Unstable Angina 

Updated: May 07, 2019
Author: Walter Tan, MD, MS; Chief Editor: Eric H Yang, MD 

Overview

Practice Essentials

Unstable angina belongs to the spectrum of clinical presentations referred to collectively as acute coronary syndromes (ACSs), which also includes ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI).[1, 2] Unstable angina is considered to be an ACS in which there is myocardial ischemia without detectable myocardial necrosis (ie, cardiac biomarkers of myocardial necrosis —such as creatine kinase MB isozyme, troponin, myoglobin—are not released into the circulation). See the image below.

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

Signs and symptoms

With unstable angina, symptoms may (1) occur at rest; (2) become more frequent, severe, or prolonged than the usual pattern of angina; (3) change from the usual pattern of angina; or (4) not respond to rest or nitroglycerin.[3]  Symptoms of unstable angina are similar to those of myocardial infarction (MI) and include the following:

  • Chest pain or pressure

  • Pain or pressure in the back, neck, jaw, abdomen, shoulders or arms

  • Sweating

  • Dyspnea

  • Nausea, vomiting

  • Dizziness or sudden weakness

  • Fatigue

The patient’s history and diagnostic testing are generally more sensitive and specific for unstable angina than the physical examination, which may be unremarkable. 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)

See Presentation for more detail.

Diagnosis

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

  • 12 lead electrocardiogram

  • Serial cardiac biomarker assays (eg, creatine kinase MB isoenzyme [CK-MB], troponin I or T)

  • Complete blood count (CBC) with hemoglobin level

  • Serum chemistry panel (including magnesium and potassium)

  • Lipid panel

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

  • Creatinine level

  • Exercise testing when patients are stable

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

  • Chest radiography

  • Echocardiography

  • Computed tomography angiography

  • Magnetic resonance angiography

  • Single-photon emission computed tomography

  • Magnetic resonance imaging

  • Myocardial perfusion imaging

See Workup for more detail.

Management

Management is directed toward (1) reducing myocardial oxygen demands; (2) improving myocardial oxygen supply; and (3) assessing the patient's risk of progression to MI or having a complication related to treatment.

Patients with unstable angina require admission to the hospital for bed rest with continuous telemetry monitoring. One should obtain intravenous (IV) access, and provide supplemental oxygen if evidence of desaturation is noted. 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, 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 or low-molecular-weight heparins [LMWHs] [eg, enoxaparin, dalteparin, and tinzaparin])

  • Thrombin inhibitors (eg, bivalirudin, lepirudin, desirudin, and argatroban)

  • Nitrates (eg, nitroglycerin IV)

  • Calcium channel blockers (diltiazem, verapamil, or nifedipine)

  • Angiotensin-converting enzyme inhibitors (ACEIs) (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.

Background

Chest pain is a nonspecific symptom that can have cardiac or noncardiac causes (see DDx). Unstable angina belongs to the spectrum of clinical presentations referred to collectively as acute coronary syndromes (ACSs), which range from ST-segment elevation myocardial infarction (STEMI) to non-STEMI (NSTEMI).[1, 2] Unstable angina is considered to be an ACS in which there is myocardial ischemia without detectable myocardial necrosis (ie, cardiac biomarkers of myocardial necrosis—such as creatine kinase MB isozyme, troponin, myoglobin—are not released into the circulation). 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.

Pathophysiology

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

  • Supply-demand mismatch

  • Plaque disruption or rupture

  • Thrombosis

  • Vasoconstriction

  • Cyclical flow

Supply-demand mismatch

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

Increased myocardial oxygen demand may be caused by the following:

  • Fever

  • Tachyarrhythmias (eg, atrial fibrillation or flutter)

  • Malignant hypertension

  • Thyrotoxicosis

  • Pheochromocytoma

  • Cocaine use

  • Amphetamine use

  • Aortic stenosis

  • Supravalvular aortic stenosis

  • Obstructive cardiomyopathy

  • Aortovenous shunts

  • High-output states

  • Congestive heart failure (CHF)

Decreased oxygen supply may be caused by the following:

  • Anemia

  • Hypoxemia

  • Polycythemia

  • Hypotension

The above causes must be investigated because a number of them are reversible. For example, anemia from chronic gastrointestinal (GI) bleeding is not uncommon in elderly patients. This can coexist with coronary artery disease (CAD). However, patients may not benefit from or may be harmed by treatments such as anticoagulants and antiplatelet drugs. Avoidance or treatment of the underlying condition is paramount.

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

Plaque disruption

Accumulation of lipid-laden macrophages and smooth muscle cells, so-called foam cells, occurs within atherosclerotic plaques. The oxidized low-density lipoprotein cholesterol (LDL-C) in foam cells is cytotoxic, procoagulant, and chemotactic. As the atherosclerotic plaque grows, production of macrophage proteases and neutrophil elastases within the plaque can cause thinning of the fibromuscular cap that covers the lipid core.

Increasing plaque instability, coupled with blood-flow shear and circumferential wall stress, leads to plaque fissuring or rupture (see the image below), especially at the junction of the cap and the vessel wall. (See Vulnerable Plaque Pathology.)

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

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

As many as 50% of MIs are due to lesions that are angiographically considered functionally insignificant.[4] 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.[5] A polymorphism in glycoprotein Ia was associated with an increased time before platelet aggregation occurs in heterozygotes for the polymorphism in a Chinese population[6] ; 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.[7, 8]

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,[9] 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.[10] Higher IL-10 levels are believed to be cardioprotective, further suggesting that ApoE4 is associated with increased risk for unstable angina.[10] 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.[11]

Epidemiology

United States demographics

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

Reasonably representative statistical estimates for unstable angina can be obtained from 2 registries, the GUARANTEE (Global Unstable Angina Registry and Treatment Evaluation) registry[12] and the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation) registry of the American College of Cardiology (ACC) and the American Heart Association (AHA).[13, 14] (See Table 1 below.)

