Unstable Angina Workup

Simply put, the 2 fundamental questions in the approach to the patient with possible angina are the following:

• Is this coronary artery disease (that is, what is the diagnosis, or what does the patient have)?
• How dangerous is this (ie, what is the prognosis, or what is the risk of something bad happening next)?

Therefore, a brief history and physical examination, resting 12-lead ECG, and blood draw for evaluation of cardiac enzymes should be accomplished expeditiously.

The following laboratory studies are recommended within the first 24 hours in the evaluation of a patient with unstable angina:

• Serial cardiac biomarkers
• Hemoglobin
• Serum chemistry
• Lipid panel

Numerous cardiac biomarker assays are currently available for the diagnosis of myocardial cell necrosis. Some of these, especially the troponin assays, are powerful prognostic tools as well and serve as important guides to the aggressiveness of approach.

Missed diagnosis

Patients in whom the diagnosis of myocardial infarction or unstable angina has been missed and those who are sent home from the emergency department have, respectively, a 2- and 1.7-fold increased risk of death compared with those who were admitted to the hospital. This a public health issue, and up to 20% of the millions of dollars awarded in malpractice suits against emergency department practitioners is for missed acute coronary syndrome.

As shown in one study, unintentional failure to recognize or hospitalize patients with myocardial infarction or unstable angina occurred in an average of 2.2 per 100 patients presenting to the emergency department with a chest pain syndrome, with rates of 0-10% across different academic centers. Even more disturbing, the presence of a well-established chest pain unit was not related to lower rates of missed diagnosis.

Although eliminating missed diagnoses of acute ischemic syndromes is impossible without undue hospitalization rates and costs, this problem could be minimized by the following means:

• Addressing factors or preconceptions that obscure correct diagnosis in women and nonwhite patients, subgroups that are at higher risk for missed diagnosis
• Recognition of angina equivalents, particularly in elderly patients
• More careful history taking to account for recent changes in the character or course of anginal symptoms
• Use of confirmatory point-of-care cardiac enzyme assays that have a high negative predictive value in patients with nonspecific or normal electrocardiographic findings
• Predischarge stress testing in stable patients at low risk who have a moderate likelihood of coronary artery disease
• Awareness that absence of ECG or early cardiac enzyme elevation does not automatically preclude the possibility of acute ischemia, because these are merely snapshots in time of a dynamic process

Observation and serial or further testing should be considered for patients who have coronary risk factors or a suspicious history.

Be aware that unstable angina or acute myocardial infarction can infrequently coexist or concurrently present with the following:

• Aortic dissection with involvement of the right coronary artery ostium
• Infective endocarditis with embolus into a coronary artery
• Periprocedural (post-PCI) reocclusion or coronary stent thrombosis
• Congestive heart failure in association with positive cardiac enzymes

Absolute elevations of creatine kinase and its MB isoenzyme (CK-MB) or troponin levels are highly specific evidence of myocardial cell death and distinguish NSTEMI from unstable angina. (See the graph below.)

In addition, biomarkers alone or as part of accelerated diagnostic protocols (ADP) may reduce the number of patients with a missed diagnosis of NSTEMI who are at increased risk for major adverse cardiac events. Furthermore, such approaches may facilitate early discharge from the ED in patients who a have a low short-term risk of a major cardiac event as reported in The Asia-Pacific Evaluation of Chest Pain Trial (ASPECT).^[6] The trial did not fully address the potentially important influence of cultural differences in chest pain perception and time to presentation.

The current standard of care includes drawing blood for total CK-MB every 6-8 hours during the first 24 hours. Also, determine cardiac-specific troponin (T or I) levels at least twice, 6-8 hours apart, because these may initially be negative, especially within 2-4 hours of chest pain. Consider additional measurements of CK-MB, or troponin if initially negative, for patients who have persistent or recurrent symptoms or if index of suspicion is high.

Troponin I levels of 0.4 ng/mL or higher or troponin T levels of 0.1 ng/mL or higher are considered positive and have been associated with higher short-term and midterm mortality. More importantly, outcomes in patients with troponin-positive results have been shown to be improved by aggressive treatment strategies that include an early cardiac catheterization strategy or use of intravenous glycoprotein IIb/IIIa platelet receptor antagonists.

