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WRHA Emergency Medicine Program Diagnostic Services of Manitoba Cardiology Program

Troponin T 6 hour testing guideline
in low likelihood for ACS patients

June 1, 2007

FRCPC Head of Cardiology Director of Echocardiography Health Sciences Centre and St. James Tam. FCACB Medical Director.0 June 1. John Sokal. 2007 (180068975. Standards Committee WRHA Emergency Medicine Program Assistant Medial Director. PhD. Boniface General Hospital Abbreviations: AMI AUC CAD CRF CV ED ESC/ACC LOS MR NLR NPV NSTEMI ROC STEMI th ile TnI TnT acute myocardial infarction area under the curve coronary artery disease chronic renal failure coefficient of variation emergency department European Society of Cardiology / American College of Cardiology length-of-stay mitral regurgitation negative likelihood ratio negative predictive value non-ST segment elevation MI receiver operating curve ST segment elevation MI percentile troponin I troponin T Versions: 1. CCFP (EM) Chairperson.Prepared by: Dr.doc) 2 . Department of Emergency Medicine Health Sciences Centre Dr. Clinical Biochemistry and Genetics Diagnostic Services of Manitoba Dr. Laurel Thorlacius.

4. Discontinue the routine measurement of myoglobin. A rising TnT level is required in order to diagnose AMI. 8.doc) 3 . Do not utilize cardiac serum marker tests to exclude unstable angina.OVERVIEW 1. sample two at 8 hours).g. In patients with a low likelihood of ACS: ⇒ ⇒ TnT must be measured at least six (6) hours after the onset of chest pain. TnT measurement may be deferred until six (6) hours after the onset of pain. AMI may be safely ruled-out in patients with a low likelihood of ACS. patients with CRF). 2.g. 7. ⇒ ⇒ If TnT measured > six (6) hours is negative. No single serum marker used alone has sufficient sensitivity or specificity to reliably identify or exclude AMI within 6 hours after symptom onset. Document the time of onset of chest pain on all patients. CK. 5. In patients with background elevations of TnT (e. 6. (180068975. and CK-MB as cardiac markers for the rule-out of AMI in the ED. two (2) measurements are required to demonstrate a rising pattern. TnT samples may be measured two (2) hours apart when measured at least 6 hours after the onset of chest pain (e.01 ug/L or and not rising on 2 samples measured at least 2 hours apart and in context of alternate etiology for elevated troponin 3.01 ug/L ⇒ > 0. sample one at 6 hours after the onset of pain. TnT is considered negative: (when measured > 6 hours after the onset of chest pain) ⇒ < 0.

g.99% likelihood) known history of prior AMI or CAD “definite angina” in males > 60 or females > 70 transient hemodynamic or ECG changes during pain ST elevation or depression > 1 mm Marked symmetrical T-wave inversion in multiple leads UCLA 2005 Chest Pain and ACS Patient Management Guideline See Appendix B: WRHA algorithm for the management of patients with suspected ACS in the ED See Appendix C: Likelihood that signs and symptoms represent an ACS (180068975. 2006) • For the definition of unstable angina. Assess Likelihood of ACS: Low Likelihood (e.14% likelihood) chest pain. 15% . “probably not angina” in patients with one or no risk factors for CAD.84% likelihood) “definite angina” in patients with no risk factors “probable angina” in patients with one or more risk factors “probably not angina” in patients with diabetes or with two or three other risk factors patients with extracardiac vascular disease ST depression 0.doc) 4 .5 – 1 mm T-wave inversion > 1 mm High Likelihood (e.Recommended TnT testing protocol for a patient with a low likelihood of ACS ⇒ Do not utilize cardiac serum marker tests to exclude unstable angina. but not diabetes T-wave flat or inverted < 1 mm normal ECG Intermediate Likelihood (e. 85% .g.g. 1% . ⇒ If the time of onset of chest pain is not known. see appendix A ⇒ Document the time of onset of chest pain on all patients. (ACEP NSTEMI Clinical Policy. then the time of presentation must be utilized for cardiac marker interpretation.