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

Characteristics

GUARANTEE, 1995-96[12]

CRUSADE, 2001-06[13]

Mean age (y)

62

69

Patients >65 y (%)

44

Female (%)

39

40

Hypertension (%)

60

73

Diabetes mellitus (%)

26

33

Current smoker (%)

25

Hypercholesterolemia (%)

43

50

Previous stroke (%)

9

Previous MI (%)

36

30

Previous angina (%)

66

CHF (%)

14

18

Previous coronary intervention (%)

23

21

Previous coronary bypass surgery (%)

25

19

CHF = congestive heart failure; CRUSADE = Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the American College of Cardiology/American Heart Association guidelines; GUARANTEE = Global Unstable Angina Registry and Treatment Evaluation; MI = myocardial infarction.

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

CRUSADE registered more than 180,000 US patients with NSTEMI from 2001 to 2006, targeting high-risk patients with unstable angina or NSTEMI according to the following inclusion criteria, either separately or in combination[13, 14] :

  • Chest pain or anginal equivalent at rest, more than 10 minutes in duration

  • Ischemic electrocardiographic (ECG) changes (ST-segment depression >0.5 mm, transient ST-segment elevation 0.5-1.0 mm lasting for < 10 minutes); or

  • Elevated markers of myocardial necrosis (CK-MB or troponin I or T exceeding the upper limit of normal for the local laboratory assay used at each institution)

International demographics

The best international demographic data available are from the OASIS-2 (Organization to Assess Strategies for Ischemic Syndromes) registry (see Table 2 below).[15]

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

Characteristics[15]

Australia

Brazil

Canada

Hungary

Poland

United States

General

Number of patients

1899

1478

1626

931

1135

918

Mean age (y)

65

62

66

65

63

66

Women (%)

37

42

37

45

40

37

Clinical

NQMI presentation (%)

7

7

14

22

17

16

Abnormal ECG (%)

74

91

82

95

97

87

Select treatments

Beta blocker (%)

67

53

73

67

59

57

Calcium blocker (%)

59

51

53

52

43

59

Invasive procedures (index hospitalization)

Cardiac catheterization (%)

24

69

43

20

7

58

PCI (%)

7

19

16

5

0.4

24

CABG (%)

4

20

10

7

0.4

17

CABG = coronary artery bypass grafting; ECG = electrocardiographic; NQMI = non-Q wave myocardial infarction; OASIS = Organization to Assess Strategies for Ischemic Syndromes; PCI = percutaneous coronary intervention.

Because unstable angina is intimately linked to the incidence of coronary events, an approximation of international trends might be found in the MONICA (Monitoring Trends and Determinants in Cardiovascular Diseases) registry sponsored by the World Health Organization (WHO).[16] This large project monitored more than 7 million people aged 35-64 years from 30 populations in 21 countries from the mid-1980s.

In the study, the highest average rates of heart disease were found in Glasgow and Belfast, United Kingdom; North Karelia and Kuopio, Finland; Newcastle, Australia; and Warsaw, Poland.[16] The lowest average MI rates, and presumably the lowest average unstable angina rates, were observed in Beijing, China; Toulouse, France; Catalonia, Spain; Vaud-Fribourg, Switzerland; and Brianza, Italy.

The GRACE (Global Registry of Acute Coronary Events) registry (http://www.outcomes-umassmed.org/grace/ ) is prospectively tracking contemporary ACS treatment and outcome across 30 countries and has accumulated more than 100,000 patients.[17]

In an international study comprising 8992 patients in two independent diagnostic trials enrolled at 11 centers to evaluate the relative incidence and outcomes of unstable angina compared with non-ST-elevation myocardial infarction (NSTEMI), investigators found that the relative incidence and mortality of unstable angina is substantially lower than that of NSTEMI, but rate of future non-fatal MI is similar.[18]

Age-related demographics

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

Sex-related demographics

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

Race-related demographics

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

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

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

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

Prognosis

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

Patients who present with new ST-segment deviation (≥1 mm) have a 1-year death or MI rate of 11%, compared with a rate of only 6.8% in patients with isolated T-wave inversion.[19]

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

Table 3. Thirty-Day Clinical Outcome in Patients With Acute Coronary Syndromes in Clinical Trials (Open Table in a new window)

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.[20] Compared with the rates in the North American studies listed earlier (see Epidemiology), these seem lower, probably because of the healthier case-mix; this illustrates the difficulties of direct outcome comparisons between institutions, countries, and trials.

A contemporary large clinical trial with centrally adjudicated outcomes showed that an ACS portends more adverse events in the year to come.[21] The following are the 12-month event rates for the ACS patients (final diagnosis of unstable angina, 16.6%; NSTEMI, 42.9%; STEMI, 37.5%), whose median age was 62 years, 25% of whom were diabetic, and fewer than 1% of whom were classified as above Killip class 2[21] :

  • Death from vascular causes - 4.3%

  • Death from nonvascular causes - 0.6%

  • MI - 5.9%

  • Stroke - 1.2%

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

Prognostic 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.[22]  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.[22]

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.

 

Presentation

History

Patients with unstable angina represent a heterogeneous population. Therefore, the clinician must obtain a focused history of the patient’s symptoms and coronary risk factors and immediately review the 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). With unstable angina, symptoms may (1) occur at rest; (2) become more frequent, severe, or prolonged than the usual pattern of angina; (3) change from the usual pattern of angina; or (4) not respond to rest or nitroglycerin.[3]

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 back, lower jaw, neck, shoulders, or arms. 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

 

DDx

Diagnostic Considerations

Observation and serial or further testing should be considered for patients who have coronary risk factors or a suspicious history. In one study, the unintentional failure to recognize or hospitalize patients with myocardial infarction or unstable angina occurred in an average of 2.2 per 100 patients presenting to the emergency department with a chest pain syndrome.[23] The rates were 0-10% across different academic centers.

