Patients who present to the emergency department (ED) with chest pain or other anginal-equivalent symptoms and have negative cardiac enzymes and nonischemic electrocardiograms (ECGs) are at low risk for having an acute coronary syndrome (ACS) and subsequent cardiovascular events . But how low is low? The answer to this question has important implications for patient safety and health policy. Here we will review the literature pertaining to this topic and highlight gaps in the current understanding.
ACS is characterized by an abrupt reduction in coronary blood flow that is most often caused by atherosclerotic plaque rupture or erosion . It is an umbrella term that now includes the conditions unstable angina (UA), non-ST segment elevation myocardial infarction (NSTEMI), and ST segment elevation myocardial infarction (STEMI). ACS meets the criteria for myocardial infarction (MI) when there is a rise or fall in cardiac troponin (I or T), with one value exceeding the 99th percentile upper reference limit of a normal population . Much confusion exists regarding the possibility of missing MI, but because it is defined by abnormal troponin it cannot be missed if suspected and if troponin is checked at least twice over a 6-hour period after the onset of symptoms . Based strictly on the current definition, the risk of MI in patients with suspected ACS and negative serial troponins is 0%; however, a miss rate of 2%–5% is frequently cited .
More than two decades ago, Pope et al. published the most influential paper on ED miss rates for ACS . Using prospective registry data from 10,689 patients enrolled in the multicenter Acute Cardiac Ischemia Time-Insensitive Predictive Instrument (ACI-TIPI) trial, investigators found that 4% of patients ultimately diagnosed with ACS were missed (2% MI, 2% UA) and inappropriately discharged. Level of evidence (LOE) 2 The results of this 1993 vintage study do not apply to contemporary practice because the definition of MI has changed. Furthermore, at the time of the ACI-TIPI trial, troponin testing was not routinely performed; instead, Creatinine kinase myocardial b fraction (CKMB) was primarily used, which is far less sensitive for detecting myocardial necrosis.
In the Thrombolysis in myocardial infarction (TIMI) 3 trial, 25% of patients classified as having UA on the basis of negative serial CKMB levels had troponin I levels ≥0.4 ng/mL (the relatively insensitive cut point used in the mid-1990s), and could therefore be reclassified as having an NSTEMI . (LOE 2) Similarly, Hamm et al. prospectively studied a cohort of 773 patients with acute chest pain but no ST segment elevation . They found that in 47 patients diagnosed with NSTEMI, CKMB was elevated in only 91% 4 hours after arrival, whereas troponin I was elevated in all . (LOE 2) And in 315 patients diagnosed with UA, troponin I was elevated in 36% . These classical studies used first-generation troponin assays. Since then, the definition of MI has changed to reflect a troponin-based definition, and troponin assays have become far more sensitive.
In the TIMI 3 trial, which was performed in 1996, the cut point for defining MI was 0.4 ng/mL, whereas in the TIMI 11B trial, performed in 2000, it was 0.10 ng/mL . In 2010, the Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndrome (MERLIN)-TIMI 36 trial used a cut point of 0.04 ng/mL . As troponin assays become more sensitive, lowered cut points for detecting myocardial necrosis have resulted in reclassifying a substantial percentage of patients previously diagnosed with UA as NSTEMI. Mills et al. reported that reducing the cut point from 0.2 to 0.05 ng/mL (the widely used current-generation assay cut point is 0.04 ng/mL) increased NSTEMI diagnoses by 27% (LOE 1).
Occurring in parallel with the rise in NSTEMI diagnoses was the development of chest pain observation units, and increased use of stress tests and coronary computed tomography angiography . From 1999 through 2008, advanced testing in ED patients with chest pain increased by 368% . Initially, this practice was important for the detection of patients with UA—the kind initially described as “preinfarctional” angina in the 1970s . However, as troponin assay sensitivity increased and UA became increasingly reclassified as NSTEMI, a new class of UA developed. This new class of disease is defined by stress test positivity or the presence of obstructive atherosclerotic disease on coronary computed tomography angiography (CCTA). Most of these patients have atypical symptoms, nonischemic ECGs, and would not have been classified as UA based on its original description. Figure 1 depicts this transition graphically, with UA-1 denoting the condition as originally described and UA-2 denoting this new condition defined by cardiac imaging.
Open full size image
Figure 1
Evolution of the diagnosis of acute coronary syndrome.
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
First-generation Data
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Second-generation Data
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Third-generation Data
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
Randomized Controlled Trials
Get Radiology Tree app to read full this article<
Conclusions
Get Radiology Tree app to read full this article<
Get Radiology Tree app to read full this article<
References
1. Amsterdam E.A., Kirk J.D., Bluemke D.A., et. al., American Heart Association Exercise CR: Testing of low-risk patients presenting to the emergency department with chest pain: a scientific statement from the American Heart Association. Circulation 2010; 122: pp. 1756-1776.
2. Amsterdam E.A., Wenger N.K., Brindis R.G., et. al.: 2014 ACC/AHA guideline for the management of patients with non-ST-elevation acute coronary syndromes: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 130: pp. 2354-2394.
3. Virmani R., Kolodgie F.D., Burke A.P., et. al.: Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000; 20: pp. 1262-1275.
4. Thygesen K., Alpert J.S., Jaffe A.S., et. al.: Third universal definition of myocardial infarction. Circulation 2012; 126: pp. 2020-2035.
5. Scheuermeyer F.X., Innes G., Grafstein E., et. al.: Safety and efficiency of a chest pain diagnostic algorithm with selective outpatient stress testing for emergency department patients with potential ischemic chest pain. Ann Emerg Med 2012; 59: pp. 256-264.
