Unstable Angina/Non–ST-Segment Elevation Myocardial Infarction

Suzanne J. Baron

Christopher P. Cannon

Marc S. Sabatine

The spectrum of acute coronary syndromes (ACS) ranges from unstable angina (UA) to non–ST-segment elevation myocardial infarction (NSTEMI) to ST-segment elevation myocardial infarction (STEMI) [1]. The latter condition is usually caused by acute total obstruction of a coronary artery [2,3], and urgent reperfusion is the mainstay of therapy. In contrast, the non–ST-segment elevation acute coronary syndromes (NSTEACS)—UA and NSTEMI—are usually associated with a severe, although nonocclusive, lesion in the culprit coronary artery [4].

Every year in the United States, approximately 1.3 million patients are admitted to the hospital with ACS; about 900,000 of these patients are suffering from UA/NSTEMI as compared with approximately 400,000 patients suffering from STEMI [5,6]. Worldwide, these numbers are each several times the totals in the United States. In the past few years, numerous advances have been made in the understanding of the pathophysiology, diagnosis, risk stratification, and management of UA/NSTEMI.

Definition

The definition of UA is largely based on the clinical presentation. Angina pectoris is characterized by a poorly localized chest or arm discomfort or pressure (rarely described by patients as “pain”) that is typically and reproducibly associated with physical exertion or emotional stress, and relieved by rest or sublingual nitroglycerin. UA is defined as angina pectoris (or equivalent type of ischemic discomfort) with one of three features: (a) occurring at rest (or with minimal exertion), usually lasting more than 20 minutes; (b) being severe and of new onset (i.e., within 1 month); or (c) occurring with a crescendo pattern (i.e., more severe, prolonged, or frequent) [7]. Some patients with this pattern of ischemic pain develop evidence of myocardial necrosis on the basis of serum biomarkers in the absence of ST-segment elevations on electrocardiogram (ECG) and thus have a diagnosis of NSTEMI. Previously, this diagnosis has been based on elevation of the creatine kinase (CK)-MB, but elevations in cardiac troponin T or I greater than the 99th percentile of the upper limit of normal now define MI on the basis of their higher sensitivity and specificity for myocardial necrosis and powerful prognostic capability [8].

Pathophysiology

The development of UA/NSTEMI is due either to a reduction in the supply of blood flow and oxygen, or to an increase in myocardial oxygen demand, or both. The five broad etiologies are (a) plaque rupture with superimposed nonocclusive thrombus; (b) dynamic obstruction (i.e., coronary spasm); (c) progressive mechanical obstruction (i.e., restenosis); (d) inflammation and arteritis; and (e) conditions leading to increased myocardial oxygen demand, such as anemia, sepsis, or hypoxia [9]. Individual patients may have several of these processes contribute to the onset of their UA/NSTEMI.

Plaque Rupture

Atherosclerosis is a silent process that usually begins 20 to 30 years prior to a patient’s clinical presentation [10,11]. Plaque rupture can be precipitated by multiple factors, including endothelial dysfunction [12], plaque lipid content [13], local inflammation [14], coronary artery tone at the site of irregular plaques and local shear stress forces, platelet function [15,16], and the status of the coagulation system (i.e., a potentially prothrombotic state) [17,18]. These processes culminate in formation of platelet-rich thrombi at the site of the plaque rupture or erosion and the resultant ACS [19,20,21].

Thrombosis

Coronary artery thrombosis plays a central role in the pathogenesis of UA/NSTEMI [4,19,20,22,23,24,25,26], as demonstrated in the Thrombolysis in Myocardial Infarction (TIMI) IIIA trial, in which 35% of patients had definite thrombus and an additional 40% had possible thrombus [4]. Thrombosis occurs in two interrelated stages: (a) primary hemostasis and (b) secondary hemostasis [27,28]. The first stage of hemostasis is initiated by platelets as they adhere to damaged vessels and form a platelet plug. With rupture or ulceration of an atherosclerotic plaque, the subendothelial matrix (e.g., collagen and tissue factor) is exposed to the circulating blood. Platelets then adhere to the subendothelial matrix via the glycoprotein (GP) Ib receptor and von Willebrand’s factor (platelet adhesion). After adhering to the subendothelial matrix, the platelet undergoes a conformational change from a smooth discoid shape to a spiculated form, which increases the surface area on which thrombin generation can occur. This leads to degranulation of the alpha- and dense granules and the subsequent release of thromboxane A2, adenosine diphosphate (ADP), serotonin, and other platelet aggregatory and chemoattractant factors, as well as the expression and activation of GP IIb/IIIa receptors on the platelet surface such that it can bind fibrinogen. This process is called platelet activation. The final step is platelet aggregation, that is, the formation of the platelet plug. Fibrinogen (or von Willebrand’s factor) binds to the activated GP IIb/IIIa receptors of two platelets, thereby creating a growing platelet aggregate. Antiplatelet therapy has been directed at decreasing the formation of thromboxane A2 (aspirin), inhibiting the ADP pathway of platelet activation (thienopyridines), and directly inhibiting platelet aggregation (GP IIb/IIIa inhibitors; Fig. 38.1).

