Unstable angina or sometimes referred to as acute coronary syndrome causes unexpected chest pain, and usually occurs while resting.  The most common cause is reduced blood flow to the heart muscle because the coronary arteries are narrowed by fatty buildups (atherosclerosis) which can rupture causing injury to the coronary blood vessel resulting in blood clotting which blocks the flow of blood to the heart muscle.

Unstable angina should be treated as an emergency. If you have new, worsening or persistent chest discomfort, you need to go to the ER. You could be having aheart attack which puts you at increased risk for severe cardiac arrhythmias orcardiac arrest, which could lead to sudden death. Learn about an unstable form of angina called Prinzmetal angina.

Causes of Unstable Angina: Blood clots that block an artery partially or totally are what causes unstable angina. Blood clots may form, partially dissolve, and later form again and angina can occur each time a clot blocks blood flow in an artery. Learn more about excessive blood clotting.

Symptoms of Unstable Angina - The pain or discomfort:

  • Often occurs while you may be resting, sleeping, or with little physical exertion
  • Comes as a surprise
  • May last longer than stable angina
  • Rest or medicine usually do not help relieve it
  • May get worse over time
  • Can lead to a heart attack
Treatment for Unstable Angina
First, your healthcare provider will need to find the blocked part or parts of the coronary arteries by performing a cardiac catheterization.  In this procedure, a catheter is guided through an artery in the arm or leg and into the coronary arteries, then injected with a liquid dye through the catheter.  High-speed X-ray movies record the course of the dye as it flows through the arteries, and doctors can identify blockages by tracing the flow.  An evaluation of how well your heart is working also can be done during cardiac catheterization. View an illustration of a cardiac catheterization.

Next, based on the extent of the coronary artery blockage(s) your doctor will discuss with you the following treatment options: 
  1. Percutaneous coronary intervention (PCI) may be required to open a blocked coronary artery.  Briefly, this procedure involves undergoing cardiac catheterization followed by using a catheter with a small inflatable balloon at the tip (View an illustration of a cardiac catheter).  The balloon is inflated, squeezing open the fatty plaque deposit located on the inner lining of the coronary artery. Then the balloon is deflated and the catheter is withdrawn. This procedure is often followed by insertion of a stent to then keep the coronary artery vessel propped open to allow for improved blood flow to the heart muscle.
  2. Coronary artery bypass graft surgery may be indicated depending on the extent of coronary artery blockages and medical history. In this procedure, a blood vessel is used to route blood around the blocked part of the artery, forming a kind of detour.

Before any of these procedures, a doctor must find the blocked part or parts of the coronary arteries. He or she will guide a catheter through an artery in the arm or leg and into the coronary arteries, then inject a liquid dye through the catheter. High-speed X-ray movies record the course of the dye as it flows through the arteries, and doctors can identify blockages by tracing the flow.  An evaluation of how the heart works also can be done during cardiac catheterization.

For more information, talk to your doctor.

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.


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.


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.

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.


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]


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]

Next Section: P

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.


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 electrocardiogram (ECG) to develop an early risk stratification. (See Prognosis.)

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.

Physical Examination

The physical examination is usually not as sensitive or specific for unstable angina as the 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 the following:

  • Aortic dissection
  • Leaking or ruptured thoracic aneurysm
  • Pericarditis with tamponade
  • Pulmonary embolism
  • Pneumothorax
  • Peptic ulcer disease

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. Such signs include the following:

  • 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 increase the likelihood of associated coronary artery disease (CAD) and are as follows:

  • Carotid bruit
  • Supraclavicular or femoral bruits
  • Diminished peripheral pulses or blood pressure

Any sign of congestive heart failure (CHF), 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.

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.

Braunwald Classification

The Braunwald classification (see Table 4 below) is conceptually useful, in that it factors in the clinical presentation (new or progressive vs rest angina), context (primary, secondary, or post-MI), and intensity of antianginal therapy.

Table 4. Braunwald Classification of Unstable Angina (Open Table in a new window)

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

Patients in Braunwald class I have new or accelerated exertional angina, whereas those in class II have subacute (>48 hours since last pain) or class III acute (< 48 hours since last pain) rest angina. The clinical circumstances associated with unstable angina are categorized as follows:

  • Secondary (anemia, fever, hypoxia)
  • Primary
  • Postinfarction (< 2 weeks after MI)

Intensity of antianginal therapy is subclassified as follows:

  • No treatment
  • Usual oral therapy
  • Intense therapy (eg, intravenous [IV] nitroglycerin)


Canadian Cardiovascular Society Grading System

Because of its simplicity and practicality, the Canadian Cardiovascular Society Grading System for effort-related angina is widely used to describe symptom severity. The grading system 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 1 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


Acute Coronary Syndrome Risk Assessment

Estimation of the likelihood of acute coronary syndrome (ACS) is a complex, multivariable problem that cannot be fully specified in the list below, which is meant more to illustrate major relations than to offer rigid algorithms. A high likelihood of ACS includes any of the following features:

  • History of previous MI, sudden death, or other known history of CAD
  • Chest, neck, jaw, or left arm pain consistent with prior documented angina
  • Transient hemodynamic or ECG changes during pain
  • ST-segment elevation or depression of 1 mm or more
  • Marked symmetrical T-wave inversion in multiple precordial leads

An intermediate likelihood of ACS includes the absence of high-likelihood features but the presence of 1 of the following risk characteristics:

  • Age greater than 70 years
  • Male sex
  • Diabetes mellitus
  • Extracardiac vascular disease (peripheral, brachiocephalic, or renal artery atherosclerosis)
  • ST depression of 0.05-1 mm
  • T-wave inversion of 1 mm or greater in leads with dominant R waves

A low likelihood of ACS includes the absence of high- or intermediate-likelihood features and the presence of any of the following:

  • Chest pain classified as probably not angina
  • Chest discomfort reproduced by palpation
  • T-wave flattening or inversion of less than 1 mm in leads with dominant R waves
  • Normal ECG findings

Thrombolysis in Myocardial Infarction Risk Score

The Thrombolysis in Myocardial Infarction (TIMI) Risk Score for unstable angina/non-ST elevation MI (UA/NSTEMI) is currently the best-validated prognostic instrument that is simple enough to use in settings such as an emergency department. The gradient of MI, severe recurrent ischemia, or death is somewhat proportionate to the TIMI Risk Score (see the image below), though an adverse prognosis appears to be mitigated by the use of newer antithrombotic strategies.

Thrombolysis in Myocardial Infarction (TIMI) Risk Thrombolysis in Myocardial Infarction (TIMI) Risk Score correlates with major adverse outcome and effect of therapy with low-molecular-weight heparin. ARD = absolute risk difference; ESSENCE = Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-wave Coronary Events; No. = number; NNT = number needed to treat.

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:

  • Age 65 years or older
  • Use of aspirin in the preceding 7 days
  • Known coronary stenosis of 50% or greater
  • Elevated serum cardiac markers
  • At least 3 risk factors for CAD (including diabetes mellitus, active smoking, family history of CAD, hypertension, or hypercholesterolemia)
  • Severe anginal symptoms (≥2 anginal events in the preceding 24 hours)
  • ST deviation on ECG

Approach Considerations

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

  • Is this coronary artery disease (CAD)? (That is, what is the diagnosis, or what does the patient have?)
  • 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 electrocardiography (ECG), and a blood draw for evaluation of cardiac enzymes should be accomplished expeditiously.

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

  • Serial cardiac biomarker assays
  • Hemoglobin level
  • Serum chemistry panel
  • Lipid panel

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

Urinary proton nuclear magnetic resonance (1H NMR) spectroscopy–based metabolomic profiling appears to have the potential for identifying diagnostic biomarkers in the investigation of unstable angin pectoris metabolic signatures.[22]

Investigators have demonstrated enhanced expression of toll-like receptors 2 and 4 (TLR-2 and TLR-4)  on platelets in patients with acute coronary syndrome, which has potential clinical implications for prophylactic and therapeutic targets.[23]

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

Missed diagnosis

Patients in whom the diagnosis of myocardial infarction (MI) or unstable angina has been missed and those who are sent home from the emergency department (ED) have, respectively, a 2-fold and a 1.7-fold increased risk of death, compared with those who were admitted to the hospital.[21] This a public health issue. Indeed, up to 20% of the millions of dollars awarded in malpractice suits against ED practitioners is for missed acute coronary syndrome (ACS).[21]

A related study reported that nearly one third (32%) of patients with ACS have normal levels (< 14 ng/L) of high-sensitivity cardiac troponin (hs-cTnT) when they present to the ED with acute chest pain.[24] The majority of these patients had unstable angina. In addition, although the death rates of patients with normal hs-cTnT levels were significantly lower 1 year later than those of patients with elevated hs-cTnT levels, their acute MI rates were significantly higher.

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

  • Addressing factors or preconceptions that obscure the correct diagnosis in women and nonwhite patients, subgroups that are at higher risk for a 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 CAD
  • Awareness that absence of ECG findings or early cardiac enzyme elevation does not automatically preclude the possibility of acute ischemia, because these are merely snapshots of particular points in the course of a dynamic process


Basic Blood Studies

The complete blood count (CBC) helps in ruling out anemia as a secondary cause of ACS. Leukocytosis has prognostic value in the setting of acute MI.

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

A creatinine level is also needed, particularly if cardiac catheterization is considered. Use of N -acetylcysteine and adequate hydration can help prevent contrast material–induced nephropathy.[25]

Cardiac Biomarkers

Creatine kinase, CK-MB, and troponin

Absolute elevations of creatine kinase and its MB isoenzyme (CK-MB) or troponin levels are highly specific evidence of myocardial cell death and distinguish non−ST-elevation MI (NSTEMI) from unstable angina (see the image below.)

Time course of elevations of serum markers after aTime course of elevations of serum markers after acute myocardial infarction. CK = creatine kinase; CK-MB = creatine kinase MB fraction; LDH = lactate dehydrogenase.

In addition, biomarkers alone or as part of accelerated diagnostic protocols (ADP) may reduce the number of patients with a missed diagnosis of NSTEMI who are at increased risk for major adverse cardiac events.

Furthermore, such approaches may facilitate early discharge from the ED in patients who have a low short-term risk of a major cardiac event, as reported by the ASPECT (ASia-Pacific Evaluation of Chest pain Trial) investigators.[26] However, the trial did not fully address the potentially important influence of cultural differences in chest pain perception and time to presentation.

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

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. Outcomes in troponin-positive patients have been improved by aggressive treatment strategies that include early cardiac catheterization. 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 the serum half-life of troponin is longer than that of CK-MB and can remain elevated for 7-14 days after an event. Because of their kinetics, however, cardiac troponins, once elevated, are much less useful in evaluating recurrent chest pain with myocardial injury, whereas CK-MB levels permit detection of reinfarction.

