Advancing ACS Diagnosis Using Serial Troponin Testing Summary of: Challenges & Pragmatic Approaches in Troponin Testing. Presented online by Francis Fesmire, MD. July 2010. Case Report: A 64-year-old Caucasian male presents to the emergency department (ED) at 10:00 am with atypical chest pain, fatigue, and dyspnea. His medical history indicates a prior diagnosis of diabetes and elevated cholesterol levels but no previous cardiac disease. Upon physical examination, the patient is alert, with a blood pressure of 140/80 mm HG, a resting heart rate of 75 beats/min, and a nondiagnostic ECG. The differential diagnosis is unclear, but acute coronary syndrome (ACS) is suspected. This scenario likely sounds familiar, as it occurs many times a day in EDs across the country and around the world. ACS is difficult to identify because of the constellation of symptoms that present, many of which mimic other disorders, including gastrointestinal, respiratory, and neurologic diseases. The diagnosis is further complicated by a complex patient population; many elderly patients with ACS complain only of weakness and dizziness, while other patients may present with multiple complaints and comorbidities. Using traditional protocols for chest pain patients, an observation period of at least 8 hours is required to identify or rule out the occurrence of a myocardial infarction (MI). Any delay in acute MI (AMI) diagnosis and treatment can exacerbate heart damage; therefore, it is essential to confirm or reject an ACS diagnosis with accuracy and expediency. What is the acceptable risk for a missed AMI? Given the available resources and diagnostic tools, it is realistic to accept that 1% of AMIs will be missed, yet neither society as a whole nor health care providers in particular expect AMI to be misdiagnosed. Our collective goal is to establish a chest pain protocol that approximates the 0% rate for missed AMI without placing an unnecessary burden on our health care system. The reach of such a protocol would be extensive, as chest pain is one of the most common reasons patients visit the ED; however, the majority of these patients will be judged not to have a cardiac problem. 1 This large heterogeneous group of patients can create a bottleneck unless an ED uses standardized, protocol-driven processes to accelerate clinical decision-making and expedite patient care. Dr. Francis Fesmire is the director of the Chest Pain Center at Erlanger Medical Center in Chattanooga, TN. He is currently the chairman of the writing committee on ACS for the American College of Emergency Physicians, and he is on the ST-elevation and non ST-elevation/unstable angina writing committees of the American College of Cardiology and the American Heart Association. He was formerly a consultant for Abbott Point of Care. The results shown here are specific to one health care facility and may differ from those achieved by other institutions.
The Value of Troponin in Diagnosing and Risk-Stratifying ACS Patients Various cardiac biomarkers have been used to aid in the diagnosis of MI since the 1960s, but cardiac troponin is now established as the cardiac biomarker of choice. New-generation assays measuring cardiac troponin in the blood have enhanced analytical sensitivities and specificities, enabling the potential for earlier MI diagnosis. The advantage of cardiac troponin over other cardiac biomarkers is based on its cardiac specificity; troponin is expressed almost exclusively in the heart and is not normally found in the circulation. When damaged, myocytes release cardiac-specific troponins (subunits TnT and TnI) into the blood, which can then be assayed as a measure of myocyte damage. Some of the additional advantages of troponin are presented in Table 1. Table 1. Advantages of troponin as a cardiac biomarker for ACS diagnosis 1-3 Feature of biomarker ACC/AHA guidelines recommendation for cardiac markers Cardiac troponin Myoglobin CK-MB IB IIB IIB Specific for myocardial injury X X Cardiac-specific expression X X Increased levels in blood hours after onset of MI Elevated levels in circulation for many days following MI X X 2-hour delta value sensitive and specific for diagnosing MI X X Multiple studies have shown that for ACS diagnosis there is no increased benefit in analyzing myoglobin and CK-MB in addition to cardiac troponin. 4,5 Also, analyzing the change in myoglobin over time has been shown to decrease specificity in diagnosing ACS when evaluating cardiac troponin. 6 Increasingly, studies demonstrate that biomarkers other than troponin do not provide additional value to ACS diagnosis. This point is reflected in the decision by the American College of Cardiology (ACC) and the American Heart Association (AHA) to downgrade the recommended use of myoglobin from a IIA to a IIB recommendation in the most recent guideline publication. 1,7