Figure 38.1. Primary hemostasis—process of platelet adhesion, activation, and aggregation. Platelets initiate thrombosis at the site of a ruptured plaque: the first step is platelet adhesion (A) via the glycoprotein (GP) Ib receptor in conjunction with von Willebrand’s factor. This is followed by platelet activation (B), which leads to a shape change in the platelet, degranulation of the alpha and dense granules, and expression of GP IIb/IIIa receptors on the platelet surface with activation of the receptor, such that it can bind fibrinogen. The final step is platelet aggregation (C), in which fibrinogen (or von Willebrand’s factor) binds to the activated GP IIb/IIIa receptors of two platelets. Aspirin (ASA) and clopidogrel act to decrease platelet activation (see text for details), whereas the GP IIb/IIIa inhibitors inhibit the final step of platelet aggregation. [Adapted from Cannon CP, Braunwald E: Unstable angina, in Braunwald E, Zipes DP, Libby P (eds): Heart Disease: A Textbook of Cardiovascular Medicine. 6th ed. Philadelphia, WB Saunders, 2001, pp 1232–1263, with permission.]

Secondary Hemostasis

Simultaneous with the formation of the platelet plug, the plasma coagulation system is activated (Fig. 38.2). Following plaque rupture, the injured endothelial cells on the vessel wall become activated and release protein disulfide isomerase, which acts to cause a conformational change in circulating tissue factor [29,30,31,32]. Tissue factor can then bind to factor VIIa and form a protein complex, leading to the activation of factor X. With the activation of factor X (to factor Xa), thrombin is generated and acts to cleave fibrinogen to form fibrin. Thrombin plays a central role in arterial thrombosis: (a) it converts fibrinogen to fibrin in the final common pathway for clot formation; (b) it is a powerful stimulus for platelet aggregation; and (c) it activates factor XIII, which leads to cross-linking and stabilization of the fibrin clot [27].

Figure 38.2. Diagram of the major components of the clotting cascade and the areas targeted by antithrombotic agents.

Coronary Vasoconstriction

Another etiologic factor in UA/NSTEMI is dynamic obstruction, that is, coronary vasoconstriction. The process is identified in three settings: (a) vasospasm in the absence of obstructive plaque, (b) vasoconstriction in the setting of atherosclerotic plaque, and (c) microcirculatory angina. Vasospasm can occur in patients without coronary atherosclerosis or in those with a nonobstructive atheromatous plaque. Vasospastic angina appears to be due to hypercontractility of vascular smooth muscle and endothelial dysfunction occurring in the region of spasm. Prinzmetal’s variant angina, with intense focal spasm of a segment of an epicardial coronary artery, is the prototypic example [33]. Such patients have rest pain accompanied by transient ST-segment elevation. Vasoconstriction more commonly occurs in the setting of significant coronary atherosclerotic plaque, especially those with superimposed thrombus. Vasoconstriction can occur as the result of local vasoconstrictors released from platelets, such as serotonin and thromboxane A2 [34,35,36]. Vasoconstriction can also result from a dysfunctional coronary endothelium, which has reduced production of nitric oxide and increased release of endothelin. Adrenergic stimuli, cold immersion [37], cocaine [38,39], or mental stress [40] can also cause coronary vasoconstriction in susceptible vessels. A third setting in which vasoconstriction is identified is microcirculatory angina (“syndrome X”). In this condition, ischemia results from constriction of the small intramural coronary resistance vessels [41]. Although no epicardial coronary artery stenoses are present, coronary flow is usually slowed and does not increase appropriately in response to a variety of signals.