Because measurement of troponin is a very sensitive assay that detects myocardial injury or necrosis in the absence of CAD (eg, in critically ill or septic patients), newer mechanistic criteria have been put forth for a universal definition of MI by a joint task force of the European Society of Cardiology (ESC), the American College of Cardiology Foundation (ACCF), the American Heart Association (AHA), and the World Heart Federation (WHF).[27]

Fundamentally, this universal definition tries to identify patients in whom there may be an ACS wherein investigation or intervention might improve outcome (type I, or “spontaneous MI”).[27] Such an individual is distinguished from the patient in an intensive care unit (ICU) who has a type 2 MI or troponin elevation that is related to myocardial necrosis due to a supply-demand mismatch (eg, anemia, tachycardia, respiratory failure, or hypotension due to sepsis).

Although elevated troponins portend a graver prognosis for all of these cohorts, the latter patients are unlikely to benefit from an ischemia workup—and may indeed be harmed by an invasive strategy.[27]

There are also data suggesting that troponin T may be falsely elevated with major injury to skeletal muscles. Furthermore, qualitative bedside troponin assay results may be difficult to interpret in patients with renal insufficiency.

Brain natriuretic peptide

The TACTICS/TIMI (Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy/Thrombolysis In Myocardial Infarction)-18 substudy showed that brain (B-type) natriuretic peptide (BNP) is an independent predictor of short- and long-term mortality and risk of CHF in patients presenting with unstable angina.[28]

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

BNP levels may add incremental information to the assessment of patients with unstable angina, but they 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.

Combination with C-reactive protein

In the future, a combination of levels of troponin (a biomarker of myocardial necrosis), N-terminal pro-B-type natriuretic peptide (NT-proBNP) (an indicator of elevated left ventricular end-diastolic pressure and wall stress), and C-reactive protein (CRP) (an estimate of extent of systemic inflammation) may prove useful for predicting the outcome of patients with ACS.

Next Section


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 in the ED. The diagnostic accuracy of an ECG is enhanced if a prior tracing is available for comparison. Serial ECG recordings taken every 15-30 minutes are recommended if the patient’s chest pain continues and ECG changes are not noted in the initial or subsequent recordings.[29]

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 MI.

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 mortalities, irrespective of cardiac biomarker level.

New or reversible ST-segment deviation of 0.5 mm or more from baseline was associated with a higher incidence (15.8% vs 8.2%) of 1-year death or MI in the TIMI-III Registry ECG Ancillary study.[17]

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

Wellens syndrome

Wellens syndrome refers to specific ECG abnormalities in the precordial T-wave segment, which are associated with critical stenosis of the proximal LAD coronary artery. De Zwaan, Wellens, and colleagues in the early 1980s recognized this subset of patients with unstable angina who had specific precordial T-wave inversions and subsequently developed a large anterior wall MY.[30] Wellens syndrome is also referred to as LAD coronary T-wave syndrome.[31] Syndrome criteria include the following:

  • Characteristic T-wave changes
  • A history of anginal chest pain
  • Normal or minimally elevated cardiac enzyme levels
  • An ECG without Q waves, without significant ST elevation, and with normal precordial R-wave progression

Recognition of this ECG abnormality is of paramount importance because LAD coronary T-wave syndrome represents a preinfarction stage of CAD that often progresses to a devastating anterior wall infarction.


If available on a prompt basis, echocardiography can provide a quick evaluation of left ventricular function either for prognosis (which is worse when the left ventricular ejection fraction [LVEF] is less than 40%) or for diagnosis, 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, it must be kept in mind that small infarcts may not be apparent on the echocardiogram.

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

Transesophageal echocardiography is highly recommended if the clinical picture suggests the possibility of a valvular or mechanical complication of MI or if the patient is not following the expected hospital course.

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


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

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

MRI is well established as a means of detecting myocardial scarring of as little as 1%, which is a powerful prognostic factor.[32, 33] It is also well established for detecting and characterizing complications of MI. MRI may find wall-motion abnormalities and infarcts missed by echocardiography, whether because of the higher resolution and full coverage of MRI, because of echocardiography dropout from the lungs or ribs, or because of the angle dependence of echocardiography, which may miss the affected area, such as the real apex.

Myocardial Perfusion Imaging

Myocardial perfusion imaging is a valuable method for triaging patients with chest pain in the ED. Myocardial perfusion imaging at rest is highly sensitive for detecting acute MI, and it can be supplemented with provocative testing after infarction is excluded. However, the results of clinical trials can be applied only in centers with proven reliability and experience.

Exercise Testing

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 after 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 MI at 1 year, compared with an incidence of only 2% for those with a negative scan.[34] Among men, shorter exercise duration, lower maximal rate-pressure product, and exercise-induced angina or ST-segment depression have correlated with unfavorable outcome.[35]

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 (31-48%) for the imaging stress tests.

Many chest pain centers are evaluating early stress testing for expeditious triage of low-risk patients. The ERASE Chest Pain (Emergency Room Assessment of Sestamibi for Evaluation of Chest Pain) randomized clinical trial compared usual care with usual care plus a resting perfusion scan in patients with and ECG that was normal or nondiagnostic for ischemia.[35] There was a 32% reduction in the odds of being unnecessarily admitted to the hospital, without sacrifice of safety, in nonischemic patients who underwent early nuclear perfusion scanning.

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

Approach Considerations

Patients with unstable angina require admission to the hospital for bed rest with continuous telemetry monitoring. Intravenous (IV) access should be obtained and supplemental oxygen started. Because the course of unstable angina is highly variable and potentially life-threatening, the aggressiveness of the therapeutic approach must be established expeditiously. The key in this decision-making is to determine whether the initial management strategy will be invasive or conservative (see the images below).

Algorithm for initial invasive strategy. ASA = aceAlgorithm for initial invasive strategy. ASA = acetylsalicylic acid (aspirin); GP IIb/IIIa= glycoprotein IIb/IIIa; IV = intravenous; LOE = level of evidence; UA/NSTEMI = unstable angina/non–ST-segment elevation myocardial infarction; UFH = unfractionated heparin. (Adapted from 2007 ACC/AHA UA/NSTEMI Guidelines.)
Algorithm for initial conservative strategy. ASA =Algorithm for initial conservative strategy. ASA = acetylsalicylic acid (aspirin); EF = ejection fraction; GP IIb/IIIa= glycoprotein IIb/IIIa; IV = intravenous; LOE = level of evidence; LVEF = left ventricular ejection fraction; UA/NSTEMI = unstable angina/non–ST-segment elevation myocardial infarction. (Adapted from 2007 ACC/AHA UA/NSTEMI Guidelines.)

An invasive strategy refers to the routine use of cardiac catheterization with possible revascularization, and a conservative strategy refers to initial medical management with the possible use of cardiac catheterization if indicated by failure of medical therapy or objective evidence of ischemia (dynamic electrocardiographic [ECG] changes or abnormal noninvasive stress test results). Determination of the preferred strategy depends on the patient’s clinical characteristics and clinical risk (see Cardiac Catheterization).

Specific therapy for primary causes of ischemia should be directed at each pathophysiologic origin of unstable angina: increased myocardial rate-pressure product, coronary vasoconstriction, platelet aggregation, and thrombosis.

Several guidelines and decision algorithms are available and are especially helpful in identifying patients at low risk for whom hospital admission can be avoided. In 2012, the ACCF/AHA published a focused update of their 2007 guideline for the management of patients with unstable angina/NSTEMI.[36]  In 2014, they published revisions of their 2007 guidelines on the management of patients with non–ST-elevation ACSs.[37, 38, 39]  The 2014 updates included 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 made

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 intensive care unit (ICU) in a community hospital setting.

Indications for intensive care

ICU or emergency revascularization disposition is indicated by the following:

  • TIMI (Thrombolysis In Myocardial Infarction) 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 left bundle branch block
  • 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 enzymes (creatine kinase [CK] or troponin)
  • Myocardial infarction or coronary stenting within the last 2 weeks

Indications for immediate care

Patients are admitted to intermediate care units when they are asymptomatic but have any of the following conditions:

  • Atrial arrhythmia, supraventricular tachycardia, or low-grade 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 advanced age or frailty

Indications for observation

Patients who are otherwise healthy without ischemic ECG changes but who have either of the following should be admitted to observation units:

  • New-onset symptoms at moderate levels of exertion
  • Known coronary artery disease (CAD) with a presentation that does not suggest true worsening but for which further observation is thought to be prudent

Medical management of adverse events

Medications that provide symptomatic relief but that have not been shown to affect long-term major events include nitrates, diltiazem or verapamil, and heparin. Medications that have been convincingly shown to be capable of reducing short- or long-term adverse events are as follows:

  • Aspirin
  • Beta-adrenergic blocking agents
  • Lipid-lowering agents (statins)
  • Angiotensin-converting enzyme (ACE) inhibitors
  • Clopidogrel
  • Glycoprotein (GP) IIb/IIIa antagonists


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.

Next Sectio

Initial Medical Management

Medications used in the initial management of unstable angina include the following:

  • Aspirin
  • Beta-adrenergic blocking agents
  • PSY12 inhibitors (thienopyridines [clopidogrel, prasugrel], nonthienopyridines [ticagrelor])
  • GP IIb/IIIa antagonists
  • Heparin
  • Direct thrombin inhibitors
  • Nitrates


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 (ACS); the peak effect can be observed within as short a time as 30 minutes. Patients with unstable angina/non–ST-segment elevation myocardial infarction (UA/NSTEMI) should continue indefinitely on aspirin, if tolerated.[40]

Pooled data from more than 2000 patients revealed a reduction in the rate of death or myocardial infarction (MI) from 11.8% to 6% with aspirin in cases of unstable angina. Several studies have shown approximately 40-50% risk reductions for death or MI 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 (PCI), oral 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, oral aspirin 75-162 mg should be continued indefinitely.

Beta blockers

Clinical trials of beta blockers in cases of unstable angina have shown decreases in ischemic symptoms and in the occurrence of MIs. 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 to IV agents. Studies have associated IV beta-blocker therapy with an increased risk of cardiogenic shock in patients presenting with heart failure or high-risk features. However, IV beta blockers may still be indicated in select patients with tachycardia or hypertension and ongoing chest pain.

In vitro studies have shown inhibition of platelet aggregation with beta blockers.


When the American College of Cardiology (ACC)/American Heart Association (AHA) 2007 guidelines for the management of patients with UA/NSTEMI were released, clopidogrel was the only thienopyridine antiplatelet agent approved by the US Food and Drug Administration (FDA). Subsequently, the FDA approved a second thienopyridine, prasugrel. The 2011 ACC Foundation (ACCF)/AHA focused update of the 2007 guidelines includes recommendations for the use of prasugrel as well as clopidogrel.[40]

The 2011 ACCF/AHA update to the guidelines recommends a loading dose of a thienopyridine for patients with UA/NSTEMI for whom PCI is planned.[40] For patients with UA/NSTEMI who are undergoing PCI, a maintenance dose of a thienopyridine should be given for at least 12 months. Early discontinuance should be considered if the risk of bleeding outweighs the expected benefits of thienopyridine therapy. Dosage and timing for each thienopyridine are specified in the class I recommendations.[40]


Clopidogrel is recommended as the antiplatelet of choice in patients who are intolerant to aspirin. It is also used as an adjunctive antiplatelet agent in conjunction with aspirin (dual antiplatelet therapy).[40, 41]

The CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) trial showed that the addition of clopidogrel to aspirin therapy reduced the incidence of cardiovascular death, MI, or stroke from 11.4% to 9.3% at 1 year, with early benefit shown at 24 hours.[42] However, the beneficial results of clopidogrel-aspirin treatment came at the cost of a higher rate of major bleeding (3.7%) than that observed in patients on aspirin therapy plus placebo (2.7%).