Be aware that unstable angina can infrequently coexist or concurrently present with the following:

  • Aortic dissection with involvement of the right coronary artery ostium

  • Infective endocarditis with embolus into a coronary artery

  • Periprocedural (post−percutaneous coronary intervention) reocclusion or coronary stent thrombosis

  • Congestive heart failure

Also consider cocaine-induced coronary spasm, which can be indistinguishable from acute coronary syndromes. (Nitroglycerin and calcium-channel antagonists are the drugs of choice; beta blockers may exacerbate cocaine-induced coronary vasoconstriction.) In patients with persistent ST elevation, coronary angiography should be performed. If this cannot be carried out immediately, consider empiric fibrinolytic therapy.

Variant (Prinzmetal) angina is characterized by transient ST-segment elevation and can involve multiple coronary arterial territories. Patients typically respond to nitroglycerin and high-dose, and sometimes even dual, calcium channel blockers.

The differential diagnoses for unstable angina fall into the following categories:

  • Cardiac (eg, acute myocarditis and right ventricular strain due to severe pulmonary hypertension)

  • Vascular (eg, microvascular disease [syndrome X])

  • Pulmonary (eg, pneumonia, pneumothorax, pulmonary hypertension, and tracheobronchitis)

  • Gastrointestinal (eg, Mallory-Weiss tear, pancreatitis, and peptic ulcer disease)

  • Musculoskeletal (eg, arthritis of the shoulder or spine, cervical disk disease, interscalene or hyperabduction syndromes, subacromial bursitis, and intercostal muscle cramps)

  • Other (eg, mediastinitis, disorders of the breast, and tumors of the chest wall)

Differential Diagnoses

 

Workup

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.[24]

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.[25]

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.[23] 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).[23]

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.[26] 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 cell (CBC) count helps in ruling out anemia as a secondary cause of acute coronary syndrome (ACS). Leukocytosis has prognostic value in the setting of acute myocardial infarction (MI). Early changes in platelet size and number appear to occur in those with ACS.[27]  In a prospective study of 134 patients with ACS (unstable angina, non-ST elevation MI [NSTEMI], STEMI), investigators found that platelets and mean platelet volume decreased within 3 hours of admission, whereas at 72 hours and 7 days, these values increased only in those with acute MI.[27]

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.[28]

Myeloperoxidase levels may be potentially useful in differentiating patients with ACS from those with chest pain from other causes. A single emergency department retrospective study (September to December 2015) of all patients older than 18 years with nontraumatic chest pain evaluated serial measurements of troponin and myeloperoxidase on admission and at 6 hours and found statistically significant differences not only in myeloperoxidase concentration at admission and at 6 hours for patients diagnosed with ACS as well as non-ACS patients, but also among ACS patients and those with heart disease other than coronary artery disease at the same time points.[29]

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 a Time 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.[30] 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. Owing to 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).[31]

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”).[31] 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.[31]

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.[32]

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.

Note: Although BNP levels may add incremental information to the assessment of patients with unstable angina, 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.

Nitric oxide

Levels of endothelial nitric oxide appears to have potential as a novel biomarker in predicting coronary complexity in patients with unstable angina. In a study that aimed to compare nitric oxide levels with the Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score in terms of predicting coronary complexity and the treatment decision for unstable angina pectoris in the emergency department, investigators found lower mean nitric oxide levels in those with unstable angina than control subjects, and that nitric oxide levels were negatively correlated with the SYNTAX score and treatment decision.[33] Decreased nitric oxide levels were noted in those who underwent coronary artery bypass graft surgery compared with those who underwent coronary angiography and those who underwent percutaneous coronary intervention.

Electrocardiography

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.[34]

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.[19]

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.[35] Wellens syndrome is also referred to as LAD coronary T-wave syndrome.[36] 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.

Echocardiography

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.

SPECT and MRI

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.[37, 38] 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.[39] Among men, shorter exercise duration, lower maximal rate-pressure product, and exercise-induced angina or ST-segment depression have correlated with unfavorable outcome.[40]

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.[40] 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.

 

Treatment

Approach Considerations

Management is directed toward (1) reducing myocardial oxygen demands; (2) improving myocardial oxygen supply; and (3) assessing the patient's risk of progression to myocardial infarction or having a complication related to treatment.

Patients with unstable angina require admission to the hospital for bed rest with continuous telemetry monitoring. One should obtain intravenous (IV) access, and provide supplemental oxygen if evidence of desaturation is noted. Because the course of unstable angina is highly variable and potentially life-threatening, the aggressiveness of the therapeutic approach must be established expeditiously. 

An invasive strategy refers to the routine use of cardiac catheterization with possible revascularization, and a ischemia-guided 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. In the After Eighty trial, in which investigators evaluated the health-related quality of life (HRQOL) in patients with ACS (NSTEMI, unstable angina) aged 80 years or more who were randomized to either invasive (n = 208) or conservative (n = 216) management, there were only minor differences in HRQOL from baseline to 1-year follow-up between these interventions, as measured by the Short Form 36 health survey (SF-36).[41]

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.

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 (eg, nitroglycerin IV), calcium channel blockers (eg, diltiazem, verapamil), and heparin. Medications that have been convincingly shown to be capable of reducing short- or long-term adverse events are as follows:

  • Aspirin

  • Clopidogrel

  • Beta-adrenergic blocking agents

  • Lipid-lowering agents (statins)

  • Angiotensin-converting enzyme (ACE) inhibitors

  • Glycoprotein (GP) IIb/IIIa antagonists

Diet

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

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

Aspirin

Administer chewable aspirin 162-325 mg promptly to patients who are not at high risk for bleeding, who do not have ongoing bleeding, or who do not have true intolerance or allergy. Timeliness of administration is essential, because platelet aggregation is central to acute coronary syndrome (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.[42]

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.