Progressive Mechanical Obstruction

Another etiology of UA/NSTEMI results from progressive luminal narrowing. This is most commonly seen in the setting of restenosis following percutaneous coronary intervention (PCI). However, angiographic [42] and atherectomy studies [43,44] have demonstrated that many patients without previous PCI show progressive luminal narrowing of the culprit vessel, likely related to rapid cellular proliferation, in the period preceding the onset of UA/NSTEMI.

Table 38.1 Braunwald Clinical Classification of Unstable Angina

Class	Definition	Death or myocardial infarction to 1 y^a (%)
Severity
Class I	New onset of severe angina or accelerated angina; no rest pain	7.3
Class II	Angina at rest within past month but not within preceding 48 h (angina at rest, subacute)	10.3
Class III	Angina at rest within preceding 48 h (angina at rest, subacute)	10.8^b
Clinical circumstances
A (secondary angina)	Develops in the presence of an extracardiac condition that intensifies myocardial ischemia	14.1
B (primary angina)	Develops in the absence of an extracardiac condition	8.5
C (postinfarction angina)	Develops within 2 wk after acute myocardial infarction	18.5^c
Intensity of treatment	Patients with unstable angina can also be divided into three groups depending on whether unstable angina occurs: (a) in the absence of treatment for chronic stable angina, (b) during treatment for chronic stable angina, or (c) despite maximal anti-ischemic drug therapy. These three groups can be designated subscripts 1, 2, or 3, respectively	—
Electrocardiographic changes	Patients with unstable angina can be further divided into those with or without transient ST-T–wave changes during pain	—
^aData from Scirica BM, Cannon CP, McCabe CH, et al: Prognosis in the thrombolysis in myocardial ischemia III registry according to the Braunwald unstable angina pectoris classification. Am J Cardiol 90(8):821, 2002. ^b p = 0.057. ^c p < 0.001. Reprinted from Braunwald E: Unstable angina: a classification. Circulation 80:410, 1989, with permission.

Secondary Unstable Angina

Secondary UA is defined as UA precipitated by conditions extrinsic to the coronary arteries in patients with prior coronary stenosis and chronic stable angina. This change could occur either as a result of an increase in myocardial oxygen demand or as a decrease in coronary blood flow. Conditions that increase myocardial demand include tachycardia (e.g., a supraventricular tachycardia or new-onset atrial fibrillation with rapid ventricular response), fever, thyrotoxicosis, hyperadrenergic states, and elevations of left ventricular (LV) afterload, such as hypertension or aortic stenosis. Secondary UA can also occur as a result of impaired oxygen delivery, as in anemia, hypoxemia (e.g., due to pneumonia or congestive heart failure), hyperviscosity states, or hypotension. Although one might expect secondary angina to be associated with a more favorable prognosis, it appears to have a worse prognosis than primary UA [45] (Table 38.1), likely due to serious patient comorbidities.

Clinical Presentation and Diagnosis

History and Physical Examination

A description of “ischemic pain” is the hallmark of UA/NSTEMI. Ischemic chest pain is usually described as a discomfort or pressure (rarely as a pain) that is brought on by exertion and relieved by rest. It is generally located in the retrosternal region but sometimes in the epigastrium and frequently radiates to the anterior neck, left shoulder, and left arm. The physical examination may be unremarkable or may support the diagnosis of cardiac ischemia [46]. Signs that suggest ischemia are sweatiness, pale cool skin, sinus tachycardia, a fourth heart sound, and basilar rales on lung examination.

Electrocardiogram

The ECG is the most widely used tool in the evaluation of ischemic heart disease. In UA/NSTEMI, ST-segment depression (or transient ST-segment elevation) and T-wave changes occur in up to 50% of patients [47,48,49]. Two analyses have shown ST-segment deviation even of only 0.5 mm to be a specific and important measure of ischemia and prognosis (see later in the chapter) [47,50]. T-wave changes are generally considered less specific than ST-segment changes and the presence of T-wave inversions of only 1 mm in patients with acute ischemic syndromes may add little to the clinical history. T-wave inversions of greater than or equal to 3 mm are considered significant [47,50].

