eMedicine Specialties > Cardiology > Coronary Artery Disease

Unstable Angina

Walter A Tan, MD, MS, Associate Professor of Medicine, Clinical Associate Professor of Surgery, Director of Stroke Interventions, Associate Director of Cardiac Catheterization, Department of Cardiovascular Sciences, Brody School of Medicine, East Carolina University
David J Moliterno, MD, Professor of Medicine, Jefferson Morris Gill Professor of Cardiology, Chief, Division of Cardiovascular Medicine, University of Kentucky; Vice Chairman of Internal Medicine, Chandler Medical Center; Medical Director, Gill Heart Institute; Steven James Filby, MD, Fellow in Interventional Cardiology, The Cleveland Clinic Foundation

Updated: May 13, 2009

Introduction

Background

The traditional term of unstable angina was first used 3 decades ago and was meant to signify the intermediate state between myocardial infarction (MI) and the more chronic state of stable angina. The old term, preinfarction angina, conveys the clinical intent of intervening to attenuate the risk of myocardial infarction or death. Patients with this condition have also been categorized according to their presentation, diagnostic test results, or course over time; these categories include new-onset angina, accelerating angina, rest angina, early postinfarct angina, and early postrevascularization angina.

For the pragmatic purposes of this article, the term unstable angina includes non–Q-wave myocardial infarction (NQMI) because this cannot be confirmed or excluded during the initial contact with the patient. Acute coronary syndromes cover an even wider spectrum, and by some definitions include Q-wave or transmural myocardial infarction.

Pathophysiology

Chest pain is a nonspecific symptom that can have cardiac or noncardiac causes (see Differentials). The term angina is typically reserved for pain syndromes arising from presumed myocardial ischemia.

Unstable angina belongs to the continuum of the acute coronary syndromes because of the shared pathophysiology, evaluation, and treatments with NQMI and Q-wave myocardial infarction. Although the etiology and definition of unstable angina can be broad, an interplay between disrupted atherosclerotic plaque and overlaid thrombi is present in many cases of unstable angina, with consequent hemodynamic deficit or microembolization. This is distinct from stable angina, in which the typical underlying cause is a fixed coronary stenosis with compromised blood flow and slow, progressive plaque growth that allows for the occasional development of collateral flow.

Other causes of angina, such as hypertrophic obstructive cardiomyopathy (HOCM) or microvascular disease (syndrome X), cause ischemia by means of different mechanisms and are considered separate entities.

Factors involved in the pathophysiology of unstable angina include supply-demand mismatch, plaque disruption or rupture, thrombosis, vasoconstriction, and cyclical flow.

The myocardial ischemia of unstable angina, like all tissue ischemia, results from excessive demand or inadequate supply of oxygen, glucose, and free fatty acids.

Secondary disorders cause ischemia by increasing myocardial oxygen demand (eg, thyrotoxicosis, cocaine, severe illness, physiologic stress) or by decreasing oxygen supply (eg, hypoxemia, anemia, hypotension). Such causes must be investigated because most of these conditions are reversible. For instance, anemia from chronic gastrointestinal bleeding is not uncommon in elderly patients. This can coexist with coronary artery disease (CAD). However, patients may not benefit or may be harmed by treatments such as anticoagulants and antiplatelet drugs. Avoidance or treatment of the underlying condition is paramount.

Excess demand from increased myocardial workload (heart rate–systolic pressure product) or wall stress is responsible for nearly all cases of stable angina and perhaps one third of all episodes of unstable angina.

Plaque disruption

Accumulation of lipid-laden macrophages and smooth muscle cells, so-called foam cells, occurs within atherosclerotic plaques. The oxidized low-density lipoprotein cholesterol (LDL-C) in foam cells is cytotoxic, procoagulant, and chemotactic. As the atherosclerotic plaque grows, production of macrophage proteases and neutrophil elastases within the plaque can cause thinning of the fibromuscular cap that covers the lipid core. Increasing plaque instability coupled with blood-flow shear and circumferential wall stress lead to plaque fissuring or rupture, especially at the junction of the cap and the vessel wall.

Pathogenesis of acute coronary syndromes.

Thrombosis

Exposure of subendothelial components provokes platelet adhesion and activation. Platelets then aggregate in response to exposed vessel wall collagen or local aggregates (eg, thromboxane, adenosine diphosphate). Platelets also release substances that promote vasoconstriction and production of thrombin. In a reciprocating fashion, thrombin is a potent agonist for further platelet activation, and it stabilizes thrombi by converting fibrinogen to fibrin.

The nonocclusive thrombus of unstable angina can become transiently or persistently occlusive. Depending on the duration of occlusion, the presence of collateral vessels, and the area of myocardium perfused, recurrent unstable angina, NQMI, or Q-wave infarction can result.

Vasoconstriction, vasospasm, and cyclic flow variation

Most patients with acute coronary syndrome have recurrent transient reduction in coronary blood supply because of vasoconstriction and thrombus formation at the site of atherosclerotic plaque rupture. These events occur because of episodic platelet aggregation and complex interactions among the vascular wall, leukocytes, platelets, and atherogenic lipoproteins.

Vasospasm, provoked by either ergonovine or acetylcholine, is a common finding in patients with acute coronary syndrome, particularly in Taiwanese and Japanese patients. Although correlated with chest pain, whether this coronary hyperreactivity causes acute coronary syndrome or is simply an associated finding is not known.¹

Frequency

United States

The incidence of unstable angina is increasing, and nearly 1 million hospitalized patients each year have a primary diagnosis of unstable angina.

A similar number of unstable angina episodes likely occur outside the hospital and are unrecognized or managed in the outpatient setting. With heightened public awareness, improved survival after myocardial infarction, and aging of the population, this number should continue to rise despite primary and secondary prevention measures.

The demographics and characteristics of patients in the GUARANTEE registry compared with the CRUSADE registry are shown in Table 1.

Table 1. Patient Characteristics, GUARANTEE Versus CRUSADE

International

The best demographic data available are from the Organization to Assess Strategies for Ischemic Syndromes (OASIS-2) registry. It included 7987 patients with acute myocardial ischemia without ST elevation from 95 hospitals across 6 countries. Table 2 lists the patients' characteristics.

Table 2. Demographic Characteristics of Patients in the International OASIS-2 Registry

Because unstable angina is intimately linked to the incidence of coronary events, an approximation of international trends might be found in the Monitoring Trends and Determinants in Cardiovascular Diseases (MONICA) Registry sponsored by the World Health Organization (WHO). This large project monitored more than 7 million people aged 35-64 years from 30 populations in 21 countries from the mid 1980s. The highest average rates of heart disease were found in Glasgow and Belfast, United Kingdom; North Karelia and Kuopio, Finland; Newcastle, Australia; and Warsaw, Poland. The lowest average myocardial infarction rates, and presumably unstable angina rates, were observed in Beijing, China; Toulouse, France; Catalonia, Spain; Vaud-Fribourg, Switzerland; and Brianza, Italy.⁵

Mortality/Morbidity

The risk of death, myocardial infarction, and complications is variable because of the broad clinical spectrum that is covered by the term unstable angina. The average risk for these patients is discussed here. More specific risk stratification is detailed in Treatment. The aggressiveness of the therapeutic approach should be commensurate to the individualized estimated risk.

• Older studies show that the incidence of death in the early weeks after hospitalization is approximately 4%, and the incidence of myocardial infarction is approximately 10%.
• Thirty-day event rates are the current standard for cross-comparing studies. The aggregate data for the more than 40,000 patients with acute coronary syndromes in studies using contemporary treatments (albeit in varying degrees) indicate improving outcomes (see Table 3). The 30-day death and myocardial infarction rates are currently around 3.5% and 8.5%, respectively, in spite of increased disease complexity and an aging cohort.
  
  Table 3. Thirty-Day Clinical Outcome in Patients With Acute Coronary Syndromes in Clinical Trials

* TIMI-3: Thrombolysis in Myocardial Infarction Clinical Trial 3  † GUSTO-IIb: Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries
‡ ESSENCE: Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-wave Coronary Events
§ PARAGON-A: Platelet IIb/IIIa Antagonism (lamifiban) for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network
|| PRISM: Platelet Receptor Inhibition in Ischemic Syndrome Management
¶ PRISM-PLUS: Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Angina Signs and Symptoms
# PURSUIT: Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy
** TIMI-11B: Thrombolysis in Myocardial Infarction Clinical Trial 11B
†† PARAGON-B: Platelet IIb/IIIa Antagonism (lamifiban) for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network    

• The Recursos Empleados en el Sindrome Coronario Agudo y Tiempos de Espera (RESCATE) investigators from Spain report a 1.8% mortality rate and a 5.1% myocardial infarction rate at 28 days (n = 791, consecutive series between 1992 and 1994, early revascularization rate about 6%).⁷ By comparison with the therapeutically aggressive and predominantly North American studies listed in Table 2, these adverse event rates seem lower, probably because of the healthier case-mix (patients with unstable angina without previous myocardial infarction), which illustrates the difficulties of direct outcome comparisons between institutions and countries and across different trials.
• The outcome in patients with abnormal electrocardiographic findings, and in particular ST-segment depression, approximates that of patients with acute myocardial infarction. Other predictors of worse long-term outcome in unstable angina include advanced age, underlying left ventricular systolic dysfunction, and more widespread extent of coronary artery disease.

Race

Disparities in outcomes and the prevalence of risk factors among different ethnic groups have been widely reported. For instance, as a group, blacks exhibit a higher prevalence of atherosclerotic risk factors (eg, hypertension, diabetes mellitus, smoking), greater left ventricular mass, and decreased peripheral vasodilatory response. Relative to whites, myocardial infarction more frequently results in death in blacks at young ages.

• Fewer myocardial events but more cerebral complications have been observed in black patients with unstable angina in randomized clinical trials of heparin versus hirudin (GUSTO II) or eptifibatide versus placebo (PURSUIT). This may be due to the enhanced fibrinolytic activity and higher prevalence of hypertension in this population.
• Differences also exist in the delivery and response to medical care. Whites have a higher rate of catheterization, angioplasty, and bypass surgery than other racial groups. An analysis of Medicare beneficiaries also showed underuse of catheterization, particularly for managed-care enrollees as opposed to fee-for-service beneficiaries. The coronary angiography rates even for those with American College of Cardiology/American Heart Association (ACC/AHA) class I indications (angiography deemed useful or effective) in this post-myocardial infarction study were 46% versus 37%, respectively (P < .001).
• Studies have shown equivalent short-term (30-day) mortality rates from unstable angina (including NQMI) for blacks, but over the long term, persistent worse outcomes have been demonstrated.

Sex

Women with unstable angina are older and have a higher prevalence of hypertension, diabetes mellitus, congestive heart failure, and family history of coronary artery disease than men. Men tend to have a higher previous incidence of myocardial infarction and revascularization, a higher proportion of positive cardiac enzymes on admission, and higher rates of catheterization and revascularization. However, outcome is related more to the severity of the illness than to sex.

Age

The mean age of presentation with unstable angina is 62 years, with an age range of 23-100 years. To put this in perspective, the mean age is 60 years for patients in clinical trials for myocardial infarction, about 67 years for carotid artery stenosis, and 63 years for congestive heart failure. On average, women with unstable angina are 5 years older than men on presentation, with approximately half of women older than 65 years, as opposed to only about a third of men. Blacks tend to present at a slightly younger age (mean ± standard deviation, 59 ± 13 y) than people of other races.

Clinical

History

Patients with unstable angina represent a heterogeneous population. Therefore, the clinician must obtain a focused history of the patient's symptoms and coronary risk factors and immediately review the ECG to develop an early risk stratification.

• Initially obtain history to determine whether any evidence of angina is present, and then aim to identify whether it is stable or unstable.
• Unstable angina differs from stable angina in that the discomfort is usually more intense and easily provoked, and ST-segment depression or elevation on ECG may occur. Otherwise, the manifestations of unstable angina are similar to those of other conditions of myocardial ischemia such as chronic stable angina and myocardial infarction.
• Angina can take many forms, and inquiry should be directed at eliciting not only chest pain but also any discomfort and its frequency, location, radiation pattern, and precipitating and alleviating factors. Ischemic pain can manifest as heaviness, tightness, aching, fullness, or burning of the chest, epigastrium, and/or arm or forearm (usually the left). These sensations less typically involve the lower jaw, neck, or shoulder. Important associated symptoms may be dyspnea, generalized fatigue, diaphoresis, nausea and vomiting, flu-like symptoms, and, less commonly, lightheadedness or abdominal pain.
• Elderly and female patients are more likely to present with atypical signs and symptoms.

Risk assessment (Diagnosis)

• Clinical tip: Simply put, the 2 fundamental questions in the approach to the patient with possible angina are the following: (1) Is this coronary artery disease? (That is, what is the diagnosis, or what does the patient have?) (2) How dangerous is this? (That is, 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.
• Estimation of likelihood of acute coronary syndrome is a complex multivariable problem that cannot be fully specified in a list such as this. The following is meant to illustrate major relationships rather than offer rigid algorithms. The likelihood of significant coronary artery disease in patients presenting with chest pain syndrome is as follows:  
  • High likelihood (includes any of the following features):
    • History of prior myocardial infarction, sudden death, or other known history of coronary artery disease
    • Chest or left arm pain consistent with prior documented angina
    • Transient hemodynamic or ECG changes during pain
    • ST-segment elevation or depression 1 mm or more
    • Marked symmetrical T-wave inversion in multiple precordial leads
  • Intermediate likelihood (includes absence of high likelihood features, but one of these risk characteristics is present):
    • Age older than 70 years
    • Male sex
    • Diabetes mellitus
    • Extracardiac vascular disease (peripheral, brachiocephalic, or renal artery atherosclerosis)
    • ST depression 0.05-1 mm
    • T-wave inversion 1 mm or greater in leads with dominant R waves
  • Low likelihood (includes absence of high or intermediate likelihood features and any of the following):
    • Chest pain classified as probably not angina
    • Chest discomfort reproduced by palpation
    • T-wave flattening or inversion less than 1 mm in leads with dominant R waves
    • Normal ECG findings

Risk stratification (Prognosis)

• After the likelihood for coronary artery disease is determined to be significant, the next step is to stratify the patient's risk for an event. The estimation of likelihood of significant coronary artery disease is critical for identifying high-risk patients who may benefit from more aggressive treatment strategy (ie, cardiac catheterization).
• The TIMI Risk Score for unstable angina/NSTEMI is currently the best-validated prognostic instrument that is simple enough to use in an emergency department setting. The gradient of death, myocardial infarction, or severe recurrent ischemia is somewhat proportionate to the TIMI Risk Score.
  