Guidelines Support Troponin as the Biomarker of Choice Globally, medical societies agree that cardiac troponin is the biomarker of choice to facilitate the diagnosis of ACS. 1-3 The ACC, AHA, European Society of Cardiology (ESC), and National Academy of Clinical Biochemistry (NACB) all make similar recommendations regarding reference intervals, decision limits, and precision of troponin testing. Importantly, recommendations from these societies also recommend serial assessments of cardiac biomarkers in all patients with chest pain and possible ACS to maximize the diagnostic value of the cardiac-specific troponins known release kinetics. With the critical role that troponin plays in ACS diagnosis, the guidelines also assert that cardiac troponin assessment should be available to the ED physician as early as possible in less than 60 minutes after blood draw. Additional recommendations are presented in Table 2. Table 2. Recommendations for the use of cardiac biomarkers in risk stratification of ACS 1-3 Recommendation ACC/AHA ESC NACB Cardiac troponin preferred biomarker for MI diagnosis Measure cardiac biomarkers in all suspected ACS patients Assess suspected MI by clinical presentation, ECG, and cardiac biomarkers Obtain troponin test results within 60 minutes of blood draw Measure cardiac biomarkers serially, at presentation and 6 12 hours thereafter A panel of experts from the ACC, AHA, ESC, and World Health Foundation met in 2007 to reach a consensus regarding the definition of MI. This universal definition is evidence of myocardial necrosis in a clinical setting consistent with myocardial ischemia. 8 Integral to this definition is the role of cardiac biomarkers to determine the extent of myocardial necrosis, and troponin is identified as the biomarker of choice for diagnosing ACS. Moreover, the universal MI definition necessitates the detection of a rise and/or fall of cardiac troponin with at least one concentration above the 99th percentile value (see Figure 1). The guidelines assert that cardiac troponin assessment should be available as early as possible in less than 60 minutes after blood draw.
Figure 1. Defining the 99th percentile reference limit 0.09 0.08 Any troponin level at or below the 99th percentile value is consistent with 99% of the healthy population. Any value above this limit may indicate abnormal cardiac pathology. The 99th percentile cutoff differs for every troponin assay. 9 Adapted from Robinson S et al. J Simulation. 2009;3:163-170. Probability density 0.07 0.06 0.05 0.04 0.03 0.02 Healthy population 99th Percentile cutoff Diseased population 0.01 0 0 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 0.09 0.10 0.11 0.12 0.13 0.14 0.15 0.16 Troponin I (ng/ml)!" The 99th percentile value of troponin is utilized to indicate abnormal cardiac pathology for patients with values above this limit 8 ; however, because this reference limit is derived from values in a healthy population, it does not represent a typical ED patient population, which often presents with other chronic symptoms causing elevated cardiac troponin levels in the absence of AMI/ACS. Additionally, 1% of the healthy population will present with troponin values above the cutoff, and ACS patients presenting soon after symptom onset may still be below the cutoff. In light of these complicating factors, it is critical to the accurate diagnosis of ACS to determine the trend in troponin levels through serial testing. Utilizing the diagnostic value of delta troponin will help rule in/rule out MI among symptomatic patients. 10 It is important to note that the presence of cardiac troponin in blood samples is indicative of myocyte damage but does not explain the etiology of the disease, and alone is not definitive proof of MI. Cardiac troponin can also be released into the blood as a result of other causes of myocardial necrosis, such as myocarditis, aortic dissection, pulmonary embolism, congestive heart failure, hypoxia, shock, renal failure, acute neurologic disease, inflammatory disease, drug toxicity, burns, or extreme exertion. 8 In the absence of clinical evidence of acute coronary-induced associated ischemia, a differential diagnosis of the underlying cause of the elevated troponin values should be investigated. As a first step, serial troponin testing should be employed to determine the change in value over time to facilitate an ACS diagnosis or initiate a search for other etiologies.