Cardiac Biomarkers

UA is not associated with any detectable damage to the myocyte. The diagnosis of NSTEMI is made if there is biochemical evidence of myocardial necrosis, that is, a positive cardiac troponin T or I or CK-MB. The cut point for definition of an MI is elevation in troponin T or I greater than the 99th percentile of the upper reference range [8]. Although false-positive troponin elevations do occur [51], elevations in cardiac biomarkers in the absence of other clinical data consistent with an ACS usually do represent true myocardial damage. In these cases, myocyte damage is due to etiologies besides atherosclerotic coronary artery disease, such as myocarditis, LV strain from congestive heart failure, hypertensive crisis, or right ventricular strain from pulmonary embolus [52].

Unfortunately, the limitation of standard troponin assays is that they tend to have a low sensitivity in the first few hours of symptom onset and become positive only usually 6 to 12 hours after symptom onset. However, the recent development of high-sensitivity troponin assays has significantly
improved the sensitivity of this test. Two recent studies have found that the use of high-sensitivity assays improve the early diagnosis of MI with sensitivity now exceeding 90% when tested in patients with chest pain at the time of presentation to the hospital [53,54]. Moreover, high-sensitivity assays can detect elevated levels of troponin in approximately 10% of outpatients with stable coronary disease, and these individuals are at a higher risk of subsequent cardiovascular death [55].

Ultrasensitive troponin assays, which have limits of detection lesser than the levels seen in a normal reference population, are also being developed. In a study looking at patients with NSTEACS, 72% of patients with NSTEMI were found to have circulating troponin levels at baseline greater than the 99th percentile (nano-cTnI > 0.003 μg/L) when ultrasensitive troponin assays were utilized; yet all of these patients had an initially negative current-generation troponin assay. When these assays were used in patients presenting with UA (defined as lack of elevation of troponin using a current-generation commercial assay), 44% of patients had circulating troponin levels greater than the 99th percentile and 8 hours later, the percentage had risen to 82% [56]. Similarly, ultrasensitive assays have been used to detect rises in circulating troponin in proportion to the amount of ischemia experienced during exercise stress testing [57]. Thus, in the future, troponin may move from a semiquantitative assay (“negative” in most individuals and quantified in a subset) to quantifiable in all patients. The clinical implications of very low level values reported from ultrasensitive assays will need to be defined.

Cardiac Imaging

Currently, cardiac imaging is assuming increasing importance in the early diagnosis of patients presenting with suspected UA/NSTEMI, especially when the ECG is normal, nonspecific, or obscured by left bundle branch block or a paced rhythm. Myocardial perfusion imaging using technetium sestamibi has been useful for patients presenting with chest pain in the emergency department without a diagnostic ECG or positive biomarkers to discriminate patients with coronary artery disease from those with noncardiac chest pain [58,59]. Similarly, echocardiography is useful to screen for regional or global LV dysfunction, which may help in establishing (or excluding) the diagnosis of ischemic heart disease in patients who present to the emergency department with chest pain [60]. Coronary computed tomography angiogram (CTA) has also been shown to be effective in excluding coronary artery disease in patients presenting to the emergency department with a low-risk story of chest pain, nondiagnostic ECG, and negative biomarkers [61]. All of these modalities can also assess LV function, a powerful determinant of subsequent prognosis after MI (and presumably after UA) [62,63,64]. Coronary angiography is also used to establish the diagnosis of ACS and is considered the gold-standard modality to define the extent of coronary disease, and as a prelude to percutaneous revascularization (see later in the chapter) [4,48,65,66].

Risk Stratification

Given the multitude of treatment options for patients with UA/NSTEMI, risk stratification currently refers to two simultaneous processes (frequently carried out at the time of hospital presentation): (a) risk assessment (i.e., prediction of mortality/morbidity risk), and (b) selection of a management strategy (i.e., an early invasive vs. early conservative approach).

Risk assessment, using clinical and laboratory markers, identifies which patients are at highest risk for adverse outcomes. Moreover, data from several trials have demonstrated that early risk assessment (especially using troponins) has also been useful in predicting which patients will derive the greatest benefit from newer and more potent antithrombotic therapies, such as low-molecular-weight heparin (LMWH) and GP IIb/IIIa inhibitors. Risk assessment can similarly be used to determine the most appropriate level of care and monitoring (i.e., between the coronary intensive care unit or the step-down/telemetry unit). The “management strategy” refers to whether early angiography is performed with revascularization as appropriate directly following the index event or whether a conservative or ischemia-driven strategy is carried out, with noninvasive assessment of residual ischemia, and angiography and revascularization performed only if recurrent ischemia is documented (see later in the chapter).