The temporal trends of these assays are helpful in interpreting difficult cases, and mild elevations of CK-MB or troponins from a lower baseline with subsequent falls in levels strongly indicate the occurrence of myonecrosis. Troponin levels also may still capture evidence of a cardiac event in patients who delay their presentation to the hospital because its serum half-life is longer than that of CK-MB and can remain elevated for 7-14 days after an event.

On the other hand, because of its kinetics, once elevated, cardiac troponins are much less useful in evaluating recurrent chest pain with myocardial injury, whereas CK-MB permits detection of reinfarction.

Qualitative bedside troponin assay results may be difficult to interpret in patients with renal insufficiency.

The Treat Angina With Aggrastat and Determine Cost of Therapy With an Invasive or Conservative Strategy (TACTICS)/TIMI 18 substudy showed that brain natriuretic peptide (BNP) is an independent predictor of short- and long-term mortality and risk of congestive heart failure in patients presenting with unstable angina.

Elevated BNP levels have also been linked to more significant coronary artery lesions in patients with unstable angina, including patients with greater left anterior descending involvement.

BNP levels may add incremental information to the assessment of patients with unstable angina but should be used in context with other cardiac markers to guide medical decision making. The cost effectiveness of routine use of multiple cardiac biomarkers has not been established.

In the future, a combination of levels of troponin (a biomarker of myocardial necrosis), NT-pro-BNP (an indicator of elevated left ventricular end-diastolic pressure and wall stress), and C-reactive protein (CRP, an estimate of extent of systemic inflammation) may prove useful for predicting the outcome of patients with acute coronary syndrome.

The CBC count helps in ruling out anemia as a secondary cause of acute coronary syndrome. Leukocytosis has prognostic value in the setting of acute myocardial infarction.

Close monitoring of potassium and magnesium levels is important in patients with acute coronary syndrome because low levels may predispose them to ventricular arrhythmias. Routine measurement of serum potassium levels and prompt correction are recommended.

A creatinine level is also needed, particularly if cardiac catheterization is considered. Use of N -acetylcysteine and adequate hydration can help to prevent contrast material–induced nephropathy.^[7]

Interleukin 6 is the major determinant of acute-phase reactant proteins in the liver, and serum amyloid A is another acute-phase reactant. Elevations of either of these can be predictive in determining increased risk of adverse outcomes in patients with unstable angina.

The first line of assessment in any patient with suspected unstable angina is the 12-lead ECG, which should be obtained within 10 minutes of the patient's arrival to the emergency department. The diagnostic accuracy of an ECG is enhanced if a prior tracing is available for comparison.

The highest-risk ECG findings (ST-segment elevation or new left bundle-branch block) necessitate immediate triage for revascularization therapy. Peaked T waves may also indicate early myocardial infarction.

The next level of high-risk patients includes those with ST depression greater than 1 mm on ECG. Approximately 50% of patients with this finding have subendocardial myocardial necrosis. The presence of ST-segment depression portends relatively high in-hospital, 30-day, and 1-year mortality rates irrespective of cardiac biomarker level.

New or reversible ST-segment deviation of 0.5 mm or more from baseline has been associated with a higher incidence (15.8% vs 8.2%) of 1-year death or myocardial infarction in the TIMI-III Registry ECG Ancillary study.

Primary T wave changes are neither sensitive nor specific for ischemia, but they become an important clue in the context of symptoms or if the QRS to T-wave angle is greater than 60°. Isolated symmetric T-wave inversion does not appear to carry additional adverse prognosis.

Wellens syndrome

Wellens syndrome was first described by de Zwaan, Wellens, and colleagues in the early 1980s when they recognized a subset of patients with unstable angina who had specific precordial T-wave changes and subsequently developed a large anterior wall myocardial infarction.^[8] Wellens syndrome refers to these specific electrocardiographic abnormalities in the precordial T-wave segment, which are associated with critical stenosis of the proximal left anterior descending (LAD) coronary artery.