The Importance of Serial Testing Because the release of cardiac troponin into the circulation after an MI follows a distinct pattern, Class I recommendations include assessing cardiac troponin levels at two time points after symptom onset to obtain powerful information regarding if and when an MI occurred. Specifically, if the cardiac troponin value is rising over time, this is indicative of an MI; if levels are declining, this may indicate a past infarction. Detectable cardiac troponin measurements that remain unchanged over time may be cause to seek an alternative etiology, while patients with undetectable levels of troponin may be candidates for discharge, following a differential diagnosis (most patients fall into this final category). 1 It is important to note that utilizing older troponin assays with poor analytical sensitivity or adoption of high cutoff values for sensitive troponin assays may result in a delay in detection of an abnormal value for 8 12 hours after symptom onset. On the other hand, if a low cutoff value is utilized with a sensitive assay, the rate of results that exceed the 99th percentile is dramatically increased, thus complicating the interpretation of the abnormal values. The distinct value of serial cardiac troponin testing is its ability to determine if cardiac troponin levels are rising, falling, or unchanged over time. Including troponin as part of an ACS diagnostic protocol is important because it can be detected in the blood as early as 2 hours after symptom onset. In fact, a recent study shows that if the difference between the cardiac troponin value at initial presentation and 2 hours later is greater than 30%, the sensitivity and specificity for detecting an MI is 100% and 87%, respectively, in a population of suspected non ST-elevation ACS patients. 4 This study demonstrates that analysis of a 2-hour delta cardiac troponin value can facilitate the rapid identification of MI. The best way to evaluate rising/falling troponin levels is through serial testing with a consistent methodology. Currently, there is no standard troponin reference material; therefore, if delta cardiac troponin values are obtained through different methodologies, it is difficult to ascertain whether changes in values are due to a cardiac etiology or simply to differences in platforms. At Erlanger Medical Center, serial TnI levels are measured at the point of care (POC) using the i-stat System.* The use of this system provides additional benefits, such as rapid turnaround times, by eliminating process steps associated with traditional lab testing. Many other POC tests are used at Erlanger Medical Center to facilitate operational efficiency for a broad range of patients (see Table 3). Table 3. Use of i-stat POC testing at Erlanger Medical Center The distinct value of serial cardiac troponin testing is its ability to determine if cardiac troponin levels are rising, falling, or unchanged over time. POC tests beyond ctnl used at Erlanger Medical Center CHEM8+ Blood gases Creatinine Lactate* Future POC tests to be employed BNP PT/INR * See Intended Use Information on back page.
The Erlanger Protocol: Accelerating Diagnosis to Improve Patient Care Dr. Fesmire developed the Erlanger Chest Pain Protocol to expedite treatment and improve patient care. This protocol, including serial 12-lead ECG monitoring, 2-hour delta cardiac troponin measurements using i-stat ctni, and selective nuclear stress testing, reduces the time required to confirm or rule out a diagnosis of ACS (see Figure 2). The Erlanger protocol is both sensitive and specific for diagnosing MI and ACS. Utilizing all six diagnostic steps improves the sensitivity and specificity of the protocol for diagnosing MI to 100% and 82%, respectively (see Table 4). 11 The biggest advantage of this protocol over traditional baseline and 8-hour blood draw protocols is the increased sensitivity for diagnosing MI, largely attributable to the 2-hour delta troponin value. In fact, 2% of patients initially stratified as probable non-acs were recategorized as possible to high likelihood of ACS only 2 hours later with the Erlanger protocol. This swift reassessment enables earlier treatment initiation (particularly for patients with non ST-elevation MI (NSTEMI), a condition far more common than STEMI but more difficult to diagnose), salvaging cardiac muscle and resources and accelerating door-to-disposition time. Figure 2. The Erlanger Chest Pain protocol Initial ECG/H&P Baseline Chest Pain Categorization I-IV Treat Category I & II According to Current ACC/AHA Guidelines Two-Hour Evaluation Protocol: Automated Serial ECG Monitoring Two-Hour Delta ctni Two-Hour Chest Pain Re-Categorization The Erlanger protocol involves risk stratification into 4 groups: Category I=high likelihood of ACS; Category II=probable ACS; Category III=possible ACS; and Category IV=probable non-acs. 11 Adapted from Fesmire FM et al. Ann Emerg Med. 2002;40(6): 584-594. Table 4. Results of the Erlanger protocol for the detection of MI 11 Sensitivity (%) Specificity (%) ECG 26.3 99.9 + Baseline markers 58.1 99.4 + SECG * 64.4 98.9 + Delta markers 93.2 93.9 + Physician judgment 97.6 89.4 + Nuclear stress 100 81.9 *SECG=serial electrocardiogram(s).