The PCI-CURE[42] and the CREDO (Clopidogrel for the Reduction of Events During Observation)[43] trials showed significant benefit from the administration of clopidogrel to patients with unstable angina who undergo coronary intervention; pretreatment with oral clopidogrel 6 hours before intervention was associated with improved outcomes. A loading dose of 600 mg may offer more effective platelet inhibition than one of 300 mg; increasing the loading dose beyond 600 mg has not shown benefit.

Patients who later undergo coronary artery bypass grafting (CABG) (eg, those with multivessel disease) while receiving clopidogrel have an increased risk of major bleeding and are more likely to undergo surgery for bleeding. Because of this increased risk of bleeding, it is recommended that clopidogrel be withheld for at least 5 days before elective CABG. 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. Clopidogrel is a prodrug that must be metabolized into the active form before it is effective. Metabolism of clopidogrel is carried out in the liver by a number of enzymes, including CYP2C19.[44, 45]

Numerous variations of CYP are described, with the wild type being CYP2C19*1. Polymorphisms for *2, *3, *4, and *8 are also described and are associated with lower efficacy of therapy. The results of some studies suggest that an additional polymorphism, designated *17, may increase the efficacy of clopidogrel therapy. However, these studies have not been consistently replicated.[44, 45]

Studies have been conducted to ascertain viable strategies for overcoming the variability in the metabolism and efficacy of clopidogrel.[46] Doubling the dose has been suggested; some studies found this to improve outcomes in poor responders, whereas others failed to show this result. Another suggestion is to add a phosphodiesterase inhibitor, such as cilostazol; some of the initial results of this strategy are promising, and a clinical trial is currently under way.

Finally, switching to more potent inhibiting agents, such as prasugrel (see below), remains a possible strategy. Despite its similarity to clopidogrel, prasugrel is not metabolized by the CYP2C19 system. Consequently, its metabolism would not be influenced by the same genetic factors as that of clopidogrel.[46, 47, 48]

For patients at intermediate or higher risk of adverse cardiovascular events, the National Institute for Health and Clinical Excellence (NICE) recommends discussing the continuation of clopidogrel with the cardiac surgeon before performing CABG so that a decision can be reached based on the balance of ischemic and bleeding risk.[49] It should be noted that although clopidogrel may be less efficacious than the newer P2Y12 inhibitors, it may carry a slightly lower bleeding risk.


The 2011 ACCF/AHA focused update to the guidelines for UA/NSTEMI recommends prasugrel as an alternative thienopyridine to clopidogrel in conjunction with PCI.[40] Head-to-head comparison has shown that whereas prasugrel is more effective at reducing clinical events than clopidogrel is, it is also associated with a higher risk of bleeding.

Prasugrel is stated to be potentially harmful as part of a dual-platelet regimen in patients with a stroke history for whom PCI is planned.[40] Therefore, it should only be used sparingly in those who weigh less than 60 kg as well as those aged 75 years or older, unless the risk of recurrent cardiac ischemia outweighs the elevated bleeding risk.

It should be noted that prasugrel remains unproven for use in patients with ST-elevation MI (STEMI) or ACS who were treated only medically. In addition, this agent must be withdrawn at least 7 days before planned CABG (compared with 5 days for clopidogrel or ticagrelor).

Nonthienopyridine P2Y12 inhibitor


The 2012 focused update of the 2007 guidelines now adds ticagrelor to the armamentarium of antiplatelet therapy for ACS patients.[50] Ticagrelor is indicated to reduce the rate of thrombotic CV events following ACS. Ticagrelor also reduces the rate of stent thrombosis in patients who have undergone stent placement for treatment of ACS. In September 2015, the indication was expanded to include patients with a history of MI more than 1 year previously. It is used in addition to low-dose aspirin (75-100 mg/day).[51]

The key points with respect to ticagrelor are (1) that this agent can also be used for STEMI patients and (2) that improved survival is achieved at 1 year, with all-cause mortality reduced from 5.9% to 4.5%.[19] This 1.4% absolute risk reduction in the death rate is attributed to a possible increase in endogenous circulating adenosine, in that ticagrelor is known to inhibit its uptake into erythrocytes. This may also be the cause of the agent’s unique side effect of transient dyspnea.

Approval of ticagrelor use beyond 1 year in patients with a history of MI is based on the PEGASUS TIMI-54 study, a large-scale outcomes trial involving over 21,000 patients.[52]PEGASUS TIMI-54 investigated ticagrelor 60 mg twice daily plus low-dose aspirin, compared to placebo plus low-dose aspirin, for the long-term prevention of CV death, heart attack, and stroke in patients who had experienced a heart attack 1-3 years prior to study enrollment. In patients with an MI more than 1 year previously, treatment with ticagrelor significantly reduced the risk of CV death, MI, or stroke compared with placebo.[52]

Glycoprotein IIb/IIIa antagonists

Because of the availability of novel oral P2Y12 platelet inhibitors, IV GP IIb/IIIa inhibitors have been relegated to use in special circumstances when a second antiplatelet agent in conjunction with aspirin cannot be promptly given (as in cases where there is a high likelihood of urgent CABG or where cardiac catheterization is delayed because of consent or staffing issues).[50] The risk must justify the bleeding risk (as in young diabetics with elevated troponin levels).

All of the currently available GP IIb/IIIa inhibitors (ie, abciximab, eptifibatide, and tirofiban) have been shown to increase the safety of acute PCI, with relative risk reductions in adverse events (including 30-day mortality and infarction) of approximately 30-50% in trials prior to the advent of the newer P2Y12 platelet inhibitors.

However, the GUSTO-IV (Global Utilization of Streptokinase and TPA [tissue plasminogen activator] for Occluded coronary arteries IV) randomized clinical trial did not show any benefit for abciximab in medically treated patients who did not undergo PCI.[53, 54] In fact, longer duration of abciximab use was associated with a negative trend in event rates; therefore, abciximab is not recommended for patients who are not undergoing PCI.[40]

Of the currently used GP IIb/IIIa inhibitors, only eptifibatide and tirofiban have been shown to be beneficial 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 meta-analysis of 6 randomized trials (with 31,400 patients) failed to show a mortality benefit in patients who did not undergo PCI.[55] Whether this small benefit offsets the risk of bleeding events is a matter for the physician’s clinical judgment.

Dual and triple antiplatelet therapies

The ACCF/AHA 2011 update to the UA/NSTEMI guidelines recommends dual-antiplatelet therapy (aspirin and a second antiplatelet agent) for medium-risk to high-risk patients with definite UA/NSTEMI for whom an initial invasive strategy is chosen.[40] Before PCI, the second antiplatelet agent may be clopidogrel or an IV GP IIb/IIIa inhibitor (preferably eptifibatide or tirofiban). At the time of PCI, the second antiplatelet agent may be clopidogrel, prasugrel, or an IV GP IIb/IIIa inhibitor.[40]

Precatheterization triple-antiplatelet therapy (aspirin, a thienopyridine, and a GP IIb/IIIa inhibitor) is associated with increased bleeding risk and is recommended only for patients at high risk for ischemic events whose risk of bleeding is not elevated.[40]


The use of low-molecular-weight heparin (LMWH) and the use of IV unfractionated heparin (UFH) are 2 comparable anticoagulation strategies in the treatment of unstable angina. The many potential benefits of using LMWH include lower bleeding rates, reduced costs, and decreased incidence of heparin-induced thrombocytopenia. However, many interventional cardiologists are uncomfortable using LMWH because anticoagulation activity cannot be measured during PCI.[56]

In the ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-wave Coronary Events) study, when LMWH (enoxaparin) was compared with UFH, the 30-day composite rates of death, MI, or recurrent angina were significantly reduced for subjects taking LMWH (19.8% vs 23.3%).[57] However, excess minor bleeding occurred in 11.9% of patients in the LMWH group, versus 7.2% of those in the non-LMWH group, many of which were due only to injection site ecchymosis.[57] The revascularization rate was intermediate (~30%).

In the SYNERGY (Superior Yield of the New strategy of Enoxaparin Revascularization and Glycoprotein IIb/IIIa Inhibitors) trial, enoxaparin was associated with more major bleeding episodes (9.1%) than UFH was (7.6%).[58] High-risk patients with NSTEMI (including those with unstable angina) were randomized into groups that received either UFH or enoxaparin. All enrolled patients were treated with an early invasive strategy.

No difference in the composite endpoint (death or MI by 30 days) was detected in the SYNERGY trial.[58] Although more major bleeding episodes occurred in the enoxaparin group, much of this effect was attributed to patients who crossed over to UFH after receiving an initial dose of enoxaparin.

In the OASIS-5 (Organization to Assess Strategies for Ischemic Syndromes-5) trial, which compared fondaparinux and enoxaparin for treatment of UA/NSTEMI, fondaparinux was associated with a low, but increased, rate of guiding catheter thrombus.[59] Fondaparinux yielded a lower major bleeding rate at 9 days, as well as significant reductions in MI, stroke, and mortality at 180 days.[59] However, this agent is not recommended if urgent PCI is foreseen, because of the increased rate of guiding catheter thrombus.

Enoxaparin, fondaparinux, and UFH are safe alternatives for the treatment of unstable angina. Switching agents (eg, from LMWH to UFH) is associated with excess bleeding and reduced clinical benefit. If a conservative strategy is intended, LMWH may be preferred. The National Institute for Health and Clinical Excellence (NICE) recommends UFH as an alternative to fondaparinux for patients with significant renal impairment (creatinine >265 mmol/L) or for those likely to undergo coronary angiography within 24 hours of admission.[29]

Reactivation of unstable angina after discontinuance of heparin has been documented among subjects not receiving concomitant aspirin therapy.[60]

Direct thrombin inhibitors

Direct thrombin inhibitors, such as hirudin, lepirudin (recombinant hirudin), and bivalirudin, 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 ACS, there was a slightly greater reduction in MI in the inhibitors group (2.8%) than in the heparin group (3.5%).[61] Treatment with hirudin was associated with an higher risk of major bleeding than treatment with heparin, whereas treatment with bivalirudin was associated with a lower risk.[61]

GUSTO IIB investigators compared recombinant hirudin with heparin in 12,142 patients, a third of whom had STEMI.[62]The hirudin group had a 9% relative risk reduction in 30-day death or MI rates (8.9% vs 9.8%) but experienced more moderate bleeding events (8.8% vs 7.7%).[62]

In the international OASIS-2 (Organisation to Assess Strategies for Ischemic Syndromes-2) clinical trial, involving 10,141 patients who were randomly assigned to receive either heparin (activated partial thromboplastin time [aPTT] maintained between 60 and 100 seconds) or lepirudin (0.4 mg/kg bolus, followed by 0.15 mg/kg/hr by IV infusion for 72 hours), investigators found no evidence indicating attenuation of myocardial necrosis (based on CK or troponin measurements), in contrast with GP IIb/IIIa antagonists.[63]

The FDA approved lepirudin for use in patients with heparin-induced thrombocytopenia (HIT) and associated thrombotic disease. The goal is 1.5-2.5 times the control aPTT values. The dosage must be adjusted for patients with renal impairment.

