Risk Stratification in Patients with Unstable Angina and Non-ST Segment Elevation Myocardial Infarction: Evidence-Based Review

Unstable angina (UA) and non-ST elevation myocardial infarction (NSTEMI) are closely related clinical syndromes; they are often undistinguishable at presentation, and often entail similar early diagnostic and therapeutic approach. Unstable angina is defined as: 1) angina that occurs at rest or with minimal exertion; 2) new onset angina (within one month) with Canadian Cardiovascular Society Classification III or IV in severity; or 3) worsening previously stable angina. First attempts in evaluating UA were directed toward ruling out myocardial infarction (MI).1–5 More modern approaches consider NSTEMI (or non-Q wave MI) to be a more severe state of the same clinical syndrome. This syndrome is often referred to as non-ST elevation acute coronary syndrome (ACS). Risk stratification is of crucial importance for the practice of contemporary medicine, especially when dealing with patients presenting with UA/NSTEMI, due to the wide range of acuity and risk of untoward outcome. The frequency of hospital admissions and the cost of diagnosis and management of suspected UA/NSTEMI make this an important health care issue. It is estimated that more than 1.4 million patients are admitted to American hospitals every year with suspected UA.6–8 The value of risk stratification is apparent, since a substantial portion of these patients are at low risk for cardiac events and can be treated as outpatients with huge cost savings, and higher risk patients can be effectively managed with aggressive medical and interventional therapy, resulting in lower event rates and costs.9 On the other hand, identifying patients at increased risk for cardiac events is crucial from the therapeutic point of view. As a general principle, patients at increased risk for unfavorable outcome have incremental benefit from therapeutic interventions. This principle is especially applicable to patients presenting with UA/NSTEMI. Early risk stratification attempts used electrocardiogram (ECG) changes as indicators of increased risk. ST-segment deviation >= 1 mm (ST depression or transient elevation) and dynamic T-wave inversion >= 3 mm were found to be important markers of adverse outcome (death, MI) and anatomic severity of coronary artery disease (CAD).10,11 More recent data from the TIMI-III registry have found left bundle branch block and ST deviation (>= 0.5 mm) to be independent predictors of death in 1 year. Other investigators found incremental risk with increasing ST-segment depression on admission ECG.12,13 GUSTO-IIb data showed that ST-segment depression carries worse prognosis than T-wave inversion.14 Braunwald was the first to establish a comprehensive classification scheme for patients presenting with UA (Table 1). He classified UA based on the acuity of the pain syndrome (progressive exertional angina, rest pain within 2 weeks but none in the past 48 hours, and rest pain within the past 48 hours) and certain clinical circumstances (extracardiac exacerbation, primary, and after MI within the past 14 days). Theses classes can be further subdivided based on the intensity of antianginal treatment at presentation, and the presence or absence of ST-segment depression during chest pain. The ability of this classification to predict risk of cardiac events has been validated in several studies.16–18 In the TIMI-III registry, the Braunwald classification was found to be an important predictor of death or MI after 1 year, both by the severity of chest pain syndrome and by the clinical circumstances in which it occurred.16 Risk stratification models The RUSH model. Calvin et al.18 have validated 4 of the Braunwald characteristics in a cohort of 393 patients admitted with clinical diagnosis of UA, who were followed for events of death, MI, congestive heart failure and ventricular arrhythmias. Using multivariate logistic regression analyses, these investigators identified 4 factors used in the Braunwald classification that predict in-hospital occurrence of cardiac complications: 1) MI within = 65 years (OR, 1.48 per decade) to be significant risk predictors beyond Braunwald classification. The need for intravenous NTG in this study seems to be equivalent to the high-risk factor of ongoing rest pain in the Agency for Health Care Policy and Research (AHCPR) guidelines published in 1994.7 These investigators have also provided a risk assessment formula to calculate risk of cardiac events (RUSH score). This is based on the multiplication of the odds ratios of a combination of risk factors in a given patient. The resulting odds ratio can help define risk for cardiac events in a given patient compared to a reference group free of these factors. The problem with such a calculation is that it is demanding and may not be practical in daily clinical encounters. The AHCPR model. In 1994, The AHCPR7 issued practice guidelines for the evaluation and management of UA. They classified patients into 3 risk categories for death or MI (low, medium and high). This is largely based on the predicted likelihood of CAD combined with history, physical, and ECG findings at presentation (Table 2). The high-risk category contains patients with prolonged ongoing chest pain, ST depression (>= 1mm) and/or hemodynamic compromise (congestive heart failure, hypotension, etc.). The intermediate-risk category contains patients with rest angina that resolved, or new onset angina ( 65 years). Low-risk patients lack all criteria for high or intermediate risk, but have progressive angina or new onset angina (2 weeks–2 months) with normal ECG. A prolonged ongoing chest pain is an indication for intravenous NTG, which suggests that the need for intravenous NTG in the RUSH model is synonymous to prolonged chest pain in AHCPR guidelines. Although the individual risk factors were validated in prior studies, this model was not validated prior to publication. In a head-to-head comparison study between the AHCPR and RUSH models, Calvin et al.19 prospectively validated both models and showed that cardiac