European Heart Journal Advance Access originally published online on April 24, 2007
European Heart Journal 2007 28(9):1043-1044; doi:10.1093/eurheartj/ehm083
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High-risk acute coronary syndrome patient and cardiac biomarkers in the emergency department: where do we stand?
Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, AR 77205-7199, USA
* Corresponding author. Tel: +1 501 296 1401; fax: +1 501 686 6180. E-mail address: mehtajl{at}uams.edu
This editorial refers to ‘Treatment and outcomes of patients with evolving myocardial infarction: experiences from the SYNERGY trial’
by C.D. Miller et al., on page 1079
Each year, more than five million patients are seen in emergency department (ED) for evaluation of symptoms of myocardial ischaemia. The use of cardiac markers is a standard practice to risk-stratify these patients. The interaction between duration of symptoms, timing of testing, and clearance kinetics of biomarkers determines whether a marker will be positive. Current guidelines of the ACC/ESC recommend serial measurements of CK-MB and/or cardiac troponins.
Cardiac troponins are regulatory proteins with cytosolic and structural pools. They are released upon myocardial necrosis. Troponin levels at admission provide much needed information for the evaluation and prognostication of patients who present with myocardial necrosis.1,2 Troponin data is additive to ECG data and superior to CK-MB results.3,4 Further, troponin elevation has been shown to correlate with the severity of coronary disease and long-term mortality in patients presenting to ED with chest pain.5
Patients with ST-elevation myocardial infarction (STEMI) are different from those with unstable angina (UA) and non-ST-elevation myocardial infarction (NSTEMI) in that they do not need biomarker measurements before institution of reperfusion therapy. However, STEMI patients presenting with elevated troponin on arrival have a lower rate of coronary recanalization, both with thrombolysis and direct percutaneous coronary intervention (PCI)6 and have adverse short- and long-term prognosis.
High-risk acute coronary syndrome (ACS) patients have been extensively studied using troponins and CK-MB. Clinical studies have demonstrated that troponin elevation is a marker of high risk of ischaemic complications and death.1 Actually, the risk of death increases proportionately with the absolute troponin level.7 The diagnostic cut-off for cardiac troponins remains a source of contention. The recommendations from the ACC/ESC document are for a diagnostic cut-off corresponding to the 99th centile of a reference population. Current assays are unable to detect troponin in the majority of normal healthy individuals. This has led to the proposal that an analytical target of percentage coefficient of variation of 10 be used as the cut-off for normal.1 However, clinical trials have used different troponin levels ranging from 0.01 to 0.1 ng/mL to define NSTEMI.8
About 30% of the patients with NSTEMI have positive troponins and negative CK-MB at presentation.9 Many studies have explored the implications of discordant cardiac markers at presentation to the hospital in the setting of ACS. Discordant markers are seen in 7–28% of patients in prospective studies.10 Rao et al.11 analysed this discordance using data form GUSTO IIa, PARAGON, and CHECKMATE studies and found troponins to be the most effective prognostic marker both at 24 h and at 30 days. Similar results were seen in the CRUSADE registry.12 High-risk ACS patients with elevated troponin do better with early invasive therapy, glycoprotein (GP) IIb/IIIa inhibitors, anti-platelet agents, and low molecular-weight heparins.1 The impact of a positive or negative troponin at presentation thus would seem to be central to the management decision. This brings us to a rather paradoxical question—what about the UA/NSTEMI patients with negative cardiac troponins in the ED?
Miller et al.13 have addressed the issue of troponin elevation in the first 12 h after presentation to ED and subsequent in-hospital clinical management and 30-day composite outcome of death and re-infarction. They analysed data from the SYNERGY trial,14 which enrolled patients meeting at least two of the following factors: age 
60 years, elevated cardiac biomarkers, and ST-segment changes. Patients were stratified by troponin results obtained within 12 h of presentation. The study highlights the temporal relationship between onset of symptoms and troponin level at presentation to ED. About 45% of the evolving MI patients had age >60 or ECG changes at presentation. It is interesting that this group took a median of about 8 h longer to get enrolled in the study as compared to the subset with age >60 years and positive ECG changes It is conceivable that this delay is directly related to the time it would have taken to get a set of positive biomarkers. About 50% of patients in the evolving MI and definite MI groups underwent PCI within 24 h and another 20% underwent coronary artery bypass grafting in both the groups. Since SYNERGY trial employed an early invasive strategy, this is not surprising. Despite earlier studies like PURSUIT12 showing an almost 1.5% absolute risk reduction in a similar population and ACC/ESC guidelines for NSTEMI,1 the utilization of GP IIb/IIIa inhibitors remains dismal in this population.
The SYNERGY trial showed no difference in the outcome of death at 30 days between enoxaparin and unfractionated heparin. Is the mortality difference at 30 days between the unfractionated heparin and enoxaparin group in the evolving MI group (1.7 vs. 3.2) then just a function of time to enrollment? Given that 77% of the patients in the evolving MI group were already on some sort of heparin, this seems unlikely. This result is intriguing, though it is tempered by the strict inclusion exclusion criteria of the SYNERGY trial and potential exclusion of many eligible patients.
The no-MI group essentially provides data about patients with unstable angina, and the outcome of these patients was comparable to that seen in GUSTO IV and CRUSADE studies. There is still a high (6–8%) incidence of MI at 30 days even with improvement in evidence-based therapy. Nonetheless, there has been a significant improvement in mortality, from about 5% in GUSTO IV study to about 1.7% in the current analysis. Aggressive therapy with beta-blockers, angiotensin converting enzyme-inhibitors, and heparin/GP IIb/IIIa probably contributed to this decline.
This analysis is a post hoc analysis and can serve as a hypothesis-generating evaluation. The study suffers from selection bias introduced by the exclusion of patients (about 15%) based on non-availability of troponin data, exclusion of sicker patients that underwent PCI or CABG prior to enrolment and patients with incomplete data sets. Nevertheless, this study suggests the potential for more aggressive application of evidence-based medicine with the help of cardiac biomarkers. It again highlights the need to better define and standardize cardiac troponin assays, so as to maximize the yield upfront in the ED. A prospective study evaluating early treatment strategies for UA/NSTEMI patients in the first 12 h and their potential outcomes is needed.
Conflict of interest: none declared.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
doi:10.1093/eurheartj/ehm016 
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[Abstract/Free Full Text]
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Related articles in EHJ:
- Treatment and outcomes of patients with evolving myocardial infarction: experiences from the SYNERGY trial
- Chadwick D. Miller, Anindita Banerjee, Kenneth W. Mahaffey, Michael C. Kontos, Gregory Fermann, Charles V. Pollack, Jr., Elliott Antman, Philip Aylward, Shaun G. Goodman, Renato Santos, James J. Ferguson, Robert M. Califf, and James W. Hoekstra
EHJ 2007 28: 1079-1084.[Abstract] [FREE Full Text]
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