  

  

  Thrombolysis in Myocardial Infarction (TIMI) Risk Score correlates with major adverse outcome and the effect of therapy with low molecular weight heparin.

  
  
• The presence of any of the following variables constitutes 1 point, with the sum constituting the patient risk score on a scale of 0-7:
  • Aged 65 years or older
  • Use of aspirin in the last 7 days
  • Known coronary stenosis of 50% or greater
  • Elevated serum cardiac markers
  • At least 3 risk factors for coronary artery disease (including diabetes mellitus, active smoker, family history of coronary artery disease, hypertension, hypercholesterolemia)
  • Severe anginal symptoms (2 or more anginal events in the last 24 h)
  • ST deviation on ECG
• Of note, studies have shown that ongoing congestive heart failure, presence/history of poor left ventricular ejection fraction (LVEF), hemodynamic instability, recurrent angina despite intensive anti-ischemic therapy, new or worsening mitral regurgitation, or sustained ventricular tachycardia are significant prognosticators for poor outcome. However, these factors were not evaluated in the TIMI Risk Score model and should be taken into consideration when the level of care is decided.
• Factors that were specifically examined but were not found to have prognostic value in the multivariate model include prior myocardial infarction, previous percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass graft, or history of congestive heart failure.
• The inflection point for death or myocardial infarction starts at a TIMI Risk Score of 3. Therefore, patients with a score of 3-7 should be considered for use of intravenous glycoprotein IIb/IIIa agents, heparin (low molecular weight or unfractionated), and early cardiac catheterization (see Treatment).
• Classification of unstable angina
  • The number and diversity of clinical conditions that cause the transient myocardial ischemia of unstable angina along with its varying intensity and frequency of pain have made classification within this disorder difficult.
  • The Braunwald classification is conceptually useful because it factors in the clinical presentation (new or progressive vs rest angina), context (primary, secondary, or post–myocardial infarction), and intensity of antianginal therapy.
  • [#targetD]Table 4. Braunwald Classification of Unstable Angina
    
    

    Characteristic	Class/Category	Details
    Severity	I	Symptoms with exertion
    	II	Subacute symptoms at rest (2-30 d prior)
    	III	Acute symptoms at rest (within prior 48 h)
    Clinical precipitating factor	A	Secondary
    	B	Primary
    	C	Postinfarction
    Therapy during symptoms	1	No treatment
    	2	Usual angina therapy
    	3	Maximal therapy

  • Patients in class I have new or accelerated exertional angina, whereas those in class II have subacute (>48 h since last pain) or class III acute (<48 h since last pain) rest angina. The clinical circumstances associated with unstable angina are categorized as (A) secondary (anemia, fever, hypoxia), (B) primary, or (C) postinfarction (<2 wk after infarction). Intensity of antianginal therapy is subclassified as (1) no treatment, (2) usual oral therapy, and (3) intense therapy, such as intravenous nitroglycerin.
• The Canadian Cardiovascular Society Grading System for effort-related angina is widely used since it is a simple and practical classification that is often used to describe symptom severity. It is as follows:
  • Grade I: Angina with strenuous, rapid, or prolonged exertion. (Ordinary physical activity such as climbing stairs does not provoke angina.)
  • Grade II: Slight limitation of ordinary activity. (Angina occurs with postprandial, uphill, or rapid walking; when walking more than 2 blocks of level ground or climbing more than one flight of stairs; during emotional stress; or in the early hours after awakening.)
  • Grade III: Marked limitation of ordinary activity. (Angina occurs with walking 1-2 blocks or climbing a flight of stairs at a normal pace.)
  • Grade IV: Inability to carry on any physical activity without discomfort. (Rest pain occurs.)

ECG evaluation

• 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.
• Clinical tip: The presence of ST-segment elevation or depression on ECG indicates high risk and must therefore be detected and acted on as soon as possible.

Physical

The physical examination is usually not as sensitive or specific for unstable angina as history or diagnostic tests. An unremarkable physical examination is not uncommon. Perform a quick assessment of patients' vital signs, and perform a cardiac examination. Specific diagnoses that must be explicitly considered are aortic dissection, leaking or ruptured thoracic aneurysm, pericarditis with tamponade, pulmonary embolism, and pneumothorax. Ideally, a 12-lead ECG should be performed within 10 minutes of presentation.

• Increased autonomic activity may manifest as diaphoresis or tachycardia, and bradycardia may result from vagal stimulation from inferior wall myocardial ischemia.
• A large area of myocardial jeopardy may manifest as signs of transient myocardial dysfunction and typically signifies a higher-risk situation.
  • Systolic blood pressure less than 100 mm Hg or overt hypotension
  • Elevated jugular venous pressure
  • Dyskinetic apex
  • Reverse splitting of the second heart sound
  • Presence of a third or fourth heart sound
  • New or worsening apical systolic murmur due to papillary muscle dysfunction
  • Rales or crackles
• Findings indicative of peripheral arterial occlusive disease or prior stroke increases the likelihood of associated coronary artery disease.
  • Carotid bruit
  • Supraclavicular or femoral bruits
  • Diminished peripheral pulses or blood pressure
• Clinical tip: Any sign of congestive heart failure, including isolated tachycardia, particularly in physiologically vulnerable populations (eg, very elderly patients), should trigger expeditious work-up, treatment, or consultation with a cardiologist. Such patients can deteriorate rapidly.

Causes

Many different conditions can provoke myocardial ischemia (Braunwald class A), including the following:

• Increased myocardial oxygen demand (See Supply-demand mismatch in Pathophysiology.)
  • Fever
  • Tachyarrhythmias (eg, atrial fibrillation or flutter)
  • Malignant hypertension
  • Thyrotoxicosis
  • Pheochromocytoma
  • Cocaine use
  • Amphetamine use
  • Aortic stenosis
  • Supravalvular aortic stenosis
  • Obstructive cardiomyopathy
  • Aortovenous shunts
  • High output states
  • Congestive failure
• Decreased oxygen supply
  • Anemia
  • Hypoxemia
  • Polycythemia

Differential Diagnoses

Other Problems to Be Considered

Cardiac

Aortic dissection
Aortic stenosis
Hypertrophic obstructive cardiomyopathy
Pericarditis
Right ventricular strain due to severe pulmonary hypertension
Microvascular disease (syndrome X)
Rare conditions (eg, spontaneous coronary artery dissection, anomalous left coronary artery passing between the aorta and pulmonary artery, embolization into coronary arteries)

Vascular

Aortic dissection
Pulmonary embolism
Pulmonary hypertension

Pulmonary

Pleuritis or pneumonia
Pneumothorax
Tracheobronchitis
Tumor
Mediastinitis or mediastinal emphysema

Gastrointestinal

Peptic ulcer disease
Esophageal reflux
Esophageal spasm
Mallory-Weiss tear
Biliary disease
Pancreatitis

Musculoskeletal

Cervical disc disease
Arthritis of the shoulder or spine
Costochondritis
Intercostal muscle cramps
Interscalene or hyperabduction syndromes
Subacromial bursitis

Other

Herpes zoster
Disorders of the breast
Tumors of the chest wall
Anxiety/hyperventilation

Workup

Laboratory Studies

The following laboratory studies are recommended in the evaluation of the patient with unstable angina: (1) serial cardiac biomarkers, (2) hemoglobin, (3) serum chemistry, and (4) lipid panel within 24 hours of presentation. A number of 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.

• Cardiac biomarkers
  • 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.
  • 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.
  • Clinical tip: Besides the ECG findings, troponin levels are now a centerpiece for diagnosis and prognostication in cases of unstable angina. Two sets of troponin results obtained 6-8 hours apart rules out non–Q-wave myocardial infarction (NQMI) but only if no new symptoms or ECG change has occurred since the last blood draw. 
• Brain natriuretic peptide (BNP)
  • A TACTICS/TIMI 18 substudy showed that 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 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. 
• C-reactive protein (CRP)
  • Elevated serum CRP levels on admission indicate worse short- and long-term mortality in patients with unstable angina.
  • Patients with elevated CRP levels at time of discharge are at greater risk for recurrent myocardial infarction.
  • In the absence of other inflammatory states, high-sensitivity CRP determination can refine risk stratification of patients with unstable angina. The TIMI 11A substudy showed that even for patients with a negative troponin test result, elevated CRP levels portend a higher mortality rate than that of patients in whom both troponin and CRP are negative (5.8% vs 0.36).
  • CRP may add incremental information to cardiac enzymes, but its role in medical decision-making in the acute setting remains unclear.

Imaging Studies

• 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 (worse when 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, CT angiography (CTA), or magnetic resonance angiography (MRA) is invaluable when aortic dissection is being ruled out.
• 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.
• Clinical tip: Transesophageal echocardiography (TEE) 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.

Other Tests

• 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.

Treatment

Medical Care

Patients with unstable angina require admission to the hospital for bed rest with continuous telemetry monitoring. Intravenous access should be obtained and supplemental oxygen started. Because the course of unstable angina is highly variable and potentially life threatening, the aggressiveness of approach needs to be established expeditiously.

The key in this decision-making is to select the initial management approach: invasive or conservative strategy.

Algorithm for Initial Invasive Strategy (Adapted from 2007 ACC/AHA UA/NSTEMI Guidelines).

Algorithm for Initial Conservative Strategy (Adapted from 2007 ACC/AHA UA/NSTEMI Guidelines).

Clinical tip: The standard of care dictates that at the minimum, aspirin, beta-blockers, and statins should be given promptly to all patients presenting with acute coronary syndrome unless they have a valid contraindication.