Risk Assessment Using Clinical Predictors

The initial clinical evaluation can be used to risk-stratify patients quickly and assist in the triage [67,68]. As described in the ACC/AHA UA/NSTEMI guideline (Table 38.2), high-risk patients can be identified by the presence of prolonged, ongoing pain at rest, ST-segment depression of greater than or equal to 0.1 mV, positive troponin value, or the presence of hypotension or congestive heart failure on physical examination [67]. Such patients should be considered for the coronary care unit although the cardiac step-down (telemetry) unit may be adequate depending on the clinical situation. Lower risk patients can be adequately monitored and managed in a step-down unit.

Individual High-Risk Subgroups

Trials have identified several clinical subgroups that are at higher risk of adverse outcomes when they present with UA/NSTEMI. These groups derive greater benefit from more aggressive therapy.

Elderly Patients

Elderly patients comprise a subgroup for which outcomes are always worse compared with younger patients. In UA/NSTEMI, elderly patients appear to derive greater benefit from the newer, more potent antithrombotic therapies. In the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE) trial, enoxaparin had greater benefit in patients 65 years or older as compared with younger patients [69]; a similar finding was noted in the TIMI 11B trial [70]. For the GP IIb/IIIa inhibitors, an equivalent relative benefit was observed in older versus younger patients, although the absolute benefit in number of events prevented is higher in elderly patients because they have higher baseline risk [49,71,72]. However, this increase in absolute benefit comes with the added price of an increased incidence of bleeding with GP IIb/IIIa inhibitors in elderly patients [71,72]. With regard to an invasive versus conservative management strategy, patients 65 years or older have better outcomes at 1 year when managed with an invasive strategy (12.5% vs. 19.5%; p = 0.03; age interaction p = 0.04) [73]. Similarly, in Fragmin and Fast Revascularization during Instability in Coronary Artery Disease (FRISC) II, and Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS)-TIMI 18, there was a greater absolute benefit of an early invasive strategy in patients 65 years and older [74,75]. Thus, in UA/NSTEMI, elderly patients are at higher risk and derive particular benefit from more aggressive antithrombotic and interventional therapy.

Table 38.2 Clinical Features Associated with Higher Likelihood of Coronary Artery Disease Among Patients Presenting with Symptoms Suggestive of Unstable Angina

Feature	High likelihood (any below)	Intermediate likelihood (no high-likelihood features, but any below)	Low likelihood (no high- or intermediate-likelihood features, but may have any below)
History	History of crescendo symptoms in prior 48 h	Prior history of CAD, PAD, or CVA Prior aspirin use
Character of pain	Ischemic chest pain that is prolonged (> 20 min), ongoing, and occurring at rest	Ischemic, prolonged chest pain that is now resolved Nocturnal angina	Atypical chest pain not consistent with cardiac chest pain
Examination	Age > 75 y Signs of CHF (pulmonary edema on CXR; rales and/or S3 on examination) Hypotension New or worsening MR murmur	Age > 70 y
ECG	Angina at rest with transient ST-segment changes > 0.5 mm Sustained VT	T-wave changes Pathological Q-waves Resting ST-segment depressions < 1 mm	Normal ECG
Cardiac markers	Positive	Normal	Normal
CAD, coronary artery disease; CHF, congestive heart failure; CVA, cardiovascular accident; CXR, chest X-ray; DM, diabetes mellitus; ECG, electrocardiogram; MR, mitral regurgitation; PAD, peripheral arterial disease; VT, ventricular tachycardia. Adapted from Anderson JL, Adams CD, Antman EM, et al: ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-segment elevation myocardial infarction-2002: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for Management of Patients With Unstable Angina/Non-ST-Segment Elevation Myocardial Infarction). Circulation 116:803–877, 2007.

