Practice EssentialsUnstable 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.Essential update: New AHA-ACC guidelines for managing non-ST-elevation ACSThe 2014 guidelines from the American Heart Association and the American College of Cardiology on the management of patients with nonST-elevation ACSs contain revisions of their 2007 guidelines.[1, 2, 3]Updates include the following: Because unstable angina and NSTEMI are on a pathophysiologic continuum and are often indistinguishable, they are considered together in the 2014 guidelines Cardiac troponin assays, not yet available in the United States, may improve the diagnosis of myocardial necrosis High-intensity statins should be used in patients with overt cardiovascular disease Risk stratification tools in these patients include the Thrombolysis in Myocardial Infarction (TIMI) risk score and the Global Registry of Acute Coronary Events (GRACE) risk score After discharge, referral to a cardiac rehabilitation program should be madeSigns and symptomsSymptoms 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[4]The patients history and diagnostic testing are generally more sensitive and specific for unstable angina than the physical examination, which may be unremarkable. Evaluate the patients 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.SeePresentationfor more detail.DiagnosisThe 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 panelOther tests that may be used to assess patients include the following: Creatinine level Exercise testing when patients are stableThe 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 imagingSeeWorkupfor more detail.ManagementPatients 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

PathophysiologyFactors involved in the pathophysiology of unstable angina include the following: Supply-demand mismatch Plaque disruption or rupture Thrombosis Vasoconstriction Cyclical flowSupply-demand mismatchThe 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 HypotensionThe 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 withcoronary 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 disruptionAccumulation 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. (SeeVulnerable Plaque Pathology.)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.[5]Angiographically mild lesions can still be dangerous because they have an unstable thin-cap fibroatheroma (TCFA). This means that focal treatments such aspercutaneous 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 thrombosisMost patients withACShave 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]GeneticsAlthough 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.[6]A polymorphism in glycoprotein Ia was associated with an increased time before platelet aggregation occurs in heterozygotes for the polymorphism in a Chinese population[7]; 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.[8, 9]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,[10]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.[11]Higher IL-10 levels are believed to be cardioprotective, further suggesting that ApoE4 is associated with increased risk for unstable angina.[11]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.[12]EpidemiologyIn 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 demographicsReasonably representative statistical estimates for unstable angina can be obtained from 2 registries, the GUARANTEE (Global Unstable Angina Registry and Treatment Evaluation) registry[13]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).[14, 15](See Table 1 below.)Table 1. Patient Characteristics, GUARANTEE Versus CRUSADE Trials(Open Table in a new window)CharacteristicsGUARANTEE, 1995-96[13]CRUSADE, 2001-06[14]

Mean age (y)6269

Patients >65 y (%)44

Female (%)3940

Hypertension (%)6073

Diabetes mellitus (%)2633

Current smoker (%)25

Hypercholesterolemia (%)4350

Previous stroke (%)9

Previous MI (%)3630

Previous angina (%)66

CHF (%)1418

Previous coronary intervention (%)2321

Previous coronary bypass surgery (%)2519

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[14, 15]: 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 demographicsThe best international demographic data available are from the OASIS-2 (Organization to Assess Strategies for Ischemic Syndromes) registry (see Table 2 below).[16]Table 2. Demographic Characteristics of Patients in International OASIS-2 Registry(Open Table in a new window)Characteristics[16]AustraliaBrazilCanadaHungaryPolandUnited States

GeneralNumber of patients1899147816269311135918

Mean age (y)656266656366

Women (%)374237454037

ClinicalNQMI presentation (%)7714221716

Abnormal ECG (%)749182959787

Select treatmentsBeta blocker (%)675373675957

Calcium blocker (%)595153524359

Invasive procedures (index hospitalization)Cardiac catheterization (%)24694320758

PCI (%)7191650.424

CABG (%)4201070.417

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).[17]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.[17]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.[18]Age-related demographicsThe 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 demographicsWomen 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 demographicsDisparities 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.PrognosisThe 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.[19]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)StudyYearNumber of PatientsDeath (%)Myocardial Infarction (%)Major Bleed (%)

TIMI-319941,4732.59.00.3

GUSTO-IIb19978,0113.86.01.0

ESSENCE19983,1713.34.51.1

PARAGON-A19982,2823.210.34.0

PRISM19983,2323.04.20.4

PRISM-PLUS19981,9154.48.11.1

PURSUIT199810,9483.612.92.1

TIMI-11B19993,9103.96.01.3

PARAGON-B20005,2253.19.31.1

Pooled40,1673.58.51.5

ESSENCE = Efficacy and Safety of Subcutaneous Enoxaparin in NonQ-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.[20]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.[21]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[21]: 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 indicatorsOf 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 tachycardiaAlthough 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.PresentationPatients with unstable angina represent a heterogeneous population. Therefore, the clinician must obtain a focused history of the patients symptoms and coronary risk factors and immediately review the electrocardiogram (ECG) to develop an early risk stratification. (SeePrognosis.)Initially, obtain a history to determine whether any evidence of angina is present, 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 (MI).Angina can take many forms, and inquiry should be directed at eliciting not only chest pain but also any associated 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, 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, flulike symptoms, and, less commonly, lightheadedness or abdominal pain. The intensity of pain on a 1-10 scale does not correlate with diagnosis or prognosis.Elderly and female patients are more likely to present with atypical signs and symptoms.Diagnostic ConsiderationsObservation and serial or further testing should be considered for patients who have coronary risk factors or a suspicious history. In one study, the 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.[22]The rates were 0-10% across different academic centers.Be aware that unstable angina 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 (postpercutaneous coronary intervention) reocclusion or coronary stent thrombosis Congestive heart failureAlso consider cocaine-induced coronary spasm, which 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 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 blockers.The differential diagnoses for unstable angina fall into the following categories: Cardiac (eg, acute myocarditis and right ventricular strain due to severe pulmonary hypertension) Vascular (eg, microvascular disease [syndrome X]) Pulmonary (eg, pneumonia, pneumothorax, pulmonary hypertension, and tracheobronchitis) Gastrointestinal (eg, Mallory-Weiss tear, pancreatitis, and peptic ulcer disease) Musculoskeletal (eg, arthritis of the shoulder or spine, cervical disk disease, interscalene or hyperabduction syndromes, subacromial bursitis, and intercostal muscle cramps) Other (eg, mediastinitis, disorders of the breast, and tumors of the chest wall)

Differential Diagnoses Anxiety Disorders Aortic Dissection Aortic Stenosis Biliary Disease Costochondritis Esophageal Reflux Esophageal Spasm Herpes zoster Hypertrophic obstructive cardiomyopathy Pericarditis Pulmonary Embolism Pulmonary hypertension