Unstable Angina and Non-ST Segment Elevation Myocardial Infarction Part 1

Definition

Acute coronary syndromes are the constellation of symptoms, signs, and electrocardiographic and laboratory findings associated with new-onset or worsening myocardial ischemia. They include the spectrum of acute ST segment elevation myocardial infarction (MI) with or without Q waves, non-ST segment elevation MI (NSTEMI), and unstable angina. The main difference between NSTEMI and unstable angina is that in the latter, the ischemia is not severe enough to cause cardiac enzyme elevation and tissue injury; however, this difference may not be apparent on initial presentation.1,2

Pathophysiology

Unstable angina/NSTEMI results from an acute reduction in myocardial oxygen supply caused by rupture or erosion of an atherosclerotic coronary plaque; this plaque disruption is associated with inflammation, thrombosis, vasoconstriction, and mi-crovascular embolization. The plaques implicated in these syndromes usually had previously produced only minor obstruction to blood flow (on angiography, up to 70% of affected vessels have less than 50% stenosis of the lumen); in addition, these plaques are characterized by a large lipid pool, reduced collagen content, a thin fibrous cap, and inflammatory cells.3-9 Emboliza-tion of platelets and clot fragments into the microvasculature results in microcirculatory ischemia, which may account for the slight elevation of cardiac biomarkers. The events leading to unstable angina/NSTEMI also affect atherosclerotic plaques in the rest of the coronary vascular tree and other vascular territories.10-12


Less common causes of unstable angina/NSTEMI include intense focal epicardial spasm, cardiac emboli, and severe progressive atherosclerotic narrowing without superimposed throm-bus.1 Rarely, secondary unstable angina can be precipitated by conditions that increase myocardial demand, such as thyrotoxi-cosis, sepsis, fever, tachycardia, and anemia. Secondary unstable angina usually occurs in patients who also have underlying stable coronary atherosclerosis. Cocaine and amphetamines can also induce the syndrome.

Diagnosis

Clinical presentation

Unstable angina/NSTEMI has three principal presentations:

(1) prolonged angina at rest, usually lasting less than 20 minutes;

(2) new-onset angina that is severe, disabling, and prolonged or frequent; and (3) established angina that has become distinctly more frequent, longer in duration, or more easily provoked.

History and physical examination

Five clinical factors are key to establishing the diagnosis and the prognosis in patients with suspected unstable angina/ NSTEMI: the anginal symptoms; any history of coronary artery disease (CAD); patient sex; patient age; and traditional risk factors for CAD [see Table 1].1

In the initial evaluation of a patient with suspected unstable angina/NSTEMI, the clinician should elicit a full description of the chest pain, including its character, onset, severity, and duration. Jaw pain, neck pain, epigastric pain, and arm pain may be experienced in isolation or in concert with the chest discomfort. In the National Registry of Myocardial Infarction, which included 440,000 patients, one third had atypical symptoms.14 In the Alabama Unstable Angina Study of Medicare beneficiaries, which included over 4,000 patients, 51.7% of patients with unstable angina had the following atypical symptoms: dyspnea (69.4%), nausea (37.7%), diaphoresis (25.2%), syncope (10.6%), arm pain (11.5%), epigastric pain (8.1%), shoulder pain (7.4%), and neck pain (5.9%).15 Atypical symptoms were more common in young patients (i.e., those 25 to 40 years of age), the elderly (i.e., those older than 75 years), diabetic patients, and women.14

Although it is important to inquire about the traditional risk factors for CAD, both to assess current risk and to guide future risk reduction, these factors are only weakly predictive of unstable angina/NSTEMI.1 Important secondary or precipitating causes of unstable angina/NSTEMI should be ruled out, including a history of cocaine or amphetamine abuse, severe hypertension, and hyperthyroidism. Myopericarditis, hypothyroidism, and renal failure are among the conditions that may mimic acute coronary syndrome and can be associated with elevated cardiac enzyme levels.

In many cases, the physical examination will be normal. The examination is nevertheless useful to establish the presence of certain prognostic factors for the purpose of risk stratification and also to rule out such potentially devastating conditions as aortic dissection, pulmonary embolus, pneumothorax, and pericarditis.

