Unstable Angina

Updated: Nov 22, 2015
  • Author: Walter Tan, MD, MS; Chief Editor: Eric H Yang, MD  more...
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Overview

Practice Essentials

Unstable angina belongs to the spectrum of clinical presentations referred to collectively as acute coronary syndromes (ACSs), which range from ST-segment elevation myocardial infarction (STEMI) to non-STEMI (NSTEMI). [1] Unstable angina is considered to be an ACS in which there is no detectable release of the enzymes and biomarkers of myocardial necrosis. See the image below.

Pathogenesis of acute coronary syndromes. Pathogenesis of acute coronary syndromes.

Signs and symptoms

Symptoms of unstable angina are similar to those of myocardial infarction (MI) and include the following:

  • Chest pain or pressure
  • Sweating
  • Dyspnea
  • Nausea, vomiting
  • Dizziness or sudden weakness
  • Fatigue
  • Pain or pressure in the back, neck, jaw, abdomen, or shoulders or arms
  • Symptoms that occur at rest; become suddenly more frequent, severe, or prolonged; are a change from the usual pattern of angina; and do not respond to rest or nitroglycerin [2]

The patient’s history and diagnostic testing are generally more sensitive and specific for unstable angina than the physical examination, which may be unremarkable. Evaluate the patient’s vital signs and perform a cardiac evaluation, which includes resting 12-lead electrocardiography (ECG).

Examination in a patient with unstable angina may yield the following findings:

  • Diaphoresis
  • Tachycardia or bradycardia
  • Transient myocardial dysfunction (eg, systolic blood pressure < 100 mm Hg or overt hypotension, elevated jugular venous pressure, dyskinetic apex, reverse splitting of S2, presence of S3 or S4, new or worsening apical systolic murmur, or rales or crackles)
  • Peripheral arterial occlusive disease (eg, carotid bruit, supraclavicular or femoral bruits, or diminished peripheral pulses or blood pressure)

Any sign of congestive heart failure, including isolated sinus tachycardia, particularly in physiologically vulnerable populations (eg, very elderly patients), should trigger expeditious workup, treatment, or consultation with a cardiologist. Such patients can deteriorate rapidly.

See Presentation for more detail.

Diagnosis

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

  • Serial cardiac biomarker assays (eg, creatine kinase MB isoenzyme [CK-MB], troponins, C-reactive protein [CRP], and brain natriuretic peptide [BNP])
  • Complete blood count (CBC) with hemoglobin level
  • Serum chemistry panel (including magnesium and potassium)
  • Lipid panel

Other tests that may be used to assess patients include the following:

  • Creatinine level
  • Exercise testing when patients are stable

The following imaging studies may be used to assess patients with suspected unstable angina:

  • Chest radiography
  • Echocardiography
  • Computed tomography angiography
  • Magnetic resonance angiography
  • Single-photon emission computed tomography
  • Magnetic resonance imaging
  • Myocardial perfusion imaging

See Workup for more detail.

Management

Patients with unstable angina require admission to the hospital for bed rest with continuous telemetry monitoring. Obtain intravenous (IV) access, and provide supplemental oxygen. The course of unstable angina is highly variable and potentially life-threatening; therefore, quickly determine whether the initial treatment approach should use an invasive (surgical management) or a conservative (medical management) strategy.

The following medications are used in the management of unstable angina:

  • Antiplatelet agents (eg, aspirin and clopidogrel)
  • Lipid-lowering statin agents (eg, simvastatin, atorvastatin, pitavastatin, and pravastatin)
  • Cardiovascular antiplatelet agents (eg, tirofiban, eptifibatide, and abciximab)
  • Beta blockers (eg, atenolol, metoprolol, esmolol, nadolol, and propranolol)
  • Anticoagulants (eg, heparin)
  • Low-molecular-weight heparins (eg, enoxaparin, dalteparin, and tinzaparin)
  • Thrombin inhibitors (eg, bivalirudin, lepirudin, desirudin, and argatroban)
  • Angina nitrates (eg, nitroglycerin IV)
  • Angiotensin-converting enzyme inhibitors (eg, captopril, lisinopril, enalapril, and ramipril)

Surgical intervention in unstable angina may include the following:

  • Cardiac catheterization
  • Revascularization

See Treatment and Medication for more detail.

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Background

Chest pain is a nonspecific symptom that can have cardiac or noncardiac causes (see DDx). Unstable angina belongs to the spectrum of clinical presentations referred to collectively as acute coronary syndromes (ACSs), which range from ST-segment elevation myocardial infarction (STEMI) to non-STEMI (NSTEMI). Unstable angina is considered to be an ACS in which there is no detectable release of the enzymes and biomarkers of myocardial necrosis. The term angina is typically reserved for pain syndromes arising from presumed myocardial ischemia.

