Does UA Still Exist in the Era of High-Sensitivity Cardiac Troponin Assays?

The clinical manifestations of acute coronary syndrome (ACS) include myocardial infarction (MI) with and without ST-segment elevation and unstable angina (UA), the latter traditionally regarded as an entity without elevated cardiac troponin (cTn) levels. Among US patients admitted in 2003 with non-ST-segment elevation ACS, the incidence of UA was 42%; that percentage has decreased considerably since then.1 It has been expected that with the introduction of high-sensitivity (hs) cTn assays, UA would become, if not extinct, a rarity.2 However, a Swedish registry-based cohort study recently demonstrated that 15% of 21,398 patients with non-ST-segment elevation ACS who were diagnosed with hs-cTnT were still regarded as having UA.3 At some of the hospitals reporting data to the registry, the incidence of UA exceeded 20%.

This unexpected finding raises several questions. Why does UA appear to be frequently diagnosed when hs-cTn assays are available? Does this reflect the difficulties that clinicians encounter when adapting to hs-cTn results or shortcomings of current diagnostic classifications?

The definition of UA in major guidelines relies on the clinical presentation together with biomarker results that do not fulfill the criteria of MI:4,5 a cTn level above the 99th percentile together with a significant rise and/or fall.6 Accordingly, patients with unstable symptoms and hs-cTn levels either below the 99th percentile or hs-cTn levels above the 99th percentile but without a significant change in serial samples (delta) could be regarded as having UA. Chronic hs-cTn elevation is commonly found in the elderly and patients with cardiovascular comorbidities or renal failure.7 These patients may be labelled with UA if typical symptoms are present. A significant change may also be absent in late presenters with true non-ST-segment elevation MI (NSTEMI) in whom hs-cTn levels have reached a plateau phase. These issues may have contributed to the fact that 60% of the patients with UA from the above-mentioned registry study had a maximum hs-cTnT level above the 99th percentile of 14 ng/L.3

Given the lack of a specific biomarker criterion, the exact definition of UA remains elusive. This introduces substantial subjectivity. Notably, patients with UA have worse outcomes compared with patients without overt cardiac disease regardless of whether the diagnosis is strictly based on criteria outlined in the guidelines or on the clinical impression (Figure 1).3

Figure 1: Risk of Major Cardiovascular Events in Patients With Non-ST-Segment Elevation ACS

Figure 1
Analyses were adjusted for admission year, hospital, age, sex, current smoking, hypertension, diabetes, previous MI, heart failure, previous stroke, ST-segment depression, estimated glomerular filtration rate, and in-hospital coronary revascularization. Controls (patients with hs-cTnT <14 ng/L, no significant coronary stenosis, and discharged without a specified diagnosis) were used as reference. Data adapted from Eggers et al.3

Apart from the overlap between UA and NSTEMI, the assignment of patients to a diagnostic category is also complicated by an overlap existing between UA and high-risk stable angina. Angiographic studies have revealed thrombus or plaque ruptures in up to 17% of patients with putative stable angina.8,9 Plaque ruptures may occur days or weeks before the onset of ischemic symptoms10 and have been found in patients who died from non-cardiac causes.11 Conversely, higher hs-cTn levels are associated with high-risk atheroma features in patients clinically regarded as having stable angina.12,13

The difficulty of defining UA is in part related to the fact that symptoms poorly correlate with the presence of both unstable coronary plaques and hs-cTn levels. A pragmatic way out of this dilemma would be the management of patients according to their cardiac risk. Comprehensive prognostic tools that integrate patient history, signs and symptoms, electrocardiographic findings, and hs-cTn results exist14 and are part of standard clinical assessment in hospitals in Australia, New Zealand, and some European countries.15-18 The use of these tools has been shown to facilitate clinical decisions (for example, hospital admission vs. outpatient assessment) and need for objective testing. The question of whether admitted patients with UA should be targeted to intensified antiplatelet treatment or an early invasive strategy is, however, unresolved. Although a risk gradient exists in these patients across increasing hs-cTn levels,19 studies have failed to prove prognostic benefit from such treatments.20,21 Coronary revascularization may, on the other hand, be considered if the patient is symptom-limited or if features of coronary instability are present (for example, recurrent angina or dynamic ST-segment changes). However, the effect on hard cardiovascular outcomes in patients with UA will be limited.

In summary, patients will likely continue to be labelled with UA even in settings where hs-cTn assays are in use. This relates to the fact that the different manifestations of unstable coronary artery disease represent a continuum as opposed to entities that can be strictly and clearly separated from each other. The use of the term non-ST-segment elevation ACS (instead of UA or NSTEMI) and the management of patients according to their cardiac risk will help to circumvent the limitations of an approach that mainly focuses on distinct diagnostic classifications.

