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

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

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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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