⇒ In most situations.doc) 5 . allowing detection of small amounts of myocardial necrosis that would have gone undetected by creatine kinase and its MB fraction (Roger. ⇒ An increased value for troponin should be defined as a value that exceeds the 99th ile in a reference control group.ESC/ACC Diagnostic Criteria for Acute Myocardial Infarction Diagnostic Criteria for AMI (one of following criteria): Typical rise and fall of biochemical markers of myocardial necrosis (troponin or CK-MB) with at least one of the following: a. 2005). 2006).high risk STEMI low probability Cannon – Circulation 2003 (180068975. elevated values for troponin should be recorded from two successive blood samples to diagnose AMI. b. diabetes ST-T wave changes ongoing pain ST elevation positive low risk medium . Troponins have replaced CK-MB as the preferred biochemical markers for the diagnosis of AMI (Roger.WHO Diagnostic Criteria for AMI • Troponins are more specific than other biomarkers in detecting myocardial injury with associated skeletal muscle injury and have a higher sensitivity. Korff. d. • • Algorithm for risk stratification of patients with unstable angina and NSTEMI non-cardiac chest pain stable angina unstable angina NSTEMI STEMI Clinical finding ECG TnT Risk assessment atypical pain exertional pain negative negative rest pain. c. 2006. 2006). ischemic symptoms development of pathologic Q waves ECG changes indicative of ischemia coronary artery intervention ⇒ Troponins are the preferred biomarker for myocardial damage. Myocardial infarction redefined – J Am Coll Cardiol 2000 See Appendix D . post-AMI. The criteria acknowledge that elevations in biomarkers are fundamental to the diagnosis of AMI because symptoms may be atypical or nonexistent and ECG changes may be absent or nonspecific (Babuin.

03ug/L have low positive predictive values. It is important to realize that the TnT assay does not have a CV less that 10% for values less than 0. two (2) measurements are required to demonstrate a rising pattern.03 ug/L. A rising TnT level is required in order to diagnose AMI.How do you interpret TnT results? Interpretation of TnT values Troponin value Below detection limit of assay Between detection limit (99th ile) and functional sensitivity (10% CV) Above functional sensitivity • • TnT (ug/L) < 0. The fact that any troponin elevation exceeding the 99 th ile is associated with an increased cardiac risk (Venge. Lindahl. In patients with background elevations of TnT (e. consider alternate etiology for elevated troponin (see Appendix A) Myocardial necrosis . patients with CRF).03 • Interpretation AMI can be ruled out repeat TnT at least two (2) hours after previous sample ⇒ if not rising.03 ug/L .01ug/L and 0. resulting in a considerable risk for diagnostic misclassification. measurements are repeatable Interpretation No myocardial necrosis Possible myocardial injury.AMI is unlikely.01 – 0. However. (180068975.g.01 0. 2001) is reflected by the recommendation of this cutoff for diagnostic purposes (ESC/ACC diagnostic criteria for AMI).03 For the 4th generation Troponin T. But if clinical suspicion remains high.03 ug/L. repeat after two (2) hours NSTEMI when seen in the context of suspected ACS 0.01 ug/L and the 10% CV is 0. a third TnT may be considered.probable NSTEMI in setting of ACS If the repeat is less than 0. the etiology may be other than ACS See Appendix E for the differential diagnoses of an elevated troponin. TnT is specific for heart cell damage . 2002.doc) 6 .03 > 0.01 0. in the context of suspected ACS. • • • • • In order to rule-out AMI in a patient with a low likelihood of ACS: • TnT must be measured at least 6 hours after the onset of chest pain. Values between 0.03 > 0. the 99th ile is 0.01 to Comment Undetectable by assay method Troponin present and can be distinguished from background but cannot be quantified repeatedly at this level Definite myocardial necrosis.any detectable level indicates myocardial damage. TnT (ug/L) > 6 hour value < 0.

