Emergent diagnosis of acute coronary syndromes: Today's challenges and tomorrow's possibilities

Resuscitation (2008) 78, 13—20

available at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/resuscitation

REVIEW

Emergent diagnosis of acute coronary syndromes: Today’s challenges and tomorrow’s possibilities夽 Richard Body ∗ Emergency Department, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, United Kingdom Received 17 September 2007; received in revised form 14 November 2007; accepted 11 February 2008

KEYWORDS Myocardial infarction; Acute coronary syndromes; Diagnosis; Angina; Unstable

Summary Prompt diagnosis and effective early management of acute coronary syndromes within the Emergency Department are imperative. Arguably the most important step in the management of the acute coronary syndromes is identifying the problem in the first place. This narrative review explores the significant but under-recognised limitations to current diagnostic strategies and addresses both contemporary and possible future solutions in a rapidly evolving field. © 2008 Elsevier Ireland Ltd. All rights reserved.

Contents Background................................................................................................................ The ECG .............................................................................................................. Clinical features........................................................................................................... Cardiac troponins..................................................................................................... Risk stratification ......................................................................................................... Rapid rule out protocols................................................................................................... Pre-discharge exercise testing............................................................................................. Future directions .......................................................................................................... Conclusions ............................................................................................................... Conflict of interest ........................................................................................................ References ..............................................................................................................

夽 A Spanish translated version of the summary of this article appears as Appendix in the final online version at doi:10.1016/j.resuscitation.2008.02.006. ∗ Tel.: +44 7880 712 929; fax: +44 161 276 6925. E-mail address: [email protected].

0300-9572/$ — see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.resuscitation.2008.02.006

14 14 14 14 15 16 17 17 17 17 17

14

Background Coronary heart disease remains the single biggest killer in the United Kingdom, accounting for around one in five deaths in men and one in six deaths in women.1 Approximately 3% of patients who attend the ED have chest pain that we suspect may be cardiac in origin.2 74—88% of these patients are admitted to hospital, making up one in five of all medical admissions.2—4 Ultimately only a quarter of these patients will be diagnosed with an acute coronary syndrome (ACS), which implies that we adopt a very cautious approach to the problem. Despite this fact, up to 6% of the patients who are discharged from the ED actually have myocardial damage that is of prognostic significance.5 This poses a question: why do we admit so many patients who do not have ACS but still miss the diagnosis in so many patients who do? In order to answer this question, this review aims to summarise the use and limitations of diagnostic strategies that are currently employed in the ED.

The ECG American Heart Association and European Society of Cardiology guidelines recommend that all patients who present to the ED with chest pain should have a 12-lead ECG recorded within 10 min of arrival.6,7 This is based upon evidence that longer delays are associated with adverse prognosis.8 The high specificity (at least 94%) of ECG criteria makes it the diagnostic test of first choice for establishing a diagnosis of STEMI and enables confident early institution of measures to achieve revascularisation.9 In patients who do not have STEMI but are suspected to have NSTE-ACS, the ECG is still an important diagnostic tool. 32% of patients with T wave inversion and 48% of patients with ST depression will have AMI, as diagnosed using serum creatine kinase (CK). Regardless of whether these patients have AMI, T wave inversion and ST depression are powerful prognostic markers (Figure 1). ST depression is an independent predictor of 30-day mortality, even among troponin-negative patients.10—14 These patients should have aggressive initial management and further investigation should be strongly considered regardless of troponin levels. The ECG is, however, an insensitive tool and cannot be used to exclude the diagnosis of AMI. Among patients who

R. Body present to the ED with suspected cardiac chest pain and have a normal ECG, 6% will have AMI.15 In fact, the sensitivity of the ECG for establishing a diagnosis of AMI is as low as 25—50%.16,17 Further, for establishing a diagnosis of acute cardiac ischaemia the ECG is less sensitive still, even using serial ECG’s (sensitivity 21—25%).18 Even during episodes of myocardial ischaemia as demonstrated on thallium scanning, 25% of patients with known left main stem or triple vessel disease will have a normal ECG.19