events (composite of death, MI and heart failure) occurred less frequently in low-risk patients in the RUSH model (3%) compared to the AHCPR low-risk group (5%). In addition, the RUSH model identified five times more low-risk patients than the AHCPR model. Adherence to AHCPR guidelines was subsequently shown to decrease cardiac events, in comparison to historical matching cohort before the publication of the AHCPR guidelines. This was a result of early intensive medical management (beta-blockers, heparin, aspirin, and nitrate) in the study patients identified to be at high risk.20 Cardiac markers and cardiac-specific troponins In the past decade, cardiac specific troponins T (cTnT) and I (cTnI) have emerged as sensitive and specific markers of myocardial necrosis.21–24 It is worth noting that when interpreting the results of cTnT or cTnI assays, clinicians must recognize several analytical issues. The first generation of cTnT assays exhibited some nonspecific binding to skeletal muscle troponin, but this was corrected in subsequent generations of assays. The cTnT assays are produced by a single manufacturer, leading to relative uniformity of diagnostic cut-off levels, whereas multiple manufacturers produce cTnI assays,25,26 which leads to variations in the cut-off concentration for abnormal levels of cTnI in the clinically available immunoassays. This resulted in differences in the diagnostic performance (sensitivity and specificity) between various assays. Thus, when using the measurement of cTnI for diagnosing acute MI, clinicians should apply the cut-off values for the particular assays used in their laboratory. Similarly, when reading and applying cardiac troponin values from a clinical trial, the type of troponin measured (T versus I) and type of assay used in the trial should always be kept in mind. For both cTnT and cTnI, the definition of an abnormally increased level is a value exceeding that of 99% of a reference control group.22 A rapid cTnT assay bedside kit is currently available, and can detect cTnT-positive patients. Also, “time to positivity” (i.e., time for the test to turn positive) correlates with cTnT level.24,27 The diagnosis of NSTEMI is associated with worse long-term prognosis than UA without evidence of myocardial necrosis.21,28 The value of cardiac-specific troponins I and T has been established as a powerful risk stratification tool in patients presenting to the emergency room with chest pain24,29 and was found to be an excellent predictor of cardiac events beyond clinical, ECG or CK-MB findings in patients with UA/NSTEMI.30,31 Cardiac troponins are more sensitive and specific markers of myocardial necrosis.32–34 The ability of troponin assays to detect minor myocardial damage or “microinfarction”, which may result from severe ischemia or downstream embolization from a coronary thrombus, enhances their prognostic value beyond CK-MB levels.35,36 In fact, “troponin-positive” patients with normal CK-MB values at presentation have increased risk of death and cardiac complications compared to those who are “troponin-negative” (Figure 1).30,31 In the TIMI-11A and TIMI-11B troponin-I substudies, there was a remarkable increase in the rate of death, MI, urgent revascularization and the composite outcome of all these adverse outcomes at 14 days in UA patients with elevated troponin I level compared to patients with normal values (Figure 2).37,38 Furthermore, the value of troponins is not limited to whether they are merely “positive” or “negative”; there is also an excellent linear correlation between troponin levels and worsening outcome, as shown in the TIMI-IIIB registry (Figure 3).31 Cardiac troponin levels also correlate with the severity of coronary artery disease, complexity of atherosclerotic lesions, thrombus burden, TIMI flow, and left ventricular function impairment.35,36 The value of cardiac troponins does not stop at risk stratification, but rather extends into predicting UA/NSTEMI patients who would benefit the most from novel medical therapies and an invasive approach. Two major studies addressing the use of the low molecular weight heparin enoxaparin versus unfractionated heparin have shown that enoxaparin therapy significantly reduces cardiac events (death, MI or urgent revascularization) beyond unfractionated heparin.39–41 In the TIMI-11B cTnI substudy,38 patients with elevated cTnI levels treated with enoxaparin had fewer adverse clinical events (death, MI and urgent revascularization) by 14 days, with a greater relative risk reduction from enoxaparin therapy compared to those with normal cTnI values (Figure 4). Several major studies have established the benefit of glycoprotein (GP) IIb/IIIa inhibitors in the management of patients with ACS in addition to standard medical therapy (aspirin and heparin ± beta-blocker) with or without percutaneous coronary intervention (PCI).42–45 Subgroup analyses of patients with elevated cardiac troponin levels in two of these studies [CAPTURE (cTnT) and PRISM (cTnI)] have shown a remarkable benefit from GP IIb/IIIa treatment in patients with elevated troponin level, with no significant benefit in patients with normal cTn levels (Figures 5A and 5B).46,47 The debate about the ideal approach for the management of patients with UA/non-Q wave MI (i.e., early invasive versus early conservative) has been ongoing for the past decade.48–50 More recently, the TACTICS-TIMI 18 trial51 has conclusively shown that an early invasive approach using the GP IIb/IIIa inhibitor tirofiban and coronary stenting in addition to standard medical therapy (aspirin + heparin ± beta-blocker) is superior to early conservative management (aspirin + heparin + tirofiban ± beta-blocker). A subgroup analysis of patients with elevated cTnT levels has shown a remarkable 40% relative risk reduction of cardiac events (death, MI, rehospitalization for ACS) at 6 months with early invasive management compared to early conservative management, whereas patients with normal cTnT level did not receive any benefit from early invasive approach (Figure 6).

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