Gender Differences

A patient’s gender may factor into the decision regarding which treatment strategy to pursue in patients presenting with UA/NSTEMI. Subgroup analyses from some trials, including FRISC II [76], Randomized Intervention Treatment of Angina (RITA) 3 [77], and Organization to Assess Strategies for Ischemic Syndromes (OASIS) 5 [78], suggested that an early invasive strategy may be associated with a higher risk of death or MI in women, whereas other studies demonstrated that an early invasive strategy resulted in improved outcomes in women as well as men [79]. Because subgroup analyses may be insufficiently powered to address this question, a meta-analysis was performed using the data of eight large-scale trials. This meta-analysis demonstrated that high-risk women (classified as patients with positive biomarkers on presentation) had a 33% lower odds of death, MI or rehospitalization with ACS (OR 0.67) with an invasive strategy, whereas low-risk women (patients with normal biomarkers on presentation) did not have a significant benefit with invasive treatment [80]. These findings are reflected in the 2007 AHA/ACC guidelines for the management of patients with UA/NSTEMI, which recommend that women with high-risk features be considered for invasive treatment, whereas women with low-risk features be treated conservatively [67].

Patients with Diabetes

Patients with diabetes have long been known to be at higher risk than those without diabetes for adverse outcomes with ACS. In a large-scale meta-analysis, patients with diabetes were found to have a significantly higher mortality at 30 days (2.1% vs. 1.1%; p < 0.001). Furthermore, having diabetes at presentation with an NSTEMI was associated with a higher mortality at 1 year as well (hazard ratio [HR] 1.65; 95% confidence interval [CI] 1.3 to 2.1) [81].

Given the high risk of adverse cardiovascular outcomes associated with diabetes, researchers have looked to see if certain treatment strategies may be of more benefit in this particular subgroup. The relative benefit of early GP IIb/IIIa inhibition has been found to be significantly higher in patients with diabetes, with a 70% relative reduction in events (p = 0.002) [82], as compared with a 30% reduction in the overall population. More recently, a meta-analysis of all placebo-controlled, IIb/IIIa inhibitor trials found a mortality benefit of early IIb/IIIa inhibition in patients with diabetes, with no mortality difference in those without nondiabetes [83]. For an invasive versus conservative strategy, the relative benefit in patients with diabetes of an early invasive strategy was similar to that of those without diabetes, but the absolute benefit was higher among those with diabetes [84]. Similarly in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel – Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 trial, patients with diabetes had a 40% reduction in MI (8.2% vs. 13.2%; p < 0.001) with the use of more intensive antiplatelet therapy with prasugrel when compared to clopidogrel. Those without diabetes saw only an 18% reduction in MI with prasugrel (7.2% vs. 8.7%; p = 0.009) [85]. Thus, patients with diabetes represent a high-risk group that deserves aggressive pharmacologic and revascularization treatments.

Risk Assessment by Electrocardiography

The admission ECG is very useful in predicting long-term adverse outcomes. In the TIMI III registry of patients with
UA/NSTEMI, multivariable predictors of 1-year death or MI included left bundle branch block and ST-segment deviation of 0.5 mm or greater [47]. The presence of only 0.5-mm ST-segment depression on the admission ECG has also been found to be an independent determinant of 4-year survival [50]. In contrast, the presence of T-wave changes was associated with only a modest [50] or no increase in subsequent death or MI risk compared with no ECG changes [47]. Similar findings were observed in predicting 30-day and 6-month outcomes in the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb study, with the presence of ST-segment deviation of greater than 0.5 mm conferring a higher mortality than T-wave changes [86].

With regard to relative treatment benefit of particular therapies, in the ESSENCE trial, patients with ST-segment deviation treated with enoxaparin had a significant reduction in cardiac events compared with patients treated with unfractionated heparin (UFH; odds ratio [OR] 0:60; p < 0.01), whereas those without ST-segment deviation did not [87]. Similar findings were observed in the TIMI 11B trial [70]. In both the FRISC II and TACTICS-TIMI 18 trials, an invasive strategy had a particular benefit in patients with ST-segment depression at presentation [84,88]. Thus, not only ST-segment deviation is a marker of increased risk of adverse outcomes, but it also indicates those patients who may derive greater benefit from aggressive antithrombotic and interventional therapy.