The benefits of bivalirudin in patients who undergo coronary stent implantation has been demonstrated in the REPLACE-2 (Randomized Evaluation in PCI Linking Angiomax to reduced Clinical Events-2) and ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trials.[63, 64] At present, however, the data are insufficient to support a recommendation of routine bivalirudin use in patients with unstable angina.

Although direct thrombin inhibitors should not be routinely used in the treatment of unstable angina, they may be of clinical benefit in special circumstances (eg, HIT).


IV nitrate agents may be used in the treatment of ischemic chest pain, symptoms of heart failure, or hypertension, but these drugs are not associated with appreciable long-term clinical benefit. Nitrate agents are contraindicated for patients with right ventricular infarction, hypertrophic cardiomyopathy (HOCM), and severe aortic stenosis.

Further Medical Management

Additional management of unstable angina includes the use of statins (lipid-lowering agents) and ACE inhibitors.

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 in patients with unstable angina.

Results from the MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering) study and the PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) TIMI trials suggested that early initiation of antilipidemic agents (statins) in patients with ACS can decrease adverse events within a relatively short term.[65, 66]

The MIRACL trial (including 3086 patients with unstable angina randomized to high-dose atorvastatin vs placebo) demonstrated that therapy with atorvastatin resulted in a reduction in the primary endpoint (ie, death, MI, resuscitated cardiac arrest, severe recurrent symptomatic ischemia) from 17.4% to 14.8% within a relatively short period (4 months) as compared with placebo.[65] The benefit was mostly for recurrent symptomatic ischemia with objective evidence and requiring emergency rehospitalization (from 8.4% to 6.2%).[65]

The PROVE-IT TIMI-22 trial demonstrated a benefit from statin therapy even in patients with ACS presenting with relatively low serum low-density lipoprotein cholesterol (LDL-C) levels (< 100 mg/dL), suggesting that the target LDL-C level should be less than 80 mg/dL in these patients.[66]

To improve patient adherence, statin therapy should be initiated before hospital discharge. Additional clinical benefit may be gained by starting therapy within 24-96 hours of admission.

FDA safety alerts

On March 1, 2012, the FDA updated healthcare professionals regarding changes to the prescribing information concerning interactions between protease inhibitors (drugs for management of HIV and hepatitis B virus [HBV] infection) and certain statins. The combination of these drugs may raise the blood levels of statins and increase the risk for myopathy. Rhabdomyolysis, the most serious form of myopathy, can cause kidney damage and lead to kidney failure, which is life-threatening.[67]

On February 28, 2012, the FDA approved important safety label changes for statins, including removal of routine monitoring of liver enzymes. Information about the potential for generally nonserious and reversible cognitive side effects and reports of increased blood sugar and glycosylated hemoglobin (HbA1c) levels was added to the statin labels. In addition, extensive contraindication and dose limitation updates were added to the lovastatin label in situations when this drug is taken with certain medicines that can increase the risk for myopathy.[68]

On June 8, 2011, the FDA notified healthcare professionals of its recommendations for limiting the use of the highest approved dose (80 mg) of simvastatin because of an increased risk of muscle damage. The FDA required that the simvastatin label be changed to add new contraindications and dose limitations for using simvastatin with certain medicines.[69]

Angiotensin-converting enzyme inhibitors

ACE inhibitors are of particular benefit in patients with large anterior infarctions, especially those with compromised left ventricular function (eg, from ST-elevation MI [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.

Other medications

Calcium-channel antagonists, antibiotics against Chlamydia pneumoniae, and fibrinolytic agents currently have no established role in the setting of unstable angina.

Most of the clinical trials of fibrinolytic therapy have shown a tendency toward more nonfatal infarctions attributed to procoagulant effects in the context of a nonocclusive thrombus.

Although the available data suggest that the efficacy of ticlopidine is similar to that of aspirin, the use of ticlopidine in the United States was drastically reduced after reports appeared of associated fatal thrombotic thrombocytopenic purpura.

Ranolazine, trimetazidine, nicorandil, and ivabradine, which have been shown to reduce myocardial ischemia through various means, have received limited testing in patients with ACS.[70]

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

Invasive versus conservative therapy

It has been questioned whether patients who have unstable angina but lack the clinical characteristics listed above receive greater benefit from an invasive strategy than from conservative management.

Among patients presenting with unstable angina, approximately 15% have 1-vessel CAD, 35% have 2-vessel CAD, and 50% have 3-vessel CAD. The incidence of left main disease is roughly 5-10%. The rate of thrombus detected at coronary angiography varies widely, ranging 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 so-called permissive revascularization.

Older clinical trials, such as TIMI III-B, the VANQWISH (Veterans Affairs Non–Q-Wave Infarction Strategies in-Hospital) study, and the MATE (Medicine versus Angiography in Thrombolytic Exclusion) trial, did not find routine catheterization to be superior to reserving catheterization for patients with recurrent ischemic symptoms or a significantly positive stress test result. Heightened abrupt vessel closure, stent thrombosis, and MI rates were early hazards observed with angioplasty performed in the acute setting of myocardial ischemia.[71, 72]

The TACTICS (Treat angina with Aggrastat and determine Cost of Therapy with Invasive or Conservative Strategy)/TIMI-18 study showed a very low 30-day and 6-month results for the composite endpoint of death, MI, or rehospitalization with the early invasive strategy.[28] The study entailed the administration of IV GP IIb/IIIa (tirofiban), coupled with angiography within 48 hours. The benefit of early invasive strategy was more substantial in intermediate- and high-risk patients (ie, those with a TIMI score of 3).

The FRISC-II (FRagmin during InStability in Coronary artery disease-II) trial showed a significant reduction in death or MI at 6 months in patients with unstable angina who underwent early catheterization and revascularization, as compared with patients who were treated with a noninvasive strategy.[73]

This treatment difference was primarily driven by a lower rate of MI in the invasive arm (7.8%) than in the noninvasive arm (10.1%). Patients in the invasive arm also had a significant reduction in angina and hospital readmission rates. The treatment benefits were more pronounced in patients with ST-segment depression and cardiac marker elevation.[73]

Investigators in the RITA-3 (Randomized Intervention Trial of unstable Angina-3) study also reported a benefit with the invasive strategy as opposed to conservative management in intermediate- to high-risk patients with NSTEMI and ischemic changes on ECG or elevated troponin levels.[74]

In this study, the combined endpoint of death, MI, and refractory angina at 4 months was significantly reduced in the invasive arm (9.6%) as compared with the conservative arm (7.6%). Although the 2 groups showed no difference in the combined endpoint (death or nonfatal MI) at 1 year, a 5-year follow-up analysis revealed that the invasive strategy was associated with significant reductions in death or nonfatal MI.[74]

In contrast to these trials, the ICTUS (Invasive vs Conservative Treatment in Unstable coronary Syndromes) trial did not find an early invasive strategy to confer any advantage over a selective invasive strategy in 1200 patients with chest pain and elevated troponin who had either a history of CAD or the presence of ischemic ECG changes.[75] However, the selective invasive group had a 40% rate of revascularization during initial hospital stay.

Timing of catheterization

With regard to the timing of catheterization, the ISAR-COOL (Intracoronary Stenting Angiographic Results COOLing-off) trial suggested that earlier catheterization provides a significant benefit over later use of the procedure.[76] Patients with NSTEMI who underwent coronary angiography within 6 hours had a lower rate of death or large MI at 30 days (5.9%) than did patients who underwent the treatment at 3-5 days (11.6%).[76]

Two meta-analyses (one of which included the ICTUS trial) 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 weight of the current evidence favors the view that an early invasive strategy benefits high-risk patients with ACS. In keeping with this determination, the ACC/AHA 2007 and updated 2011 guidelines recommend an invasive treatment strategy for patients with high-risk clinical predictors (see Table 5 below).[40, 39]

Table 5. ACC/AHA Recommendations for Preferred Invasive Strategy (Open Table in a new window)

Preferred Strategy [39] Patient Characteristics
Invasive Recurrent angina/ischemia at rest or with low-level activities despite intensive medical therapy
Elevated cardiac biomarkers (TnT or TnI)
New or presumably new ST-segment depression
Signs or symptoms of heart failure or new or worsening mitral regurgitation
High-risk findings on noninvasive stress testing
High-risk score (eg, TIMI, GRACE)
Reduced LV systolic function (LVEF < 40%)
Hemodynamic instability
Sustained ventricular tachycardia
PCI within 6 months
Previous CABG
Conservative Low-risk score (eg, TIMI, GRACE)
Patient or physician preference in the absence of high-risk features
ACC/AHA = American College of Cardiology/American Heart Association; CABG = coronary artery bypass grafting; GRACE = Global Registry of Acute Coronary Events; LV = left ventricle; LVEF = left ventricular ejection fraction; PCI = percutaneous coronary intervention; TIMI = Thrombolysis in Myocardial Infarction Clinical Trial; TnI = troponin I; TnT = troponin T.



Patients at moderate to high risk for adverse events, such as persons with ST depression greater than 1 mm on ECG, troponin positivity or non–Q-wave myocardial infarction (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, MI, or rehospitalization for unstable angina from 19.4% to 15.9%.[28]

The FRISC II study showed that even a delayed invasive strategy (mean time to revascularization, 4 days; 71% revascularization rate vs 9% in the conservative arm), coupled with LMWH (dalteparin) therapy, provides durable benefit for individual hard endpoints.[73] At 1 year, the study’s invasive strategy group had statistically significant reductions in MI (8.6% vs 11.6%) and death (2.2% vs 3.9%), compared with the noninvasive group.

To date, FRISC II is the only randomized clinical trial showing a mortality benefit—probably because of the very strict criteria for revascularization, which resulted in only 9% of the conservative arm receiving PCI or CABG. In the TACTICS/TIMI-18 study and other North American trials, about 50% of the patients in the conservative arm had some form of revascularization, and not all of those in the invasive arm had indications for PCI or CABG. Consequently, the benefits of revascularization appeared less striking.

Notably, 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 (see the image below).

Rate and timing of revascularization for patients Rate and timing of revascularization for patients with unstable angina using invasive versus conservative approach (FRagmin during InStability in Coronary artery disease [FRISC] II).

Cost-to-benefit ratio of revascularization

Wallentin et al estimated the cost-to-benefit ratio of an initial invasive approach based on the FRISC II trial.[77] At the cost of 15 extra CABG and 21 PCI procedures, the benefits per 100 patients per year were as follows:

  • 1.7 lives saved
  • 2 MIs prevented
  • 20 readmissions prevented
  • Symptoms relieved earlier and better

CABG 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 CAD or 2-vessel disease that involves the proximal left anterior descending (LAD) artery
  • Diabetes mellitus with focal stenosis in more than 1 vessel
  • Concomitant severe valvular disease that necessitates open heart surgery

Patient monitoring

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, the incidence of abnormal ST-segment shifts has been reported to be 11-66% in unstable angina. As many as 92% of these abnormal ST-segment shifts are asymptomatic; more important, patients who experienced such episodes had an associated higher adverse event rate than those who did not (48% and 20%, respectively).