Clinical features Traditional teaching that 90% of diagnoses can be established by history and examination alone does not apply to ED patients with suspected ACS. Clinical features are notoriously unreliable for establishing this diagnosis. Over half of patients with unstable angina and a third of patients with AMI will report atypical symptoms.20,21 Up to one-third of patients with ACS do not experience any chest pain. They may present with dyspnoea, syncope, diaphoresis, pain in the epigastrium, arms or neck or they may report no symptoms at all. As a result, up to one-third of AMI’s are initially unrecognised.22,23 The prognosis for these patients is no better than patients with AMI that is initially recognised. Given the high prevalence of atypical symptoms in patients with ACS, it is no surprise that systematic review has failed to identify any atypical features that help to exclude the diagnosis of ACS. On multivariate analysis, pleuritic pain carries an odds ratio of 0.6 (95% confidence intervals 0.2—1.7) for the diagnosis of ACS, while a tender chest wall also has an odds ratio of 0.6 (0.3—1.2) far from excluding the diagnosis.24 Many atypical clinical features that physicians often believe help to ‘exclude’ the diagnosis of ACS may actually be positive predictors of the diagnosis. Among ED patients with an 18% prevalence of AMI, pain that radiates to the right shoulder may shift the post-test probability of AMI to 39%.15 Burning or indigestion-like pain may yield a post-test probability of 43%.24 Despite these statistics, a careful history remains an important diagnostic tool for the prudent physician who has a good appreciation of Bayesian principles. While no combination of clinical features has shown to accurately exclude ACS, combinations of typical or atypical features will shift the probability of the diagnosis. Among patients with suspected stable angina, combinations of typical symptoms give a very high probability of significant coronary artery disease (at least 90%) whereas combinations of decidedly atypical symptoms in low-risk groups such as young women are associated with low probability (about 5%) of disease.25,26

Cardiac troponins

Figure 1 Prognostic value of the admission electrocardiogram.10

The troponins are subunits of the thin filament associated troponin—tropomyosin complex, which helps to regulate muscle contraction. Genetic differences between skeletal and cardiac muscle have enabled the development of monoclonal antibodies to the cardiac troponins, which enables their quantification in peripheral blood.27,28 Contemporary assays are available for troponins T and I, which are essentially equivalent.29 Troponins represent the most sensitive

Emergent diagnosis of acute coronary syndromes: Today’s challenges and tomorrow’s possibilities and specific biochemical markers of AMI30—32 and confer prognostic information that is convincingly superior to other biochemical markers of myocardial necrosis.29,33 In addition to being extremely sensitive and specific markers of myocardial necrosis, cardiac troponins are excellent independent markers of prognosis.29,34—37 There is a positive correlation between troponin levels and risk of mortality.38,39 Notably, however, even minimal troponin elevations may be important markers of adverse prognosis in patients with ACS. In the CAPTURE trial, 14.7% of patients with troponin T between 0.05 and 0.12 ng/ml developed death or AMI within 6 months, compared with 10.1% of patients with troponin T between 0.02 and 0.04 ng/ml and 6.5% in patients whose troponin T was ≤0.01 ng/ml.40 The troponins too have significant disadvantages as a diagnostic test for ACS. Firstly, although troponins are extremely sensitive markers of myocardial necrosis, the rise in concentrations may not be detectable for several hours after necrosis has occurred. A meta-analysis of 10 studies involving 2497 patients found that troponin levels at presentation have a sensitivity of less than 40% for the diagnosis of AMI.30 Even using serial estimations, troponins are insufficiently sensitive until at least 6 h after the onset of pain41 and sensitivity remains suboptimal until 12 h after the onset of pain (Figure 2).42,43 The disadvantages of this are clear. The majority of patients are admitted to hospital to await diagnostic blood tests, at considerable expense to the Health Service and inconvenience to the patient. Further, many patients in whom the diagnosis has neither been established nor excluded are ineligible for early intensive treatment at a time when it is likely to be most beneficial.44—49 Alternatively, many patients who have non-cardiac chest pain may receive unnecessary treatment with co-existent risks. Finally, troponins are markers of myocardial necrosis, the end-point in the pathophysiological evolution of ACS. Patients with unstable angina are, by definition, troponin negative. Perhaps it is not surprising, therefore, that normal troponin levels do not uniformly equate with a favourable prognosis. A large meta-analysis including a total of 11,963 patients who were investigated for suspected NSTE-ACS found those who tested negative for troponin (T or I) had a 1.6% incidence of death and a 5.9% incidence of death or AMI after a median of 12 weeks follow-up (mean 24 weeks).29 As such, one-third of patients who went on to develop death or AMI were not identified by troponin testing. Further, while a negative troponin does not exclude ACS a positive troponin does not indisputably prove the diagnosis.

Figure 2

Sensitivity of troponin T by time of presentation.43

Table 1

15

Non-coronary causes of troponin elevations7

Heart failure (acute or chronic) Aortic dissection Valvular heart disease Cardiomyopathies Cardiac contusion Myocarditis Hypertensive crisis Pulmonary embolism Renal failure Subarachnoid haemorrhage Infiltrative diseases, e.g. amyloidosis, haemochromatosis, sarcoidosis, scleroderma Drug toxicity, e.g. adriamycin, 5-fluorouracil, herceptin, snake venoms Burns (>30% body area) Critically ill patients (sepsis, respiratory failure)

Because of the high specificity of modern assays a positive troponin almost universally indicates myocardial necrosis but tells us nothing regarding the aetiology. There are therefore many non-coronary causes of troponin elevations, many of which may present with chest pain (Table 1). Elevation of troponins is also frequently found in patients with chronic renal failure even in the apparent absence of myocardial injury. In this context troponin I may yield fewer false positives than troponin T although the reasons for this are not entirely clear.50 The importance of serial troponin estimation should be emphasised in this population, as sequential changes support a diagnosis of myocardial injury. Troponin levels that remain unchanged over a period of time are more consistent with a chronic disease state.6 It is important to emphasise that troponin elevations are powerful markers of adverse prognosis regardless of the aetiology.33,51 However, the diagnosis of ACS cannot be established or excluded using troponin levels alone. Careful consideration of other clinical information is crucial.