The i-stat POC system is well suited to the design and goals of the Erlanger protocol because it provides accurate and reliable cardiac troponin test results within minutes, facilitating the analysis of the 2-hour delta value. In the DISPO-ACS* Trial, the i-stat System helped physicians meet the guideline-recommended 60-minute turnaround time 98% of the time notably, when central laboratory testing was used in the trial, these goals were achieved only 53% of the time. 12 POC systems have also been demonstrated to decrease time to anti-ischemic therapy in patients with suspected NSTEMI. 13 Additionally, POC testing has been shown to reduce time spent in the ED, 14 reduce overall length of stay in the hospital, 15 and expedite disposition 16 and may reduce ambulance diversion 17 and increase the number of patients seen per day. 17 Empirically, use of the i-stat System in the Erlanger protocol expedites the diagnosis, treatment, and disposition of patients. To return to our patient example, the 64-year-old patient presented with atypical chest pain and a nondiagnostic ECG. Table 5 compares the care of this patient using the Erlanger protocol versus using a traditional baseline/8-hour protocol. With the Erlanger protocol, which included the 2-hour delta troponin value, the ED physician advanced the patient s diagnosis and disposition saving a total of 24 hours. Table 5. Case report: Erlanger protocol offers time advantage vs traditional protocol in care of suspected ACS patient Hospital A (8-hour blood draw) Hospital E (Erlanger protocol) At hospital A, a traditional baseline/8-hour blood draw protocol is used. The vein-to-brain time for the first troponin blood draw is 2 hours. Based on the troponin value, the ED physician deems the patient low-tointermediate risk for ACS and admits him for 23-hour observation. The second blood draw occurs 8 hours later, and the troponin value is 0. The admitting physician is informed of the result and orders a nuclear stress test and a repeat troponin test the following morning. The nuclear stress test is negative and the admitting physician discharges the patient on afternoon rounds. A second patient with identical symptoms and ECG presents at hospital E, where the Erlanger protocol is used. The results of the first and second serial POC troponin tests are verbalized to the ED physician 15 minutes following the test, permitting a nuclear stress test to be ordered and performed in the early afternoon. The stress test is negative, and the patient is discharged on the same day. Presentation: 10:00 am Nondiagnostic ECG Blood draw: 10:30 am Troponin: 0.01 ng/ml Admitted for observation Blood draw: 6:30 pm Troponin: 0.00 Stress test: Negative (Day 2) Discharge: 4:00 pm (Day 2) Total door-to-disposition time: 30 hours Presentation: 10:00 am Nondiagnostic ECG Blood draw: 10:30 am Troponin: 0.01 ng/ml Blood draw: 12:30 pm Troponin: 0.01 ng/ml Stress test: Negative Discharge: 4:00 pm Total door-to-disposition time: 6 hours Time saved using the Erlanger protocol: 24 hours * DISPO-ACS=the Disposition Impacted by Serial Point of Care Markers in Acute Coronary Syndromes.