Approximately 1-3 months after the acute phase of unstable angina, the risk of major adverse events typically declines to that observed in patients with chronic stable angina. The goals are to prepare patients for resumption of their normal activities as safely as possible, to preserve left ventricular function, and to prevent future events.

Although secondary prevention is the responsibility of the primary care provider and the cardiologist, some centers have specialized teams (eg, cardiac rehabilitation and preventive services) that offer more intensive, and perhaps more effective, counseling and follow-up.

Smoking cessation

Aggressive attempts should be made to convince the patient and the rest of his or her household to cease smoking. The target is for the patient and his or her cohabitants to abstain completely from all tobacco products for 12 months or longer. Patients who have expressed a decision to quit should be supported with counseling, follow-up, and pharmacotherapy, and possibly with acupuncture or hypnosis (if necessary). Patients should avoid secondhand smoke.

Lipid lowering

The target is an LDL-C level of 70 mg/dL or lower, a high-density lipoprotein cholesterol (HDL-C) level higher than 35 mg/dL, and a triglyceride level below 200 mg/dL. Diet modification, exercise, and drug therapy are indicated as per National Cholesterol Education Program (NCEP) guidelines.

Control of hypertension

The target blood pressure is below 140/90 mm Hg or below 130/80 mm Hg if the 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

The ACCF/AHA 2011 update to the UA/NSTEMI guideline states that it is reasonable to achieve and maintain glucose levels lower than 180 mg/dL for hospitalized patients, avoiding hypoglycemia.[40] Thereafter, the guideline defers to the 2010 American Diabetes Association standard of care guideline.[40, 78] Diet modification, exercise, pharmacotherapy (including ACE inhibitor therapy), preventive counseling regarding foot care, and ophthalmic examinations are indicated.

Weight management and nutritional counseling

The target body mass index (BMI) is below 25 kg/m2, in conjunction with a waist circumference of less than 40 inches in men and of less than 35 inches in women. Diet modification with adequate intake of fruits and vegetables, exercise, and behavioral modification and counseling are indicated.

Psychosocial management

The targets in psychosocial management are lifestyle modification, recognition and treatment of substance abuse (whether involving alcohol or psychotropics), management of depression or hostile attitude, and compliance with health maintenance. Education, counseling, support groups, and social or religious resources are indicated.

Activity management

Patients at risk for MI should avoid sudden strenuous activities, especially in cold weather (eg, shoveling snow).


When a clinician is presented with a patient with suspected or confirmed unstable angina, consultation with a cardiologist is indicated to assist in risk stratification and decision making, to expedite further cardiac testing (eg, with echocardiography, stress testing, or angiography), and to treat unstable patients. A critical care or telemetry unit specialist is helpful for acute care and monitoring. A cardiothoracic surgeon should be consulted when CABG is indicated.

Medication Summary

Medications that provide symptomatic relief but have not been found to have an effect on long-term major events include nitrates, diltiazem or verapamil, and heparin. Medications that have been convincingly shown to reduce short- or long-term adverse events are as follows:

  • Aspirin
  • P2Y12 inhibitors
  • Lipid-lowering agents (statins)
  • Glycoprotein (GP) IIb/IIIa antagonists
  • Beta-adrenergic blocking agents
  • Angiotensin-converting enzyme (ACE) inhibitors

Antiplatelet agents

Class Summary

Antiplatelet agents prevent the formation of thrombi associated with myocardial infarction (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.

Aspirin (Anacin, Bayer Buffered Aspirin, Ecotrin)

Aspirin prevents the formation of thrombi associated with MI and inhibits 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.

Clopidogrel (Plavix)

Clopidogrel selectively inhibits adenosine diphosphate (ADP) binding to platelet receptors and subsequent ADP-mediated activation of GP llb/llla complex, thereby inhibiting platelet aggregation. This agent is used as an alternative to aspirin or in addition to aspirin after coronary stenting.

Ticagrelor (Brilinta)

Ticagrelor and its major metabolite reversibly interact with the platelet P2Y12 ADP-receptor to prevent signal transduction and platelet activation. This agent is indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS)—that is, unstable angina, non-ST elevation MI (NSTEMI), or ST-elevation MI (STEMI). It also reduces the rate of stent thrombosis in patients who have undergone stent placement for treatment of ACS, and is indicated in patients with a history of MI more than 1 year previously. Patients can be transitioned from clopidogrel to ticagrelor without interruption of the antiplatelet effect.

Lipid-Lowering Agents, Statins

Class Summary

Lipid lowering agents, specifically the HMG-CoA reductase inhibitors, also known as the statins, are used to treat hypercholesterolemia; they are highly efficacious and very well tolerated. The statins are highly effective in reducing low-density lipoprotein cholesterol (LDL-C), total cholesterol, and triglycerides, and they also increase high-density lipoprotein cholesterol (HDL-C) levels.

Simvastatin (Zocor)

Simvastatin inhibits HMG-CoA reductase, and this, in turn, inhibits cholesterol synthesis and increases cholesterol metabolism. This agent is used to decrease increased cholesterol levels associated with nephrotic syndrome.

Atorvastatin (Lipitor)

Atorvastatin can provide up to 60% reduction in LDL-C. It inhibits HMG-CoA reductase, thereby inhibiting cholesterol synthesis and increasing cholesterol metabolism. The half-life of atorvastatin and its active metabolites is longer than those of all the other statins (ie, approximately 48 hours, as opposed to 3-4 hours). Atorvastatin is one of the most extensively studied statins, and many long term evidence-based medicine trials support its benefits.

Pitavastatin (Livalo)

Pitavastatin is an HMG-CoA reductase inhibitor (statin) indicated for primary or mixed hyperlipidemia. In clinical trials, pitavastatin 2 mg/day achieved reductions in total cholesterol and LDL-C similar to those seen with atorvastatin 10 mg/day and simvastatin 20 mg/day.

Pravastatin (Pravachol)

Pravastatin competitively inhibits HMG-CoA reductase, which catalyzes the rate-limiting step in cholesterol synthesis. This agent is a good alternative if other statins are not tolerated.

Antiplatelet Agent, Cardiovascular

Class Summary

Specific cardiovascular antiplatelet agents work via GP IIb/IIIa receptor antagonists to reversibly prevent fibrinogen, von Willebrand factor (vWF), and other adhesion ligands from binding to the GP IIb/IIIa receptor, thereby inhibiting platelet aggregation. 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.

Tirofiban (Aggrastat)

Tirofiban is a nonpeptide antagonist of the platelet GP IIb/IIIa receptor; it reversibly prevents vWF, fibrinogen, and other adhesion ligands from binding to the receptor, thus inhibiting platelet aggregation. Effects persist over the duration of maintenance infusion and are reversed after the infusion ends. Tirofiban is approved by the US Food and Drug Administration (FDA) to reduce the rate of thrombotic cardiovascular events (combined endpoint of death, myocardial infarction, or refractory ischemia/repeat cardiac procedure) in patients with non-ST elevation acute coronary syndrome (NSTE-ACS).

Eptifibatide (Integrilin)

Eptifibatide is a cyclic heptapeptide antagonist of the platelet GP IIb/IIIa receptor; its effects are the same as those of tirofiban. This agent has been approved by the FDA for use in combination with heparin for patients with ACS, patients who are being managed medically, and patients undergoing PCI.

Abciximab (ReoPro)

Abciximab is a chimeric human-murine monoclonal antibody approved for use in elective, urgent, and emergency PCI. Abciximab binds to receptors with high affinity and reduces platelet aggregation by 80% for up to 48 hours following infusion.

Beta-Blockers, Beta-1 Selective

Class Summary

Selective beta1-adrenergic blocking agents limit heart rate, reduce blood pressure, and exert antiarrhythmic effects by targeting beta1 receptor sites. All beta-adrenergic blocking agents thus decrease myocardial oxygen demand and oppose the effects of elevated catecholamines. 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.

Atenolol (Tenormin)

Atenolol (Tenormin)

Atenolol blocks beta1 receptors but has little or no effect on beta2 types. Beta blockers affect blood pressure via multiple mechanisms, including a negative chronotropic effect that decreases heart rate at rest and after exercise, a negative inotropic effect that decreases cardiac output, reduction of sympathetic outflow from the central nervous system (CNS), and suppression of renin release. Atenolol improves and preserves hemodynamic status by acting on myocardial contractility, reducing congestion, and decreasing myocardial energy expenditure.

Metoprolol (Lopressor, Toprol XL)

Metoprolol is a selective beta1-adrenergic receptor blocker that decreases the automaticity of contractions. During intravenous (IV) administration, carefully monitor blood pressure, heart rate, and the electrocardiogram (ECG).

Beta-Blockers, Beta-1 Selective; Antidysrhythmics, II

Class Summary

Esmolol acts as a beta-adrenergic blocking agent to limit heart rate and reduces blood pressure by selectively targeting beta1 receptor sites; this drug also has class II antiarrhythmic properties. All beta-adrenergic blocking agents decrease myocardial oxygen demand and oppose the effects of elevated catecholamines. 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.

Esmolol (Brevibloc)

Esmolol has been shown to reduce episodes of chest pain and clinical cardiac events. Its very short half-life (8 minutes) allows a large degree of dosing flexibility, so that its cardiovascular benefits are comparable to those of oral propranolol, yet its adverse effects can be managed promptly. Esmolol is particularly useful for patients at risk for complications with beta blockade (eg, reactive airway disease or chronic obstructive pulmonary disease [COPD], severe bradycardia, or poor left ventricular function).

Beta-Blockers, Nonselective

Class Summary

Nadolol is a nonselective beta-adrenergic blocking agent that limits heart rate, reduces blood pressure, and have antiarrhythmic properties. All beta-adrenergic blocking agents thus decrease myocardial oxygen demand and oppose the effects of elevated catecholamines. 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.

Nadolol (Corgard)

Nadolol competitively blocks beta1 and beta2 receptors. It does not exhibit membrane-stabilizing activity or intrinsic sympathomimetic activity.

Beta-Blockers, Nonselective; Antidysrhythmics, II

Class Summary

Propranolol is a beta blocker that limits heart rate and reduces blood pressure by nonselectively targeting beta receptor sites; it also has class II antiarrhythmic properties. All beta-adrenergic blocking agents thus decrease myocardial oxygen demand and oppose the effects of elevated catecholamines. 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.

Propranolol (Inderal)

Propranolol is a nonselective beta blocker that is lipophilic (ie, penetrates the CNS). Although it is generally a short-acting agent, long-acting preparations are also available.


Class Summary

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, along with tissue factor VIIa). It prevents clot reaccumulation after endogenous fibrinolysis. When unfractionated heparin (UFH) is used, the activated partial thromboplastin time (aPTT) should not be checked until 6 hours after the initial heparin bolus.