The pulse is carefully evaluated to assess for significant bradycardia, tachycardia, or irregularity. Blood pressure is measured, to look for uncontrolled hypertension or significant hypotension (suggesting cardiogenic shock); pressure should be measured in both arms, to assess for aortic dissection [see 1:X1I Diseases of the Aorta]. Examination of the thyroid may suggest hypothyroidism or hyperthyroidism. Heart failure should be suspected if there is evidence of pulmonary rales, an elevated jugular venous impulse, an S3 gallop, or a displaced and diffuse apical impulse. A murmur of acute mitral regurgitation may be a consequence of ischemia. Thrills, bruits, or pulse deficits may indicate coexisting peripheral vascular disease.

Table 1 Clinical Factors for Determining Diagnosis and Prognosis in Patients with Suspected Unstable Angina or Non-ST Segment Myocardial Infarction

Nature of the anginal symptoms

History of coronary artery disease

Sex

Age > 65 years

Number of traditional risk factors (smoking, diabetes, hypertension, hyperlipidemia, family history)

Laboratory tests

Biochemical Cardiac Markers

Cardiac biomarkers—specifically, troponins, cardiac creatine kinase, and myoglobin—have important diagnostic, prognostic, and therapeutic implications in unstable angina/NSTEMI and for detection of MI generally. After ischemia-induced myocar-dial injury, loss of myocyte membrane integrity results in the release of various intracellular molecules into the interstitial space, lymphatics, and, eventually, into the peripheral circulation. Critical to the interpretation of these tests is the precise time of onset of ischemic symptoms.

Troponin Troponin I and T (TnI and TnT) are cardiac-specific subunits of the thin filament-associated troponin-tropomyo-sin complex, which regulates striated muscle contraction. Tro-ponins have become the primary biomarkers in the evaluation of patients with acute coronary syndromes. These markers are detected in about one third of patients without elevation in the level of creatine kinase-myocardial band (CK-MB). Troponins may be detectable 3 to 4 hours after the onset of ischemic symptoms; they peak at 12 to 48 hours and persist for 4 to 10 days.16,17 Generally, they are not detectable in the blood of healthy persons. However, both TnI and TnT are exceptionally sensitive to the presence of even minor myocardial necrosis, such as in supraventricular tachycardia, heart failure, and myocarditis, and they may also be elevated in severe renal impairment. Therefore, they should be evaluated in the context of the patient’s clinical presentation.

Creatine kinase Before the advent of troponin assays, CK-MB was the primary cardiac biomarker. The CK-MB assay has considerable sensitivity and specificity for detecting myocardial necrosis at 6 to 48 hours after symptom onset or earlier. Abnormal CK-MB levels can be occasionally found in patients with high total CK levels; on clinical grounds, the CK-MB in such cases is thought to originate from skeletal muscle. Elevations in levels of the CK-MB isoforms CK-MB2 and CK-MB1 are very early markers of myocardial necrosis, but these assays are generally not part of the clinical routine.

Myoglobin Myoglobin is a nonspecific biomarker found both in cardiac and skeletal muscle. It is released rapidly in response to muscle injury and is detectable 2 hours after the onset of ischemia.17 Serial determination of myoglobin is not useful, but because of its high sensitivity in early ischemia, a negative myoglobin assay could potentially rule out myocardial necrosis.

Twelve-lead electrocardiogram ECG results may be important for determining treatment; patients with acute ST segment elevation should be considered for immediate reperfusion thera-py.19 In patients with suspected unstable angina/NSTEMI, ST segment depression of 0.05 mV or more in two or more contiguous leads is highly consistent with myocardial ischemia (this is especially the case if the ST segment depression is present during chest pain and resolves with the easing of pain). Deep, symmetrical T wave inversion is also highly consistent with myocar-dial ischemia. Other nonspecific abnormalities, such as transient bundle branch block, atrial or ventricular arrhythmias, and QT prolongation, can also occur with unstable angina/NSTEMI but are not useful for diagnosis. Interestingly, a quarter of patients diagnosed with unstable angina/NSTEMI will go on to develop Q waves,2 and up to 60% may have a normal 12-lead ECG.20