ECG abnormalities.No Should TnT always be performed at the time of ED presentation? • For patients with low likelihood of ACS. the diagnostic value of a TnT drawn at the time of ED presentation (which is often less than 2 hours after the onset of chest pain) is very low and very unlikely to permit earlier consultation and/or admission decisions. or intermediate to high clinical suspicion. immediate treatment for presumed ACS should take place. Consider discharge of patients with low likelihood of ACS if all of the following are met: • • • no recurrent chest pain no ECG changes negative TNT measured six (6) hrs after the onset of chest pain TnT is considered negative: (when measured > 6 hours after the onset of chest pain) ⇒ < 0. In patients with recurrent chest pain. ⇒ When the time from onset of symptoms was included in the specimen selection algorithm. The TnT measurement may be deferred until six hours after the onset of chest pain.01 ug/L ⇒ > 0. or to improve ED throughput. In these cases.doc) 7 . when a negative TnT test result may be most helpful. including prompt consultation when appropriate. performing TnT earlier than six hours may be permissible. a one hour interval between troponin samples was sufficient provided that at least one specimen was collected > 6 hours after the onset of chest pain. • What is the rationale for two hour intervals between TnT samples? • A recent study (MacRae. 2006) provided support for measuring TnT at six (6) hours after onset of chest pain and for two (2) hour intervals between TnT samples: ⇒ A troponin (TnI) assay in specimen sets having one specimen > 6 hours after the onset of chest pain gave an AMI prevalence equivalent to the AHA definition.01 ug/L or and not rising on 2 samples measured at least 2 hours apart and in context of alternate etiology for elevated troponin (180068975.

2 (96. TnT sample 2 was drawn at six (6) hours from the onset of chest pain and at least two (2) hours after sample 1.989 (0. with a negative predictive value (NPV) > 99.2) < 0. AMI may be safely ruled-out in patients with a low likelihood of ACS. 2004).999 – 1. Use of a single marker such as myoglobin for the evaluation of chest pain should be avoided – a positive result only leads to additional lab testing because confirmation by a more definitive cardiac marker (troponin) will be needed (Eggers. In this study.3 (97.4-99.Annal Clin Biochem 2006 • • • TnT sample 1 was drawn at the time of presentation.02 99.000) after 6 hrs Interpretation: If TnT measured > 6 hours is negative.966 – 1.No Can single markers be utilized to safely rule out AMI less than 6 hours after the onset of chest pain? • • • No single serum marker used alone has sufficient sensitivity or specificity to reliably identify or exclude AMI within 6 hours after symptom onset (ACEP 2006 NSTEMI Clinical Policy). The ACEP 2006 NSTEMI Clinical Policy refers only to an option of performing myoglobin in conjunction with a more definitive cardiac marker (a level B recommendation).000) 98 (89. the optimal decision threshold from the ROC curves for TnT was 0.9) 98.001 100 1.doc) 8 .1 – 99.6 – 99.02 ug/L) Negative Likelihood Ratio Negative Predictive Value % AUC (95%CI) Specificity % (95%CI) 6 to 12 hrs after the onset of chest pain all times 100 (90. No Can TnT be utilized to safely rule out AMI less than 6 hours after the onset of chest pain? There are no published studies that demonstrate that AMI can be safely ruled out using TnT measured at less that six hours after the onset of chest pain.02 ug/L. ⇒ The sensitivity of TnT (0. YES Can TnT be utilized to safely rule out AMI > 6 hours after the onset of pain? Collinson P . (180068975.02.000 (0.1) 0.9 0.02ug/L cutoff) exceeds 98% if measured at least six (6) hours after the onset of chest pain.100) 98. 6 hour Troponin T measurement TnT sample 2 was drawn: only between Sensitivity % (95%CI) (TnT 0.9% and a negative likelihood ratio (NLR) of 0.7 .

