiologists have brought a few cases of elevated troponins to my attention, where the other markers (ekg, ck total, ckmb and so on) don't warrant an elevated troponin. Mechanical and tech error have been eliminated and I need to find out other causes of false positives. Both manufacturers assure me their technology is not to blame but interfering substances and other medical factors must be affecting the assays. Any help you can offer would be appreciated.

Thank you

Bree Ann Boroff MT 

I assume renal failure was not the problem.  Anyone else come across this problem?  -- mj


November 17, 2001
The following comments were received over the past few months.  I am posting them now.

 

Date: June 14, 2001
From: Pete Chamlis [chamlis-p@mail.tmh.org]

Regarding the issue of "false positive" troponin-I results obtained from the Abbott AxSym...

There is a lot of discussion throughout the field of medical technology about the need to re-evaluate the "cut-off" point for a positive troponin I. It is pretty much common thought that the AxSym cut-off suggestion of 2.0 ng/ml is certainly calling positive some patients who are not. Although, expensive, the rapid bedside Cardiac Status test from Spectral labs seems to do a good job of matching result to patient condition. We're re-evaluating our AxSym cutoff point using the Spectral kit, along with chart and progress review.

Pete Chamlis,
Tallahassee, FL
chamlis-p@mail.tmh.org

Also, any comments that any pathologists or physicians out there might have regarding updated Troponin T testing (on the Roche Elecsys) vs Troponin I would be appreciated. Please feel free to privately email me, as well as posting to the board.


Date: August 2, 2001
From: nabila.babar@cinhlthe.rcc.org

Responding to Bree Ann Borof's comments from Jan. 2000, I have faced similar problems in at least three of my patients.  One of them had elevated creatinine of 2.4 but the other two did not.  In both of these two, CPK's were negative, history was atypical and repeat troponin was negative.  So I do not know what the real significance of troponin is.

 


Date: August 4, 2001
From: tjrahaim@mindspring.com

A 20% false positive is high but what is the false positive in mammo?


It's true that all tests have false positive and false negative rates.  But it is hard to compare these rates in settings that are so different -- screening for malignancy and ruling out myocardial infarction in the ER.  The costs and consequences of false positives and false negatives are very different and would need to be taken into account in any comparison.  --mj


Date: September 28, 2001
From: P. Smith, RN [biscuit54@hotmail.com]

In response to the request for more info regarding falsely elevated Troponins I, have one case study that is baffling. It is a 28y female with elevated Troponin I, negative CK-MB, negative EKG, negative history other than recent history of atypical and reproducible chest pain. In addition, this patient had normal renal function. Errors in performance and technique were ruled out. I am currently searching for more information about falsely positive Troponins and would be interested in any insight you can offer.

Sincerely, P. Smith, RN


Date: November 6, 2001
From: No valid return email address or name received

We have changed our specimen requirement to green top tubes (na heparin) to eliminate false positive due to fibrin clots. In cases where the green top is not available an extra spin is done before assaying for troponin.Our methodology is the Axsym. lg
 

 


December 27, 2001
From: Olawale Ogunnuga MBChB [olawaleo@hotmail.com]

Causes of raised Troponin T/I include

Severe Renal Dsease 
Pulmonary Emboli 
Pericarditis 
Cardiomyopathies 

The last two causes probably due to concomitant mild cardiac damage. Ref. JAMA, November 21, 2001-Vol 286, No 19

Olawale Ogunnuga MBChB

The reference in JAMA, particularly the editorial in this issue, gives a good summary of some of the issues involved with Troponin testing.  --mj


 

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