6. Pope J.H., Aufderheide T.P., Ruthazer R., et. al.: Missed diagnosis of acute cardiac ischemia in the emergency department. N Engl J Med 2000; 342: pp. 1163-1170.
7. TIMI III B Investigators : Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non-Q-wave myocardial infarction: results of the TIMI III B trial. Circulation 1994; 89: pp. 1545-1556.
8. Hamm C.W., Goldmann B.U., Heeschen C., et. al.: Emergency room triage of patients with acute chest pain by means of rapid testing for cardiac troponin T or troponin I. N Engl J Med 1997; 337: pp. 1648-1653.
9. Morrow D.A., Antman E.M., Tanasijevic M., et. al.: Cardiac troponin I for stratification of early outcomes and the efficacy of enoxaparin in unstable angina: a TIMI-11B substudy. J Am Coll Cardiol 2000; 36: pp. 1812-1817.
10. Morrow D.A., Scirica B.M., Karwatowska-Prokopczuk E., et. al.: MERLIN-TIMI 36 trial investigators. Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 Trial. JAMA 2007; 297: pp. 1775-1783.
11. Mills N.L., Churchhouse A.M., Lee K.K., et. al.: Implementation of a sensitive troponin I assay and risk of recurrent myocardial infarction and death in patients with suspected acute coronary syndrome. JAMA 2011; 305: pp. 1210-1216.
12. Bhuiya F., Pitts S.R., McCaig L.F.: Emergency department visits for chest pain and abdominal pain: United States, 1999–2008.NCHS Data Brief, No 432010.National Center for Health StatisticsHyattsville, MD
13. Fowler N.O.: “Preinfarctional” angina: a need for an objective definition and for a controlled clinical trial of its management. Circulation 1971; 44: pp. 755-758.
14. Hulten E., Pickett C., Bittencourt M.S., et. al.: Outcomes after coronary computed tomography angiography in the emergency department. J Am Coll Cardiol 2013; 61: pp. 880-892.
15. Boden W.E., O’Rourke R.A., Teo K.K., et. al.: Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007; 356: pp. 1503-1516.
16. Shaw L.J., Weintraub W.S., Maron D.J., et. al.: Baseline stress myocardial perfusion imaging results and outcomes in patients with stable ischemic heart disease randomized to optimal medical therapy with or without percutaneous coronary intervention. Am Heart J 2012; 164: pp. 243-250.
17. Braunwald E., Jones R.H., Mark D.B., et. al.: Diagnosing and managing unstable angina. Circulation 1994; 90: pp. 613-622.
18. Braunwald E., Antman E.M., Beasley J.W., et. al.: ACC/AHA Guidelines 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. J Am Coll Cardiol 2000; 36: pp. 970-1062.
19. Braunwald E., Morrow D.A.: Unstable angina. Is it time for a requiem?. Circulation 2013; 127: pp. 2452-2457.
20. Goff D.C., Lloyd-Jones D.M., Bennett G., et. al.: 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 129: pp. S49-S73.
21. Bholasingh R., Cornel J.H., Kamp O., et. al.: Prognostic value of predischarge dobutamine stress echocardiography in chest pain patients with a negative cardiac troponin T. J Am Coll Cardiol 2003; 41: pp. 596-602.
22. Chan G.W., Sites F.D., Shofer F.S., et. al.: Impact of stress testing on 30-day cardiovascular outcomes for low-risk patients with chest pain admitted to floor telemetry beds. Am J Emerg Med 2003; 21: pp. 282-287.
23. Sun B.C., Laurie A., Fu R., et. al.: Association of early stress testing with outcomes for emergency department evaluation of suspected acute coronary syndrome. Crit Pathw Cardiol 2016; 15: pp. 60-68.
24. Cremer P.C., Khalaf S., Agarwal S., et. al.: Myocardial perfusion imaging in emergency department patients with negative cardiac biomarkers. Yield for detecting ischemia, short-term events, and impact of downstream revascularization on mortality. Circ Cardiovasc Imaging 2014; 7: pp. 912-919.
25. Kelly A.-M., Klim S.: What is the yield of testing for coronary artery disease after an emergency department attendance with chest pain. Heart Lung Circ 2016; 25: pp. 12-18.
26. Safavi K.C., Li S., Dharmarajan K., et. al.: Hospital variation in the use of noninvasive cardiac imaging and its association with downstream testing, interventions, and outcomes. JAMA Intern Med 2014; 174: pp. 546-553.
27. Foy A.J., Liu G., Davidson W.R., et. al.: Comparative effectiveness of diagnostic testing strategies in emergency department patients with chest pain: an analysis of downstream testing, interventions, and outcomes. JAMA Intern Med 2015; 175: pp. 428-436.
28. Foy A.J., Liu G., Davidson W.R.: Noninvasive testing in patients with chest pain—in reply. JAMA Intern Med 2015; 175: pp. 1728-1729.
29. Goldstein J.A., Gallagher M.J., O’Neill W.W., et. al.: A randomized controlled trial of multi-slice coronary computed tomography for evaluation of acute chest pain. J Am Coll Cardiol 2007; 49: pp. 863-871.
30. Goldstein J.A., Chinnaiyan K.M., Abidov A., et. al.: The CT-STAT (coronary computed tomographic angiography for systematic triage of acute chest pain patients to treatment) trial. J Am Coll Cardiol 2011; 58: pp. 1414-1422.
31. Hoffmann U., Truong Q.A., Schoenfeld D.A., et. al.: Coronary CT angiography versus standard evaluation in acute chest pain. N Engl J Med 2012; 367: pp. 299-308.
32. Litt H.I., Gatsonis C., Snyder B., et. al.: CT Angiography for safe discharge of patients with possible acute coronary syndromes. N Engl J Med 2012; 366: pp. 1393-1403.