the median time of presentation after the onset of chest pain was 4. • All AMI’s were diagnosed within 90 minutes of presentation: 100% sensitivity. Therefore. 98% of patients were male.Am J Cardio 2004 • This is the same study of population as McCord.3%. CK-MB.25).doc) 9 . TnT alone has a sensitivity for the detection of AMI of >98%. and 40% of patients were discharged without complete recording of outcome. and TnI in concert with clinical history and ECG. At six hours after the onset of chest pain. • Even in patients with an onset of chest pain less than four hours before presentation.Ann Emerg Med 2003 • The authors report that using myoglobin in combination with TnI at 0 and 90 minutes had a sensitivity of 84.6% specificity.3% sensitivity and 86.3 hours. We found no studies that looked at the use of myoglobin alone for the rule-out of AMI. • The combined sensitivity of TnI and myoglobin at 90 minutes after presentation was 97.5% NPV and an NLR of 0. 100% NPV. in both McCord and Sallach studies. there is insufficient evidence to justify the use of myoglobin as a cardiac marker. meaning that most of the delta measurements were performed at six hours or more after the onset of chest pain.19 for AMI.No Does the measurement of myoglobin provide any additional value? The first three studies below are widely quoted as supporting the use of myoglobin: McCord .4% (NLR 0. • Over 50% of patients presented more than six hours after onset of pain. low TnI cutoffs demonstrated higher early sensitivities than myoglobin.Am J Cardio 2001 • This study looked at using a combination of delta myoglobin. • The maximum sensitivity at 94% was reached at nine hours using a combination of TnI. 94% specificity. and myoglobin (the likely reason for the low sensitivity is that an insensitive TnI assay was used in this study). CK-MB. Interpretation: performance of myoglobin does not improve sensitivity or NLR Recommendation: • discontinue use of myoglobin as a cardiac marker. the potential use of myoglobin as an early marker for • • • No Does the measurement of CK provide any additional information? (180068975. • Their results for a change of > 20 ng/ml of myoglobin at 90 minutes after presentation produced 83. Interpretation: delta myoglobin performed at six hours after onset of chest pain has a lower sensitivity and NLR than a TnT performed at six hours Ng . Based on the above studies. Interpretation: unlikely to be applicable given reservations about methods Eggers . 99.Am Heart J 2004 • Multi-marker strategies using TnI and myoglobin did not provide a superior overall diagnostic performance as compared to TnI alone. suggesting a post-hoc analysis. Interpretation: the maximum sensitivity attained is not sufficient Sallach . • However. which exceeds the sensitivity of other single markers or combinations of markers.

(180068975.Numerous studies have demonstrated that measurement of CK and its isoforms does not improve diagnostic accuracy for AMI or facilitate more rapid decision-making than TnT alone.doc) 10 .

8% of all ED visits > 200.Clin Chem 2006 The AHA Scientific Statement previously defined an adequate set of biomarkers as at least two measurements of the same marker taken at least six hours apart. Adoption of a more rapid diagnostic approach would potentially: • • reduce LOS between one to six hours reduce utilization of monitored beds by 5% . MacRae .000 to 20.0%) patients typically present 2 to 4 hours after the onset of chest pain if the average LOS could be reduced by even 1 to 2 hours: ⇒ ~10.15% Projections: • • chest pain represents ~5% . whereas in the study protocol the interval was timed from the onset of chest pain .doc) 11 . The time to diagnosis for the candidate time-from onset specimen sets were subtracted from the identically calculated interval in the AHA-adequate sets to estimate the reduction in time to diagnosis afforded by the time-from-onset protocols.000 monitored bed hours (180068975. the required time to diagnosis was calculated as the time from the presentation specimen to the time of the second specimen in the set.000 patients per year • prevalence ACS ~15% of chest pain ⇒ • • ~1. For each of these sets.500 ACS patients per year (5.000 WRHA adult ED visits annually ⇒ ~10. The “AHA adequate set” was a set of markers measured over a six hour interval from the time of ED presentation . without incorporating an assay turnaround time.Implications for ED throughput Potential Reduction in the time to Diagnosis Patient distribution in terms of the reduction in time (h) to achieve a diagnosis with the >6 h from onset protocol compared with the AHA case definition.

please refer to the following: • • • • • • • Lippi. 2006 Innes.doc) 12 . 2003 Korff.For more detailed discussions of the cardiac markers. 2006 Jaffe. 2005 Carreiro-Lewandowski. 2006 reviews of troponins discussion of the clinical utility of new cardiac markers reviews of markers of necrosis and ischemia Carreiro-Lowski (180068975. 2006 Aviles. 2005 Collison.