• Aspirin
  • Administer chewable aspirin 162-325 mg promptly to patients who are not at high risk for bleeding, who do not have ongoing bleeding, or who do not have true intolerance or allergy.
  • Timeliness of administration is essential because platelet aggregation is central to acute coronary syndrome, and the peak effect of aspirin can be observed within as short a time as 30 minutes.
  • Several studies have shown approximately 40-50% risk reductions for death or myocardial infarction with aspirin at 30-day follow-up and at up to 1-year follow-up in this patient population.
  • In the event of percutaneous coronary intervention, aspirin 162-325 mg should be given for at least 1 month after bare metal stent implantation, 3 months after sirolimus-eluting stent implantation, or 6 months after paclitaxel-eluting stent implantation. Thereafter, aspirin 75-162 mg should be continued indefinitely.
• Beta-blockers
  • Several controlled trials have demonstrated the benefits of beta-blockers in the treatment of myocardial infarction. These benefits have to be counterbalanced by the potential complications of heart failure or cardiogenic shock that have been demonstrated when beta-blockers are used in hemodynamically compromised patients.
  • Oral beta-blockers (eg, metoprolol) are preferred over intravenous therapy. Recent studies have associated intravenous beta-blocker therapy with an increased risk of cardiogenic shock in patients presenting with heart failure or high-risk features.
  • Intravenous beta-blockers may still be indicated in select patients with tachycardia or hypertension and ongoing chest pain.
• HMG coenzyme A reductase inhibitors (statins)
  • Multiple large, randomized, secondary prevention trials including the Heart Protection Study have demonstrated significant mortality benefit from statin therapy.
  • Recent results from the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study and Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) TIMI trials suggest that early initiation of antilipidemic agents (statins) in patients with ACS can decrease adverse events within a relatively short term.⁸
  • The PROVE-IT TIMI 22 trial demonstrated a benefit from statin therapy even in patients with acute coronary syndrome presenting with relatively low serum LDL-C levels (LDL-C <100 mg/dL suggesting that the target LDL-C level should be less than 80 mg/dL in these patients.
  • Statin therapy should be initiated before hospital discharge to improve patient adherence. Additional clinical benefit may be gained by starting therapy within 24-96 hours of admission.
• ACE inhibitors
  • ACE inhibitors are of particular benefit in patients with large anterior infarctions especially with compromised left ventricular function (eg, from STEMI) but without hypotension. The benefit in patients with unstable angina is less clear.
  • Currently, ACE inhibitors are recommended in patients with left ventricular dysfunction or congestive heart failure, diabetes, and hypertension.
  • ACE inhibitor therapy may be started within 24 hours of admission and titrated for blood pressure effect.
• Clopidogrel
  • Clopidogrel is recommended as the antiplatelet of choice in those patients who are intolerant to aspirin, and it is also used adjunctive antiplatelet agent in addition to aspirin.
  • The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial showed that clopidogrel in addition to aspirin (vs aspirin alone) significantly reduced the composite primary end point of cardiovascular death, myocardial infarction, or stroke with early benefit shown at 24 hours.
  • Percutaneous coronary intervention CURE and Clopidogrel for the Reduction of Events During Observation (CREDO) trials have shown significant benefit in those patients with unstable angina who undergo coronary intervention; pretreatment 6 hours before intervention was associated with improved outcomes. A loading dose of 600 mg may offer more effective platelet inhibition than 300 mg; increasing the loading dose beyond 600 mg has not shown benefit.
  • Patients who later undergo coronary artery bypass graft (eg, those with multivessel disease) while receiving clopidogrel have an increased risk of major bleeding and requirement for surgery for bleeding. Clopidogrel is recommended to be withheld for at least 5 days prior to elective coronary artery bypass graft because of this increased risk of bleeding. Thus, many physicians choose to hold clopidogrel until the patient's coronary anatomy is defined during coronary angiography.
  • Even with the above discussion in mind, patients who are clinically unstable should receive clopidogrel or be taken immediately for coronary angiography.
• Glycoprotein IIb/IIIa antagonists
  • In patients who are undergoing percutaneous coronary intervention (ie, those with high-risk characteristics), therapy should be started with a small-molecule intravenous glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitor for medical stabilization.
  • If the patient can be catheterized within the first few hours of presentation and is pain free, an acceptable alternative is to simply commence GP IIb/IIIa inhibitor in the catheterization laboratory in conjunction with percutaneous revascularization.
  • All of the currently available GP IIb/IIIa inhibitors, namely, abciximab, eptifibatide, and tirofiban, have been shown to increase the safety of acute percutaneous coronary intervention, with relative risk reductions in adverse events (including 30-d mortality and infarction) of approximately 30-50%.
  • Of the currently used GP IIb/IIIa inhibitors, only eptifibitide and tirofiban have been shown to be of benefit in high-risk patients treated with medical management alone. The relative reduction in adverse events observed in this setting is on the order of 5-7%. In addition, a recent meta-analysis of 6 randomized trials (with 31,400 patients) failed to show a mortality benefit in those patients who did not undergo percutaneous coronary intervention. Judgment is required to decide whether this small benefit offsets the risk of bleeding events.
• Heparin
  • Low molecular weight heparin (LMWH) and intravenous unfractionated heparin (UH) are 2 comparable anticoagulation strategies in the treatment of unstable angina.
  • The many potential benefits of using LMWH include lower rates of bleeding, cost savings, and reduced incidence of heparin-induced thrombocytopenia. Many interventional cardiologists are uncomfortable using LMWH because anticoagulation activity cannot be measured during percutaneous coronary intervention.
  • The Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-wave Coronary Events (ESSENCE) investigators compared LMWH (enoxaparin) with unfractionated heparin. The revascularization rate in this study was intermediate at about 30%. The 30-day composite rates of death, myocardial infarction, or recurrent angina were significantly reduced for subjects taking LMWH (19.8% vs 23.3%, relative risk reduction of 15%). However, excess minor bleeding occurred in 11.9% versus 7.2% of cases, an important proportion of which were only due to injection site ecchymosis.
  • The Superior Yield of the New strategy of Enoxaparin Revascularization and Glycoprotien IIb/IIIa Inhibitors (SYNERGY) trial randomized high-risk patients with NSTEMI (including those with unstable angina) to unfractionated heparin or enoxaparin. All enrolled patients were treated with an early invasive strategy. No difference in composite end point (death or myocardial infarction by 30 d) was detected. Enoxaparin was associated with more major bleeding episodes than with unfractionated heparin (9.1% vs 7.6%); however, much of this effect was attributed to patients who crossover to unfractionated heparin after receiving an initial dose of enoxaparin.
  • The Organization to Assess Strategies for Ischemic Syndromes-5 (OASIS-5) trial compared fondaparinux and enoxaparin in the treatment of unstable angina and NSTEMI. The number of patients with death, myocardial infarction, or refractory ischemia was similar in both treatment groups. The rate of major bleeding was lower in the fondaparinux group than the enoxaparin group at 9 days; and fondaparinux treatment was associated with significant reductions in death, myocardial infarction, and stroke at 180 days. However, fondaparinux was associated with a low but increased rate of guiding catheter thrombus, and therefore not recommended if urgent percutaneous coronary intervention is foreseen.
  • Enoxaparin, fondaparinux, and unfractionated heparin are safe alternative agents used in the treatment of unstable angina. Switching agents (ie, from LMWH to UH) has been associated with excess bleeding and reduced clinical benefit. In patients with an intended conservative strategy, treatment with LMWH may be preferred.
• Nitrates
  • Intravenous nitrate agents may be used in the treatment of ischemic chest pain, symptoms of heart failure, or hypertension but are not associated with appreciable long-term clinical benefit.
  • These agents are contraindicated for those with right ventricular infarction, hypertrophic cardiomyopathy, and severe aortic stenosis.
• Direct thrombin inhibitors
  • Direct thrombin inhibitors, such as hirudin, lepirudin, or bivalrudin, are potential alternatives to heparin. These agents are much more costly than conventional anticoagulation agents and may be associated with higher rates of bleeding.
  • In a large meta-analysis comparing direct thrombin inhibitors and heparin in the treatment of patients with acute coronary syndrome, there was a slight reduction in myocardial infarction (2.8% vs 3.5%). Treatment with hirudin was associated with an increased risk of major bleeding compared with heparin, whereas treatment with bivalirudin was associated with a lower risk of major bleeding.
  • The benefits of bivalirudin in patients who undergo coronary stent implantation has been demonstrated in the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events-2 (REPLACE-2) and Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trials. However, at present, data to recommend routine bivalirudin in patients with unstable angina are insufficient.
  • Direct thrombin inhibitors should not be routinely used in the treatment of unstable angina but may be of clinical benefit in special circumstances (eg, heparin-induced thrombocytopenia).
• Other medications
  • Calcium channel antagonists, antibiotics against Chlamydia pneumoniae, or fibrinolytic agents currently have no established role in the setting of unstable angina.
  • Most of the clinical trials of fibrinolytic therapy showed a tendency for more nonfatal infarctions attributed to procoagulant effects in the context of a nonocclusive thrombus.
  • While the available data suggest similar efficacy of ticlopidine to aspirin, the use of this drug in the United States has been drastically reduced since reports of associated fatal thrombotic thrombocytopenic purpura.

Cardiac Catheterization

• Patients with unstable angina and the following clinical characteristics should be referred for immediate cardiac catheterization:
  • Cardiogenic shock
  • Severe left ventricular dysfunction
  • Angina refractory to medical therapy
  • Acute mitral regurgitation
  • New ventricular septal defect
  • Unstable tachyarrhythmias
  • In patients with unstable angina but without the clinical characteristics listed above, whether an invasive strategy yields benefits over conservative management is controversial. The debate has been settled in light of data from large randomized clinical trials.
  • Among patients presenting with unstable angina, approximately 15% have 1-vessel coronary artery disease, 35% have 2-vessel coronary artery disease, and 50% have 3-vessel coronary artery disease. The incidence of left main disease is roughly 5-10%. The rate of thrombus detected at coronary angiography ranges widely from less than 10% among those with chest pain in the previous month to more than 50% among those with rest angina in the preceding 24 hours. This high prevalence of significant disease has led some to advocate routine angiography, whereas the imperfect ability to predict who will develop long-term adverse events has encouraged a tendency toward permissive revascularization.
  • Older clinical trials, such as TIMI III-B, the Veterans Affairs Non–Q-wave Infarction Strategies In-Hospital (VANQWISH) study, and the Medicine Versus Angiography in Thrombolytic Exclusion (MATE) trial did not show superiority of routine catheterization compared with the conservative approach of performing catheterization in only those with recurrent ischemic symptoms or a significantly positive stress test result. This is because of the early hazard observed with angioplasty performed in the acute setting of myocardial ischemia, which resulted in heightened rates of abrupt vessel closure, stent thrombosis, or myocardial infarction.^9,10
  • The introduction of platelet GP IIb/IIIa inhibitors has neutralized most of these periprocedural complications so that an early benefit is now observed with contemporary percutaneous coronary intervention. The Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS/TIMI-18) study showed very low 30-day and 6-month composite end point of death, myocardial infarction, or rehospitalization for the early invasive strategy. This entailed the administration of intravenous GP IIb/IIIa (tirofiban) coupled with angiography within 48 hours and a 60% revascularization rate within the index hospitalization compared with 36% for conservative therapy. The benefit of early invasive strategy was more substantial in intermediate- and high-risk patients (ie, those with TIMI score 3).
  • The Fragmin During Instability in Coronary Artery Disease II (FRISC-II) trial showed a significant reduction in death or myocardial infarction at 6 months in patients with unstable angina who underwent early catheterization and revascularization as compared with a noninvasive strategy. This treatment difference was primarily driven by a lower rate of myocardial infarction in the invasive arm (7.8% vs 10.1%). Patients in the invasive arm also had a significant reduction in angina and hospital readmission rates. Again, the treatment benefits were more pronounced in those with ST-segment depression and cardiac marker elevation.¹¹
  • RITA 3 also found benefit with the invasive strategy over conservative management in intermediate- to high-risk patients with NSTEMI and ischemic changes on ECG or elevated troponin levels. The combined end point of death, myocardial infarction, and refractory angina at 4 months was significantly reduced in the invasive arm (9.6%) versus the conservative arm (7.6%) at 4 months. While the two groups showed no difference in the combined end point (death or nonfatal myocardial infarction) at 1 year, a 5-year follow-up analysis revealed that the invasive strategy was associated with significant reductions in death or nonfatal myocardial infarction.
  • With regard to timing of catheterization, the Intracoronary Stenting Angiographic Results Cooling-Off (ISAR-COOL) trial suggested a significant benefit from earlier catheterization. Patients with NSTEMI who underwent coronary angiography within 6 hours had a lower rate of death or large myocardial infarction at 30 days than those who underwent coronary angiography at 3-5 days (5.9% vs 11.6%).
  • In contrast to these trials, the ICTUS trial showed no advantage of an early invasive over a selective invasive strategy in 1200 patients with chest pain and elevated troponin who had either a history of coronary artery disease or the presence of ischemic ECG changes. However, the selective invasive group had a 40% rate of revascularization during initial hospital stay.
  • Two subsequent meta-analyses (one of which included Invasive vs Conservative Treatment in Unstable Coronary Syndromes [ICTUS]) have also supported the use of an early invasive strategy in the management of patients with NSTEMI with the most prominent benefit occurring in those patients with high-risk features.
  • The results of the COURAGE Trial, which suggest that percutaneous coronary intervention is no better at preventing events than medical therapy do not pertain to the management of unstable angina as this trial focused on patients with stable disease.
  • Based on the weight of the current evidence, early invasive strategy benefits high-risk patients with acute coronary syndrome. In keeping with this, the current AHA/ACC Guidelines recommend an invasive treatment strategy for patients with high-risk clinical predictors.^12,13
  • [#Table5]Table 5. AHA/ACC Recommendations for a Preferred Invasive Strategy

Surgical Care

Patients at moderate-to-high risk for adverse events, such as those with ST depression greater than 1 mm on ECG, troponin positivity or NQMI, or chest pain refractory to medical therapy should be scheduled for cardiac catheterization with likely revascularization within the next 48 hours. The TACTICS/TIMI-18 trial showed that this early invasive strategy reduced 30-day rates of death, myocardial infarction, or rehospitalization for unstable angina from 19.4% to 15.9%, or a relative risk reduction of 18%.

• FRISC II showed that even a delayed invasive strategy (mean time to revascularization 4 d, 71% revascularization rate vs 9% in the conservative arm) coupled with LMWH (dalteparin) therapy provides durable benefit for individual hard end points. At 1 year, the invasive group had statistically significant reductions in death (2.2% vs 3.9%, relative risk reduction, 43%) and myocardial infarction (8.6% vs 11.6%, relative risk reduction, 26%).¹¹
  • FRISC II has been the only randomized clinical trial able to show a mortality benefit. This was likely because of the very strict criteria for revascularization, which resulted in only 9% of the conservative arm receiving percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG). For example, in the TACTICS/TIMI-18 study and other North American trials, approximately 50% of the patients in the conservative arm had some form of revascularization, and not all in the invasive strategy arm had indications for percutaneous coronary intervention or coronary artery bypass graft. Therefore, the benefits of revascularization were less striking because of the narrower differences in rates of revascularization.
  • Of note, by 1 year, a catch-up phenomenon was observed in patients who had initial conservative management. By then, 52% had undergone angiography, and 43% required revascularization.
    
    

    

    Rate and timing of revascularization for patients with unstable angina using an invasive versus a conservative approach (Fragmin during instability in coronary artery disease [FRISC II]).

    
    
  • The cost-benefit ratio of an initial invasive approach based on the FRISC II trial has been estimated. At the cost of 15 extra coronary artery bypass graft and 21 percutaneous coronary intervention procedures, the benefit per 100 patients per year is as follows:
    • 1.7 lives saved
    • 2 myocardial infarctions prevented
    • 20 readmissions prevented
    • Earlier and better symptom relief
  • Coronary artery bypass graft is usually the preferred method for revascularization in patients with the following conditions:
    • Left main trunk artery stenosis
    • Poor left ventricular function
    • Significant 3-vessel coronary artery disease or 2-vessel disease that involves the proximal left anterior descending artery
    • Diabetes mellitus with focal stenosis in more than one vessel
    • Concomitant severe valvular disease that requires open heart surgery
• Continuous observation by Holter monitoring can provide helpful information. Depending on the criteria of ST-segment deviation, the timing of monitoring relative to disease instability, and the intervening medical therapy incidence of abnormal ST-segment shifts has been reported at 11-66% in unstable angina.
  • Up to 92% of these abnormal ST-segment shifts are asymptomatic, and more importantly, patients experiencing such episodes had an associated higher adverse event rate than those without (48% vs 20%).
  • Other studies have documented unfavorable outcomes at up to 6 months with the presence of at least 1 hour of silent ischemia during initial admission

Consultations

• Cardiologist - To assist in risk stratification and decision-making, to expedite further cardiac testing (eg, echocardiography, stress testing, angiography), and to treat unstable patients
• Critical care or telemetry unit specialist - For acute care and monitoring
• Cardiothoracic surgeon - In case coronary artery bypass graft is necessary

Diet

Unstable angina may require patients to take nothing orally if stress testing or an invasive procedure is anticipated. Otherwise, a diet low in cholesterol and saturated fat is recommended. Sodium restriction should be instituted for patients with heart failure or hypertension.

Activity

• Rehabilitation and preventive services: While secondary prevention is the responsibility of the primary care provider and the cardiologist, some centers have specialized and more effective teams (eg, cardiac rehabilitation, preventive services) that can offer more intensive and perhaps more effective counseling and follow-up.
• Bed rest is indicated until clinical risk stratification is accomplished.
• For patients at high risk for adverse events, bed rest is indicated until definitive therapy is administered.
• For patients at intermediate risk for adverse events, bed rest is indicated until further testing or definitive therapy.