The traditional term unstable angina 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 MI or death. Patients with this condition have also been categorized by 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.

Although the etiology and definition of unstable angina can be broad, interplay between disrupted atherosclerotic plaque and overlaid thrombi is present in many cases of unstable angina, with consequent hemodynamic deficit or microembolization. Thus, the condition 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 potential development of collateral vessels.

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.

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Pathophysiology

Factors involved in the pathophysiology of unstable angina include the following:

  • Supply-demand mismatch
  • Plaque disruption or rupture
  • Thrombosis
  • Vasoconstriction
  • 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.

Increased myocardial oxygen demand may be caused by the following:

  • 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 heart failure (CHF)

Decreased oxygen supply may be caused by the following:

  • Anemia
  • Hypoxemia
  • Polycythemia
  • Hypotension

The above causes must be investigated because a number of them are reversible. For example, anemia from chronic gastrointestinal (GI) bleeding is not uncommon in elderly patients. This can coexist with coronary artery disease (CAD). However, patients may not benefit from 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 (the product of heart rate and systolic blood pressure) 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, leads to plaque fissuring or rupture (see the image below), especially at the junction of the cap and the vessel wall. (See Vulnerable Plaque Pathology.)

Pathogenesis of acute coronary syndromes. Pathogenesis of acute coronary syndromes.

The degree and consequences of plaque disruption cover 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.

As many as 50% of MIs are due to lesions that are angiographically considered functionally insignificant. [3] Angiographically mild lesions can still be dangerous because they have an unstable thin-cap fibroatheroma (TCFA). This means that focal treatments such as percutaneous coronary intervention (PCI) are incomplete and that medical therapy to protect the entire vascular tree is complementary and crucial, particularly in patients with a history of ACS.

Vasoconstriction and thrombosis

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

Exposure of subendothelial components provokes platelet adhesion and activation. Platelets then aggregate in response to exposed vessel wall collagen or local aggregates (eg, thromboxane and 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.

ACS may involve a clot in flux (ie, forming and enlarging, chipping off and embolizing). Over time, this dynamic clot formation or lysis, in conjunction with coronary vasoreactivity and resistance in the microvascular bed, causes intermittent and alternating (or cyclical) occlusion and flow.

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

[#IntroductionEpidemiology] Genetics

Although the etiology of cardiovascular disease is strongly linked to modifiable environmental factors, it is known that genetics also play a significant part in the development of CAD and unstable angina. Much of the literature regarding the genetics of cardiovascular disease concerns MI and the development of CAD; however, there is a growing body of literature concerning unstable angina itself.

A number of genetic contributions are known to play a part in unstable angina. Genome-wide association studies (GWAS) have found linkage with unstable angina at chromosome 2q36-q37.3, chromosome 3q26-q27, and chromosome 20q11-13. [4] A polymorphism in glycoprotein Ia was associated with an increased time before platelet aggregation occurs in heterozygotes for the polymorphism in a Chinese population [5] ; it was postulated that the difference in platelet aggregation affected the pathogenesis of unstable angina.

Polymorphisms in several matrix metalloproteinase (MMP) genes have also been described. A guanine insertion in MMP1 is associated with smaller and more stable plaques, whereas the presence of more than 22 “CA” microsatellite repeats in MMP9 is associated with a worse prognosis for unstable angina. [6, 7]

Polymorphisms of interleukin (IL)-1 receptor antagonist (IL-1Ra) are suspected of having a role in the development of unstable angina. Studies conducted to date suggest that persons with allele-2 of IL-2Ra have increased inflammation, as measured by C-reactive protein (CRP) levels. There was an increased frequency of younger presentation in one study, [8] but a clear association between this polymorphism and an increased risk for unstable angina has not been found.

Apolipoprotein E (ApoE) polymorphisms also may play a pathogenetic role. In a study assessing the relation of ApoE4 to serum IL-10 levels, IL-10 levels were found to be lower in patients with at least 1 copy of ApoE4. [9] Higher IL-10 levels are believed to be cardioprotective, further suggesting that ApoE4 is associated with increased risk for unstable angina. [9] Ultimately, the genetics of unstable angina appear to be most closely linked with markers of inflammation and mediated by their effects on the risk of plaque rupture. [10]

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Epidemiology

In the United States, the incidence of unstable angina is increasing, and each year, nearly 1 million hospitalized patients have a primary diagnosis of unstable angina. A similar number of unstable angina episodes likely occur outside the hospital and either go unrecognized or are managed in the outpatient setting. However, even with heightened public awareness, improved survival after MI, and an aging population, the incidence of unstable angina should continue to rise despite primary and secondary prevention measures.