Risk stratification As has been demonstrated clinical features, ECG findings and cardiac troponins when measured at the time of presentation are actually fairly insensitive tools for exclusion of ACS. Further, many patients must wait in hospital for an appropriately timed troponin test, which enables highly sensitive detection of myocardial necrosis but does not identify unstable angina. Risk stratification is a simple contemporary method of addressing this problem. Successful risk stratification will identify populations of patients who are at high and low risk of being diagnosed with AMI and of developing adverse events in the near future. The aims of this are threefold. First, by identifying a high-risk population more aggressive early treatment may be instituted without subjecting lower risk patients to the risks of unnecessary treatment.48,49 Second, the population who are at higher risk of adverse events should be considered for further in-patient investigation and treatment regardless of their troponin result. Finally, a population with a low pretest probability of AMI and at low risk of adverse cardiac

16

R. Body

Table 2

The TIMI risk score for NSTE-ACS100

The TIMI risk score Age ≥65 years ≥3 risk factors for coronary artery disease Significant coronary stenosis (e.g. prior coronary stenosis ≥50%)a Use of aspirin in last 7 days Severe anginal symptoms (e.g. ≥2 anginal events in last 24 h) ST segment deviation Elevated serum cardiac markers

1 point 1 point 1 point 1 point 1 point 1 point 1 point

a

For ED purposes, this may be modified to prior coronary stenosis ≥50%, past history of MI or past history of coronary intervention.56

events in the near future may be suitable for investigation in an ED observation ward. There are multiple risk stratification algorithms available. Many have been validated in large cohorts of patients yet have not been universally adopted. In the absence of direct comparisons between these algorithms in ED cohorts, an outright recommendation cannot be provided for a single algorithm. It is currently reasonable for a risk stratification algorithm to be locally agreed. Perhaps the most widely known algorithm is the Thrombolysis in Myocardial Infarction (TIMI) risk score for non-ST elevation ACS (NSTE-ACS). This score was originally derived using data from 7081 patients with confirmed NSTE-ACS who were enrolled in trials of low molecular weight versus unfractionated heparin.52,53 It is a simple seven-point score that combines historical, ECG and biochemical data and can be easily calculated at the bedside (Table 2). Several studies have shown that the TIMI risk score is a powerful tool for risk stratification of undifferentiated ED patients with suspected ACS.54—58 While the TIMI risk score is correlated with the incidence of adverse events it cannot, alone, be used to guide patient disposition. ED patients with low (0—2) TIMI risk score still have a 5% risk of significant adverse events within 30 days.55,56 A further disadvantage of the TIMI risk score is that it incorporates ECG and troponin results, factors that are already known to independently identify high-risk populations.12—14 Finally, many elements of the TIMI risk score have a fixed value for a particular patient. Thus a high-risk patient is always likely to be high risk, regardless of their current symptoms. Despite these limitations the TIMI risk score is a popular and commonly used risk stratification algorithm. Several other risk stratification algorithms have been described. The Global Registry of Acute Events (GRACE) score incorporates eight independent variables. It has been derived and validated for predicting prognosis among patients with a discharge diagnosis of ACS and in ED patients with undifferentiated chest pain.59—63 Its accuracy appears to be similar to the TIMI risk score.63 Again the GRACE score cannot be used to guide disposition as patients in the bottom quintile still have a 4% risk of adverse events within 1 month. Further, as the score is calculated using a rather complex unequal weighting of variables, a computer pro-

Figure 3

The Goldman risk stratification algorithm.65

gram is necessary for calculation, limiting the applicability within the ED. A computer protocol derived in the pre-troponin era using data from the Multicentre Chest Pain Study was shown to exclude AMI with a sensitivity of 88% (negative predictive value 85%).64 Clearly this is insufficient to facilitate early patient discharge but the algorithm did appear to marginally improve accuracy of triage to a Coronary Care Unit when compared with physician judgement. Using the same patient cohort a second algorithm was also derived, which has arguably had greater clinical impact (Figure 3).65 The algorithm accurately categorised patients into four risk groups according to their probability of developing a major adverse cardiac event within 72 h. While the algorithm itself does not enable early discharge, it may be used to accurately triage patients to an appropriate level of care within the hospital.