Thienopyridines

Clopidogrel

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).[42, 43]

The Food and Drug Administration approved clopidogrel for the medical management of unstable angina/NSTEMI, STEMI in those receiving fibronolytic therapy, and for secondary prevention in recent MI, recent stroke, and peripheral artery disease.[44]

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.[45] 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[45] and the CREDO (Clopidogrel for the Reduction of Events During Observation)[46] 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.[47, 48]

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.[47, 48]

Studies have been conducted to ascertain viable strategies for overcoming the variability in the metabolism and efficacy of clopidogrel.[49] 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.[49, 50, 51]  However, Rudolph et al reported that compared to clopidogrel, prasugrel improves endothelial nitric oxide bioavailability and reduces platelet-leukocyte interaction and levels of inflammatory markers in patients with unstable angina undergoing PCI.[52]

It should be noted that although clopidogrel may be less efficacious than the newer P2Y12 inhibitors, it may carry a slightly lower bleeding risk.

Prasugrel

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 potentially harmful as part of a dual-platelet regimen in patients with a stroke history for whom PCI is planned.[42] Owing to excess bleeding without clinical benefit, the US Food and Drug Administration lists a Black Box warning that does not recommend administration of prasugrel to patients 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.[42]

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).

Prasugrel should not be used prior to coronary angiography. Thus, based on current guidelines, patients with unstable angina being treated with upfront dual antiplatelet therapy should be given either clopidogrel or ticagrelor.

Findings from a 1-year clinical effectiveness retrospective observational comparison of prasugrel with ticagrelor using data from an integrated claims database from 15,788 patients with ACS managed with PCI revealed noninferiority of prasugrel for rates of postdischarge net adverse clinical events (NACEs), major adverse cardiovascular events (MACEs), and rehospitalization for bleeding.[53] However, prasugrel use was associated with a significantly lower NACEs and MACEs, mostly driven by heart failure, but with no significant difference in all-cause death, MI, unstable angina, stroke/transient ischemic attack, or bleeding. The investigators noted that physicians preferentially used prasugrel rather than ticagrelor in younger ACS-PCI patients with lower risk of bleeding or comorbidities.[53]

Nonthienopyridine P2Y12 inhibitor

Ticagrelor

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).[54]

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%.[21] 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.[55] 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.[55]

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).[42] 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.[56, 57] In fact, longer duration of abciximab use was associated with a negative trend in event rates.

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.[58] Whether this small benefit offsets the risk of bleeding events is a matter for the physician’s clinical judgment.

Heparin

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.[59]

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%).[60] 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.[60] 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%).[61] 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.[61] 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.[62] Fondaparinux yielded a lower major bleeding rate at 9 days, as well as significant reductions in MI, stroke, and mortality at 180 days.[62] 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. 

Reactivation of unstable angina after discontinuance of heparin has been documented among subjects not receiving concomitant aspirin therapy.[63]

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%).[64] 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.[64]

GUSTO IIB investigators compared recombinant hirudin with heparin in 12,142 patients, a third of whom had STEMI.[65] 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%).[65]

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.[66]

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.[66, 67] 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).

Nitrates

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.[68, 69]

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.[68] The benefit was mostly for recurrent symptomatic ischemia with objective evidence and requiring emergency rehospitalization (from 8.4% to 6.2%).[68]

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.[69]

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.[70]

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.[71]

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.[72]

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.[73]

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.[74, 75]

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.[32] 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.[76]

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.[76]

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.[77]

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.[77]

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.[78] 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.[79] 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%).[79]

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. 

Revascularization

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%.[32]

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.[76] 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.[80] 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).

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.

Prevention

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.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (eg, evolocumab, alirocumab) are indicated to not only lower LDL-C but also to reduce the risk of unstable angina requiring hospitalization in adults with established CV disease.[81, 82]

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

Diet modification, exercise, pharmacotherapy (including ACE inhibitor therapy), preventive counseling regarding foot care, and ophthalmic examinations are indicated.[83]

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).

Consultations

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.

 

Guidelines

Guidelines Summary

Guidelines for the management of non–ST-elevation acute coronary syndromes (NSTE-ACS) have been issued by:

  • American Heart Association/American College of Cardiology (AHA/ACC)
  • European Society of Cardiology (ESC)

In 2014, the AHA/ACC published a full revision of their 2007 guidelines which included the following key changes[42] :

  • Because unstable angina and non-ST-segment elevation myocardial infarction (NSTEMI) are on a pathophysiologic continuum and are often indistinguishable, they are considered together in the 2014 guidelines

  • To more clearly convey this physiology-based patient-management approach, the guideline has replaced the term "initial conservative management" with "ischemia-guided strategy" 

  • Cardiac troponin assays 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

In 2015, the ESC release its guidelines which define unstable angina as "myocardial ischemia at rest or minimal exertion in the absence of cardiomyocyte necrosis."[84]

Evaluation

The 2014 AHA/ACC revised guidelines include the following recommendations for evaluation of patients with suspected ACS[42] :

Class I

Patients with suspected ACS should be risk stratified based on the likelihood of ACS and adverse outcome(s) to decide on the need for hospitalization and assist in the selection of treatment options. (Level of evidence: B)

Patients with suspected ACS and high-risk features such as continuing chest pain, severe dyspnea, syncope/presyncope, or palpitations should be referred immediately to the emergency department (ED) and transported by emergency medical services when available. (Level of evidence: C)

In patients with chest pain or other symptoms suggestive of ACS, a 12-lead electrocardiogram (ECG) should be performed and evaluated for ischemic changes within 10 minutes of the patient’s arrival at an emergency facility. (Level of evidence: C)

Serial ECGs (eg, 15- to 30-minute intervals during the first hour) should be performed to detect ischemic changes if the initial ECG is not diagnostic but the patient remains symptomatic. (Level of evidence: C)

Serial cardiac troponin I or T levels (when a contemporary assay is used) should be obtained at presentation and 3 to 6 hours after symptom onset in all patients who present with symptoms consistent with ACS to identify a rising and/or falling pattern of values. If the time of symptom onset is ambiguous, the time of presentation should be considered the time of onset for assessing troponin values. (Level of evidence: A)