References

  1. Sandoval Y, Apple FS, Smith SW. High-sensitivity cardiac troponin assays and unstable angina. Eur Heart J Acute Cardiovasc Care 2018;7:120-8.
  2. Braunwald E, Morrow DA. Unstable angina: is it time for a requiem? Circulation 2013;127: 2452-7.
  3. Eggers KM, Jernberg T, Lindahl B. Unstable Angina in the Era of Cardiac Troponin Assays with Improved Sensitivity-A Clinical Dilemma. Am J Med 2017;130:1423-30.e5.
  4. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: executive summary and recommendations. 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). Circulation 2000;102:1193-209.
  5. Roffi M, Patrono C, Collet JP, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016;37:267-315.
  6. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Circulation 2012;126:2020-35.
  7. Thygesen K, Mair J, Katus H, et al. Recommendations for the use of cardiac troponin measurement in acute cardiac care. Eur Heart J 2010;31:2197-204.
  8. de Feyter PJ, Ozaki Y, Baptista J, et al. Ischemia-related lesion characteristics in patients with stable or unstable angina. A study with intracoronary angioscopy and ultrasound. Circulation 1995;92:1408-13.
  9. Lee T, Murai T, Yonetsu T, et al. Relationship between subclinical cardiac troponin I elevation and culprit lesion characteristics assessed by optical coherence tomography in patients undergoing elective percutaneous coronary intervention. Circ Cardiovasc Interv 2015;8:e001727.
  10. Rittersma SZ, van der Wal AC, Koch KT, et al. Plaque instability frequently occurs days or weeks before occlusive coronary thrombosis: a pathological thrombectomy study in primary percutaneous coronary intervention. Circulation 2005;111:1160-5.
  11. Arbustini E, Grasso M, Diegoli M, et al. Coronary thrombosis in non-cardiac death. Coron Artery Dis 1993;4:751-9.
  12. Korosoglou G, Lehrke S, Mueller D, et al. Determinants of troponin release in patients with stable coronary artery disease: insights from CT angiography characteristics of atherosclerotic plaque. Heart 2011;97:823-31.
  13. Brown AJ, Shah ASV, West NEJ, et al. High-Sensitivity Troponin I Is Associated With High-Risk Plaque and MACE in Stable Coronary Artery Disease. JACC Cardiovasc Imaging 2017;10:1200-3.
  14. Alley W, Mahler SA. Clinical decision aids for chest pain in the emergency department: identifying low-risk patients. Open Access Emerg Med 2015;7:85-92.
  15. Poldervaart JM, Reitsma JB, Backus BE, et al. Effect of Using the HEART Score in Patients With Chest Pain in the Emergency Department: A Stepped-Wedge, Cluster Randomized Trial. Ann Intern Med 2017;166:689-97.
  16. Ljung L, Lindahl B, Eggers KM, et al. A rapid rule-out strategy based on high sensitive troponin and HEART score implemented in clinical routine is safe and reduces admission to hospital. Eur Heart J 2017;38(Suppl):454.
  17. Parsonage WA, Milburn T, Ashover S, et al. Implementing change: evaluating the Accelerated Chest pain Risk Evaluation (ACRE) project. Med J Aust 2017;207:201-5.
  18. Than MP, Pickering JW, Dryden JM, et al. ICare-ACS (Improving Care Processes for Patients With Suspected Acute Coronary Syndrome): A Study of Cross-System Implementation of a National Clinical Pathway. Circulation 2018;137:354-63.
  19. Bohula May EA, Bonaca MP, Jarolim P, et al. Prognostic performance of a high-sensitivity cardiac troponin I assay in patients with non-ST-elevation acute coronary syndrome. Clin Chem 2014;60:158-64.
  20. James SK, Lindb├Ąck J, Tilly J, et al. Troponin-T and N-terminal pro-B-type natriuretic peptide predict mortality benefit from coronary revascularization in acute coronary syndromes: a GUSTO-IV substudy. J Am Coll Cardiol 2006;48:1146-54.
  21. Wallentin L, Lindholm D, Siegbahn A, et al. Biomarkers in relation to the effects of ticagrelor in comparison with clopidogrel in non-ST-elevation acute coronary syndrome patients managed with or without in-hospital revascularization: a substudy from the Prospective Randomized Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation 2014;129:293-303.

Clinical Topics: Acute Coronary Syndromes, Invasive Cardiovascular Angiography and Intervention, Prevention, Stable Ischemic Heart Disease, Interventions and ACS, Interventions and Imaging, Angiography, Nuclear Imaging, Hypertension, Chronic Angina

Keywords: Acute Coronary Syndrome, Myocardial Infarction, Troponin, Angina, Unstable, Percutaneous Coronary Intervention, Angiography, Stroke, Hypertension, Diabetes Mellitus, Heart Diseases, Thrombosis, Angina, Stable, Platelet Aggregation Inhibitors


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