Rapid rule out protocols In recent years there has been growing interest in developing rapid rule out protocols that will enable accurate exclusion of AMI earlier than standard troponin testing, thus reducing unnecessary admissions. Several have been described. Serial estimation of CK-MB is a commonly used strategy in clinical practice. However, a meta-analysis of 11,625 patients found that the strategy has a disappointing sensitivity of only 79% for the diagnosis of AMI.18 The concept of multi-marker strategies has also become increasingly popular in recent years. In particular, combinations of three biochemical markers of myocardial necrosis (troponins, CK-MB and myoglobin) have been investigated. Such strategies are theoretically promising as myoglobin and CK-MB are known to rise and fall within hours of onset of AMI. Troponins are not released until several hours following the onset of AMI but the elevated levels are sustained for much longer.18,30,66 While these multi-marker strategies have already been adopted in a number of ED’s, high-quality evidence is still

Emergent diagnosis of acute coronary syndromes: Today’s challenges and tomorrow’s possibilities lacking for their efficacy.67 Even using serial estimations, sensitivity may be below 90% for the detection of AMI, below 80% for the detection of all ACS and around 70% for the prediction of adverse events within 1 month.68—70 Although several other groups have reported high sensitivities and negative predictive values with similar protocols many of them utilised now outdated gold standard criteria for diagnosing AMI and several did not uniformly subject included patients to appropriately timed robust gold standard investigations.71—78,16—26 Current guidelines from the International Liaison Committee on Resuscitation based upon their own systematic review do not recommend the use of rapid rule out protocols within the first 4—6 h of ED evaluation.67 It is important that future research should mandate appropriately timed troponin testing and AMI should be diagnosed according to current guidelines.79 Evaluation of cost-effectiveness is also important. Finally and importantly, it is important to be aware that protocols incorporating markers of myocardial necrosis alone can only, at best, exclude AMI. Patients with unstable angina, who have no significant myocardial necrosis, will not be identified. Protocols incorporating novel markers of alternative aspects of the disease process may help to address this problem.69

Pre-discharge exercise testing The exercise ECG or exercise tolerance test (ETT) is a well-established investigation. It carries a sensitivity of approximately 68% and specificity of 77% for the diagnosis of coronary artery disease.80—82 It is a relatively safe investigation but death and AMI have been reported in up to 1 per 2500 tests.83 Early research suggested that the use of pre-discharge ETT in a Chest Pain Unit (CPU) was associated with a similar rate of complications to routine care but reduced admissions, leading to cost savings.84—86 However, a recent large multicentre randomised controlled trial of CPU versus routine care (the ESCAPE trial) found that CPUs led to an increase in ED attendances for chest pain with no change in the proportion admitted. CPU care was associated with small increases in re-attendances and re-admission.87,88

Future directions There are presently two great challenges in this area: to identify those patients with NSTEMI without needing to wait for the 12-h troponin and to identify those patients with unstable angina who have a normal ECG and troponin but are still at risk of adverse events in the near future. Enhanced understanding of the pathophysiological evolution of ACS is likely to yield growing numbers of imaginative diagnostic strategies. Coronary atherosclerosis is not the bland lipid storage disease it was once thought to be. It is in fact a dynamic inflammatory disease, often characterised by alternating periods of stability and instability with swift and sudden increases in plaque size.89—92 Indeed, two thirds of AMI’s are provoked by plaques that cause less than 50% stenosis on angiography.93 Through intravascular ultrasound it has been possible to characterise the morphology of the vulnerable or unstable plaque.89,94—99

17

While present techniques rely upon identification of the downstream effects of the disease, future research may focus upon diagnostic techniques that identify the unstable or ruptured plaque itself. Novel biochemical markers could potentially identify coronary inflammation (e.g. selectins, myeloperoxidase and C-reactive protein), plaque vulnerability (e.g. pregnancy-associated plasma protein A, choline and soluble CD40 ligand) and activation of the coagulation cascade (e.g. P-selectin, thrombospondin and D-dimer). Their incorporation into multi-marker strategies and clinical decision rules may facilitate earlier and more sensitive diagnosis or exclusion of ACS. The rapid evolution of imaging technologies including computed tomography could soon enable sensitive visualisation of coronary disease. If such techniques are successful they may open up a whole new world of possibilities for the recognition and management of this important disease.

Conclusions The diagnosis of ACS is fraught with difficulty. All of the currently available diagnostic strategies have limitations and it is inevitable that a small proportion of discharged patients will experience adverse events in the near future. Recognition of these limitations and the need for further risk stratification to complement current diagnostic strategies will help the cautious emergency physician to minimise this probability. In order to overcome these limitations and to open up new therapeutic possibilities, future research may focus upon novel diagnostic strategies that aim to directly identify the processes involved in plaque instability and rupture.

Conflict of interest Richard Body has accepted honoraria from Bristol Myers Squibb and PASTEST for lectures given at sponsored meetings. Richard Body is the lead investigator for research into novel biochemical markers of acute coronary syndromes, which is supported by a collaborative agreement with Biosite.