United States demographics

Reasonably representative statistical estimates for unstable angina can be obtained from 2 registries, the GUARANTEE (Global Unstable Angina Registry and Treatment Evaluation) registry [11] and the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation) registry of the American College of Cardiology (ACC) and the American Heart Association (AHA). [12, 13] (See Table 1 below.)

Table 1. Patient Characteristics, GUARANTEE Versus CRUSADE Trials (Open Table in a new window)

Characteristics GUARANTEE, 1995-96  [11] CRUSADE, 2001-06  [12]
Mean age (y) 62 69
Patients >65 y (%) 44
Female (%) 39 40
Hypertension (%) 60 73
Diabetes mellitus (%) 26 33
Current smoker (%) 25
Hypercholesterolemia (%) 43 50
Previous stroke (%) 9
Previous MI (%) 36 30
Previous angina (%) 66
CHF (%) 14 18
Previous coronary intervention (%) 23 21
Previous coronary bypass surgery (%) 25 19
CHF = congestive heart failure; CRUSADE = Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the American College of Cardiology/American Heart Association guidelines; GUARANTEE = Global Unstable Angina Registry and Treatment Evaluation; MI = myocardial infarction.

GUARANTEE involved 3000 consecutive hospital admissions for unstable angina in 35 US hospitals in 6 geographic regions (Northeast, Mideast, Midwest, Southeast, Southwest, Northwest) from September 1995 to August 1996.

CRUSADE registered more than 180,000 US patients with NSTEMI from 2001 to 2006, targeting high-risk patients with unstable angina or NSTEMI according to the following inclusion criteria, either separately or in combination [12, 13] :

  • Chest pain or anginal equivalent at rest, more than 10 minutes in duration
  • Ischemic electrocardiographic (ECG) changes (ST-segment depression >0.5 mm, transient ST-segment elevation 0.5-1.0 mm lasting for < 10 minutes); or
  • Elevated markers of myocardial necrosis (CK-MB or troponin I or T exceeding the upper limit of normal for the local laboratory assay used at each institution)

International demographics

The best international demographic data available are from the OASIS-2 (Organization to Assess Strategies for Ischemic Syndromes) registry (see Table 2 below). [14]

Table 2. Demographic Characteristics of Patients in International OASIS-2 Registry (Open Table in a new window)

Characteristics  [14] 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
PCI (%) 7 19 16 5 0.4 24
CABG (%) 4 20 10 7 0.4 17
CABG = coronary artery bypass grafting; ECG = electrocardiographic; NQMI = non-Q wave myocardial infarction; OASIS = Organization to Assess Strategies for Ischemic Syndromes; PCI = percutaneous coronary intervention.

Because unstable angina is intimately linked to the incidence of coronary events, an approximation of international trends might be found in the MONICA (Monitoring Trends and Determinants in Cardiovascular Diseases) registry sponsored by the World Health Organization (WHO). [15] This large project monitored more than 7 million people aged 35-64 years from 30 populations in 21 countries from the mid-1980s.

In the study, 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. [15] The lowest average MI rates, and presumably the lowest average unstable angina rates, were observed in Beijing, China; Toulouse, France; Catalonia, Spain; Vaud-Fribourg, Switzerland; and Brianza, Italy.

The GRACE (Global Registry of Acute Coronary Events) registry (http://www.outcomes-umassmed.org/grace/ ) is prospectively tracking contemporary ACS treatment and outcome across 30 countries and has accumulated more than 100,000 patients. [16]

Age-related demographics

The mean age of presentation with unstable angina is 62 years (range, 23-100 years). To put this in perspective, the mean age is 60 years for patients in clinical trials for MI, 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 one third of men. Black individuals tend to present at a slightly younger age than people of other races do.

Sex-related demographics

Women with unstable angina are older and have a higher prevalence of hypertension, diabetes mellitus, CHF, and family history of CAD than men. Men tend to have a higher previous incidence of MI 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.

Race-related demographics

Disparities in outcome and risk-factor prevalence among different ethnic groups have been widely reported. For instance, as a group, black persons exhibit a higher prevalence of atherosclerotic risk factors (eg, hypertension, diabetes mellitus, and smoking), greater left ventricular mass, and decreased peripheral vasodilatory response. Relative to white persons, MI more frequently results in death in black individuals at young ages.

Fewer myocardial events but more cerebral complications have also been observed in black patients with unstable angina in randomized clinical trials of heparin versus hirudin (the Global Utilization of Streptokinase and TPA [tissue plasminogen activator] for Occluded coronary arteries II [GUSTO II] trial) or eptifibatide versus placebo (the Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy [PURSUIT] trial), possibly because of enhanced fibrinolytic activity and a higher prevalence of hypertension.