Collectively, we have identified the value of serial troponin testing in diagnosing ACS and developed a mechanism to obtain those measurements with accuracy and expediency. Capitalizing on the Value of Troponin to Advance Patient Care As discussed here, diagnosing ACS is challenging, and in the current clinical environment a missed AMI diagnosis is considered unacceptable. Fortunately, we have made great strides in the effort to collectively improve the quality of care provided to chest pain patients. We have recognized the value of troponin as the preferred cardiac biomarker, and we have realized the significance of serial troponin values in making a diagnosis. Furthermore, we have identified the rapidity (2 hours) with which delta values can provide useful information to influence subsequent testing or treatment. Importantly, we have developed a mechanism in POC testing to obtain those valuable measurements with accuracy and expediency in turn advancing patient care and operational efficiency. References: 1. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation. 2007;116(7):e148-e304. 2. Bassand JP, Hamm CW, Ardissino D, et al. Guidelines for the diagnosis and treatment of non-st-segment elevation acute coronary syndromes. Eur Heart J. 2007;28(13):1598-1660. 3. Morrow DA, Cannon CP, Jesse RL, et al. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: clinical characteristics and utilization of biochemical markers in acute coronary syndromes. Clin Chem. 2007;53(4):552-574. 4. Scharnhorst V, Krasznai K, van t Veer M, et al. Rapid detection of myocardial infarction with a sensitive troponin test. Am J Clin Pathol. 2011;135(3):424-428. 5. Eggers KM, Oldgren J, Nordenskjöld A, et al. 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;148(4):574-581. 6. Fesmire FM, Christenson RH, Fody EP, et al. Delta creatine kinase-mb outperforms myoglobin at two hours during the emergency department identification and exclusion of troponin positive non-st-segment elevation acute coronary syndromes. Ann Emerg Med. 2004;44(1):12-19. 7. Braunwald E, Antman EM, Beasley JW, et al. 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). 2002. Available at: stage.acc.org/qualityandscience/clinical/guidelines/unstable/unstable.pdf. 8. Thygesen K, Alpert JS, White HD; Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction. Universal definition of myocardial infarction. J Am Coll Cardiol. 2007;50(22):2173-2195. 9. Robinson S, FitzGibbon F, Eatock J, et al. Application of synthetic patient data in the assessment of rapid rule-out protocols using Point-of-Care testing during chest pain diagnosis in a UK emergency department. J Simulation. 2009;3:163-170. 10. Wu AH, Lu QA, Todd J, et al. Short- and long-term biological variation in cardiac troponin I measured with a high-sensitivity assay: implications for clinical practice. Clin Chem. 2009;55(1):52-58. 11. Fesmire FM, Hughes AD, Fody EP, et al. The Erlanger chest pain evaluation protocol: a one-year experience with serial 12-lead ECG monitoring, two-hour delta serum marker measurements, and selective nuclear stress testing to identify and exclude acute coronary syndromes. Ann Emerg Med. 2002;40(6):584-594. 12. Ryan RJ, Lindsell CJ, Hollander JE, et al. A multicenter randomized controlled trial comparing central laboratory and point-of-care cardiac marker testing strategies: the Disposition Impacted by Serial Point of Care Markers in Acute Coronary Syndromes (DISPO-ACS) trial. Ann Emerg Med. 2009;53(3):321-328. 13. Renaud B, Maison P, Ngako A, et al. Impact of point-of-care testing in the emergency department evaluation and treatment of patients with suspected acute coronary syndromes. Acad Emerg Med. 2008;15(3):216-224. 14. Singer AJ, Ardise J, Gulla J, et al. Point-of-care testing reduces length of stay in emergency department chest pain patients. Ann Emerg Med. 2005;45(6):587-591. 15. Loten C, Attia J, Hullick C, et al. Point of care troponin decreases time in the emergency department for patients with possible acute coronary syndrome: a randomised controlled trial. Emerg Med J. 2010;27(3):194-198. 16. Hsiao AL, Santucci KA, Dziura J, et al. A randomized trial to assess the efficacy of point-of-care testing in decreasing length of stay in a pediatric emergency department. Pediatr Emerg Care. 2007;23(7):457-462. 17. Storrow AB, Zhou C, Gaddis G, et al. Decreasing lab turnaround time improves emergency department throughput and decreases emergency medical services diversion: a simulation model. Acad Emerg Med. 2008;15(11):1130-1135. For in vitro diagnostic use only. Intended Use ctni The i-stat cardiac troponin I (ctni) test is an in vitro diagnostic test for the quantitative measurement of cardiac troponin I (ctni) in whole blood or plasma. Measurements of cardiac troponin I are used in the diagnosis and treatment of myocardial infarction and as an aid in the risk stratification of patients with acute coronary syndromes with respect to their relative risk of mortality. CG4+ The test for lactate, as part of the i-stat System, is intended for use in the in vitro quantification of lactate in arterial, venous, or capillary whole blood. The i-stat lactate test is useful for (1) the diagnosis and treatment of lactic acidosis in conjunction with measurements of blood acid/base status, (2) monitoring tissue hypoxia and strenuous physical exertion, and (3) diagnosis of hyperlactatemia. Abbott Point of Care Inc. 400 College Road East, Princeton, NJ 08540 (609) 454-9000 (609) 419-9370 (fax) www.abbottpointofcare.com i-stat is a registered trademark of the Abbott group of companies in various jurisdictions. Advancing ACS Diagnosis Using Serial Troponin Testing 031356 Rev A 04/13