References 1. British Heart Foundation. Mortality statistics 2004. www. heartstats.com; 2005. 2. Fothergill NJ, Hunt MT, Touquet R. Audit of patients with chest pain presenting to an accident and emergency department over a 6-month period. Arch Emerg Med 1993;10:155— 60. 3. Ekelund U, Nilsson HJ, Frigyesi A, Torffvit O. Patients with suspected acute coronary syndrome in a university hospital emergency department: an observational study. BMC Emerg Med 2002;2(1) [1471-227X]. 4. Blatchford O, Capewell S, Murray S, Blatchford M. Emergency medical admissions in Glasgow: general practices vary despite adjustment for age, sex and deprivation. Br J Gen Pract 1999;49:551—4. 5. Collinson P, Premachandram S, Hashemi K. Prospective audit of incidence of prognostically important myocardial damage in patients discharged from emergency department. Br Med J 2000;320:1702—5.

18 6. 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. J Am Coll Cardiol 2007;50(7):e1—157. 7. Bassand JP, Hamm CW, Ardissino D, et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. The Task Force for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes of the European Society of Cardiology. Eur Heart J 2007;28:1598—660. 8. Diercks DB, Peacock WF, Hiestand BC, et al. Frequency and consequences of recording an electrocardiogram >10 min after arrival in an emergency room in non-ST-segment elevation acute coronary syndromes (from the CRUSADE initiative). Am J Cardiol 2006;97:432—42. 9. Menown IB, Mackenzie G, Adgey JA. Optimizing the initial 12-lead electrocardiographic diagnosis of acute myocardial infarction. Eur Heart J 2000;21:275—83. 10. Savonitto S, Ardssino D, Granger CB, et al. Prognostic value of the admission electrocardiogram in acute coronary syndromes. JAMA 1999;281:707—13. 11. Norgaard BL, Andersen K, Thygesen K, et al. Long term risk stratification of patients with acute coronary syndromes: characteristics of troponin T testing and continuous ST segment monitoring. Heart 2004;90:739—44. 12. Jernberg T, Lindahl B. A combination of troponin T and 12lead electrocardiography: a valuable tool for early prediction of long-term mortality in patients with chest pain without STsegment elevation. Am Heart J 2002;144:804—10. 13. Eggers KM, Oldgren J, Nordenskjold A, Lindahl B. Risk prediction in patients with chest pain: early assessment by the combination of troponin I results and electrocardiographic findings. Coronary Artery Dis 2005;16:181—9. 14. Diderholm E, Andren B, Frostfeldt G, et al. The prognostic and therapeutic implications of increased troponin T levels and ST depression in unstable coronary artery disease: the FRISC II invasive troponin T electrocardiogram substudy. Am Heart J 2007;143:760—7. 15. Panju AA, Hemmelgam BR, Guyatt GH, Simei DL. The rational clinical examination: is this patient having a myocardial infarction. JAMA 1998;280(14):1256—63. 16. Speake D, Terry P. First ECG in chest pain. Emerg Med J 2001;18:61—2. 17. Cragg DR, Friedman HZ, Bonema JD, et al. Outcome of patients with acute myocardial infarction who are ineligible for thrombolytic therapy. Ann Int Med 1991;115:173—7. 18. Lau J, Ionnidis JP, Balk EM, et al. Diagnosing acute cardiac ischemia in the emergency department: a systematic review of the accuracy and clinical effect of current technologies. Ann Emerg Med 2001;37(5):453—60. 19. Christian TF, Miller TD, Bailey KR, et al. Exercise tomographic thallium-201 imaging in patients with severe coronary artery disease and normal electrocardiograms. Ann Int Med 1994;121:825—32. 20. Canto JG, Fincher C, Kiefe CI, et al. Atypical presentations among Medicare beneficiaries with unstable angina pectoris. Am J Cardiol 2002;90:248—53. 21. Summers RL, Cooper GJ, Carlton FB, Andrews ME, Kolb JC. Prevalence of atypical chest pain descriptions in a pop-