Low Molecular Weight Heparins

Class Summary

Low-molecular-weight heparin (LMWH) represents an anticoagulation option for unstable angina. The many potential benefits of using LMWH include lower rates of bleeding, cost savings, and reduced incidence of heparin-induced thrombocytopenia (HIT). LMWH is prepared by selectively treating UFH to isolate the low-molecular-weight (< 9 kDa) fragments. Its activity is measured in units of factor X inactivation; monitoring of aPTT is not required, and the dose is weight-adjusted.

Enoxaparin (Lovenox)

Enoxaparin (Lovenox)

Enoxaparin is the only LMWH now approved by the FDA for treatment of and prophylaxis for deep venous thrombosis 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 UFH. Except in overdoses, checking the prothrombin time (PT) or aPTT is not useful, because aPTT does not correlate with the anticoagulant effect of fractionated LMWH.

Dalteparin (Fragmin)

Dalteparin enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, it preferentially increases inhibition of factor Xa. Except in overdoses, checking PT or aPTT is not useful, because aPTT does not correlate with the anticoagulant effect of fractionated LMWH. The average duration of treatment is 7-14 days.

Tinzaparin (Innohep)

Tinzaparin enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, it preferentially increases inhibition of factor Xa. Average duration of treatment is 7-14 days.

Thrombin inhibitors

Class Summary

Direct thrombin inhibitors, such as hirudin, lepirudin (recombinant hirudin), and bivalirudin, are potential alternatives to heparin. Their advantages over heparin are efficacy against clot-bound thrombin, resistance to inactivation by platelet factor 4 and thrombospondin, and nondependence on antithrombin III pathways. Although direct thrombin inhibitors should not be routinely used in the treatment of unstable angina, they may be of clinical benefit in special circumstances, such as HIT.

Bivalirudin (Angiomax)

Bivalirudin is a synthetic analogue of recombinant hirudin. It is used for anticoagulation in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA).

With provisional use of an GP IIb/IIIa inhibitor, bivalirudin is indicated for use as an anticoagulant in patients undergoing PCI. Its 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 and heparinase), and continued efficacy after clearance from plasma (because of binding to thrombin).

Lepirudin (Refludan)

Lepirudin is recombinant hirudin derived from yeast cells; it is a 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 the 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. Lepirudin has been approved by the FDA for use in patients with HIT and associated thrombotic disease.

Desirudin (Iprivask)

Desirudin is a selective inhibitor of free circulating and clot-bound human thrombin, with protein structures similar to those of naturally occurring hirudin (an anticoagulant present in medicinal leeches). It prolongs thrombin-dependent coagulation assays (eg, activated partial thromboplastin time [aPTT] and thrombin time [TT]).


Argatroban is used as an anticoagulant for prophylaxis or treatment of thrombosis in HIT. This agent inhibits fibrin formation, platelet aggregation, and activation of coagulation factors V, VIII, and XIII, as well as protein C.

Nitrates, Angina

Class Summary

Nitrates are vasodilators that relieve chest discomfort (angina) by improving myocardial oxygen supply, thereby, in turn, dilating epicardial and collateral vessels and thus improving blood supply to the ischemic myocardium. Vasodilators oppose coronary artery spasm, which augments coronary blood flow and reduces cardiac work by decreasing preload and afterload.

These drugs are 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 intravenously (IV). In acute MI, topical administration is a less desirable route because of unpredictable absorption and the onset of clinical effects.

Nitroglycerin IV

Nitroglycerin causes relaxation of vascular smooth muscle by stimulating intracellular cyclic guanosine monophosphate production. Whether administered topically, sublingually, orally, 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 a transient inhibition of platelet aggregation, an increase in coronary collateral blood flow, and a favorable redistribution of regional flow. Notably, induction of heparin resistance has been reported.

ACE Inhibitors

Class Summary

ACE inhibitors reduce angiotensin II levels, thus decreasing aldosterone secretion. They are of particular benefit in patients with large anterior infarctions, especially those 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.

Captopril (Capoten)

Captopril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion.

Lisinopril (Zestril)

Lisinopril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.

Enalapril (Vasotec)

Enalapril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion. This agent helps to control blood pressure and proteinuria.

Enalapril decreases pulmonary-to-systemic flow ratio in the catheterization laboratory and increases systemic blood flow in patients with relatively low pulmonary vascular resistance. It has a favorable clinical effect when administered over a long period. Enalapril helps to prevent potassium loss in distal tubules. The body conserves potassium; thus, less oral potassium supplementation is needed.

Ramipril (Altace)

Ramipril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.















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.


The ACC/AHA 2007 UA/NSTEMI guideline recommended that aspirin (75-162 mg/day) be continued indefinitely for patients with UA/NSTEMI who tolerate it.[39] For patients with UA/NSTEMI who are treated medically without stenting, clopidogrel (75 mg/day) should be prescribed for at least 1 month and ideally for up to 1 year.

The 2011 update to the ACCF/AHA guideline for UA/NSTEMI stated that for patients treated with PCI, clopidogrel or prasugrel (10 mg/day) should be given for at least 12 months. For post-PCI patients with a drug-eluting stent, clinicians may consider continuing clopidogrel or prasugrel beyond 15 months.[40]


CLASSIFICATION OF UNSTABLE ANGINA — Unstable angina can have a variety of different presentations which, as will be described in more detail below, may correlate with prognosis in the absence of intervention. Regardless of type, the risk is greatest with angina that is refractory to or occurs despite maximal medical therapy and with an accelerating tempo of ischemic symptoms in the preceding 48 hours (crescendo angina) (table 1). (See 'Prognosis according to type'below.)

New onset angina — The natural history of new onset angina depends in part upon the degree of exertion required to induce chest pain. Patients with new onset angina occurring only after heavy physical exertion have a prognosis similar to patients with chronic stable angina. In comparison, new angina occurring after minimal exercise or at rest, particularly if prolonged, carries a worse prognosis in the absence of intervention. In the original Braunwald classification of unstable angina, new onset was defined as less than two months in duration [3].

Rest angina — Rest angina, particularly if prolonged and/or associated with transient ST segment changes >0.05 mV, identifies patients at increased risk (table 1).

Early post-MI angina — Early post-infarction angina (defined as chest pain occurring within 48 hours after an acute myocardial infarction [MI]) is typically associated with complex lesions and/or persistent intracoronary thrombus and with more severe coronary disease [4,5]. The recurrent chest pain may signify either remaining viable myocardium in the infarct zone or a different area of myocardium at risk [6]. In a report from the GISSI-3 trial, angina occurred at rest in 94 percent of patients; one-third of episodes occurred within 72 hours of the MI and between 6 and 10 AM [7].

Angina occurring soon after an acute MI is associated with high risk in the absence of intervention [5,7-9]. This was illustrated in a report from the GUSTO-IIb trial [8]. Among 3513 patients with a non-ST elevation (non-Q wave) MI (NSTEMI) (using the old definition that did not include serum troponins), 36 percent had recurrent ischemia that was responsive to medical therapy in 79 percent. Patients with recurrent ischemia that was refractory or responsive to medical therapy had a higher rate of reinfarction at 30 days (29 and 12 versus 3 percent in those without recurrent ischemia) and six months. In addition, the occurrence of refractory ischemia was associated with a higher mortality compared to responsive ischemia or no ischemia at 30 days (16 versus 6 and 4.3 percent) and one year. Similar findings were noted among 4125 patients with an STEMI and in over 40,000 patients with an STEMI in GUSTO-I [9].

GUSTO IIb also included 4488 patients with UA; 34 percent had recurrent ischemia that was responsive to medical therapy in 82 percent [8]. Patients with recurrent ischemia that was refractory or responsive to medical therapy had a higher rate of reinfarction at 30 days (22 and 7.2 versus 2.3 for in without recurrent ischemia) and six months. In addition, the occurrence of refractory ischemia was associated with a higher 30 day mortality compared to responsive ischemia or no ischemia (8.2 versus 2.9 and 1.6 percent).

Postrevascularization angina — Angina after percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG) can reflect a procedural event or, over the long-term, restenosis after PCI (less with stenting compared to angioplasty alone, particularly with drug-eluting stents), stenosis in a graft (usually with saphenous vein grafts), or progression of native disease. (See "Periprocedural complications of percutaneous coronary intervention" and "Drug-eluting intracoronary stents: General principles" and "Early noncardiac complications of coronary artery bypass graft surgery" and "Coronary artery bypass graft surgery: Prevention and management of vein graft stenosis", section on 'Clinical presentation'.)

Periprocedural — Ischemic chest pain within 48 hours after stenting usually results from procedural events such as abrupt vessel closure (usually due to stent thrombosis or progression of an untreated dissection), transient coronary spasm, side branch occlusion, or distal embolization of atherosclerotic or thrombotic debris. Some patients have asymptomatic enzyme elevations indicative of small infarctions. (See 'After PCI' below and "Periprocedural complications of percutaneous coronary intervention".)

In the EPISTENT trial, the incidence of ischemic chest pain was 11 percent, 12 percent of whom had associated ECG changes [10]. When ECG changes were present, there was a significantly increased risk (42 percent) of a cardiac event (death, all MI, repeat revascularization) compared to an intermediate risk of a cardiac event (13 percent) when chest pain without ECG changes was present, and the low risk (5 percent) in the absence of chest pain.

An important diagnostic consideration soon after PCI is the distinction between ischemic and nonischemic chest pain. Nonischemic chest pain is typically manifested at rest, without ECG changes or elevation of cardiac enzymes [11,12]. Most patients describe pain characteristics different from their typical angina (more localized and frequently pleuritic). This discomfort lasts for less than 72 hours in about 80 percent of patients, and less than two weeks in the remainder [11]. Overexpansion of the stent is thought to be responsible in most cases. (See "Periprocedural complications of percutaneous coronary intervention".)

As after PCI, recurrent angina during the postoperative period after CABG is usually due to a technical problem with a graft or with early graft closure. It is therefore an indication for prompt catheterization with revascularization by PCI, if feasible. The diagnosis of recurrent ischemia may be difficult to make after CABG, since cardiac enzyme elevations occur as a result of the surgical procedure and since electrocardiographic changes may reflect postoperative pericardial inflammation. (See "Early noncardiac complications of coronary artery bypass graft surgery".)

Late — The delayed onset of angina (30 days or more after PCI) can reflect restenosis after PCI, graft stenosis after CABG, or progression of native disease. Affected patients typically present with the gradual and progressive return of effort angina. Prompt stress testing should be performed, since these patients are at increased risk. Stress radionuclide myocardial perfusion imaging or echocardiography is preferred over exercise ECG testing, since these modalities can document both the site and extent of ischemia. (See "Role of stress testing after coronary revascularization".)

While less common, some patients with recurrent ischemia present with UA. Such patients should be evaluated with cardiac catheterization after adequate medical stabilization.

Unstable angina can also occur in patients with prior CABG; such patients have an increased rate of significant coronary events [13,14]. This issue was best illustrated in the PURSUIT trial of almost 11,000 patients with a non-ST ACS, 12 percent (1134 patients) of whom had a prior CABG [13]. Patients with a prior CABG had a significantly higher mortality at 30 days (5.2 versus 3.4 percent without a prior CABG, adjusted hazards ratio 1.45) and six months (8 versus 6.6 percent, adjusted hazards ratio 1.32). This difference may reflect a greater degree of cardiac disease.