Clinical Chemistry 2006.111:2699-2710. et al.48(3:270-310). MacRae AR et al. Emerg Med Clin N Am 2005.med. McCord J et al. Are Troponins confusing? Heart 2003. J Am Coll Cardiol 2000.doc) 13 . Troponin: the biomarker of choice for the detection of cardiac injury. Annals Emerg Med 2006. Stubbs PJ. Babuin L and Jaffe AS. CJEM 2006. Clinical utility of novel cardiac markers: Let the buyer beware.173(10): Cannon CP and Turpie AGG. UCLA Medical Center.89:1035–41. LAB MED 2006. Circulation.ucla.94:864–867. Ann Emerg Med.23:453–465. Beasley JW. Mechanisms behind the prognostic value of troponin T in unstable coronary artery disease: a FRISC II substudy.23:959-975. Jaffe AS. 2006.americanheart. Lindahl B et al. Carreiro-Lewandowski E. Eggers KM et al.42:343-350. 2003. Clinical Policy: Critical Issues in the Evaluation and Management of Adult Patients with Non–ST-Segment Elevation Acute Coronary Syndromes. Innes G. Redefinition of Myocardial Infarction: Prospective Evaluation in the Community.References Braunwald E. Practical Implementation of the Guidelines for Unstable Angina/Non–ST Segment Elevation Myocardial Infarction in the Emergency Department. Aviles JM and Aviles RJ.edu/champ/ACS05%20booklet.43:273-280. 2006. Available at: http://www. Circulation 2005.52(5):812-818. Unstable Angina and Non–ST-Elevation Myocardial Infarction: Initial Antithrombotic Therapy and Early Invasive Strategy. J Am Coll Cardiol 2001. Advances in Cardiac Biomarkers.8(1):32-36. A Change in Serum Myoglobin to Detect Acute Myocardial Infarction in Patients With Normal Troponin I Levels.a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction.88:611– 617. Myocardial infarction redefined . Am J Cardiol 2001. Diagnostic value of serial measurement of cardiac markers in patients with chest pain: Limited value of adding myoglobin to troponin I for exclusion of myocardial infarction Am Heart J 2004.2640-2645. Gibler BW et al. Ng SM et al. Update on Cardiac Biomarkers. Differential diagnosis of elevated troponins.148:574-581. (180068975. Antman EM. Use of Biomarkers in the Emergency Department and Chest Pain Unit.89:1285-1287. Am J Cardiol 2002. Korff S et al. Troponin I. Assessing The Requirement For The 6-Hour Interval Between Specimens In The American Heart Association Classification Of Myocardial Infarction In Epidemiology And Clinical Research Studies.37(10):597-605. Cardiol Clin 2005. Annal Clin Biochem. Heart 2006. Available at: http://www.107.114:790-797.36:959-969. Sallach SM et al. CMAJ 2005. Ninety-Minute Accelerated Critical Pathway for Chest Pain Evaluation. Clinical performance of three cardiac troponin assays in patients with unstable coronary artery disease (a FRISC II substudy). UCLA Chest Pain and ACS Patient Management Guideline. Am J Cardiol 2004. Collinson PO. and Creatine Kinase–MB Measurements in Patients Evaluated in the Emergency Department for Acute Coronary Syndrome. The Prognostic Significance of Serial Myoglobin.pdf Venge P et al. Comparison of biomarker strategies for rapid rule out of myocardial infarction in the emergency department using ACC/ESC diagnostic criteria. Collinson P et al. Roger VL et al. 2005. 92:987–993. 2002. Circulation 2003.38:979–86.pdf ACEP. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina).org/downloadable/heart/1044991838085StableAnginaNewFigs.

Appendix A Presentations of Unstable Angina CCS Grading of Angina ACC/AHA 2002 Unstable angina / NSTEMI guideline update (180068975.doc) 14 .

Appendix B WRHA algorithm for the management of patients with suspected ACS in the ED (180068975.doc) 15 .

Appendix C Likelihood that signs and symptoms represent an ACS Braunwald – AHCPR Publication No. 94-0602 ACC/AHA 2002 Unstable angina / NSTEMI guideline update Appendix D WHO Diagnostic Criteria for Acute Myocardial Infarction ACC/AHA 2002 Unstable angina / NSTEMI guideline update (180068975.doc) 16 .

Heart 2003 (180068975.doc) 17 .Appendix E Differential Diagnosis of Elevated Troponin Collinson .