Additional troponin levels should be obtained beyond 6 hours after symptom onset in patients with normal troponin levels on serial examination when changes on ECG and/or clinical presentation confer an intermediate or high index of suspicion for ACS. (Level of evidence: A)

Class IIa 

It is reasonable to give low-risk patients who are referred for outpatient testing daily aspirin, short-acting nitroglycerin, and other medication if appropriate (eg, beta blockers), with instructions about activity level and clinician follow-up. (Level of evidence: C)

Observe patients with symptoms consistent with ACS without objective evidence of myocardial ischemia (nonischemic initial ECG and normal cardiac troponin) in a chest pain unit or telemetry unit with serial ECGs and cardiac troponin levels at 3- to 6-hour intervals. (Level of evidence: B)

For patients with possible ACS who have normal serial ECGs and cardiac troponin levels, it is reasonable to obtain a treadmill ECG (level of evidence: A), stress myocardial perfusion imaging, or stress echocardiography before discharge or within 72 hours after discharge (level of evidence: B).

In patients with possible ACS and a normal ECG, normal cardiac troponin levels, and no history of coronary artery disease (CAD), it is reasonable to initially perform (without serial ECGs and troponin levels) coronary computed tomography angiography to assess coronary artery anatomy (level of evidence: A) or rest myocardial perfusion imaging with a technetium-99m radiopharmaceutical to exclude myocardial ischemia (level of evidence: B).

The 2015 ESC guidelines are in general agreement with the 2014 AHA/ACC. Additional Class I recommendations are summarized below[84]

Base the diagnosis and initial short-term ischemic and bleeding risk stratification on a combination of clinical history, symptoms, vital signs, other physical findings, ECG, and laboratory results. (Level of evidence: A) 

Measure cardiac troponin levels with sensitive or high-sensitivity assays, and obtain the results within 60 minutes. (Level of evidence: A) 

A rapid rule-out protocol at 0 h and 3 h if high-sensitivity cardiac troponin tests are available. (Level of evidence: B) 

A rapid rule-out and rule-in protocol at 0 h and 1 h if a high-sensitivity cardiac troponin test with a validated 0 h/1 h algorithm is available. Additional testing after 3 to 6 hours is indicated if the first two troponin measurements are not conclusive and the clinical condition is still suggestive of ACS.(Level of evidence: B) 

Continuous rhythm monitoring should be performed until the diagnosis of NSTEMI is established or ruled out. (Level of evidence: C)

In the absence of signs or symptoms of ongoing ischemia, rhythm monitoring in unstable angina may be considered in selected patients (eg, suspicion of coronary spasm or associated symptoms suggestive of arrhythmic events).

Selection of management strategy

Determination of the preferred management strategy depends on the patient’s clinical characteristics and clinical risk. The AHA/ACC and ESC provide similar recommendations for selection of the preferred managment stategy which are summarized in Table 5 below.[42, 84]

Table 5.  Recommendations for Selection of Preferred Managment Strategy (Open Table in a new window)

Preferred Strategy  Patient Characteristic/Clinical Risk

Immediate Invasive Strategy

(< 2 hours)

Refractory angina
Signs/symptoms of heart failure or new or worsening mitral regurgitation
Hemodynamic instability or cardiogenic shock
Recurrent angina/ischemia at rest or with low-level activities despite intensive medical therapy
Sustained ventricular tachycardia or ventricular fibrillation
Ischemia-Guided Strategy Low-risk score (eg, TIMI 0 or 1, GRACE < 109)
Low-risk Tn-negative female
Patient or physician preference in the absence of high-risk features

Early Invasive Strategy

(< 24 hours)

GRACE score >140
Rise or fall in Tn compatible with myocardial infarction
New or presumably new ST-segment depression

Delayed Invasive Strategy

(24-72 hours)

Diabetes mellitus
Renal insufficiency (GFR < 60 mL/min/1.73m2)
Reduced LV systolic function (LVEF < 40%)
Early postinfarction angina
PCI within 6 months
Prior CABG
GRACE score 109-140; TIMI Score ≥2
ACC/AHA = American College of Cardiology/American Heart Association; CABG = coronary artery bypass grafting; GFR = glomerular filtration rate; 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; Tn = troponin.

Initial hospital care

The 2014 AHA/ACC recommendations for initial hospital care are summarized below.[42]

Oxygen

Administer supplemental oxygen only with oxygen saturation below 90%, respiratory distress, or other high-risk features for hypoxemia. (Class I; level of evidence C)

Nitrates 

Administer sublingual nitroglycerin (NTG) every 5 minutes three times for continuing ischemic pain, and then assess need for intravenous (IV) NTG. (Class I; level of evidence: C) 

Administer IV NTG for persistent ischemia, heart failure (HF), or hypertension. (Class I; level of evidence: B) 

Nitrates are contraindicated with recent use of a phosphodiesterase inhibitor. (Class III; level of evidence: B)  

Analgesic therapy

IV morphine sulfate may be reasonable for continued ischemic chest pain despite maximally tolerated anti-ischemic medications. (Class IIb; level of evidence: B)  

Nonsteroidal anti-inflammatory agents (NSAIDs) (except aspirin) should not be initiated and should be discontinued because of the increased risk of a major adverse cardiac event associated with their use. (Class III; level of evidence: B)  

Beta-adrenergic blockers

Initiate oral beta blockers in the absence of HF, low-output state, risk for cardiogenic shock, or other contraindications to beta blockade. (Class I; level of evidence: A)  

Use sustained-release metoprolol succinate, carvedilol, or bisoprolol for beta-blocker therapy with concomitant NSTE-ACS, stabilized HF, and reduced systolic function. (Class I; level of evidence: C)  