Risk stratification

Determining whether a patient is at low, medium, or high risk for ischemic complications (e.g., full-blown MI) is important for deciding treatment of unstable angina/NSTEMI. Depending on whether the therapeutic strategy will be invasive or conservative (see below), the degree of risk can be used to determine the level of therapy. Older age, positive cardiac biomarkers, rales, ST segment depression, hypotension and tachycardia,21 and reduced left ventricular ejection fraction (< 40%) have been associated with increased mortality. Clinical diabetes mellitus is also associated with higher risk. One specific and widely used method of risk stratification, the Antman/Thrombolysis in Myocardial Infarction (TIMI) risk score, is a seven-point scoring system that helps to predict death, reinfarction, or recurrent ischemia requiring revascularization [see Table 2].22 This risk score was developed from the TIMI 11B23 and Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events (ESSENCE)24 trial and has been validated in two other large trials: Therapy with an Invasive or Conservative Strategy— Thrombolysis (TACTICS)-TIMI 18 and Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS).25,26 The risk of adverse outcomes ranges from 5% to 41%, according to the simple sum of the individual variables.

Table 2 Thrombolysis in Myocardial Infarction (TIMI) Risk Score for Unstable Angina or Non-ST Segment Myocardial Infarction*

Variable

Points

Age > 65 years

1

More than three coronary risk factors

1

History of coronary artery disease

1

ST segment deviation

1

More than two anginal events within 24 hr

1

Use of aspirin within past 7 days

1

Elevated cardiac markers

1

Total Score

Risk of a Cardiac Event (%) Within 14 Days

0/1

5

2

8

3

13

4

20

5

26

6/7

41

*To determine a patient’s level of risk, the clinician determines the total score, based on the presence of specific risk markers.

+Death, recurrent myocardial infarction, or recurrent ischemia requiring urgent revascularization.

Electrocardiographic Changes

Patients with unstable angina/NSTEMI and ECG findings of bundle branch block, ventricular hypertrophy, paced rhythm, or severe ST segment depression (> 0.2 mV) in multiple leads are independently at high risk for subsequent adverse events.1,20 Considered at low risk are those with isolated T wave abnormalities or a normal ECG pattern. Continuous ECG monitoring may detect transient ischemic episodes, which have been shown in small studies to have prognostic value, but the use of this technique as a risk marker is not widely recommended.1,27,28

Blood Tests

Both TnI and TnT are markers of increased risk in that they reflect the presence and level of myocardial necrosis.1,16 High-sensitivity C-reactive protein (hsCRP), which is produced by the liver in response to inflammation,29,30 and other acute-phase reac-tants such as plasma fibrinopeptide, fibrinogen, serum amyloid A, and interleukin-6, have demonstrated similar predictive value for adverse outcomes.31-33 B-type natriuretic peptide (BNP), released in response to ventricular wall stress, may also independently predict mortality.34 Measurement of hsCRP and BNP may be of use at times, but more studies are needed to clarify the roles of these markers in routine care.

Stress Testing

Stress testing for assessment of risk may be performed in patients who have been stable and asymptomatic for 24 to 48 hours and in all patients before discharge. Stress testing is a necessary component of an early conservative strategy (see below). Briefly, stress test results that show the patient to be at high risk for significant ischemia are as follows:

1. Treadmill ECG: inability to achieve a workload of greater than two metabolic equivalents (mets); early and persistent ST segment depression of greater than 2 mm; symptom on set at less than 6.5 mets; or hypotension or ST segment elevation during exercise in the absence of Q waves

2. Stress nuclear scintigraphy: evidence of left ventricular dilation or thallium lung uptake during stress, or moderate to large reversible perfusion defects

3. Stress echocardiography: more than two myocardial wall segments demonstrating reversible impairment of thickening with stress or evidence of left ventricular dilation with stress35

Treatment

Where to hospitalize

In most medical centers in the United States, patients with definite features of unstable angina/NSTEMI are admitted to a cardiac care unit that provides continuous ECG monitoring and specialized nursing. Patients with less than definite features of unstable angina or those in whom the chest pain has ceased by the time of arrival may be admitted to a chest pain unit with telemetry (sometimes called a step-down cardiac unit).

Ideally, patients with unstable angina/NSTEMI should be hospitalized in an institution that offers mechanical revascular-ization, because these procedures are frequently needed in such patients, especially those who have high-risk features. If this is not possible, high-risk patients should receive interim treatment with an intensive pharmacologic regimen until arrangements can be made for transfer to a facility with interventional capability.