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Antiplatelet agents

These agents prevent formation of thrombi associated with MI and inhibit platelet function by blocking aggregation. Antiplatelet therapy has been shown to reduce mortality by reducing the risk of fatal MIs, fatal strokes, and vascular death. Pooled data from more than 2,000 patients revealed reduction of death or MI from 11.8% to 6% with aspirin in cases of unstable angina. A recent randomized clinical trial involving 12,562 patients showed a reduction of cardiovascular death, MI, or stroke from 11.4% to 9.3% by adding clopidogrel to aspirin therapy.

Aspirin (Anacin, Bayer Buffered Aspirin, Ecotrin)

Administer as soon as possible. Inhibits cyclo-oxygenase, which produces thromboxane A2, a potent platelet activator. Early administration has been shown to reduce mortality.

Dosing

Adult

160-324 mg PO qd

Pediatric

Not established

Interactions

Effects may decrease with antacids and urinary alkalinizers; corticosteroids decrease salicylate serum levels; additive hypoprothrombinemic effects and increased bleeding time may occur with coadministration of anticoagulants; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; doses > 2 g/d may potentiate glucose-lowering effect of sulfonylurea drugs

Contraindications

Documented hypersensitivity; liver damage; hypoprothrombinemia; vitamin K deficiency; bleeding disorders; asthma; patients <16 y with influenza (because of association of aspirin with Reye syndrome)

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

May cause transient decrease in renal function and aggravate chronic renal disease; avoid use in patients with severe anemia, those with history of blood coagulation defects, or those taking anticoagulants

Clopidogrel (Plavix)

Selectively inhibits adenosine diphosphate (ADP) binding to platelet receptor and subsequent ADP-mediated activation of glycoprotein llb/llla complex, thereby inhibiting platelet aggregation. This agent is used as an alternative to aspirin or in addition to aspirin after coronary stenting.¹⁴
The randomized clinical trial Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) showed an absolute risk reduction in cardiac death, MI, or stroke of 2.1% (11.4% down to 9.3% at 1 - y) at the cost of increased major bleeding by 1.0% (3.7% vs 2.7%).

Dosing

Adult

CURE protocol for patients with unstable angina within 24 h of symptom onset: 300 mg loading dose PO followed by 75 mg PO qd for 3-12 mo (mean 9 mo) in conjunction with aspirin 75-325 mg/d PO

Pediatric

Not established

Interactions

Coadministration with naproxen is associated with increased occult GI blood loss; clopidogrel prolongs bleeding time; safety of coadministration with warfarin not established

Contraindications

Documented hypersensitivity; active pathological bleeding, such as peptic ulcer, or intracranial hemorrhage
One study showed that omeprazole decreased clopidogrel's inhibitory effect on platelets.

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in patients at increased risk of bleeding from trauma, surgery, or other pathological conditions; caution in patients with lesions with propensity to bleed (eg, ulcers)

HMG-CoA reductase inhibitors

Used to treat hypercholesterolemia. Highly efficacious and very well tolerated.

Atorvastatin (Lipitor)

Can provide up to 60% reduction in LDL-C. Inhibits 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase), which in turn inhibits cholesterol synthesis and increases cholesterol metabolism. The half-life of atorvastatin and active metabolites is longer than that of all the other statins (ie, approximately 48 h compared to 3-4 h).
The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) clinical trial randomized 3,086 patients with unstable angina to high-dose atorvastatin versus placebo. Therapy resulted in a reduction in the primary end point (ie, death, MI, resuscitated cardiac arrest, severe recurrent symptomatic ischemia) from 17.4% to 14.8% (P = .048) within a relatively short period of 4 mo. The benefit was mostly for recurrent symptomatic ischemia with objective evidence and requiring emergency rehospitalization (8.4% down to 6.2%, P = .02).⁸

Dosing

Adult

10 mg PO qd in the evening; titrate to a maximum 80 mg/d prn
MIRACL protocol: 80 mg PO qd commenced within 1-4 d after admission for unstable angina, continue for at least 16 wk

Pediatric

Not established

Interactions

Toxicity increases when coadministered with triazole antifungals, CNS depressants, macrolide antibiotics, and mibefradil; atorvastatin increases the action of anticoagulants and levothyroxine

Contraindications

Documented hypersensitivity; significant hepatic impairment; pregnancy; breastfeeding

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Out of 1.33 million total prescriptions, 31 cases of rhabdomyolysis were reported in Canada, which resulted in 1 death associated with concomitant use of gemfibrozil, a fibric acid derivative; concomitant use with nicotinic acid (niacin) also advised
Stop drug use or decrease doses for elevations of transaminases more than 3 times the upper limit of the reference range; elevations generally resolve upon withdrawal of drug; if symptoms of myopathy and rhabdomyolysis occur, stop the drug and obtain a CK
Do not exceed daily dose; caution in patients receiving drugs that prolong QRS or Q-T interval; monitor transaminase levels before treatment, at 6 wk and 12 wk, then q6mo

Glycoprotein IIb/IIIa receptor antagonists

Up to 80,000 copies of these integrins on the platelet cell surface serve as ligands for fibrinogen cross-linkage, the final common pathway for platelet aggregation and thrombus formation, even under arterial shear stress conditions. To date, more than 40,000 patients have been enrolled in randomized clinical trials evaluating glycoprotein IIb/IIIa antagonists in ACS. These trials have shown 30-day relative risk reductions of 22-56% in composite end points, with beneficial trends in each of the component outcomes, largely in association with percutaneous coronary intervention.

Tirofiban (Aggrastat)

Nonpeptide antagonist of platelet GP IIb/IIIa receptor that reversibly prevents von Willebrand factor, fibrinogen, and other adhesion ligands from binding to the GP IIb/IIIa receptor, thereby inhibiting platelet aggregation. Effects persist over the duration of maintenance infusion and are reversed after stopping the infusion. Approved by the FDA for use in combination with heparin for patients with ACS who are being managed medically and for those undergoing PCI.
Dose should be halved in patients with severe renal insufficiency (CrCl <30 mL/min).

Dosing

Adult

0.4 mcg/kg/min IV for 30 min, followed by 0.1 mcg/kg/min for up to 72 h
If CrCl <30 mL/min, then reduce dose by 50%

Pediatric

Not established

Interactions

Possible increased risk of bleeding with coadministration of heparin or aspirin; closely monitor when using concurrently with drugs that affect hemostasis (eg, warfarin)

Contraindications

Documented hypersensitivity; severe hypertension (systolic BP >200 mm Hg); active internal bleeding; history of intracranial hemorrhage, intracranial neoplasm, arteriovenous malformation, or aneurysm; acute pericarditis; bleeding diathesis; trauma or stroke within previous 30 d; platelet count <100,000/mm³; history of thrombocytopenia following exposure to this product; serum creatinine > 2 mg/dL (for 180 mcg/kg bolus and 2 mcg/kg/min infusion) or >4 mg/dL (for 135 mcg/kg bolus and 0.5 mcg/kg/min infusion); history of bleeding diathesis within 30 d; intracranial hemorrhage; history of hemorrhagic stroke; severe hypertension (systolic BP >200 mm Hg or diastolic BP >110 mm Hg); major surgical procedure within past mo

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Bleeding events are the most common complications encountered during therapy with eptifibatide; caution with platelet count <150,000/mm³ and hemorrhagic retinopathy; prior to treatment, monitor platelet counts, serum creatinine, hemoglobin, hematocrit, and PT/aPTT within 6 h after loading infusion and at least daily thereafter (more frequently if evidence of significant decline)
Because these agents inhibit platelet aggregation, caution when using concurrently with drugs that affect hemostasis (eg, thrombolytics, ticlopidine, NSAIDs, warfarin, dipyridamole, clopidogrel); measure ACT and maintain aPTT 50-70 seconds unless a PCI needs to be performed; maintain ACT 300-350 seconds during PCI; if platelet count decreases to <100,000/mm³, perform additional platelet counts to exclude pseudothrombocytopenia; if thrombocytopenia is confirmed, discontinue GP IIb/IIIa inhibitors and heparin and appropriately monitor and treat the condition; to monitor unfractionated heparin, monitor aPTT 6 h after beginning heparin infusion; adjust to maintain aPTT higher than 2 times baseline

Eptifibatide (Integrilin)

Cyclic heptapeptide antagonist of the platelet GP IIb/IIIa receptor that reversibly prevents von Willebrand factor, fibrinogen, and other adhesion ligands from binding to the GP IIb/IIIa receptor, thereby inhibiting platelet aggregation. Effects persist over duration of maintenance infusion and are reversed when infusion ends. Approved by the FDA for use in combination with heparin for patients with ACS, patients who are being managed medically, and for those undergoing PCI.

Dosing

Adult

Unstable angina: 180 mcg/kg IV bolus, followed by continuous infusion of 2 mcg/kg/min for up to 72 h
Undergoing PCI: Additional 180 mcg/kg IV bolus 10 min after the first bolus
For patients with serum Cr > 2 mg/dL: Lower dose to 135 mcg/kg bolus and 0.5 mcg/kg/min infusion

Pediatric

Not established

Interactions

Possible increased risk of bleeding with coadministration of heparin, warfarin, or aspirin; closely monitor when using other drugs that affect hemostasis

Contraindications

Documented hypersensitivity; severe hypertension (systolic BP >200 mm Hg); active internal bleeding; history of intracranial hemorrhage, intracranial neoplasm, arteriovenous malformation or aneurysm, acute pericarditis, or bleeding diathesis; trauma or stroke within previous 30 d; platelet count <100,000/mm³; history of thrombocytopenia following prior exposure to this product; serum Cr > 4 mg/dL

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Bleeding events are the most common complications encountered during therapy with eptifibatide; caution in platelet count <150,000/mm³ and hemorrhagic retinopathy; because agent inhibits platelet aggregation, caution when using concurrently with drugs that affect hemostasis (eg, thrombolytics, ticlopidine, NSAIDs, warfarin, dipyridamole, clopidogrel); measure ACT and maintain aPTT 50-70 seconds unless a PCI needs to be performed; maintain ACT 250-350 seconds during a PCI; if platelets decrease to <100,000/mm³, perform additional platelet counts to exclude possibility of pseudothrombocytopenia; if thrombocytopenia is confirmed, discontinue GP IIb/IIIa inhibitors and heparin and appropriately monitor and treat the condition; monitor aPTT 6 h after start of heparin infusion and at least daily thereafter

Platelet aggregation inhibitors

Inhibit platelet aggregation.

Abciximab (ReoPro)

Chimeric human-murine monoclonal antibody approved for use in elective/urgent/emergent PCI. Binds to receptor with high affinity and reduces platelet aggregation by 80% for up to 48 h following infusion. The GUSTO-4 randomized clinical trial did not show any benefit for abciximab in medically treated patients who do not undergo PCI. In fact, longer duration of abciximab use was associated with a negative trend in event rates. On the other hand, in the context of PCI, it has been shown to be superior to tirofiban.

Dosing

Adult

0.25 mg/kg IV bolus, followed by 10 mcg/min IV for 12 h after PCI

Pediatric

Not established

Interactions

Possible increased risk of bleeding with coadministration with heparin, warfarin, or aspirin; closely monitor when using other drugs that affect hemostasis

Contraindications

Documented hypersensitivity; severe hypertension (systolic BP >200 mm Hg); active internal bleeding; history of intracranial hemorrhage, intracranial neoplasm, arteriovenous malformation or aneurysm, acute pericarditis, or bleeding diathesis; trauma or stroke within previous 30 d; platelet count <100,000/mm³; history of thrombocytopenia following prior exposure to this product

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Bleeding events are the most common complications encountered during therapy with abciximab; caution in platelet count <150,000/mm³ and hemorrhagic retinopathy; because agent inhibits platelet aggregation, caution when using concurrently with drugs that affect hemostasis (eg, thrombolytics, ticlopidine, NSAIDs, warfarin, dipyridamole, clopidogrel); measure ACT and maintain aPTT 50-70 seconds unless a PCI needs to be performed; maintain ACT 250-350 seconds during a PCI; if platelets decrease to <100,000/mm³, perform additional platelet counts to exclude possibility of pseudothrombocytopenia; if thrombocytopenia is confirmed, discontinue GP IIb/IIIa inhibitors and heparin and appropriately monitor and treat condition; monitor aPTT 6 h after start of heparin infusion and at least daily thereafter; abciximab is associated with an incidence of thrombocytopenia in approximately 2% of patients

Beta-adrenergic blocking agents

Limit heart rate and reduce blood pressure to decrease myocardial oxygen demand, oppose effects of elevated catecholamines, and produce antiarrhythmic properties. Clinical trials of beta-adrenoreceptor blockers in cases of unstable angina have shown decreases in ischemic symptoms and in occurrence of MIs. In vitro studies have shown inhibition of platelet aggregation with this drug class. Infrequent situations in which beta-blocker therapy should be avoided in patients with unstable angina include nonischemic exacerbation of heart failure, cocaine-induced coronary vasoconstriction, and vasospastic angina.

Metoprolol (Lopressor, Toprol XL)

Selective beta1-adrenergic receptor blocker that decreases automaticity of contractions. During IV administration, carefully monitor blood pressure, heart rate, and ECG.