The older the saphenous vein graft, the higher the likelihood that UA is due to a culprit lesion within the graft (figure 1) [15]. Grafts are more likely than native vessels to show total occlusion or thrombus, complications that are more refractory to medical therapy. Among patients who undergo PCI for saphenous vein graft disease, the development of restenosis is manifested by an UA presentation in as many as 25 percent of patients [16]. (See "Coronary artery bypass graft surgery: Prevention and management of vein graft stenosis".)

Absence of significant coronary disease — In different clinical trials and the CRUSADE registry, 9 to 14 percent of patients with a non-ST elevation ACS have, on coronary angiography, either normal vessels or no vessel with ≥50 to 60 percent stenosis [17-23].

Possible mechanisms for the absence of marked coronary disease in these patients include coronary thrombosis with rapid clot lysis, vasospasm, macroemboli and microemboli, coagulopathy, vasculitis, small vessel disease, coronary microvascular dysfunction and myocarditis. In favor of the last mechanism is the observation in a report from the TIMI IIIA trial that approximately one-third of these patients had abnormally slow angiographic filling (TIMI flow grade 2 or less) [18]. The absence of significant coronary disease has also been described in patients with stable angina. (See "Cardiac syndrome X: Angina pectoris with normal coronary arteries".)

In the TIMI IIIA trial of 391 patients with rest angina who did or did not receive fibrinolytic therapy, 53 (14 percent) fulfilled this criterion; one-half had no visually detectable coronary stenosis on angiography, and one-half had a noncritical coronary narrowing without findings suggestive of an unstable lesion such as ulceration or thrombosis [18]. When compared to patients with UA and a culprit coronary lesion on angiography, those with relatively normal coronary arteries were more likely to be women and to have no ST segment deviation.

The characteristics of patients with UA who have mild or no coronary disease was further examined in a study of 5767 patients with a non-ST segment elevation ACS who were enrolled in the PURSUIT trial and who underwent angiography: 6 percent had mild coronary disease (>0 to ≤50 percent stenosis) and 6 percent had no disease [19]. The strongest independent predictors of insignificant coronary disease were:

●Younger age.

●Female sex; a greater prevalence of mild or no coronary disease in women was also noted in the TACTICS-TIMI 18 trial (17 versus 9 percent in men) [22].

●Absence of enrollment MI, prior angina, diabetes, or ST segment depression.

Similar predictors of insignificant coronary disease, as well as lack of current/recent smoking, were found in the CRUSADE registry [23].

The possible role of cardiovascular magnetic resonance imaging in patients who present with chest pain, elevated troponin levels and absence of significant coronary artery disease on angiography is discussed separately. (See "Clinical utility of cardiovascular magnetic resonance imaging".)

Patients with a non-ST elevation ACS who do not have significant coronary disease have a better outcome than those with a culprit coronary lesion. (See "Risk stratification after non-ST elevation acute coronary syndrome", section on 'Absence of significant coronary disease'.)



An acute coronary syndrome occurs when atherosclerotic coronary plaque becomes unstable leading to a series of events eventually resulting in partial or total thrombotic occlusion of a coronary artery. Acute coronary syndromes are categorized into unstable angina, non-ST segment elevation myocardial infarctions and ST segment elevation myocardial infarction. The terms “transmural”, “non-transmural”, “Q wave MI” and “non-Q wave MI” are no longer recommended. The differences between the types of acute coronary syndromes are below:

Unstable angina pectoris: Three different presentations of unstable angina exist.

  1. Exertional angina of new onset. Even if relieved with rest and requiring a consistent amount of exertion to procedure symptoms, when angina first occurs it is considered unstable.
  2. Exertional angina that was previously stable and now occurs with less physical exertion.
  3. Anginal symptoms at rest without physical exertion.

Non-ST segment elevation myocardial infarction: Anginal symptoms at rest that result in myocardial necrosis as identified by elevated cardiac biomarkers (see Cardiac Enzymes) with no ST segment elevation on the 12-lead electrocardiogram.

ST segment elevation myocardial infarction: Anginal symptoms at rest that result in myocardial necrosis as identified by elevated cardiac biomarkers with ST segment elevation on the 12-lead electrocardiogram.

Pathophysiology - UA/NSTEMI

The “vulnerable plaque” that formed from the atherosclerotic process (see Atherosclerosis) is responsible for acute coronary syndromes and ultimately, coronary artery thrombosis is the endpoint. A substance known as “tissue factor” is located within the necrotic core of the plaque. When exposed to the bloodstream, tissue factor activates the clotting cascade and thrombosis occurs.

Tissue factor is exposed when the fibrous cap that covers the plaque becomes disrupted or ulcerated. This disruption of the fibrous cap is called “plaque rupture” or “plaque erosion”. Surprisingly, plaque rupture and thrombosis frequently occurs at the site of modest coronary stenosis (less than 50% luminal narrowing), thus even if stress testing is normal, the risk of an acute coronary syndrome is still present. Recall that stress testing is the most sensitive to detect stenosis of 70% or greater.

Some atherosclerotic plaques have a more stable fibrous cap and others are thin and considered vulnerable. A clinically useful means to distinguish these types of plaque is not currently available.

Unstable angina has a lower incidence of coronary thrombosis compared to non-ST elevation MI (NSTEMI) or ST elevation MI (STEMI) and is more often the result of fixed atherosclerotic stenosis. Plaque rupture or erosion resulting in coronary occlusion is the predominant mechanism in NSTEMI and STEMI.

Physical Examination - UA/NSTEMI

Physical examination findings are relatively non-specific and similar to that described in the stable angina section. They are usually only present during the anginal episode making this a less helpful means of diagnosis. When examined during an anginal attack, the heart rate and blood pressure may be elevated due to increased sympathetic tone.

An S4 heart sound may be present during myocardial ischemia due to the lack of ATP production impairing left ventricular relaxation. Recall that myocardial relaxation is an active process requiring ATP which is reduced during ischemia and a S4 heart sound occurs when a non-compliant, stiffened left ventricle receives blood after atrial contraction.

During inferior ischemia, posteromedial papillary muscle dysfunction can cause mitral regurgitation resulting in a holosystolic murmur at the cardiac apex radiating to the axilla (see Heart Murmurs). This rarely occurs during anterior or lateral ischemia since the anterolateral papillary muscle has dual supply from the left anterior descending and circumflex coronary artery.

When the left ventricular end-diastolic pressure (LVEDP) increases during myocardial ischemia, that pressure can be transmitted backward to the pulmonary veins and into the pulmonary vasculature causing transient pulmonary edema resulting in dyspnea and rales on lung examination.

Diagnosis - UA/NSTEMI

The diagnosis of unstable angina (UA) and non-ST elevation MI (NSTEMI) is predominantly based on the ECG and cardiac enzymes. Physical examination, as previously described, is non-specific.

The ECG tracing can have multiple abnormalities, however by definition there is no ST segment elevation. The most common finding is ST segment depression. This ST depression is horizontal or downsloping in shape. The T waves may be inverted, usually symmetrically.

Surprisingly, UA and NSTEMI can both occur even with a completely normal ECG making diagnosis quite a challenge. Observation in the hospital for serial ECGs cardiac enzymes (usually 6-8 hours apart) is required to completely exclude UA or NSTEMI as the ECG changes can be dynamic (come and go) and initially be normal. Also, cardiac enzymes (troponin and creatine kinase) require 3-4 hours after the injury before they are significantly elevated (see review on Cardiac Enzymes).

During NSTEMI there will be elevation of the cardiac enzymes indicative of myocardial necrosis, however during unstable angina there is no or only very minimal elevation. This is the main distinguishing feature between these two diagnoses.

Symptoms - UA/NSTEMI

The symptoms of occlusive coronary artery disease can manifest as chronic stable angina pectoris or angina as a part of an acute coronary syndrome, both of which the symptoms are similar, except the latter frequently occurs at rest. Substernal chest pressure with radiation to the medial portion of the left arm or left jaw is the classic description.

Angina can be described as a “tightness”, “discomfort, not pain”, “squeezing,” “indigestion,” “heaviness,” or an “elephant sitting on my chest”. Levine sign is when a patient places their fist in the center of their chest to describe the squeezing/tightness feeling of angina. Pain from angina is gradual in onset and must last for at least 5 minutes. Also, the pain is diffuse and difficult to localize to one part of the chest (large area of pain, not small which can help distinguish from musculoskeletal pain).

Less common presentations include only shoulder pain, pain down both arms, left wrist pain, right-sided chest or jaw pain, radiation to the right arm, mid-thoracic back pain and only dyspnea without chest pains. Rarely the pain of angina is described as sharp.

Some associated symptoms that occur simultaneously with the classic anginal symptoms above include dyspnea, diaphoresis (cold sweats), fatigue/weakness, nausea and dizziness. Women, elderly patients and diabetics tend to have more atypical presentations of angina.

Many non-cardiac disease states can cause chest pain as well (see Evaluation of Chest Pain). Important features that would suggest non-cardiac causes of chest pain include worsening with inspiration (pleuritic pain), the duration of the pain (less than 5 minutes), a small pinpoint area of pain (angina is more diffuse) and no relief with nitroglycerine. Note that esophageal spasm, a relatively uncommon cause of chest pain, can be relieved with nitroglycerine causing it to mimic symptoms of angina. Sharp, shooting chest pains lasting a few seconds to a minute are common and are usually musculoskeletal related.

When an atherosclerotic plaque ulcerates and thrombosis, an acute coronary syndrome develops and the above mentioned anginal symptoms can occur at rest. In this setting, the pain is frequently more severe and has a longer duration.

Treatment - UA/NSTEMI - Prevention

Primary prevention refers to controlling cardiovascular disease risk factors to stop the first cardiovascular event from occurring. Secondary prevention refers to therapy aimed to reduce the risk of acute coronary syndromes in a patient with diagnosed coronary artery disease or a coronary risk equivalent.

Primary prevention

Primary prevention consists predominantly of controlling cardiovascular disease risk factors such as LDL cholesterol, tobacco use, hypertension and obesity. Since the risk of a cardiovascular event in a primary prevention patient is lower at baseline than that of a secondary prevention patient, the absolute benefit of reducing risk factors is less.

Treatment of lipid disorders for primary prevention include dietary and lifestyle modifications and medical therapy with HMG CoA reductase inhibitors. The new ACC/AHA guidelines released in 2013 recommend high intensity statin therapy (defined as a > 50% reduction in LDL) without any specific target LDL levels in patients with clinical vascular disease such as acute coronary syndromes less than age 75. Those older than 75 should reveive moderate intensity statin therapy (defines as 30-50% reduction of LDL) without specific targets to achieve. Medications other than HMG CoA reductase inhibitors to lower LDL levels are not recommended at this time.

Antiplatelet therapy is not recommended for all patients for primary prevention of cardiovascular disease, however an individualized approach should be taken. If the risk of bleeding is low, yet there is a significant risk of cardiovascular disease that does not meet a coronary risk equivalent (which would put the patient in the secondary prevention category, see below), antiplatelet therapy can be considered.