Re-evaluate to determine subsequent eligibility in patients with initial contraindications to beta blockers. (Class I; level of evidence: C)

It is reasonable to continue beta-blocker therapy in patients with normal LV function with NSTE-ACS. (Class IIa; level of evidence: C)

IV beta blockers are potentially harmful when risk factors for shock are present. (Class III; level of evidence: B)

Calcium channel blockers (CCBs)

CCBs are recommended for ischemic symptoms when beta blockers are not successful, are contraindicated, or cause unacceptable side effects. (Class I; level of evidence: C) 

Long-acting CCBs and nitrates are recommended for patients with coronary artery spasm. (Class I; level of evidence: C)

Administer initial therapy with nondihydropyridine CCBs with recurrent ischemia and contraindications to beta blockers in the absence of LV dysfunction, increased risk for cardiogenic shock, PR interval above 0.24 s, or second- or third-degree atrioventricular block without a cardiac pacemaker. (Class I; level of evidence: B)

Administer oral nondihydropyridine calcium antagonists with recurrent ischemia after use of beta blocker and nitrates in the absence of contraindications. (Class I; level of evidence: C) 

Immediate-release nifedipine is contraindicated in the absence of a beta blocker. (Class III; level of evidence: B) 

Cholesterol management

Initiate or continue high-intensity statin therapy in patients with no contraindications. (Class I; level of evidence: A) 

Obtain a fasting lipid profile in patients with NSTE-ACS, preferably within 24 hours of presentation. (Class IIa; evel of evidence:C) 

Angiotensin-converting enzyme (ACE) inhibitors (ACEIs)

Class I

ACEIs should be started and continued indefinitely in all patients with an LVEF) below 0.40 and in those with hypertension, diabetes mellitus, or stable chronic kidney disease (CKD), unless contraindicated. (Level of evidence: A)

Angiotensin receptor blockers are recommended in patients with heart failure or MI with LVEF below 0.40 who are intolerant to ACEIs. (Level of evidence: A)

Aldosterone blockade is recommended in post–MI patients who are without significant renal dysfunction or hyperkalemia who are receiving therapeutic doses of ACEI and beta blocker and have an LVEF below 0.40, diabetes mellitus, or heart failure. (Level of evidence: A)

Antiplatelet therapy

Recommendations for initial antiplatelet/anticoagulation therapy in patients with NSTE-ACS are summarized below.[42]

Aspirin

Nonenteric-coated, chewable aspirin (162 mg to 325 mg) should be given to all patients without contraindications as soon as possible after presentation, and a maintenance dose of aspirin (81 mg/d to 325 mg/d) should be continued indefinitely. (Class I; level of evidence A) 

In patients who are unable to take aspirin because of hypersensitivity or major gastrointestinal intolerance, a loading dose of clopidogrel followed by a daily maintenance dose should be administered. (Class I; level of evidence B) 

Anticoagulation

Anticoagulation, in addition to antiplatelet therapy, is recommended for all patients irrespective of the initial treatment strategy. Treatment options (all Class I) include:

  • Subcutaneous (SC) enoxaparin for duration of hospitalization or until percutaneous coronary intervention (PCI) is performed (Level of evidence: A)  
  • Bivalirudin until diagnostic angiography or PCI is performed in patients with early invasive strategy only (Level of evidence: B)
  • SC fondaparinux for the duration of hospitalization or until PCI is performed (Level of evidence: B)
  • IV unfractionated heparin (UFH) for 48 h or until PCI is performed (Level of evidence: B)

IV fibrinolytic treatment is not recommended in patients with NSTE-ACS. (Class III, level of evidence: A)

Dual antiplatelet therapy

In 2016, the ACC/AHA released updated guidelines on the duration of dual antiplatelet therapy (DAPT) in patients with CAD. In this focused update, the term and acronym DAPT is used to specifically to refer to combination antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor (clopidogrel, prasugrel, or ticagrelor). Key recommendations for patients with NSTE-ACS treated with DAPT are summarized below.[85] :

Class I

For all patients treated with DAPT, a daily aspirin dose of 81 mg (range, 75 mg to 100 mg) is recommended. (Level of evidence: B-R)

After bare metal stent (BMS) or drug-eluting stent (DES) implantation, P2Y12 inhibitor therapy (clopidogrel, prasugrel, or ticagrelor) should be given for at least 12 months. (Level of evidence: B-R)

For patients who subsequently undergo CABG after coronary stent implantation, P2Y12 inhibitor therapy should be resumed postoperatively so that DAPT continues until the recommended duration of therapy is completed. (Level of evidence: C-EO)

In patients who undergo CABG, P2Y12 inhibitor therapy should be resumed after CABG to complete 12 months of DAPT therapy. (Level of evidence: C-LD) 

Class IIa

After coronary stent implantation, it is reasonable to use ticagrelor in preference to clopidogrel for maintenance P2Y12 inhibitor therapy. (Level of evidence: B-R)

After coronary stent implantation in patients who are not at high risk for bleeding complications and who do not have a history of stroke or transient ischemic attack (TIA), it is reasonable to choose prasugrel over clopidogrel for maintenance P2Y12 inhibitor therapy. (Level of evidence: B-R)

Class IIb

In patients treated with coronary stent implantation who have tolerated DAPT without a bleeding complication and who are not at high bleeding risk, continuation of DAPT (clopidogrel, prasugrel, or ticagrelor) for longer than 12 months may be reasonable. (Level of evidence: A)

After DES implantation, patients who develop a high risk of bleeding, or are at high risk of severe bleeding complication, or develop significant overt bleeding, discontinuation of P2Y12 inhibitor therapy after 6 months may be reasonable. (Level of evidence: C-LD)

Class III

Prasugrel should not be administered to patients with a prior history of stroke or TIA. (Level of evidence: B-R)

Hospital discharge and follow-up

The 2014 AHA/ACC guidelines include the following Class 1 recommendations for posthospital care[42] :