Dosing

Adult

5 mg IV slow infusion q5min up to 3 times until resolution of angina or titrate to reduce heart rate to 50-70 bpm

Pediatric

Not established

Interactions

Aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may decrease bioavailability and plasma levels of metoprolol, possibly resulting in decreased pharmacologic effects; toxicity of metoprolol may increase with coadministration of sparfloxacin, phenothiazines, astemizole, calcium channel blockers, quinidine, flecainide, and contraceptives; may increase toxicity of digoxin, flecainide, clonidine, epinephrine, nifedipine, prazosin, verapamil, and lidocaine

Contraindications

Documented hypersensitivity; uncompensated congestive heart failure; bradycardia; asthma; cardiogenic shock; AV conduction abnormalities

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Beta-adrenergic blockade may reduce signs and symptoms of acute hypoglycemia and may decrease clinical signs of hyperthyroidism; abrupt withdrawal may exacerbate symptoms of hyperthyroidism, including thyroid storm; closely monitor patient and slowly withdraw the drug; caution in patients taking other negative chronotropes or inotropes (eg, verapamil)

Esmolol (Brevibloc)

Shown to reduce episodes of chest pain and clinical cardiac events compared to placebo. The very short half-life (8 min) allows a large degree of dosing flexibility, such that cardiovascular benefits are comparable to PO propranolol, yet adverse effects can be managed promptly. It is particularly useful for patients at risk for complications with beta-blockade (eg, reactive airway disease or COPD, severe bradycardia, or poor left ventricular function).

Dosing

Adult

0.05 mg/kg/min IV over 1 min initially; 0.1 mg/kg/min IV maintenance; titrate in increments of 0.05 mg/kg/min q10-15min until resolution of angina, until heart rate of 50-70 bpm is attained, or until maximum dose of 0.2 mg/kg/min is reached

Pediatric

Not established

Interactions

Aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may decrease bioavailability and plasma levels of metoprolol, possibly resulting in decreased pharmacologic effects; toxicity of metoprolol may increase with coadministration of sparfloxacin, phenothiazines, astemizole, calcium channel blockers, quinidine, flecainide, and contraceptives; metoprolol may increase toxicity of digoxin, flecainide, clonidine, epinephrine, nifedipine, prazosin, verapamil, and lidocaine

Contraindications

Documented hypersensitivity; uncompensated congestive heart failure; bradycardia; asthma; cardiogenic shock; AV conduction abnormalities

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Beta-adrenergic blockade may mask signs and symptoms of acute hypoglycemia and may decrease clinical signs of hyperthyroidism; abrupt withdrawal may exacerbate symptoms of hyperthyroidism, including thyroid storm; closely monitor patient and slowly withdraw the drug; during IV administration, carefully monitor blood pressure, heart rate, and ECG

Propranolol (Inderal)

Nonselective beta-blocker that is lipophilic (penetrates CNS). Although generally short-acting agent, long-acting preparations are also available.

Dosing

Adult

IR: 40-160 mg PO bid
SR: 60-320 mg PO qd

Pediatric

Not established

Interactions

Coadministration with aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may decrease propranolol effects; calcium channel blockers, cimetidine, loop diuretics, and MAOIs may increase toxicity of propranolol; toxicity of hydralazine, haloperidol, benzodiazepines, and phenothiazines may increase with propranolol

Contraindications

Documented hypersensitivity; history of bronchospasm; uncompensated congestive heart failure; bradycardia; cardiogenic shock; AV conduction abnormalities

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Beta-adrenergic blockade may hide signs of acute hypoglycemia and hyperthyroidism; abrupt withdrawal may exacerbate symptoms of hyperthyroidism, including thyroid storm; slowly withdraw drug and closely monitor patient; adverse effects include bronchial constriction, Raynaud phenomenon, hypotension, decreased libido, impotence, lethargy, depression, and decreased HDL; caution in Wolff-Parkinson-White syndrome and renal or hepatic dysfunction

Nadolol (Corgard)

Competitively blocks beta-1 and beta-2 receptors. Does not exhibit membrane stabilizing activity or intrinsic sympathomimetic activity.

Dosing

Adult

40 mg/d PO initially; gradually increase dose by 40- to 80-mg increments at 3- to 7-d intervals up to 160-240 mg/d

Pediatric

Not established

Interactions

Coadministration with aluminum salts, barbiturates, calcium salts, cholestyramine, NSAIDs, penicillins, and rifampin may decrease effects; haloperidol, hydralazine, loop diuretics, and MAOIs may increase toxicity of nadolol

Contraindications

Documented hypersensitivity; congestive heart failure; pulmonary edema; cardiogenic shock; AV conduction abnormalities; heart block (without a pacemaker)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Beta-adrenergic blockade may reduce symptoms of acute hypoglycemia and mask signs of hyperthyroidism; abrupt withdrawal may exacerbate symptoms of hyperthyroidism and cause thyroid storm; closely monitor patients and slowly withdraw drug; during an IV, carefully monitor BP, heart rate, and ECG

Antithrombotic agents

Thrombin, the end product of the coagulation mechanism, initiates transformation of fibrinogen to a fibrin clot and activates platelets. Its antagonist, antithrombin III, is the major endogenous inhibitor of the coagulation cascade and is the essential cofactor for heparin.

Heparin

Catalyzes the effect of antithrombin III on coagulative proteinases (eg, factors II, XII, XI, IX, and X; tissue factor VIIa). Prevents reaccumulation of clot after endogenous fibrinolysis. Meta-analysis shows modest benefit (when compared to aspirin alone) and slight increase in bleeding. Reactivation of unstable angina after discontinuation of heparin has been documented among subjects not receiving concomitant aspirin therapy. When unfractionated heparin is used, the aPTT should not be checked until 6 h after initial heparin bolus.

Dosing

Adult

80 U/kg IV bolus, followed by infusion of 18 U/kg/h; titrate to maintain aPTT 1.5-2.5 times control; decrease initial bolus dose to 50 U/kg IV when used in conjunction with GP IIb/IIIa antagonist

Pediatric

Not established

Interactions

Digoxin, nicotine, tetracycline, and antihistamines may decrease effects; NSAIDs, aspirin, dextran, dipyridamole, and hydroxychloroquine may increase heparin toxicity

Contraindications

Documented hypersensitivity; subacute bacterial endocarditis; active bleeding; history of heparin-induced thrombocytopenia

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Most important risk with unfractionated heparin is ineffectiveness because of insufficient dose; may cause hemorrhagic complications; if significant bleeding complications develop, 15 mg protamine sulphate (infused over 3 min) usually reverses anticoagulant effect; can trigger immune thrombotic thrombocytopenia 1-2 wk after beginning of treatment; heparin-associated thrombocytopenia is serious, causes widespread thrombosis refractory to treatment, and can be fatal if not recognized quickly and managed appropriately; some preparations contain benzyl alcohol as a preservative, which can be associated with fetal toxicity (gasping syndrome) when used in large amounts; use of preservative-free heparin is recommended in neonates; caution in shock or severe hypotension

Enoxaparin (Lovenox)

Only LMWH now approved by the FDA both for treatment and for prophylaxis of deep venous thrombosis (DVT) and pulmonary embolism. LMWH has been widely used in pregnancy, although clinical trials are not yet available to demonstrate that it is as safe as unfractionated heparin. Except in overdoses, checking PT or aPTT is not useful because aPTT does not correlate with the anticoagulant effect of fractionated LMWH.

Dosing

Adult

1 mg/kg SC q12h or 1.5 mg/kg SC qd
Prophylaxis against DVT: 30 mg SC q12h

Pediatric

Not established

Interactions

Platelet inhibitors or PO anticoagulants (eg, dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, ticlopidine) may increase risk of bleeding

Contraindications

Documented hypersensitivity; major bleeding; thrombocytopenia

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

If thromboembolic event occurs despite LMWH prophylaxis, discontinue drug and initiate alternate therapy; elevation of hepatic transaminases may occur but is reversible; heparin-associated thrombocytopenia may occur with fractionated LMWHs; 1 mg of protamine sulfate reverses effect of approximately 1 mg of enoxaparin if significant bleeding complications develop; if necessary, 1 mg of protamine can neutralize 100 U dalteparin

Dalteparin (Fragmin)

Enhances inhibition of Factor Xa and thrombin by increasing antithrombin III activity. In addition, preferentially increases inhibition of Factor Xa.
Except in overdoses, checking PT or aPTT is not useful because aPTT does not correlate with anticoagulant effect of fractionated LMWH.
Average duration of treatment is 7-14 d.

Dosing

Adult

120 IU/kg SC q12h; not to exceed 10,000 IU for at least 5 d

Pediatric

Not established

Interactions

Platelet inhibitors or oral anticoagulants such as dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, and ticlopidine may increase risk of bleeding

Contraindications

Documented hypersensitivity; major bleeding, thrombocytopenia; regional anesthesia

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

If thromboembolic event occurs despite LMWH prophylaxis, discontinue drug and initiate alternate therapy; elevation of hepatic transaminases may occur but is reversible; heparin-associated thrombocytopenia may occur with fractionated LMWHs; protamine sulfate will reverse effect if significant bleeding complications develop; cases of epidural/spinal hematomas have been reported in adults receiving spinal or epidural anesthesia (holding 2 doses prior to LP or surgery is recommended); when using for extended treatment in patients with cancer, if platelet count decrease <100,000/mm³, reduce dose by 2500 IU until platelet count recovers, and discontinue if platelet count <50,000/mm³ (may resume previous dose when platelets recover); reduce dose with impaired renal function (monitor anti-Xa levels)

Thrombin inhibitors

Lepirudin and bivalirudin are direct thrombin inhibitors. Advantages over heparin are efficacy against clot-bound thrombin, resistance to inactivation by platelet factor 4 and thrombospondin, and nondependence on antithrombin III pathways. Data to date suggest only a modest reduction in adverse events at the cost of increased nonmajor bleeding complications. GUSTO IIB investigators compared recombinant hirudin and heparin in 12,142 patients, a third of whom had ST elevation MI. The hirudin group had a 9% relative risk reduction in 30-d death or MI rates (8.9% vs 9.8%), but more moderate bleeding events occurred (8.8% vs 7.7%).¹⁵

OASIS-2 was an international randomized clinical trial that involved 10,141 patients. Patients were randomized between heparin (aPTT maintained between 60 and 100 seconds) or lepirudin, which is recombinant hirudin (0.4 mg/kg bolus followed by 0.15 mg/kg/h 72-h IV infusion). Unlike for GP IIb/IIIa antagonists, no evidence indicates attenuation of myocardial necrosis (based on CK or troponin measurements). Approved by the FDA in patients with heparin-induced thrombocytopenia and associated thrombotic disease. Goal is 1.5-2.5 times the control aPTT values. Dose needs to be adjusted for patients with renal impairment.

Bivalirudin (Angiomax) is a thrombin inhibitor used as alternative anticoagulation in patients with unstable angina undergoing PTCA.

Bivalirudin (Angiomax)

Synthetic analogue of recombinant hirudin. Inhibits thrombin. Used for anticoagulation in patients with unstable angina undergoing PTCA. With provisional use of GP IIb/IIIa inhibitor indicated for use as anticoagulant in patients undergoing PCI. Potential advantages over conventional heparin therapy include more predictable and precise levels of anticoagulation, activity against clot-bound thrombin, absence of natural inhibitors (eg, platelet factor 4, heparinase), and continued efficacy following clearance from plasma (because of binding to thrombin).

Dosing

Adult

Administer IV bolus dose of 0.75 mg/kg followed by infusion of 1.75 mg/kg/h for duration of procedure; continuation of infusion following PCI for up to 4 h postprocedure optional; after 4 h, additional IV may be initiated at rate of 0.2 mg/kg/h for up to 20 h; may administer with 300-325 mg/d aspirin

Pediatric

Not established

Interactions

Clinical trials have shown that patients undergoing PTCA/PCI, coadministration of bivalirudin with heparin, warfarin, or thrombolytics may increase risks of major bleeding events compared with patients not receiving these medications concomitantly

Contraindications

Documented hypersensitivity; cerebral aneurysm; intracranial hemorrhage, general uncontrollable hemorrhage, or active major bleeding

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in renal impairment (dose only needs adjustment in patients with severe renal impairment of CrCl <30 mL/min and patients who are hemodialysis dependent), recent surgery or trauma, GI ulceration; risk of bleeding; may cause back pain, nausea, headache, hypotension

Lepirudin (Refludan)

Recombinant hirudin derived from yeast cells. Highly specific direct inhibitor of thrombin. Natural hirudin is produced in trace amounts as a family of highly homologous isopolypeptides by the leech Hirudo medicinalis. Biosynthetic lepirudin is identical to natural hirudin except for substitution of leucine for isoleucine at the N -terminal end of the molecule and the absence of a sulfate group on the tyrosine at position 63.
Activity of lepirudin is measured in a chromogenic assay. One antithrombin unit (ATU) is the amount of lepirudin that neutralizes one unit of WHO's preparation 89/588 of thrombin. Specific activity of lepirudin is >16,000 ATU/mg. Mode of action is independent of antithrombin III. Platelet factor 4 does not inhibit lepirudin. One molecule of lepirudin binds to one molecule of thrombin and thereby blocks the thrombogenic activity of thrombin. As a result, all thrombin-dependent coagulation assays are affected (eg, aPTT values increase in a dose-dependent fashion).
Goal is 1.5-2.5 times the control aPTT values. Dose needs to be adjusted for patients with renal impairment.

Dosing

Adult

0.4 mg/kg IV bolus over 15-20 seconds, followed by continuous infusion of 0.15 mg/kg/h

Pediatric

Not established

Interactions

Intracranial bleeding may be life threatening following concomitant fibrinolytic therapy

Contraindications

Documented hypersensitivity; major bleeding; thrombocytopenia

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Associated with increased need for transfusion (vs unfractionated heparin) and slightly increased risk of intracranial hemorrhage; no specific antidote

Vasodilators

Relieve chest discomfort by improving myocardial oxygen supply, which in turn dilates epicardial and collateral vessels, improving blood supply to the ischemic myocardium. Opposes coronary artery spasm, which augments coronary blood flow and reduces cardiac work by decreasing preload and afterload. Effective in the management of symptoms in acute MI but may reduce mortality only slightly. Nitroglycerin can be administered sublingually by tablet or spray, topically, or by IV. In acute MI, topical administration is a less desirable route because of unpredictable absorption and onset of clinical effects.