Risk Assessment by Cardiac Markers

Creatine Kinase-MB and the Troponins

Patients with NSTEMI have a worse long-term prognosis than those with UA [73,89]. It has now been shown that patients with elevated troponins, even if their CK-MB is normal, also have a significantly worse prognosis, with a higher risk of subsequent cardiac complications, including mortality [90,91,92]. Beyond just a positive versus negative test result, there is a linear relationship between the level of troponin T or I in the blood and subsequent risk of death: the higher the troponin, the higher the mortality risk (Fig. 38.3). Furthermore, elevated markers (both troponin T and CK-MB) have been shown to correlate with a higher rate of thrombus at angiography [4,93,94,95,96]. Thus, cardiac biomarkers are very useful not only in diagnosing infarction [97] but also in assessing risk for patients who present with acute UA/NSTEMI.

Figure 38.3. TIMI IIIB: a direct relationship was observed between increasing levels of troponin I and a higher 42-day mortality. cTnI, cardiac specific troponin I; Ng, negative. [Adapted from Antman EM, Tanasijevic MJ, Thompson B, et al: Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med 335:1342–1349, 1996, with permission.]

The presence of elevated biomarkers also correlates with the utility of particular therapies. In a trial examining the benefit of abciximab in patients with NSTEMI, the reduction in death or MI at 6 months was 70% in those who were troponin T positive, whereas there was no significant benefit for those who were troponin T negative (p < 0.001) [98] (Fig. 38.4, left). These findings have been duplicated with tirofiban versus heparin in the Platelet Receptor Inhibition for Ischemic Syndrome Management (PRISM) (Fig. 38.4, right) and PRISM in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trials [99,100] and more recently in the Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment 2 (ISAR-REACT 2) trials [96]. In the TIMI 11B trial, even when looking at patients who were CK-MB negative, those who were troponin I positive derived a significantly greater benefit from the enoxaparin versus UFH, compared with those who had both markers negative [101]. Research has also demonstrated that biomarkers are useful when choosing an invasive versus conservative strategy in patients with UA/NSTEMI. In both the FRISC II and TACTICS-TIMI 18 trials, patients who had a positive troponin T or I (including those who had very low levels of troponin) had a dramatic reduction in cardiac events after allocation to an invasive strategy [91,102]. Thus, there is now evidence from multiple trials that the use of troponins can assist in both assessing the risk and determining which patients should be treated with newer antithrombotic agents and an invasive management strategy.

Other Biomarkers

Patients with an elevated C-reactive protein (CRP) have an increased risk of death and adverse cardiovascular events [103,104]. Even among patients with negative troponin I at baseline, CRP is able to discriminate high- and low-risk groups [105]. Recently, CRP levels have been shown to significantly add to low-density lipoprotein (LDL) levels in predicting recurrent adverse cardiovascular events in patients’ post-ACS [106]. B-type natriuretic peptide (BNP) as well as N-terminal probrain natriuretic peptide (NT-proBNP), both biomarkers of LV wall stress, have also been shown to be a powerful predictor of mortality and heart failure in patients with NSTEMIs [107,108,109,110]. More recently, studies involving growth-differentiation factor 15 (GDF-15), a molecule that is induced by inflammation and cellular injury, have shown this molecule to be a similarly powerful predictor of adverse cardiovascular outcomes after NSTEMI [111]. Researchers have even suggested that GDF-15 may be able to direct treatment strategies after NSTEMI. A retrospective study looking at GDF-15 levels in patients with NSTEMI found that patients with markedly elevated GDF-15 levels had lower mortality when an invasive treatment strategy was used as opposed to conservative management [112]. Larger prospective studies are needed to see if GDF-15 will be a useful tool when deciding on the management of patients with NSTEMI. Multimarker strategies have also been employed to improve risk stratification. When using CRP and troponin T together, mortality is 0.4% for patients with both markers negative, 4.7% if either CRP or troponins are positive, and 9.1% if both are positive [105]. Similarly, the combination of troponin, CRP, and BNP can predict up to a 13-fold gradient in mortality post-ACS [113]. It should be noted that although CRP and BNP can be used as prognostic indicators, only troponin and potentially GDF-15 can identify patients who may derive greater benefit from specific interventions.

Combined Risk Assessment Scores

The TIMI risk score uses clinical factors, the ECG, and cardiac markers. It was developed using multivariate analysis, which identified seven risk factors: age 65 years or older, more than
three risk factors for coronary artery disease, documented coronary artery disease at catheterization, ST-segment deviation of 0.5 mm or greater, more than two episodes of angina in the past 24 hours, aspirin use within prior week, or elevated serum cardiac markers. Use of this scoring system was able to risk-stratify patients across a 10-fold gradient of risk, from 4.7% to 40.9% (p < 0.001) [114]. Most importantly, this risk score identified patients who derived the greatest benefit from enoxaparin versus UFH [114], from use of a GP IIb/IIIa inhibitor [115], and from an early invasive management strategy [84].