Medications required in the hospital to control ischemia should be continued after hospital discharge in patients with NSTE-ACS who do not undergo coronary revascularization, patients with incomplete or unsuccessful revascularization, and patients with recurrent symptoms after revascularization. Titration of the doses may be required. (Level of evidence: C)

All patients should be given sublingual or spray NTG with verbal and written instructions for its use. (Level of evidence: C)

Before hospital discharge, patients should be informed about symptoms of worsening myocardial ischemia and Ml, and they should be given verbal and written instructions about how and when to seek emergency care for such symptoms. (Level of evidence: C)

For patients who have initial angina lasting more than 1 minute, NTG (1 dose sublingual or spray) if angina does not subside within 3 to 5 minutes; call 9-1-1 immediately to access emergency medical services. (Level of evidence: C)

If the pattern or severity of angina changes, suggesting worsening myocardial ischemia (eg, pain is more frequent or severe or is precipitated by less effort or occurs at rest), patients should contact their clinician without delay to assess the need for additional treatment or testing. (Level of evidence: C)

Before discharge, patients should be educated about modification of cardiovascular risk factors. (Level of evidence: C)

Diabetes

The 2014 AHA/ACC guidelines recommend that treatment in the acute phase of NSTE-ACS and decisions to perform stress testing, angiography, and revascularization should be similar in patients with and without diabetes mellitus. (Level of evidence: A)

The 2015 ESC guidelines offer the following recommendations[84] :

Class I

Screen all patients for diabetes and monitor blood glucose levels frequently in patients with known diabetes or admission hyperglycaemia. (Level of evidence: C)

Administer the same antithrombotic treatment in diabetic and nondiabetic patients. (Level of evidence: C) 

An invasive strategy is recommended over noninvasive management. (Level of evidence: A) 

Monitor renal function for 2-3 days after coronary angiography or PCI in patients with baseline renal impairment or on metformin. (Level of evidence: C) 

In patients undergoing PCI, new-generation DESs are recommended over BMSs. (Level of evidence: A) 

In patients with stabilised multivessel CAD and an acceptable surgical risk, CABG is recommended over PCI. (Level of evidence: A) 

Class IIa

Glucose-lowering therapy should be considered in ACS patients with blood glucose above 10 mmol/L (>180 mg/dL), with the target adapted to comorbidities, whereas episodes of hypoglycemia should be avoided. (Level of evidence: C) 

Less stringent glucose control should be considered in patients with more advanced cardiovascular disease, older age, longer diabetes duration, and more comorbidities. (Level of evidence: C) 

 

Medication

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

  • Clopidogrel

  • P2Y12 inhibitors

  • Lipid-lowering agents (statins)

  • Glycoprotein (GP) IIb/IIIa antagonists

  • Beta-adrenergic blocking agents

  • Angiotensin-converting enzyme (ACE) inhibitors

  • Proprotein convertase subtilisin/kexin type 9 (PCSK9) 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.

PCSK9 Inhibitors

Class Summary

Over the last decade, inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising target to reduce residual cardiovascular disease risk. PCSK9 is a protein that binds to low-density lipoprotein (LDL) receptors (LDLR) to promote their degradation. Monoclonal antibodies inhibit PCSK9 and thus prevent LDLR degradation. This action will increase the number of LDLRs and subsequently increase the clearance of LDL, ultimately lowering LDL-C levels. 

In December 2017, the FDA approved the first PCSK9 inhibitor, evolocumab (Repatha), for the prevention of strokes, heart attacks, and coronary revascularizations.[86] The approval was based on data from the evolocumab cardiovascular outcomes study (FOURIER). In the FOURIER clinical trial, evolocumab demonstrated significant benefits for 27,564 patients with established cardiovascular disease. The study revealed that when used in addition to optimized statin therapy, evolocumab reduced the risk of heart attack by 27%, the risk of stroke by 21%, and the risk of coronary revascularization by 22%. In addition, evolocumab showed a statistically significant 15% reduction in the risk of the primary composite endpoint, which included hospitalization for unstable angina, coronary revascularization, heart attack, stroke, or cardiovascular death.[81]

In April 2019, the FDA expanded the indication for alirocumab (Praluent) to include risk reduction of MI, stroke, and unstable angina requiring hospitalization in adults with established cardiovascular disease.[87] Approval was based on the ODYSSEY OUTCOMES trial (N=18,924) in patients with elevated LDL-C despite treatment with maximally tolerated statins. Patients who received injections of alirocumab 75 mg or 150 mg every other week achieved reduction in the risk for major cardiovascular events by 15% and all-cause death by 15% at a median follow-up of 2.8 years compared with those who received placebo.[82]

Evolocumab (Repatha)

Human monoclonal IgG2 directed against PCSK9. Evolocumab binds to PCSK9 and inhibits circulating PCSK9 from binding to the LDLR, preventing PCSK9-mediated LDLR degradation and permitting LDLR to recycle back to the liver cell surface. By inhibiting the binding of PCSK9 to LDLR, evolocumab increases the number of LDLRs available to clear LDL from the blood, thereby lowering LDL-C levels.

Alirocumab (Praluent)

Monoclonal antibody that binds to PCSK9. LDL-C is cleared from the circulation preferentially through the LDL receptor (LDLR) pathway. PCSK9 is a serine protease that destroys LDLR in the liver, resulting in decreased LDL-C clearance and increased plasma LDL-C.

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.

Anticoagulant

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

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.

ACE Inhibitors

Class Summary

Angiotensin-converting enzyme (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 the 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.

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

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.

 

Questions & Answers

Overview

What is unstable angina?

Which physical findings suggest unstable angina?

What are the symptoms of unstable angina?

Which lab studies are included in the evaluation of unstable angina?

Which tests may be considered in the evaluation of unstable angina?

Which imaging studies are performed in the evaluation of unstable angina?

What is the focus of treatment for unstable angina?

What is the initial treatment for unstable angina?