Nitroglycerin (Minitran, Nitrogard, Nitrol, Nitrolingual, Nitrostat, Nitro-Dur)

Causes relaxation of vascular smooth muscle by stimulating intracellular cyclic guanosine monophosphate production. Whether administered topically, SL, PO, or IV, nitrates ameliorate several pathways of unstable angina and reduce the incidence of symptomatic ischemia. Nitrates lower systemic arterial pressure and decrease venous return to the heart, both of which reduce myocardial wall stress. Similarly, nitrates are excellent coronary vasodilators. Other possible beneficial effects include transient inhibition of platelet aggregation, increase in coronary collateral blood flow, and a favorable redistribution of regional flow. Of note, induction of heparin resistance has been reported.

Dosing

Adult

400 mcg SL tab or spray q5min, repeated up to 3 times; if symptoms persist, infuse IV at a rate of 5-10 mcg/min; titrate dose to a 10% reduction in mean arterial pressure

Pediatric

Not established

Interactions

Aspirin may increase nitrate serum concentrations; marked symptomatic orthostatic hypotension may occur with coadministration of calcium channel blockers (dose adjustment of either agent may be necessary)

Contraindications

Documented hypersensitivity; severe anemia; shock; postural hypotension; head trauma; closed-angle glaucoma; cerebral hemorrhage; known right ventricular infarct

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in CAD and low systolic blood; limiting adverse effects include hypotension (>30% reduction in mean arterial pressure or systolic BP <90 mm Hg) or severe headache

Follow-up

Further Inpatient Care

• Several guidelines and decision algorithms are available and are especially helpful in identifying patients at low risk in whom hospital admission can be avoided.
• The level of care and expertise of the different units vary from hospital to hospital. For example, the intermediate care unit in certain tertiary cardiac centers may be equipped and appropriately staffed for treatment of asymptomatic patients, but high-risk patients with unstable angina would be more appropriately cared for in an ICU in a community hospital setting.
• The following are general guidelines for patient disposition:
  • Intensive care unit and/or emergency revascularization
    • TIMI Risk Score of 3-7
    • New ECG changes in 2 or more leads
    • ST elevation greater than 1 mm or Q waves 0.04 seconds or longer
    • ST depression greater than 1 mm or T-wave inversion in the context of angina
    • New LBBB
    • Signs and symptoms of incipient or florid heart failure
    • Syncope or sudden death presentation
    • Serious new arrhythmias including second-degree or complete heart block and ventricular tachyarrhythmias
    • Refractory angina
    • Hypoxia
    • Positive cardiac enzyme (CK or troponin)
    • Myocardial infarction or coronary stenting within the last 2 weeks
  • Intermediate care unit (Patients are asymptomatic but have any of the following conditions:)
    • Atrial arrhythmia, supraventricular tachycardia, or low-grade second-degree atrioventricular block[second-degree atrioventricular block]
    • Isolated basilar rales
    • Borderline blood pressure
    • Symptoms with minimal activity
    • Presence of major comorbidity (eg, severe pulmonary, renal, or hepatic disease; bleeding history or dyscrasia)
    • Very elderly or frail
  • Observation unit (Patients are otherwise healthy individuals without ischemic ECG changes but with either of the following:)
    • New-onset symptoms at moderate levels of exertion
    • Known coronary artery disease with a presentation that does not suggest true worsening but for which further observation is thought to be prudent

Further Outpatient Care

• After 1-3 months beyond the acute phase of unstable angina, the risk of major adverse events typically declines to that for patients with chronic stable angina. The goal is to prepare patients for resumption of their normal activities as safely as possible, to preserve left ventricular function, and to prevent future events.
  • Institute aggressive secondary prevention and schedule appropriate follow-up care. Aggressive attempts should be made to convince both the patient and the rest of the household to cease smoking. Patients should avoid second-hand smoke.
  • The usual follow-up visit for low-risk or successfully revascularized patients is around 2-6 weeks after discharge. Patients at higher risk should probably be seen again within 2 weeks.

Transfer

In general, a facility that can provide prompt percutaneous or surgical revascularization is preferred for patients who are stratified to be at moderate-to-high risk for adverse events.

Deterrence/Prevention

• Smoking cessation
  • Target - Complete abstinence by patient and cohabitants from all tobacco products for 12 months or more
  • If patient has expressed decision to quit, support with counseling, follow-up, and pharmacotherapy, acupuncture, or hypnosis (if necessary).
• Lipid lowering
  • Target - LDL-C of ≤70 mg/dL, HDL-C >35 mg/dL, and triglycerides <200 mg/dL
  • Diet modification, exercise, and drug therapy are indicated as per National Cholesterol Education Program (NCEP) guidelines.
• Control of hypertension
  • Target - <140/90 mm Hg or <130/80 mm Hg if patient has diabetes mellitus or chronic kidney disease
  • Diet modification, moderation of sodium and alcohol intake, exercise, smoking cessation, and pharmacotherapy are indicated.
• Diabetes mellitus management
  • Target - Fasting plasma glucose level <110 mg/dL or hemoglobin A1C (HbA1C) value <7.0
  • Diet modification, exercise, pharmacotherapy including ACE-I, preventive counseling regarding foot care, and ophthalmologic examinations are indicated.
• Weight management and nutritional counseling
  • Target - Body mass index (BMI) <25 kg/m² and a waist circumference <40 inches for men and <35 inches for women
  • Diet modification and adequate intake of fruits and vegetables, exercise, and behavioral modification and counseling are indicated.
• Psychosocial management
  • Target - Lifestyle modification, recognition and treatment of substance abuse (alcohol or psychotropics) and depression or hostile attitude, and compliance with health maintenance
  • Education, counseling, support groups, and social or religious resources are indicated.

Complications

• In the United States, death occurs in approximately 1% of all patients (as opposed to patients eligible for clinical trials). Outcomes during initial hospitalization (GUARANTEE registry) are as follows:
  • Death - 0.94%
  • Myocardial infarction after admission (About 8 or 9 per 1000 patients hospitalized with a diagnosis of unstable angina incur a myocardial infarction.) - 0.84%
  • Death or myocardial infarction - 1.72%
  • Recurrent angina (At least 1 in 5 patients experience recurrent angina.)
    • With ECG changes - 6.6%
    • Without ECG changes - 17.6%
    • Exercise treadmill - 15.6%
    • Coronary angiography - 50.1%
    • Coronary intervention - 17.6%
    • Bypass surgery (At least 1 in 4 patients receive some form of revascularization therapy.) - 9.1%
    • Initial ICU or critical care unit (CCU) admission - 39.8%
    • Length of stay (mean ± standard deviation) - 4.1 days ± 4.1
• In the PURSUIT trial, the rate of all strokes (hemorrhagic and nonhemorrhagic) was about 0.7%.
  • Nonhemorrhagic - 0.6%
  • Primary hemorrhagic - Less than 0.1%
  • Cerebral infarction with hemorrhagic conversion - Less than 0.1%
• Bleeding events with contemporary antithrombotic regimens are as follows:
  • Transfusions are administered to 5-10% of hospitalized patients with acute coronary syndrome.
  • Severe bleeding, usually defined as more than 5 g of hemoglobin loss or bleeding that results in hemodynamic compromise, occurs at a lower frequency (1-1.5%).
• In the international OASIS registry, major adverse events within 1 week were as follows:
  • Cardiovascular death or myocardial infarction - 4.4% in United States and Brazil; 4.9% in other countries
  • Stroke - 3.8% versus 5.6%
  • Major bleeding - 0.96% versus 0.36%
  • Refractory angina - 3.8% versus 5.6%

Prognosis

• The prognosis varies greatly, depending on where the individual patient falls along the wide spectrum of unstable angina.
• A direct correlation exists between death or myocardial infarction and the TIMI Risk Score (see Media file 2). An adverse prognosis appears to be mitigated by the use of newer antithrombotic strategies.
• Patients who present with new ST-segment deviation (1 mm or greater) have a 1-year death or myocardial infarction rate of 11% compared with only 6.8% in patients with isolated T-wave inversion.
• In the international OASIS Registry, major adverse events occurring within 6 months were as follows:
• Cardiovascular death or myocardial infarction - 10.5% in United States and Brazil; 10.8% in other countries
• Stroke - 1.9% versus 1.2%
• Major bleeding - 1.9% versus 1.1%
• Refractory angina - 13.9% versus 20.1%
• The Spanish RESCATE investigators studied patients with unstable angina without prior myocardial infarction who survived beyond a month and compared the 6-month outcomes for patients initially admitted to tertiary hospitals with those initially admitted to nontertiary hospitals. Results were as follows:⁷
• Death - 2.0% versus 3.6%
• Myocardial infarction - 3.4% versus 6.2%
• Angina requiring hospital readmission - 14.5% versus 16%
• Ventricular tachycardia or fibrillation - 1.0% versus 0.8%
• Heart failure requiring hospital readmission - 1.0% versus 1.7%
• The level of troponin positivity correlates with intermediate-term death in a dose-dependent fashion (ranging from 1.0-7.5% at 6 wk) independent of age, CK-MB levels, and ST-segment deviation.

Patient Education

• Consider referral to the appropriate service or person, including cardiac rehabilitation program, preventive cardiology, or programs that can improve long-term medical compliance and lifestyle/behavioral modification.
• Patients at risk for myocardial infarction should avoid sudden strenuous activities, especially in cold weather (eg, shoveling snow).
• Before hospital discharge, patients and their family members should be educated about the manifestations of myocardial infarction and actions that need to be taken in that eventuality. They should also receive cardiopulmonary resuscitation (CPR) training.
• For excellent patient education resources, visit eMedicine's Cholesterol Center, Circulatory Problems Center, and Heart Center. Also, see eMedicine's patient education articles, High Cholesterol, Understanding Your Cholesterol level, Lifestyle Cholesterol Management, Understanding Cholesterol-Lowering Medications, Chest Pain, Coronary Heart Disease, and Heart Attack.

Miscellaneous

Medicolegal Pitfalls

• Patients in whom the diagnosis of myocardial infarction or unstable angina was 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 diagnosis of acute ischemic syndromes is impossible without undue hospitalization rates and costs, this problem could be minimized means of by the following:
  • Improved ECG interpretation
    • 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 ECG 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.)
  • Being 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

Special Concerns

• Cocaine-induced coronary spasm
  • This can be indistinguishable from acute coronary syndromes.
  • Nitroglycerin and calcium channel antagonists are the drugs of choice.
  • Beta-blockers may exacerbate cocaine-induced coronary vasoconstriction.
  • In patients with persistent ST elevation, coronary angiography should be performed. If this cannot be carried out immediately, consider empiric fibrinolytic therapy.
• Variant (Prinzmetal) angina
  • This is characterized by transient ST-segment elevation and can involve multiple coronary arterial territories.
  • Patients typically respond to nitroglycerin and high-dose, and sometimes even dual, calcium channel blocker therapy.

Multimedia

Media file 1: Pathogenesis of acute coronary syndromes.

Media file 2: Thrombolysis in Myocardial Infarction (TIMI) Risk Score correlates with major adverse outcome and the effect of therapy with low molecular weight heparin.

Media file 3: Algorithm for Initial Invasive Strategy (Adapted from 2007 ACC/AHA UA/NSTEMI Guidelines).

Media file 4: Algorithm for Initial Conservative Strategy (Adapted from 2007 ACC/AHA UA/NSTEMI Guidelines).

Media file 5: Rate and timing of revascularization for patients with unstable angina using an invasive versus a conservative approach (Fragmin during instability in coronary artery disease [FRISC II]).

Media file 6: Time course of elevations of serum markers after acute myocardial infarction.

References

1. Ong P, Athanasiadis A, Hill S, Vogelsberg H, Voehringer M, Sechtem U. Coronary artery spasm as a frequent cause of acute coronary syndrome: The CASPAR (Coronary Artery Spasm in Patients With Acute Coronary Syndrome) Study. J Am Coll Cardiol. Aug 12 2008;52(7):523-7. [Medline].

2. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. Apr 4 2001;285(13):1711-8. [Medline].

3. Scirica BM, Moliterno DJ, Every NR, et al. Differences between men and women in the management of unstable angina pectoris (The GUARANTEE Registry). The GUARANTEE Investigators. Am J Cardiol. Nov 15 1999;84(10):1145-50. [Medline].

4. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. Aug 16 2001;345(7):494-502. [Medline].

5. Theroux P, Waters D, Lam J, Juneau M, McCans J. Reactivation of unstable angina after the discontinuation of heparin. N Engl J Med. Jul 16 1992;327(3):141-5. [Medline].

6. GRACE, Global Registry of Acute Coronary Events. Available at http://www.outcomes-umassmed.org/grace/. Accessed March 30, 2009.

7. Lupón J, Valle V, Marrugat J, et al. Six-month outcome in unstable angina patients without previous myocardial infarction according to the use of tertiary cardiologic resources. RESCATE Investigators. Recursos Empleados en el Síndrome Coronario Agudo y Tiempos de Espera. J Am Coll Cardiol. Dec 1999;34(7):1947-53. [Medline].

8. Scanlon PJ, Nemickas R, Moran JF, Talano JV, Amirparviz F, Pifarre R. Accelerated angina pectoris. Clinical, hemodynamic, arteriographic, and therapeutic experience in 85 patients. Circulation. Jan 1973;47(1):19-26. [Medline].

9. Anderson HV, Cannon CP, Stone PH, et al. One-year results of the Thrombolysis in Myocardial Infarction (TIMI) IIIB clinical trial. A randomized comparison of tissue-type plasminogen activator versus placebo and early invasive versus early conservative strategies in unstable angina and non-Q wave myocardial infarction. J Am Coll Cardiol. Dec 1995;26(7):1643-50. [Medline].

10. Boden WE, O'Rourke RA, Crawford MH, et al. Outcomes in patients with acute non-Q-wave myocardial infarction randomly assigned to an invasive as compared with a conservative management strategy. Veterans Affairs Non-Q-Wave Infarction Strategies in Hospital (VANQWISH) Trial Investigators. N Engl J Med. Jun 18 1998;338(25):1785-92. [Medline].