Initial therapy

The initial management of unstable angina/NSTEMI includes resuscitation and supportive measures for patients who present with hemodynamic instability, as well as prompt administration of medication of proven, evidence-based value [see Pharmaco-logic Therapy, below, and Figure 1]. Bed rest with continuous ECG monitoring for ischemia and arrhythmia detection is a class I recommendation for patients who have ongoing anginal pain at rest, on the basis of level C evidence [see Table 3]. The strictness of the bed rest requirement can be tailored to the severity of symptoms. For instance, patients can be mobilized to a chair or bedside commode when symptom free.

Diagnostic and management steps in patients with unstable angina or non-ST segment elevation myocardial infarction (UA/NSTEMI). (LMWH—low-molecular-weight heparin; MI— myocardial infarction)

Figure 1 Diagnostic and management steps in patients with unstable angina or non-ST segment elevation myocardial infarction (UA/NSTEMI). (LMWH—low-molecular-weight heparin; MI— myocardial infarction)

Table 3 Recommendation Classes and Evidence Levels1

Class I: Conditions for which there is evidence or general agreement that a given procedure or treatment is useful and effective

Class II: Conditions for which there is conflicting evidence or a divergence of opinion about the usefulness/efficacy of a procedure or treatment

Class IIa: Weight of evidence or opinion is in favor of usefulness/efficacy

Class IIb: Usefulness/efficacy is less well established by evidence or opinion

Class III: Conditions for which there is evidence and/or general agreement that the procedure or treatment is not useful/effective and in some cases may be harmful

Level A: Data are derived from multiple randomized clinical trials that involved large numbers of patients Level B: Data are derived from a limited number of randomized trials that involved small numbers of patients or from careful analyses of nonrandomized studies or observational registries

Level C: Expert consensus

Oxygen Inhaled oxygen therapy should be reserved for those patients with clear respiratory distress, cyanosis, or arterial hypoxemia. In the absence of these high-risk features, time and resources need not be spent for the sole purpose of oxygen administration. Supplemental oxygen is recommended for patients with cyanosis or respiratory distress. Finger pulse oximetry or arterial blood gas measurements should be done to determine whether the patient has adequate arterial oxygen saturation (SaO2 > 90%) or has hypoxemia and requires supplemental oxygen. These class I recommendations are supported by level C evidence.

Early invasive versus early conservative strategy

The first decision in management (and one that is often a matter of dispute) is to choose between the two reigning strategies for unstable angina/NSTEMI: early invasive management and early conservative management [see Figures 2 and 3]. In the early invasive strategy, early coronary angiography is performed unless contraindicated. In the early conservative strategy, angiography is reserved for those patients who have indications of being at high risk for cardiac events; such indications include evidence of significant ischemia on a noninvasive stress test and recurrent ischemia despite adequate medical therapy. It should be noted that although many patients assigned to the conservative strategy undergo angiography and receive interventions (e.g., in one study, 51% of patients underwent angiography and 36% received subsequent revasculariza-tion25), in these patients there was an additional indication for the angiography, based on risk, besides the diagnosis of unstable angina/NSTEMI.

Advocates of an early conservative strategy suggest that an-giography—and its associated risks—can be avoided in low-risk patients and that costs and resources can be conserved by not performing these procedures in all patients. Advocates of an early invasive strategy suggest that this approach can result in superior clinical outcomes through early identification of patients with high-risk lesions, including those with critical left main coronary artery stenosis or triple-vessel coronary disease. In addition, advocates of an early invasive strategy argue that such intervention results in shorter hospital stays for patients found to have low-risk anatomy; these proponents also note that cardiac catheterization is now available to almost all patients and that catheterization has a very low procedural risk.

Early invasive strategy in unstable angina or non-ST segment elevation myocardial infarction. (CABG—coronary artery bypass grafting; GPIIa-IIIb, glycoprotein Ila-IIIb; LMWH—low-molecular-weight heparin; PCI—percutaneous coronary intervention)

Figure 2 Early invasive strategy in unstable angina or non-ST segment elevation myocardial infarction. (CABG—coronary artery bypass grafting; GPIIa-IIIb, glycoprotein Ila-IIIb; LMWH—low-molecular-weight heparin; PCI—percutaneous coronary intervention)

Early conservative strategy in unstable angina/non-ST segment elevation myocardial infarction.

Figure 3 Early conservative strategy in unstable angina/non-ST segment elevation myocardial infarction.

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