Secondary prevention

Coronary risk equivalents (10 year risk of cardiac event > 20%) include:

  1. Non-coronary atherosclerotic disease: Peripheral arterial disease, carotid artery disease, renal artery disease, abdominal aortic aneurysm
  2. Diabetes mellitus type II
  3. Multiple risk factors: Using the Framingham risk score, if the 10 year risk of a cardiac event is > 20%, then the patient is considered to have a coronary risk equivalent
  4. Chronic kidney disease

Secondary prevention includes anti-platelet therapy and a HMG-CoA reductase inhibitor regardless of the serum LDL cholesterol level. Smoking cessation, control of blood pressure, and HDL/triglyceride therapy, exercise and weight loss will be discussed elsewhere.

Aspirin therapy has been shown to significantly reduce the risk of acute coronary syndromes in those with established coronary disease. The data to support this in coronary risk equivalent patients is not as robust, however it is still recommended. There is a risk of major bleeding with aspirin therapy, especially from the gastrointestinal tract. This risk is acceptable considering the cardiovascular benefits of aspirin in secondary prevention patients, however the risk/benefit ratio is not as favorable in primary prevention since their cardiovascular risk at baseline is lower than a secondary prevention patient, but bleeding risk similar. Clopidogrel can be used in aspirin intolerant patients.

A moderate dose of an HMG-CoA reductase inhibitor is recommended initially (such as atorvastatin 40 mg or simvastatin 40 mg). The actual goal LDL cholesterol is < 100 in most coronary artery disease or risk equivalent patients, however the goal is < 70 if high risk features are present. High risk features include prior acute coronary syndromes, poorly controlled risk factors (hypertension, tobacco use) and diabetes mellitus type II. The PROVE IT-TIMI 22 and TNT trial support these recommendations.

Treatment - Early Invasive versus Initial Conservative

An early invasive strategy refers to proceeding to coronary angiography with possible percutaneous coronary intervention (PCI or coronary stenting) within 4 to 24 hours of hospital admission. An initial conservative management consists of medical therapy only without plans to proceed to coronary angiography and PCI.

Factors that would warrant an early invasive strategy include:

1. Increased cardiac biomarkers (troponin, CK-MB)
2. New ST segment depression
3. Signs or symptoms of congestive heart failure (rales on examination, hypoxia with pulmonary edema on chest x-ray)
4. Hemodynamic instability
5. Sustained ventricular tachycardia or ventricular fibrillation
6. Recent coronary intervention within 6 months
7. Prior coronary artery bypass grafting
8. High TIMI risk score
9. Reduced left ventricular systolic function (EF < 40%)
10. Recurrent angina at rest or with low level activity
11. High risk findings from non-invasive testing

The ICTUS trial showed no difference in the above approaches in 3 years. The RITA-3 trial showed no difference at 1 year, but there was a reduction of death or myocardial infarction at 5 years in the early invasive arm, mainly in high risk patients which justifies the above approach (only performing angiography/PCI on high risk patients).

When an initial conservative is undertaken, further risk stratification must be done to see if high risk features are present that would warrant changing to an invasive approach. If any high risk features as mentioned above develop, then an invasive approach should be undertaken. If there are no high risk features, then an evaluation of left ventricular systolic function should be done (by echocardiography or myocardial perfusion imaging). If the ejection fraction is < 40%, then the patient is at high risk and invasive coronary angiography should be performed. When the ejection fraction is > 40%, a stress test with imaging should be performed. If the findings are intermediate or high risk (not low risk), then invasive coronary angiography should be performed. For example, an echocardiogram showed an ejection fraction of 45% so a stress test is performed. If normal or only a small defect is seen, medical therapy can be undertaken, however if a moderate or large area of ischemia is present, invasive coronary angiography is recommended.

Treatment - UA/NSTEMI - Medical Therapy

The medical management of UA/NSTEMI consists of beta-blocker therapy, ACE inhibitors/angiotensin receptor blockers, aldosterone antagonists, HMG-CoA reductase inhibitors, calcium channel blockers, nitrates, antiplatelet therapy and anticoagulation therapy. Treatment with fibrinolytics (tPA) is NOT recommended for UA/NSTEMI management, only for STEMI in certain instances (see review of ST elevation myocardial infarction).


While there is little data in regards to the efficacy of beta-blockers during UA/NSTEMI, there is an abundance during STEMI. Guidelines from the American Heart Association recommend early intravenous beta-blockers when no contraindication exists and there is angina, hypertension or tachycardia not related to heart failure. Long-term therapy (lifetime) has been shown to reduce MI incidence and improve mortality.

ACE inhibitors/Angiotensin Receptor Blockers

There is less data to support using ACE inhibitors during UA/NSTEMI than during STEMI where definite benefit is seen. The ACC/AHA guidelines recommend that ACE inhibitors should be given upon hospital discharge in patients with hypertension, diabetes, LV systolic dysfunction (EF < 40%), and/or heart failure symptoms. There may be a benefit to all patients, although the data is limited and thus a recommendation to use ACE inhibitors in all patients following UA/NSTEMI is yet to be made. When a patient does not tolerate an ACE inhibitor due to cough, an angiotensin receptor blocker is a good alternative.

Aldosterone antagonists

The aldosterone antagonist eplerenone was evaluated in the EPHESUS trial leading to the recommendation for their with an ACE inhibitor prior to hospital discharge after UA/NSTEMI if there is left ventricular systolic dysfunction (EF < 40%) and either diabetes or symptomatic heart failure present and no contraindication (serum creatinine > 2.5 and or potassium > 5.0). A class effect is likely present and thus spironolactone is frequently used instead of eplerenone due to cost concerns, although there is no direct data to support this practice.

HMG-CoA Reductase Inhibitors

Every patient with UA/NSTEMI should receive at least moderate dose and preferably high dose statin therapy. The MIRACLE and PROVE-IT TIMI 22 trial used atorvastatin 80 mg PO daily with good results. Statin therapy should be lifetime after a person has an acute coronary syndrome unless a contraindication exists.

Calcium Channel Blockers

The non-dihydropyridine calcium channel blockers diltiazem and verapamil can be used when there is a contraindication to beta-blockers (such as asthma) and there is no heart failure or significant left ventricular systolic dysfunction present. Sublingual nifedipine is contraindicated due to a reflexive increase in the sympathetic nervous system which can be harmful.


Nitrates are helpful to treat angina symptoms, hypertension and heart failure during UA/NSTEMI, however no clinical data exists to show a mortality benefit and thus their use is individualized. The use of nitrates should not preclude using drugs that do show a mortality benefit.

Antiplatelet Therapy

There are three main categories of antiplatelet therapy:

Aspirin: Aspirin acts by blocking the enzyme cyclooxygenase resulting in decreased thomboxane A2 produciton and platelet inhibition.

Thienopyridines: Also known as P2Y12 receptor blockers (clopidogrel, prasugrel, ticagrelor, and ticlopidine). Clopidogrel has delayed onset of action, no means of reversing the effects, and a significant percentage of people simply do not respond to this therapy. Prasugrel and ticagrelor have a fast onset and few if any non-responders, however a higher risk of bleeding. Prasugrel is not recommended if there is a prior history of TIA or stroke as it may cause harm (class III).

Glycoprotein IIb/IIIa inhibitors: These include abciximab, eptifibatide, and tirofiban. They very strongly inhibit platelet function by blocking the binding of fibrinogen to the activated glycoprotein IIb/IIIa receptor complex.

Regardless of an early invasive versus initial conservative approach, all patients with UA/NSTEMI should receive aspirin AND treatment with a P2Y12 receptor blocker. Clopidogrel therapy is frequently used, however ticagrelor or prasugrel can be given instead of clopidogrel as there are fewer non-responders to these drugs and a quicker onset of action. Even when no PCI is performed (initial conservative), a P2Y12 receptor blocker should be continued for 12 months.

When an early invasive strategy is used, a glycoprotein IIb/IIIa inhibitor could be given in addition to aspirin and clopidogrel (class IIa, C) based on the patient’s risk. When high risk features are present, such as delay to angiography and early recurrent anginal chest pains, a glycoprotein IIb/IIIa inhibitor should definitely be utilized prior to angiography. Eptifibatide and tirofiban are the preferred glycoprotein IIb/IIIa inhibitors in this setting. Low risk patients (TIMI risk score < 2) should not get glycoprotein IIb/IIIa therapy (class III).

Note that abciximab is not recommended for initial conservative therapy based on the GUSTO IV-ACS trial, but only if PCI is planned. Eptifibatide and tirofiban can be used for initial conservative therapy (class IIb). If a patient in the initial conservative category develops high risk features and PCI is planned, a glycoprotein IIb/IIIa inhibitor should be started.


Full anticoagulation should be started in all UA/NSTEMI patients unless a contraindication exists, however based on available data and guidelines, the choice of anticoagulant differs between early invasive and initial conservative groups.

When initial conservative management is undertaken, anticoagulation with either unfractionated heparin or low molecular weight heparin (enoxaparin or fondaparinux) should be started if no contraindication exists. Unfractionated heparin therapy should be for 48 hours, however guidelines state based on clinical trials that low molecular weight heparin (enoxaparin or fondaparinux) should be continued for the entire length of hospitalization or 8 days.

When an early invasive strategy is employed, anticoagulation should be with unfractionated heparin, low molecular weight heparin (enoxaparin or fondaparinux) or bivalirudin (Angiomax). Bivalirudin is not recommended for initial conservative management.

Special Situations

Wellens syndrome: Although no formal guidelines exist specifically for this ECG change, an early invasive strategy makes sense due to the high risk nature of proximal LAD disease. Wellen’s ECG changes have two types. The first has biphasic T waves in the anterior precordial leads and the second deep inverted T waves throughout the precordial leads.


Non-cardiac chest pains: There are multiple causes of chest pains and when the diagnosis is in question, a cardiac etiology must be assumed due to the life-threatening nature of acute coronary syndromes. The term unstable angina is frequently used in chest pain patients even if the etiology is in question as long as the primary reason for observing the patient in the hospital is to assure that an acute coronary syndrome is not present.

Platelet assays: Some institutions use platelet assays to identify clopidogrel non-responders. Those patients are treated with prasugrel or ticagrelor instead. These platelet assays are not recommended in the AHA/ACC guidelines, however do not pose any harm.

Arrhythmia during ACS: Ventricular tachycardia and ventricular fibrillation are life threatening and are a common complication of acute coronary syndromes. Atrial fibrillation and atrial flutter are less common, but can be troublesome as well. The only measures that should be routinely taken to prevent arrhythmias during an acute coronary syndrome include beta-blocker therapy and maintaining electrolytes (potassium and magnesium) within normal limits. The prophylactic administration of lidocaine to suppress premature ventricular contractions or prevent ventricular tachycardia/fibrillation is not recommended. Likewise, the CAST trial demonstrated increased mortality using encainide, flecainide and moricizine to suppress premature ventricular contractions after an acute coronary syndrome.

Anemia during ACS: There are no official guidelines in regards to the threshold to transfuse a patient who is anemic during an acute coronary syndrome. In general, the hematocrit should be kept greater than 21% and preferably above 30%.