R. Body

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

ulation from the southern United States. Am J Med Sci 1999;318(3):142. Kannel WB, Abbott RD. Incidence and prognosis of unrecognized myocardial infarction. An update on the Framingham study. N Engl J Med 1984;311:1144—7. Sigurdsson E, Thorgeirsson G, Sigvaldason H, Sigfusson N. Epidemiology, clinical characteristics and the prognostic role of angina pectoris: the Reykjavik Study. Ann Int Med 1995;122(2):96—102. Goodacre S, Locker T, Morris F, Campbell S. How useful are clinical features in the diagnosis of acute, undifferentiated chest pain? Acad Emerg Med 2002;9(3):203—8. Diamond GA, Forrester JS, Hirsch M, et al. Application of conditional probability analysis to the clinical diagnosis of coronary artery disease. J Clin Invest 1980;65:1210. Diamond GA, Forrester JS. Analysis of probability as an aid in the clinical diagnosis of coronary artery disease. N Engl J Med 1979;300:1350. Katus HA, Looser S, Hallermayer K, et al. Development and in vitro characterization of a new immunoassay of cardiac troponin T. Clin Chem 1992;38(3):386—93. Larue C, Ferrieres G, Laprade M, Calzolari C, Graner C. Antigenic definition of cardiac troponin T. Clin Chem Lab Med 1998;36:361—5. Heidenreich PA, Alloggiamento T, Melsop K, McDonald KM, Go AS, Hlatky MA. The prognostic value of troponin in patients with non-ST elevation acute coronary syndromes: a metaanalysis. J Am Coll Cardiol 2001;38(2):478—85. Balk EM, Ioannidis JPA, Salem D, Chew PW, Lau J. Accuracy of biomarkers to diagnose acute cardiac ischemia in the emergency department: a meta-analysis. Ann Emerg Med 2001;37(5):478—94. Ferguson JL, Beckett GJ, Stoddart M, Walker SW, Fox KAA. Myocardial infarction redefined: the new ACC/ESC definition, based on cardiac troponin, increases the apparent incidence of infarction. Heart 2002;88:343—7. Collinson PO, Stubbs PJ, Kessler AC, for the Multicentre Evaluation of Routine Immunoassay of Troponin T study (MERIT). Multicentre evaluation of the diagnostic value of cardiac troponin T, CK-MB mass, and myoglobin for assessing patients with suspected acute coronary syndromes in routine clinical practice. Heart 2003;89:280—6. Srivathsan K, Showalter J, Wilkens J, Hurley B, Abbas A, Loutfi H. Cardiovascular outcome in hospitalized patients with minimal troponin I elevation and normal creatine phosphokinase. Int J Cardiol 2004;97:221—4. Benamer H, Steg PG, Benessiano J, et al. Comparison of the prognostic value of C-reactive protein and troponin I in patients with unstable angina pectoris. Am J Cardiol 1998;82:845—50. Ebell MH, White LL, Weismantel D. A systematic review of troponin T and I values as a prognostic tool for patients with chest pain. J Fam Pract 2000;49:746—53. Hamm CW, Ravkilde J, Gerhardt W, et al. The prognostic value of serum troponin T in unstable angina. N Engl J Med 1992;327(3):146—50. Waxman DA, Hecht S, Schappert J, Husk G. A model for troponin I as a quantitative predictor of in-hospital mortality. J Am Coll Cardiol 2006;48:1755—62. Antman EM, Tanasijevic MJ, Thompson B, et al. Cardiacspecific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med 1996;335:1342—9. Ohman EM, Armstrong PW, Christenson RH, et al. Cardiac troponin T levels for risk stratification in acute myocardial ischaemia. N Engl J Med 1996;335:1333—41. Hamm CW, Heeschen C, Goldmann B, et al. Benefit of abciximab in patients with refractory unstable angina in rela-

Emergent diagnosis of acute coronary syndromes: Today’s challenges and tomorrow’s possibilities

41.

42.

43.

44.

45.

46.

47.

48. 49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

tion to serum troponin T levels. N Engl J Med 1999;340: 1623—9. Hamm CW, Goldmann BU, Heeschen C, Kreymann G, Berger J, Meinertz T. 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;337:1648—53. Richell-Herren K, Maurice S. Troponin T does not rule out myocardial damage until 12 h after the onset of chest pain. Emerg Med J 2000;17:213—4. Tucker JF, Collins RA, Anderson AJ, Hauser J, Kalas J, Apple FS. Early diagnostic efficiency of cardiac troponin I and troponin T for acute myocardial infarction. Acad Emerg Med 1997;4(1):13—21. Fibrinolytic Therapy Trialists Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all major randomised trials of more than 1000 patients. Lancet 1994;343:311—22. Boersma E, Maas ACP, Deckers JW, Simoons ML. Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour. Lancet 1996;348:771—5. Norris RM, et al. Fatality outside hospital from acute coronary events in three British health districts, 1994—5. Br Med J 1998;316:1065—70. The Task Force on Beta-Blockers of the European Society of Cardiology. Expert consensus document on beta-adrenergic receptor blockers. Eur Heart J 2004;25:1341—62. Gidwani S, Body R. Clopidogrel plus aspirin or aspirin alone in unstable angina. Emerg Med J 2006;23:140—2. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;245:494—502. Freda BJ, Tang WH, Van Lente F, Peacock WF, Francis GS. Cardiac troponins in renal insufficiency: review and clinical implications. J Am Coll Cardiol 2002;40:2065—71. Aviles RJ, Askari AT, Lindahl B, et al. Troponin T levels in patients with acute coronary syndromes, with or without renal dysfunction. N Engl J Med 2002;346:2047—52. Antman EM, McCabe CH, Gurfinkel EP, et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q wave myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) 1B trial. Circulation 1999;100:1593—601. Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med 1997;337:447—52. Karounos M, Chang AM, Robey JL, et al. TIMI risk score: does it work equally well in both males and females? Emerg Med J 2007;24:471—4. Chase M, Robey JL, Zogby KE, Sease KL, Shofer FS, Hollander JE. Prospective validation of the thrombolysis in myocardial infarction risk score in the emergency department chest pain population. Ann Emerg Med 2006;48(3):252—9. Pollack CV, Sites FD, Shofer FS, Sease KL, Hollander JE. Application of the TIMI risk score for unstable angina and non-ST elevation acute coronary syndrome to an unselected emergency department population. Acad Emerg Med 2006;13:13—8. Ramsay G, Podogrodzka M, McClure C, Fox KAA. Risk prediction in patients presenting with suspected cardiac pain: the GRACE and TIMI risk scores versus clinical evaluation. Q J Med 2006;100:11—8. Soiza RL, Leslie SJ, Williamson P, et al. Risk stratification in acute coronary syndromes—–does the TIMI risk score work in unselected cases? Q J Med 2005;99:81—7. Eagle KA, Lim MJ, Dabbous OH, et al. A validated prediction model for all forms of acute coronary syndrome. Estimating