Racial differences also exist with regard to the delivery and response to medical care. White individuals have a higher rate of catheterization, angioplasty, and bypass surgery than individuals from other racial groups do.

Studies have shown equivalent short-term (30-day) mortality figures from unstable angina (including NQMI) for black individuals, but over the long term, persistent worse outcomes have been demonstrated.

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Prognosis

The risk of MI, complications, and death in unstable angina varies because of the broad clinical spectrum that is covered by the term unstable angina. The aggressiveness of the therapeutic approach should be commensurate with the individualized estimated risk.

Patients who present with new ST-segment deviation (≥1 mm) have a 1-year death or MI rate of 11%, compared with a rate of only 6.8% in patients with isolated T-wave inversion. [17]

The current standard for cross-comparing studies is the 30-day event rate. The aggregate data for the more than 40,000 patients with ACSs (excluding STEMI), as derived from studies using contemporary treatments (albeit in varying degrees), indicate improving outcomes (see Table 3 below). The 30-day MI and death rates are currently around 8.5% and 3.5%, respectively, despite 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 a new window)

Study Year Number of Patients Death (%) Myocardial Infarction (%) 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
ESSENCE = Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-wave Coronary Events; GUSTO-IIb = Global Utilization of Streptokinase and TPA (tissue plasminogen activator) for Occluded Coronary Arteries; PARAGON-A = Platelet IIb/IIIa Antagonism (lamifiban) for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network; PARAGON-B = 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; TIMI-3 = Thrombolysis in Myocardial Infarction Clinical Trial 3.

The RESCATE (Recursos Empleados en el Sindrome Coronario Agudo y Tiempos de Espera) investigators from Spain reported a 1.8% death rate and a 5.1% MI rate at 28 days (consecutive series, 1992-1994; early revascularization rate, ~6%) in 791 patients with unstable angina. [18] Compared with the rates in the North American studies listed earlier (see Epidemiology), these seem lower, probably because of the healthier case-mix; this illustrates the difficulties of direct outcome comparisons between institutions, countries, and trials.

A contemporary large clinical trial with centrally adjudicated outcomes showed that an ACS portends more adverse events in the year to come. [19] The following are the 12-month event rates for the ACS patients (final diagnosis of unstable angina, 16.6%; NSTEMI, 42.9%; STEMI, 37.5%), whose median age was 62 years, 25% of whom were diabetic, and fewer than 1% of whom were classified as above Killip class 2 [19] :

  • Death from vascular causes - 4.3%
  • Death from nonvascular causes - 0.6%
  • MI - 5.9%
  • Stroke - 1.2%

These findings present an opportunity for secondary prevention of such adverse events.

Prognostic indicators

Of note, studies have shown that the following are significant prognosticators for poor outcome in patients with unstable angina:

  • Ongoing CHF
  • Presence or history of poor left ventricular ejection fraction (LVEF)
  • Hemodynamic instability
  • Recurrent angina despite intensive anti-ischemic therapy
  • New or worsening mitral regurgitation
  • Sustained ventricular tachycardia

Although these factors were not evaluated in the Thrombolysis in Myocardial Infarction (TIMI) Risk Score model (see Physical Examination), they should be taken into consideration when the level of care is decided.

Other predictors of worse long-term outcome in unstable angina include underlying left ventricular systolic dysfunction and more widespread extent of CAD.

The level of troponin positivity correlates with intermediate-term death in a dose-dependent fashion (range, 1.0-7.5% at 6 weeks) independent of age, creatine kinase MB isoenzyme (CK-MB) levels, and ST-segment deviation.

More recent studies indicate that epicardial adipose tissue thickness (EAT) can also be used to predict major adverse cardiac events. [20]  In a study of 200 patients hospitalized with stable angina pectoris, unstable angina pectoris, or acute myocardial infarction who underwent coronary angiography, patients with a baseline EAT of more than 7 mm suffered significantly more revascularizations, nonfatal myocardial infarction, and cardiovascular death. [20]

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Patient Education

Before hospital discharge, patients with unstable angina and their family members should be educated about the manifestations of MI and the actions that must to be taken in that eventuality. They should also receive training in cardiopulmonary resuscitation (CPR).

For patient information, see Cholesterol Center and Heart Health Center, as well as Cholesterol FAQs, Heart Disease FAQs, Angina Pectoris, Chest Pain, High Cholesterol, Cholesterol Charts (What the Numbers Mean), Lifestyle Cholesterol Management, Cholesterol-Lowering Medications, and Heart Attack.

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