11. FRISC Investigators. Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. FRagmin and Fast Revascularisation during InStability in Coronary artery disease Investigators. Lancet. Aug 28 1999;354(9180):708-15. [Medline].

12. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation. Aug 14 2007;116(7):e148-304. [Medline].

13. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation. Aug 14 2007;116(7):e148-304. [Medline].

14. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet. Nov 16 1996;348(9038):1329-39. [Medline].

15. GUSTO Investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb investigators. N Engl J Med. Sep 12 1996;335(11):775-82. [Medline].

16. Akkerhuis KM, Deckers JW, Boersma E, et al. Geographic variability in outcomes within an international trial of glycoprotein IIb/IIIa inhibition in patients with acute coronary syndromes. Results from PURSUIT. Eur Heart J. Mar 2000;21(5):371-81. [Medline].

17. Alexander JH, Sparapani RA, Mahaffey KW, et al. Association between minor elevations of creatine kinase-MB level and mortality in patients with acute coronary syndromes without ST-segment elevation. PURSUIT Steering Committee. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy. JAMA. Jan 19 2000;283(3):347-53. [Medline].

18. Ambrose JA, Winters SL, Stern A, et al. Angiographic morphology and the pathogenesis of unstable angina pectoris. J Am Coll Cardiol. Mar 1985;5(3):609-16. [Medline].

19. Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for unstable angina/non-ST elevation MI: A method for prognostication and therapeutic decision making. JAMA. Aug 16 2000;284(7):835-42. [Medline].

20. 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. Oct 31 1996;335(18):1342-9. [Medline].

21. Asher CR, Topol EJ, Moliterno DJ. Insights into the pathophysiology of atherosclerosis and prognosis of black Americans with acute coronary syndromes. Am Heart J. Dec 1999;138(6 Pt 1):1073-81. [Medline].

22. Balady GJ, Ades PA, Comoss P, et al. Core components of cardiac rehabilitation/secondary prevention programs: A statement for healthcare professionals from the American Heart Association and the American Association of Cardiovascular and Pulmonary Rehabilitation Writing Group. Circulation. Aug 29 2000;102(9):1069-73. [Medline].

23. Balsano F, Rizzon P, Violi F, Scrutinio D, Cimminiello C, Aguglia F. Antiplatelet treatment with ticlopidine in unstable angina. A controlled multicenter clinical trial. The Studio della Ticlopidina nell'Angina Instabile Group. Circulation. Jul 1990;82(1):17-26. [Medline].

24. [Best Evidence] Bavry AA, Kumbhani DJ, Rassi AN, Bhatt DL, Askari AT. Benefit of early invasive therapy in acute coronary syndromes: a meta-analysis of contemporary randomized clinical trials. J Am Coll Cardiol. Oct 3 2006;48(7):1319-25. [Medline].

25. Bennett CL, Weinberg PD, Rozenberg-Ben-Dror K, Yarnold PR, Kwaan HC, Green D. Thrombotic thrombocytopenic purpura associated with ticlopidine. A review of 60 cases. Ann Intern Med. Apr 1 1998;128(7):541-4. [Medline].

26. Bhatt DL, Houghtaling P, Harrington RA, et al. Black patients presenting with acute coronary syndromes have better outcomes due to less extent of disease. J Am Coll Cardiol. 1999;33(2):365A.

27. Bittner V, Weiner DH, Yusuf S, et al. Prediction of mortality and morbidity with a 6-minute walk test in patients with left ventricular dysfunction. SOLVD Investigators. JAMA. Oct 13 1993;270(14):1702-7. [Medline].

28. Boden WE, O'Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. Apr 12 2007;356(15):1503-16. [Medline].

29. Boden WE, O'Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. Apr 12 2007;356(15):1503-16. [Medline].

30. Braunwald E. Unstable angina. A classification. Circulation. Aug 1989;80(2):410-4. [Medline].

31. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol. Sep 2000;36(3):970-1062. [Medline].

32. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: executive summary and recommendations. A report of the American College of Cardiology/American Heart Association task force on practice guidelines (committee on the management of patients with unstable angina). Circulation. Sep 5 2000;102(10):1193-209. [Medline].

33. Braunwald E, Mark DB, Jones RH, et al. Agency for Health Care and Policy Research (AHCPR). Unstable Angina. In: Diagnosis and Management. US Department of Health and Human Services. Washington, DC; 1994.

34. Brown KA. Prognostic value of thallium-201 myocardial perfusion imaging in patients with unstable angina who respond to medical treatment. J Am Coll Cardiol. Apr 1991;17(5):1053-7. [Medline].

35. Butman SM, Olson HG, Butman LK. Early exercise testing after stabilization of unstable angina: correlation with coronary angiographic findings and subsequent cardiac events. Am Heart J. Jan 1986;111(1):11-8. [Medline].

36. Calvin JE, Klein LW, VandenBerg EJ, Meyer P, Parrillo JE. Validated risk stratification model accurately predicts low risk in patients with unstable angina. J Am Coll Cardiol. Nov 15 2000;36(6):1803-8. [Medline].

37. Campeau L. Letter: Grading of angina pectoris. Circulation. Sep 1976;54(3):522-3. [Medline].

38. Cannon CP, McCabe CH, Stone PH, et al. Prospective validation of the Braunwald classification of unstable angina: results from the Thrombolysis in Myocardial Ischemia (TIMI) III registry. Circulation. 1995;95(92):1-19.

39. Cannon CP, McCabe CH, Stone PH, et al. The electrocardiogram predicts one-year outcome of patients with unstable angina and non-Q wave myocardial infarction: results of the TIMI III Registry ECG Ancillary Study. Thrombolysis in Myocardial Ischemia. J Am Coll Cardiol. Jul 1997;30(1):133-40. [Medline].

40. Capone G, Wolf NM, Meyer B, Meister SG. Frequency of intracoronary filling defects by angiography in angina pectoris at rest. Am J Cardiol. Sep 1 1985;56(7):403-6. [Medline].

41. Chew DP, Moliterno DJ. A critical appraisal of platelet glycoprotein IIb/IIIa inhibition. J Am Coll Cardiol. Dec 2000;36(7):2028-35. [Medline].

42. Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. N Engl J Med. Aug 14 1997;337(7):447-52. [Medline].

43. Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration. BMJ. Jan 8 1994;308(6921):81-106. [Medline].

44. Das P, Moliterno DJ. Fractionating heparins and their clinical trial data--something for everyone. JAMA. Jul 7 2004;292(1):101-3. [Medline].

45. de Winter RJ, Windhausen F, Cornel JH, et al. Early invasive versus selectively invasive management for acute coronary syndromes. N Engl J Med. Sep 15 2005;353(11):1095-104. [Medline].

46. Eagle KA, Kline-Rogers E, Goodman SG, et al. Adherence to evidence-based therapies after discharge for acute coronary syndromes: an ongoing prospective, observational study. Am J Med. Jul 15 2004;117(2):73-81. [Medline].

47. EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. The EPILOG Investigators. N Engl J Med. Jun 12 1997;336(24):1689-96. [Medline].

48. EPISTENT Investigators. Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. Lancet. Jul 11 1998;352(9122):87-92. [Medline].

49. ESPRIT Investigators. Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomised, placebo-controlled trial. Lancet. Dec 16 2000;356(9247):2037-44. [Medline].

50. Falk E. Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death. Autopsy evidence of recurrent mural thrombosis with peripheral embolization culminating in total vascular occlusion. Circulation. Apr 1985;71(4):699-708. [Medline].

51. Fowler NO. "Preinfarctional" angina. A need for an objective definition and for a controlled clinical trial of its management. Circulation. Nov 1971;44(5):755-8. [Medline].

52. Fox KA, Poole-Wilson P, Clayton TC, et al. 5-year outcome of an interventional strategy in non-ST-elevation acute coronary syndrome: the British Heart Foundation RITA 3 randomised trial. Lancet. Sep 10-16 2005;366(9489):914-20. [Medline].

53. Freeman MR, Chisholm RJ, Armstrong PW. Usefulness of exercise electrocardiography and thallium scintigraphy in unstable angina pectoris in predicting the extent and severity of coronary artery disease. Am J Cardiol. Dec 1 1988;62(17):1164-70. [Medline].

54. Freeman MR, Williams AE, Chisholm RJ, Armstrong PW. Intracoronary thrombus and complex morphology in unstable angina. Relation to timing of angiography and in-hospital cardiac events. Circulation. Jul 1989;80(1):17-23. [Medline].

55. Gasser JA, Betterridge DJ. Comparison of the effects of carvedilol, propranolol, and verapamil on in vitro platelet function in healthy volunteers. J Cardiovasc Pharmacol. 1991;18 Suppl 4:S29-34. [Medline].

56. Goldman L, Cook EF, Johnson PA, Brand DA, Rouan GW, Lee TH. Prediction of the need for intensive care in patients who come to the emergency departments with acute chest pain. N Engl J Med. Jun 6 1996;334(23):1498-504. [Medline].

57. Gotoh K, Minamino T, Katoh O, et al. The role of intracoronary thrombus in unstable angina: angiographic assessment and thrombolytic therapy during ongoing anginal attacks. Circulation. Mar 1988;77(3):526-34. [Medline].

58. Gottlieb SO, Weisfeldt ML, Ouyang P, Mellits ED, Gerstenblith G. Silent ischemia as a marker for early unfavorable outcomes in patients with unstable angina. N Engl J Med. May 8 1986;314(19):1214-9. [Medline].

59. Guadagnoli E, Landrum MB, Peterson EA, Gahart MT, Ryan TJ, McNeil BJ. Appropriateness of coronary angiography after myocardial infarction among Medicare beneficiaries. Managed care versus fee for service. N Engl J Med. Nov 16 2000;343(20):1460-6. [Medline].

60. Harrington RA. Platelet IIb/IIIa in Unstable Angina:. Receptor Suppression Using Integrilin Therapy (PURSUIT) Trial. For the PURSUIT Investigators. 1998.

61. Heeschen C, Hamm CW, Goldmann B, Deu A, Langenbrink L, White HD. Troponin concentrations for stratification of patients with acute coronary syndromes in relation to therapeutic efficacy of tirofiban. PRISM Study Investigators. Platelet Receptor Inhibition in Ischemic Syndrome Management. Lancet. Nov 20 1999;354(9192):1757-62. [Medline].

62. Hochman JS, McCabe CH, Stone PH, et al. Outcome and profile of women and men presenting with acute coronary syndromes: a report from TIMI IIIB. TIMI Investigators. Thrombolysis in Myocardial Infarction. J Am Coll Cardiol. Jul 1997;30(1):141-8. [Medline].

63. Hohnloser SH, Meinertz T, Klingenheben T, Sydow B, Just H. Usefulness of esmolol in unstable angina pectoris. European Esmolol Study Group. Am J Cardiol. Jun 15 1991;67(16):1319-23. [Medline].

64. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. N Engl J Med. May 21 1998;338(21):1488-97. [Medline].

65. Kirk JD, Turnipseed S, Lewis WR, Amsterdam EA. Evaluation of chest pain in low-risk patients presenting to the emergency department: the role of immediate exercise testing. Ann Emerg Med. Jul 1998;32(1):1-7. [Medline].

66. Krone RJ, Greenberg H, Dwyer EM Jr, Kleiger RE, Boden WE. Long-term prognostic significance of ST segment depression during acute myocardial infarction. The Multicenter Diltiazem Postinfarction Trial Research Group. J Am Coll Cardiol. Aug 1993;22(2):361-7. [Medline].

67. Lange RA, Cigarroa RG, Flores ED, et al. Potentiation of cocaine-induced coronary vasoconstriction by beta-adrenergic blockade. Ann Intern Med. Jun 15 1990;112(12):897-903. [Medline].

68. Langer A, Freeman MR, Armstrong PW. ST segment shift in unstable angina: pathophysiology and association with coronary anatomy and hospital outcome. J Am Coll Cardiol. Jun 1989;13(7):1495-502. [Medline].

69. Larsson H, Areskog M, Areskog NH, et al. Should the exercise test (ET) be performed at discharge or one month later after an episode of unstable angina or non-Q-wave myocardial infarction?. Int J Card Imaging. 1991;7(1):7-14. [Medline].

70. Levine HD. Subendocardial infarction in retrospect: pathologic, cardiographic, and ancillary features. Circulation. Oct 1985;72(4):790-800. [Medline].

71. Lewis WR, Amsterdam EA, Turnipseed S, Kirk JD. Immediate exercise testing of low risk patients with known coronary artery disease presenting to the emergency department with chest pain. J Am Coll Cardiol. Jun 1999;33(7):1843-7. [Medline].

72. Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. N Engl J Med. Oct 19 2000;343(16):1139-47. [Medline].

73. Lubsen J, Tijssen JG. Efficacy of nifedipine and metoprolol in the early treatment of unstable angina in the coronary care unit: findings from the Holland Interuniversity Nifedipine/metoprolol Trial (HINT). Am J Cardiol. Jul 15 1987;60(2):18A-25A. [Medline].

74. Mahaffey KW, Harrington RA, Simoons ML, et al. Stroke in patients with acute coronary syndromes: incidence and outcomes in the platelet glycoprotein IIb/IIIa in unstable angina. Receptor suppression using integrilin therapy (PURSUIT) trial. The PURSUIT Investigators. Circulation. May 11 1999;99(18):2371-7. [Medline].

75. [Best Evidence] Mehta SR, Cannon CP, Fox KA, et al. Routine vs selective invasive strategies in patients with acute coronary syndromes: a collaborative meta-analysis of randomized trials. JAMA. Jun 15 2005;293(23):2908-17. [Medline].

76. [Best Evidence] Mehta SR, Cannon CP, Fox KA, et al. Routine vs selective invasive strategies in patients with acute coronary syndromes: a collaborative meta-analysis of randomized trials. JAMA. Jun 15 2005;293(23):2908-17. [Medline].

77. Moliterno D, Sapp S, Topol E. The paradoxical effect of thrombolytic therapy for unstable angina: meta-analysis. J Am Coll Cardiol. 1994;23:288A.