Wellens syndrome is also referred to as LAD coronary T-wave syndrome.^[9] Syndrome criteria include characteristic T-wave changes; a history of anginal chest pain; normal or minimally elevated cardiac enzyme levels; and finally, an ECG without Q waves, without significant ST elevation, and normal precordial R-wave progression. Recognition of this electrocardiographic abnormality is of paramount importance, because this syndrome represents a preinfarction stage of coronary artery disease that often progresses to a devastating anterior wall infarction.

Perform chest radiography to evaluate patients for signs of congestive heart failure and for other causes of chest symptoms such as pneumothorax, pulmonary infection or masses, pulmonary hypertension, and mediastinal widening.

If available on a prompt basis, echocardiography can provide a quick evaluation of left ventricular function for prognosis (which is worse when the left ventricular ejection fraction is < 40%) or for diagnosis, such as when new segmental wall motion abnormality is detected (eg, in postinfarction or postrevascularization chest pain in which baseline left ventricular function is known). However, keep in mind that small infarcts may not manifest on the echocardiogram.

Important causes of chest pain, such as aortic stenosis and hypertrophic obstructive cardiomyopathy, can be readily detected by echocardiography.

Transesophageal echocardiography is highly recommended if the clinical picture suggests the possibility of a valvular or mechanical complication of myocardial infarction, or for patients who are not following the expected hospital course.

Transesophageal echocardiography, CT angiography (CTA), or magnetic resonance angiography (MRA) is invaluable when aortic dissection is being ruled out.

The sensitivity of single-photon emission computed tomography (SPECT) is sufficient to detect infarcts of at least 10 g, but MRI with gadolinium enhancement may depict infarcts as small as 1–5 g.

Magnetic resonance imaging (MRI) has emerging applications for identifying ischemia (space-time maps of impaired blood arrival), infarction (wall thinning, scar, delayed enhancement), and wall-motion abnormalities that may be coupled with coronary artery assessment with MRA in the future.

MRI is well-established and is able to detect as little as 1% scar, which is a powerful prognostic factor.^{[10, 11]} MRI is also well-established for detection and characterization of complications of myocardial infarction. MRI may find wall motion abnormalities and infarcts missed by echocardiography because of the higher resolution and full coverage of MRI, echocardiography drop out from lung or rib, and angle dependence of echocardiography, which may miss the affected area, such as the real apex.

Myocardial perfusion is a valuable method for triaging patients with chest pain in the emergency department. Myocardial perfusion imaging at rest is highly sensitive for detecting acute myocardial infarction, and it can be supplemented with provocative testing after infarction is excluded.

However, the results of clinical trials can be applied only in centers with proven reliability and experience.

Exercise testing is not typically performed in the acute phase of unstable angina or in subjects with recent rest angina. However, subjects in whom disease activity becomes controlled after several days of medical therapy may safely undergo stress testing before hospital discharge.

When feasible, predischarge testing is preferential to testing weeks to months following discharge because no prognostic value is lost with early testing and because a relatively high proportion of adverse cardiac events occur earlier rather than later.

Predischarge exercise tests add independent prognostic information to known important clinical descriptors, such as recurrent rest pain and evolutionary T-wave changes. For example, patients who had a reversible defect on nuclear stress testing had a 25% incidence of death or myocardial infarction at 1 year compared with only 2% for those with a negative scan. Among men, shorter exercise duration, lower maximal rate-pressure product, and exercise-induced angina or ST-segment depression have correlated with unfavorable outcome.

Although the negative predictive value is on the order of 90% across the board for all modalities of stress tests, the positive predictive value is poor (16-19%) for exercise or adenosine stress tests and only moderately better for the imaging stress tests (31-48%).

Many chest pain centers are evaluating the strategy of early stress testing to triage low-risk patients expeditiously. The Emergency Room Assessment of Sestamibi for Evaluation of Chest Pain (ERASE Chest Pain) randomized clinical trial compared usual care versus usual care plus a resting perfusion scan in patients with normal or nondiagnostic ECG for ischemia. The study showed a 32% reduction in the odds of being unnecessarily admitted to the hospital without sacrificing safety in patients without ischemia who underwent early nuclear perfusion scanning. Patients who have a moderate likelihood of coronary artery disease but are stratified to be at low risk for events probably can safely perform the exercise stress test at 6 hours.

No large studies comparing the performance characteristics of the different stress-testing modalities in the specific setting of unstable angina are available.