60.

61.

62.

63.

64.

65.

66.

67. 68.

69.

70.

71. 72.

73.

74.

75.

76.

77.

19

the risk of 6-month postdischarge death in an international registry. JAMA 2004;291:2727—33. Fox KAA, Dabbous OH, Goldberg RJ, et al. Prediction of risk of death and myocardial infarction in the six months after presentation with acute coronary syndrome: prospective multinational study (GRACE). Br Med J 2006;333:1091—4. Granger CB, Goldberg RJ, Dabbous O, et al. Predictors of hospital mortality in the Global Registry of Acute Coronary Events. Arch Int Med 2003;163:2345—53. The GRACE Investigators. Rationale and design of the GRACE (Global Registry of Acute Coronary Events) project: a multinational registry of patients hospitalized with acute coronary syndromes. Am Heart J 2001;141:190—9. Lyon R, Conway Morris A, Caesar D, Gray S, Gray A. Chest pain presenting to the emergency department—–to stratify risk with GRACE or TIMI? Resuscitation 2007;74:90—3. Goldman L, Cook EF, Brand DA, et al. A computer protocol to predict myocardial infarction in emergency department patients with chest pain. N Engl J Med 1988;318:797—803. Goldman L, Francis Cook E, Johnson PA, Brand DA, Rouan GW, Lee TH. Prediction of the need for intensive care in patients who come to emergency departments with acute chest pain. N Engl J Med 1996;334:1498—504. Nagurney JT, Brown DFM, Chae C, et al. The sensitivity of cardiac markers stratified by symptom duration. J Emerg Med 2005;39(4):409—15. International Liaison Committee on Resuscitation. Part 5: acute coronary syndromes. Resuscitation 2005;67:249—69. Apple FS, Christenson RH, Valdes R, et al. Simultaneous rapid measurement of whole blood myoglobin, creatine kinase MB, and cardiac troponin I by the Triage Cardiac Panel for detection of myocardial infarction. Clin Chem 1999;45(2):199—205. Brown AM, Sease KL, Robey JL, Shofer FS, Hollander JE. The impact of B-type natriuretic peptide in addition to troponin I, creatine kinase-MB, and myoglobin on the risk stratification of emergency department chest pain patients with potential acute coronary syndrome. Ann Emerg Med 2007;49: 153—63. Eggers KM, Oldgren J, Nordenskjold A, Lindahl B. Combining different biochemical markers of myocardial ischemia does not improve risk stratification in chest pain patients compared to troponin I alone. Coronary Artery Dis 2005;16:315—9. Engel G, Rockson SG. Feasibility and reliability of rapid diagnosis of myocardial infarction. Am J Med Sci 2001;322(6):339—44. Fesmire FM. Delta CK-MB outperforms delta troponin I at 2 h during the ED rule out of acute myocardial infarction. Am J Emerg Med 2000;18:1—8. 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—94. Young GP, Murthi P, Levitt MA, Gawad Y. Serial use of bedside CKMB/myoglobin device to detect acute myocardial infarction in emergency department chest pain patients. J Emerg Med 1999;17(5):769—75. Ng SM, Krishnaswamy P, Morissey R, Clapton P, Fitzgerald R, Maisel AS. Ninety-minute accelerated critical pathway for chest pain evaluation. Am J Cardiol 2001;88:611—7. Caragher TE, Fernandez BB, Jacobs FL, Barr LA. Evaluation of quantitative cardiac biomarker point-of-care testing in the emergency department. J Emerg Med 2001;22(1):1—7. Kratz A, Januzzi JL, Lewandrowski KB, Lee-Lewandrowski E. Positive predictive value of a point-of-care testing strategy on first-draw specimens for the emergency department-based detection of acute coronary syndromes. Arch Pathol Lab Med 2002;126:1487—93.

