Unstable Angina

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.
Supply-demand mismatch

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.

The pathogenesis of acute coronary syndrome is shown in the image below.


Pathogenesis of acute coronary syndromes.


The degree and consequence of plaque disruption covers a wide spectrum. Minor fissuring is typically nonocclusive and hence clinically silent, and repeat occult episodes of plaque ulceration and healing with a gradual growth of plaque volume have been histologically documented. Moderate-to-large plaque disruptions commonly result in unstable angina or acute infarction.

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.
Reasonably representative statistical estimates for unstable angina can be obtained from 2 registries, the Global Unstable Angina Registry and Treatment Evaluation (GUARANTEE) registry2,3 or the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA (CRUSADE) registry.4 GUARANTEE involved 3000 consecutive hospital admissions for unstable angina in 35 hospitals in 6 geographic regions (Northeast, Mideast, Midwest, Southeast, Southwest, Northwest) from September 1995 to August 1996. CRUSADE registered more than 180,000 patients with non–ST-segment elevation myocardial infarction (NSTEMI) in the US from 2001-2006, targeting high-risk patients with unstable angina or NSTEMI using the following inclusion criteria: (1) chest pain or anginal equivalent at rest, more than 10 minutes in duration; (2) ischemic ECG changes (ST-segment depression >0.5 mm, transient ST-segment elevation 0.5–1.0 mm lasting for<10min);and/or (3) elevated markers of myocardial necrosis (CK-MB and/or troponin I or T > the upper limit of normal for the local laboratory assay used at each institution).

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

Open table in new window GUARANTEE, 1995-96 CRUSADE, 2001-06
Mean age 62 y 69 y
Patients older than 65 y 44%
Female 39% 40%
Hypertension 60% 73%
Diabetes mellitus 26% 33%
Current smoker 25%
Hypercholesterolemia 43% 50%
Previous stroke 9%
Previous myocardial infarction 36% 30%
Previous angina 66%
Congestive heart failure 14% 18%
Previous coronary intervention 23% 21%
Previous coronary bypass surgery 25% 19%




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

Open table in new windowCharacteristics Australia Brazil Canada Hungary Poland United States
General Number of patients 1899 1478 1626 931 1135 918
Mean age (y) 65 62 66 65 63 66
Women (%) 37 42 37 45 40 37
Clinical NQMI presentation (%) 7 7 14 22 17 16
Abnormal ECG (%) 74 91 82 95 97 87
Select treatments Beta-blocker (%) 67 53 73 67 59 57
Calcium blocker (%) 59 51 53 52 43 59
Invasive procedures (index hospitalization) Cardiac catheterization (%) 24 69 43 20 7 58
Percutaneous coronary intervention (PCI) (%) 7 19 16 5 0.4 24
Coronary artery bypass graft (CABG) (%) 4 20 10 7 0.4 17


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

The GRACE registry is prospectively tracking contemporary ACS treatment and outcome across 30 countries, now accumulating more than 100,000 patients.6
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

Open table in new windowStudy Year Number of Patients Death (%) MI (%) Major Bleed (%)
TIMI-3* 1994 1,473 2.5 9.0 0.3
GUSTO-IIb† 1997 8,011 3.8 6.0 1.0
ESSENCE‡ 1998 3,171 3.3 4.5 1.1
PARAGON-A§ 1998 2,282 3.2 10.3 4.0
PRISM|| 1998 3,232 3.0 4.2 0.4
PRISM-PLUS¶ 1998 1,915 4.4 8.1 1.1
PURSUIT# 1998 10,948 3.6 12.9 2.1
TIMI-11B** 1999 3,910 3.9 6.0 1.3
PARAGON-B†† 2000 5,225 3.1 9.3 1.1
Pooled 40,167 3.5 8.5 1.5


* 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


Open table in new windowCharacteristic 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

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