Figure 38.4. Use of troponin to determine benefit of GP IIb/IIIa inhibition. Benefit of abciximab in the CAPTURE trial of patients with refractory unstable angina treated with angioplasty in those with positive versus negative troponin T at study entry (left panel). Greater benefit of tirofiban versus heparin in patients with UA/NSTEMI was also seen in patients with positive troponin I values in the PRISM trial, with a nearly 70% reduction in death or MI at 30 days with the IIb/IIIa inhibitor (right panel). [Data from Hamm CW, Heeschen C, Goldmann B, et al: Benefit of abciximab in patients with refractory unstable angina in relation to serum troponin T levels. N Engl J Med 340(21):1623–1629, 1999; and Heeschen C, Hamm CW, Goldmann B, et al: Troponin concentrations for stratification of patients with acute coronary syndromes in relation to therapeutic efficacy of tirofiban. Lancet 354(9192):1757–1762, 1999, with permission.]

The GRACE (Global Registry of Acute Coronary Events) risk score also utilized multiple variables to identify those patients who would be at greatest risk of death in the 6 months following an ACS. Those variables that conferred the greatest risk included older age, prior history of congestive heart failure or MI, elevated heart rate and relative hypotension at presentation, the presence of ST-segment depressions, elevated serum creatinine at presentation, elevated cardiac biomarkers, and lack of in-hospital PCI [116]. When applied to patients with NSTEMI, the GRACE risk score is also able to identify those patients who will benefit most from an early invasive strategy. In the Timing of Intervention in Patients with Acute Coronary Syndromes (TIMACS) trial, NSTEMI patients with a GRACE risk score of greater than 140 had a reduction of 35% in the primary end point (composite of death, MI, or stroke) with early coronary angiography when compared to delayed intervention of greater than 36 hours (13.9% vs. 21%; p = 0.006). In patients with a GRACE risk score of less than 140, there was no difference between the two groups (7.6% vs. 6.7%; p = 0.48) [117]. Therefore, combined risk assessment scores can not only identify those patients at the highest risk for an adverse cardiovascular event, but can also assist the clinician in management decisions regarding angiography and medication choices.

Medical Therapy

Treatment Goals

The treatment objectives for patients with UA/NSTEMI are focused on stabilizing and “passivating” the acute coronary lesion, treatment of residual ischemia, and long-term secondary prevention. Antithrombotic therapy (e.g., aspirin, P₂Y₁₂ ADP receptor blockers such as clopidogrel, anticoagulants, and GP IIb/IIIa inhibitors) is used to prevent further clotting in the coronary artery and allow endogenous fibrinolysis to dissolve the thrombus and reduce the degree of coronary stenosis. Antithrombotic therapy is continued long term so that if future events occur, the degree of thrombosis is reduced. Anti-ischemic therapies (e.g., beta-blockers, nitrates, and calcium antagonists) are used to reduce myocardial oxygen demand. Coronary revascularization is frequently needed to treat recurrent or residual ischemia. After stabilization of the acute event, the many factors that led up to the event need to be reversed. Treatment of atherosclerotic risk factors such as hypercholesterolemia, hypertension, and cessation of smoking, which contributes to stabilization of the cholesterol-laden plaque and healing of the endothelium, is critical.

Aspirin

Several major studies have demonstrated clear beneficial effects of aspirin, with a more than 50% reduction in the risk of death or MI in patients who present with UA/NSTEMI [89,118,119,120]. Thus, aspirin has had a dramatic effect in reducing adverse clinical events early in the course of treatment of UA/NSTEMI, and is primary therapy for these patients. An antiplatelet meta-analysis found that any dose greater than 75 mg was associated with the same overall benefit [121]. However, preliminary data from the Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events – Seventh Organization to Assess Strategies in Ischemic Syndromes (CURRENT-OASIS 7) trial, presented at the European Society of Cardiology Annual Conference in 2009, showed that patients undergoing PCI who were treated with double-dose clopidogrel and high-dose aspirin (300 to 325 mg) had the lowest rate of cardiovascular death, recurrent MI, or stroke at 1 year.

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