20 78. Jernberg T, Lindahl B, James S, Ronquist G, Wallentin L. Comparison between strategies using creatine kinase-MB (mass), myoglobin, and troponin T in the early detection or exclusion of acute myocardial infarction in patients with chest pain and a nondiagnostic electrocardiogram. Am J Cardiol 2000;86:1367—71. 79. The Joint European Society of Cardiology/American College of Cardiology Committee. Myocardial infarction redefined— –a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction. Eur Heart J 2000;21:1502—13. 80. Gibbons RJ, Balady GJ, Beasley JW, et al. ACC/AHA guidelines for exercise testing: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on exercise testing). J Am Coll Cardiol 1997;30:260—315. 81. Gianrossi R, Detrano R, Mulvihill D, et al. Exercise-induced ST depression in the diagnosis of coronary artery disease: a metaanalysis. Circulation 1989;80(1):87—98. 82. Detrano R, Gianrossi R, Froelicher V. The diagnostic accuracy of the exercise electrocardiogram: a meta-analysis of 22 years of research. Prog Cardiovasc Dis 1989;32(3):173—206. 83. Stuart Jr RJ, Ellestad MH. National survey of exercise stress testing facilities. Chest 1980;77(1):94—7. 84. Goodacre SW. Should we establish chest pain observation units in the UK? A systematic review and critical appraisal of the literature. J Accid Emerg Med 2000;17(1):1—6. 85. Goodacre SW, Morris FM, Campbell S, Arnold J, Angelini K. A prospective, observational study of a chest pain observation unit in a British hospital. Emerg Med J 2002;(2):117—21. 86. Goodacre S, Nicholl J, Dixon S, et al. Randomised controlled trial and economic evaluation of a chest pain observation unit compared with routine care. Br Med J 2004. 87. Goodacre S, et al. The ESCAPE trial: effectiveness and safety of chest pain assessment to prevent emergency admissions. Emerg Med J 2007;24(10):A5 [ref type: abstract]. 88. Goodacre S, et al. Effectiveness and safety of chest pain assessment to prevent emergency admissions: ESCAPE cluster randomised trial. Br Med J 2007;335(7621):659.

R. Body 89. Davies MJ. Stability and instability: two faces of coronary atherosclerosis. The Paul Dudley White Lecture 1995. Circulation 1996;(94):2013—20. 90. Kher N, Marsh JD. Pathobiology of atherosclerosis—–a brief review. Semin Thromb Haemost 2004;30(6):665—72. 91. Libby P. Molecular bases of the acute coronary syndromes. Circulation 1995;91:2844—50. 92. Libby P, Ridker PM. Inflammation and atherothrombosis: from population biology and bench research to clinical practice. J Am Coll Cardiol 2006;48(9 (Suppl. A)):33—46. 93. Little WC, Constantinescu M, Applegate RJ, et al. Can coronary angiography predict the site of subsequent myocardial infarction in patients with mild-to-moderate coronary artery disease? Circulation 1988;78:1157—66. 94. Ge J, Erbel R, Gerber T, et al. Intravascular ultrasound imaging of angiographically normal coronary arteries: a prospective study in vivo. Br Heart J 1994;71:572—8. 95. Ge J, Erbel R, Zamorano J, et al. Coronary artery remodeling in atherosclerotic disease: an intravascular ultrasound study in vivo. Coronary Artery Dis 1993;4:981—6. 96. Losordo DW, Rosenfield K, Kaufman J, Pieczek A, Isner JM. Focal compensatory enlargement of human arteries in response to progressive atherosclerosis: in vivo documentation using intravascular ultrasound. Circulation 1994;89:2570—7. 97. Nissen SE, Gurley JC, Grines CL, et al. Intravascular ultrasound assessment of lumen size and wall morphology in normal subjects and patients with coronary artery disease. Circulation 1991;84:1087—99. 98. Rioufol G, Finet G, Ginon I, et al. Multiple atherosclerotic plaque rupture in acute coronary syndrome: a threevessel intravascular ultrasound study. Circulation 2002;106: 804—8. 99. Schoenhagen P, White RD, Nissen SE, Tuzcu EM. Coronary imaging: angiography shows the stenosis, but IVUS, CT, and MRI show the plaque. Cleveland Clin J Med 2003;70(8):713—9. 100. Antman EM, Cohen M, Bernink PJLM, et al. The TIMI risk score for unstable angina/non-ST elevation MI: a method for prognostication and therapeutic decision making. JAMA 2000;284(7):835—42.