78. Moliterno D, Sgarbossa E, Armstrong P, et al. A major dichotomy in unstable angina outcome: ST depression vs. T-wave inversion--GUSTO II results. J Am Coll Cardiol. 1996;27:182A.

79. Moliterno DJ, Aguirre FV, Cannon CP, et al. The global unstable angina registry and treatment evaluation. Circulation. 1996;1:94.

80. Moliterno DJ, Asher CA, Califf RM, et al. Less myocardial but more cerebral ischemic events in African Americans than Caucasians with acute coronary syndromes: tesults from GUSTO-II. J Am Coll Cardiol. 1997;29:131A.

81. Moliterno DJ, Topol EJ. A direct comparison of tirofiban and abciximab during percutaneous coronary revascularization and stent placement: rationale and design of the TARGET study. Am Heart J. Nov 2000;140(5):722-6. [Medline].

82. Moliterno DJ, Topol EJ. Meta-analysis of platelet GP IIb/IIIa antagonist randomized clinical trials: consistent, durable, salutary effects [abstract]. Circulation. 1997;96:I-475.

83. Moliterno DJ, White HD. Unstable angina: PARAGON, PURSUIT, PRISM, and PRISM-PLUS. In: Lincoff A, Topol E, eds. Contemporary Cardiology: Platelet Glycoprotein IIb/IIIa Inhibitors in Cardiovascular Disease. Totowa,. NJ: Humana; 1999:201-27.

84. Nichol G, Walls R, Goldman L, et al. A critical pathway for management of patients with acute chest pain who are at low risk for myocardial ischemia: recommendations and potential impact. Ann Intern Med. Dec 1 1997;127(11):996-1005. [Medline].

85. Nichol G, Walls R, Goldman L, et al. A critical pathway for management of patients with acute chest pain who are at low risk for myocardial ischemia: recommendations and potential impact. Ann Intern Med. Dec 1 1997;127(11):996-1005. [Medline].

86. NINDS. Carotid endarterectomy for patients with asymptomatic internal carotid artery stenosis. National Institute of Neurological Disorders and Stroke. J Neurol Sci. Mar 1995;129(1):76-7. [Medline].

87. OASIS-2 Investigators. Effects of recombinant hirudin (lepirudin) compared with heparin on death, myocardial infarction, refractory angina, and revascularisation procedures in patients with acute myocardial ischaemia without ST elevation: a randomised trial. Organisation to Assess Strategies for Ischemic Syndromes (OASIS-2) Investigators. Lancet. Feb 6 1999;353(9151):429-38. [Medline].

88. Ohman EM, Armstrong PW, Christenson RH, et al. Cardiac troponin T levels for risk stratification in acute myocardial ischemia. GUSTO IIA Investigators. N Engl J Med. Oct 31 1996;335(18):1333-41. [Medline].

89. Ondriasova E, Ondrias K, Stasko A, Nosal R, Csollei J. Comparison of the potency of five potential beta-adrenoceptor blocking drugs and eight calcium channel blockers to inhibit platelet aggregation and to perturb liposomal membranes prepared from platelet lipids. Physiol Res. 1992;41(4):267-72. [Medline].

90. Parker FB Jr, Neville JF Jr, Hanson EL, Webb WR. Retrograde and antegrade pressures and flows in preinfarction syndrome. Circulation. Aug 1974;50(2 Suppl):II122-6. [Medline].

91. Pearlman JD, Gertz ZM, Wu Y, Simons M, Post MJ. Serial motion assessment by reference tracking (SMART): application to detection of local functional impact of chronic myocardial ischemia. J Comput Assist Tomogr. Jul-Aug 2001;25(4):558-62. [Medline].

92. Pearlman JD, Laham RJ, Simons M. Coronary angiogenesis: detection in vivo with MR imaging sensitive to collateral neocirculation--preliminary study in pigs. Radiology. Mar 2000;214(3):801-7. [Medline].

93. Peterson ED. What Have We Learned from the CRUSADE Registry? Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the AHA and ACC Guidelines. Available at www.clintrialresults.org/Slides/Crusade%20what%20have%20we%20learned.ppt. Accessed Dec. 28, 2008.

94. Piegas LS, Flather M, Pogue J, et al. The Organization to Assess Strategies for Ischemic Syndromes (OASIS) registry in patients with unstable angina. Am J Cardiol. Sep 2 1999;84(5A):7M-12M. [Medline].

95. Pope JH, Aufderheide TP, Ruthazer R, et al. Missed diagnoses of acute cardiac ischemia in the emergency department. N Engl J Med. Apr 20 2000;342(16):1163-70. [Medline].

96. Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE Study. Lancet. May 17 1997;349(9063):1429-35. [Medline].

97. RISC Group. Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. The RISC Group. Lancet. Oct 6 1990;336(8719):827-30. [Medline].

98. Robertson RM, Wood AJ, Vaughn WK, Robertson D. Exacerbation of vasotonic angina pectoris by propranolol. Circulation. Feb 1982;65(2):281-5. [Medline].

99. Scirica BM, Moliterno DJ, Every NR, et al. Racial differences in the management of unstable angina: results from the multicenter GUARANTEE registry. Am Heart J. Dec 1999;138(6 Pt 1):1065-72. [Medline].

100. Selker HP, Beshansky JR, Griffith JL, et al. Use of the acute cardiac ischemia time-insensitive predictive instrument (ACI-TIPI) to assist with triage of patients with chest pain or other symptoms suggestive of acute cardiac ischemia. A multicenter, controlled clinical trial. Ann Intern Med. Dec 1 1998;129(11):845-55. [Medline].

101. Shaw LJ, Peterson ED, Kesler K, Hasselblad V, Califf RM. A metaanalysis of predischarge risk stratification after acute myocardial infarction with stress electrocardiographic, myocardial perfusion, and ventricular function imaging. Am J Cardiol. Dec 15 1996;78(12):1327-37. [Medline].

102. Steinhubl SR, Tan WA, Foody JM, Topol EJ. Incidence and clinical course of thrombotic thrombocytopenic purpura due to ticlopidine following coronary stenting. EPISTENT Investigators. Evaluation of Platelet IIb/IIIa Inhibitor for Stenting. JAMA. Mar 3 1999;281(9):806-10. [Medline].

103. Stubbs P, Collinson P, Moseley D, Greenwood T, Noble M. Prognostic significance of admission troponin T concentrations in patients with myocardial infarction. Circulation. Sep 15 1996;94(6):1291-7. [Medline].

104. Swahn E, Areskog M, Berglund U, Walfridsson H, Wallentin L. Predictive importance of clinical findings and a predischarge exercise test in patients with suspected unstable coronary artery disease. Am J Cardiol. Feb 1 1987;59(4):208-14. [Medline].

105. Tan WA, Ellis SG. Interventional cardiology. In: Marso SP, Griffin BP, Topol EJ, eds. Manual of Cardiovascular Medicine. Philadelphia, PA: Lippincott Williams & Wilkins; 1999:722-43.

106. Tan WA, Moliterno DJ. Aspirin, ticlopidine, and clopidogrel in acute coronary syndromes: underused treatments could save thousands of lives. Cleve Clin J Med. Nov-Dec 1999;66(10):615-8, 621-4, 627-8. [Medline].

107. Tan WA, Moliterno DJ. TIMI flow and surrogate end points: what you see is not always what you get. Am Heart J. Oct 1998;136(4 Pt 1):570-3. [Medline].

108. Taneva E, Bogdanova V, Shtereva N. Acute coronary syndrome, comorbidity, and mortality in geriatric patients. Ann N Y Acad Sci. Jun 2004;1019:106-10. [Medline].

109. Tatum JL, Jesse RL, Kontos MC, et al. Comprehensive strategy for the evaluation and triage of the chest pain patient. Ann Emerg Med. Jan 1997;29(1):116-25. [Medline].

110. Theroux P, Lidon RM. Unstable angina: pathogenesis, diagnosis, and treatment. Curr Probl Cardiol. Mar 1993;18(3):157-231. [Medline].

111. Theroux P, Ouimet H, McCans J, et al. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med. Oct 27 1988;319(17):1105-11. [Medline].

112. Tunstall-Pedoe H, Kuulasmaa K, Mahonen M, Tolonen H, Ruokokoski E, Amouyel P. Contribution of trends in survival and coronary-event rates to changes in coronary heart disease mortality: 10-year results from 37 WHO MONICA project populations. Monitoring trends and determinants in cardiovascular disease. Lancet. May 8 1999;353(9164):1547-57. [Medline].

113. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. The EPIC Investigation. N Engl J Med. Apr 7 1994;330(14):956-61. [Medline].

114. VAKIL RJ. PREINFARCTION SYNDROME--MANAGEMENT AND FOLLOW-UP. Am J Cardiol. Jul 1964;14:55-63. [Medline].

115. Wallentin L, Lagerqvist B, Husted S, Kontny F, Stahle E, Swahn E. Outcome at 1 year after an invasive compared with a non-invasive strategy in unstable coronary-artery disease: the FRISC II invasive randomised trial. FRISC II Investigators. Fast Revascularisation during Instability in Coronary artery disease. Lancet. Jul 1 2000;356(9223):9-16. [Medline].

116. Wallis DE, Pope C, Littman WJ, Scanlon PJ. Safety and efficacy of esmolol for unstable angina pectoris. Am J Cardiol. Nov 15 1988;62(16):1033-7. [Medline].

117. Wilcox I, Freedman SB, Allman KC, et al. Prognostic significance of a predischarge exercise test in risk stratification after unstable angina pectoris. J Am Coll Cardiol. Sep 1991;18(3):677-83. [Medline].

118. WooD P. Acute and subacute coronary insufficiency. Br Med J. Jun 24 1961;1(5242):1779-82. [Medline].

119. Yeghiazarians Y, Braunstein JB, Askari A, Stone PH. Unstable angina pectoris. N Engl J Med. Jan 13 2000;342(2):101-14. [Medline].

Keywords

unstable angina, myocardial infarction, acute coronary syndrome, preinfarction angina, intermediate coronary syndrome, accelerated angina, crescendo angina, chest pain, heart attack, coronary disease, hypertrophic obstructive cardiomyopathy, HOCM, microvascular disease, atherosclerotic plaque, atherosclerosis, plaque rupture, cholesterol, new-onset angina, accelerating angina, rest angina, early postinfarct angina, early postrevascularization angina, non–Q-wave myocardial infarction, non–Q-wave MI, NQMI, non-STEMI, NSTEMI, UA, MI, ACS

Contributor Information and Disclosures

Author

Walter A Tan, MD, MS, Associate Professor of Medicine, Clinical Associate Professor of Surgery, Director of Stroke Interventions, Associate Director of Cardiac Catheterization, Department of Cardiovascular Sciences, Brody School of Medicine, East Carolina University
Walter A Tan, MD, MS is a member of the following medical societies: American Association for the Advancement of Science, American College of Cardiology, American Heart Association, American Stroke Association, National Stroke Association, Society for Vascular Medicine and Biology, and Society of Interventional Radiology
Disclosure: Novartis Honoraria Other

Coauthor(s)

David J Moliterno, MD, Professor of Medicine, Jefferson Morris Gill Professor of Cardiology, Chief, Division of Cardiovascular Medicine, University of Kentucky; Vice Chairman of Internal Medicine, Chandler Medical Center; Medical Director, Gill Heart Institute
David J Moliterno, MD is a member of the following medical societies: American College of Cardiology, American College of Physicians, American Heart Association, American Medical Association, Association of Professors of Cardiology, and European Society of Cardiology
Disclosure: Nothing to disclose.

Steven James Filby, MD, Fellow in Interventional Cardiology, The Cleveland Clinic Foundation
Disclosure: Nothing to disclose.

Medical Editor

Justin D Pearlman, MD, PhD, ME, MA, Director of Advanced Cardiovascular Imaging, Professor of Medicine, Professor of Radiology, Adjunct Professor, Thayer Bioengineering and Computer Science, Dartmouth-Hitchcock Medical Center
Justin D Pearlman, MD, PhD, ME, MA is a member of the following medical societies: American College of Cardiology, American College of Physicians, American Federation for Medical Research, International Society for Magnetic Resonance in Medicine, and Radiological Society of North America
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Marschall S Runge, MD, PhD, Charles and Anne Sanders Distinguished Professor of Medicine, Chairman, Department of Medicine, Vice Dean for Clinical Affairs, University of North Carolina at Chapel Hill School of Medicine
Marschall S Runge, MD, PhD is a member of the following medical societies: American Association for the Advancement of Science, American College of Cardiology, American College of Physicians-American Society of Internal Medicine, American Federation for Clinical Research, American Federation for Medical Research, American Heart Association, American Physiological Society, American Society for Clinical Investigation, American Society for Investigative Pathology, Association of American Physicians, Association of Professors of Cardiology, Association of Professors of Medicine, Southern Society for Clinical Investigation, and Texas Medical Association
Disclosure: Pfizer Honoraria Speaking and teaching; Merck Honoraria Speaking and teaching; Orthoclinica Diagnostica Consulting fee Consulting

CME Editor

Amer Suleman, MD, Consultant in Electrophysiology and Cardiovascular Medicine, Department of Internal Medicine, Division of Cardiology, Medical City Dallas Hospital
Amer Suleman, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Institute of Stress, American Society of Hypertension, Federation of American Societies for Experimental Biology, Royal Society of Medicine, and Society of Cardiac Angiography and Interventions
Disclosure: Nothing to disclose.

Chief Editor

Eric H Yang, MD, Assistant Professor of Medicine, Director of Coronary Care Unit, University of North Carolina at Chapel Hill School of Medicine
Eric H Yang, MD is a member of the following medical societies: Alpha Omega Alpha
Disclosure: Up to Date Royalty Review panel membership

The authors want to thank the Kathy Cable, MLS and the staff of the East Carolina University William E. Laupus Health Sciences Library for their superb assistance, and Mackzine Brown for support in preparing this manuscript.

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