Which medications are used in the treatment of unstable angina?

What are the surgical options for the treatment of unstable angina?

What is unstable angina?

How is unstable angina distinct from stable angina?

Which factors are involved in the pathophysiology of unstable angina?

What is the pathophysiology of the myocardial ischemia of unstable angina?

What causes myocardial oxygen demand in unstable angina?

What causes a decreased oxygen supply in unstable angina?

Which causes of the supply-demand mismatch in the pathophysiology of unstable angina may be reversible?

What is the role of plaque disruption in the pathophysiology of unstable angina?

What is the role of vasoconstriction and thrombosis in the pathophysiology of unstable angina?

What is the role of genetics in the pathophysiology of unstable angina?

What is the incidence of unstable angina in the US?

What are the patient characteristics for unstable angina in the US?

What is the patient characteristics for unstable angina globally?

How does the mean age for presentation of unstable angina vary among patient groups?

How does the incidence of unstable angina vary by sex?

What are the racial predilections of unstable angina?

What is the prognosis of unstable angina?

What are 30 day clinical outcomes for unstable angina?

What are the 12-month event rates for unstable angina?

What are the prognostic indicators of poor outcome in unstable angina?

How does epicardial adipose tissue thickness (EAT) affect the prognosis of unstable angina?

What is included in patient education about unstable angina?

Presentation

What is the focus of clinical history for unstable angina?

How does the presentation of unstable angina differ from stable angina?

What should be included in the history of chest pain in suspected unstable angina?

How is chest pain characterized in unstable angina?

Which conditions should be considered during the physical exam of unstable angina?

What is the presentation of increased autonomic activity in patients with unstable angina?

What are the signs and symptoms of myocardial jeopardy in unstable angina?

Which physical findings indicate peripheral arterial occlusive or prior stroke in unstable angina?

What are signs suggestive of congestive heart failure (CHF) in unstable angina?

Why is the classification of unstable angina challenging?

What is the Braunwald classification for unstable angina?

How is unstable angina categorized in the Braunwald classification system?

How is the intensity of antianginal therapy classified for unstable angina?

What is the Canadian Cardiovascular Society Grading System for unstable angina?

Which factors indicate a high risk of acute coronary syndrome (ACS) in unstable angina?

Which factors indicate an intermediate risk of acute coronary syndrome (ACS) in unstable angina?

Which factors indicate a low risk for acute coronary syndrome (ACS) in unstable angina?

What is the Thrombolysis in Myocardial Infarction (TIMI) Risk Score for unstable angina/non-ST elevation MI (UA/NSTEMI)?

DDX

When is serial testing indicated for unstable angina?

Which condition may present with unstable angina?

Which conditions should be considered in the differential diagnoses for unstable angina?

How is variant (Prinzmetal) angina characterized?

How can the differential diagnoses for unstable angina be categorized?

What are the differential diagnoses for Unstable Angina?

Workup

What is included in the initial workup for unstable angina?

Which lab studies should be performed within the first 24 hours of suspected unstable angina?

What is the role of cardiac biomarkers in the diagnosis of unstable angina?

What is the role of chest radiography in the workup of unstable angina?

What is the prognosis of undiagnosed unstable angina?

How can missed diagnosis of unstable angina be prevented?

What is the role of the CBC count in the workup of unstable angina?

What is the role of potassium and magnesium level monitoring in patients with unstable angina?

What is the role of creatinine measurement in the workup of unstable angina?

What is the role of myeloperoxidase measurement in the workup of unstable angina?

Which cardiac markers are useful in the evaluation of unstable angina?

What is the current standard of care for use of creatine kinase, CK-MB, and troponin cardiac biomarkers in the evaluation of unstable angina?

What do troponin levels indicate in the evaluation of unstable angina?

What should be considered when using troponin levels in the diagnosis of unstable angina?

What is the role of brain (B-type) natriuretic peptide (BNP) in the workup of unstable angina?

Which combination of biomarkers may be useful in the workup of unstable angina?

What is the first line of assessment in suspected unstable angina?

How are electrocardiographic (ECG) findings used in the management of unstable angina?

What is the significance of primary T wave changes on electrocardiography for unstable angina?

What is the Wellens syndrome in unstable angina?

What are the benefits of echocardiography in the workup of unstable angina?

What is the sensitivity of single-photon emission computed tomography (SPECT) for unstable angina?

What is the role of MRI in the workup of unstable angina?

What is the role of myocardial perfusion imaging in the workup of unstable angina?

What is the role of exercise testing in the workup of unstable angina?

What are the benefits of predischarge exercise testing for patients with unstable angina?

What are the predictive values of stress tests in the workup of unstable angina?

What is the efficacy of early stress testing for triage in unstable angina?

Treatment

What is the focus of treatment for unstable angina?

What is included in the initial inpatient treatment of unstable angina?

What are the treatment strategies for unstable angina?

How should primary causes of ischemia be managed in unstable angina?

What is the proper level of care and expertise for the treatment of unstable angina?

When is admission to an ICU indicated for the treatment of unstable angina?

When is admission to an intermediate care unit indicated for the treatment of unstable angina?

When is admission to an observation unit indicated for the treatment of unstable angina?

What is the role of medications in the treatment of unstable angina?

Which dietary modifications are used in the treatment of unstable angina?

Which medications are used in the initial management of unstable angina?

How is aspirin administered for the treatment of unstable angina?

What is the role of beta blockers in the treatment of unstable angina?

What is the role of clopidogrel in the treatment of unstable angina?

What are the benefits of clopidogrel for the treatment of unstable angina?

What risks are associated with the use of clopidogrel for the treatment of unstable angina?

What are strategies to overcome the variability in the metabolism and efficacy of clopidogrel for the treatment of unstable angina?

What advantages of clopidogrel over prasugrel for the treatment of unstable angina?

What are the benefits and risks of prasugrel for the treatment of unstable angina?

What are contraindications for prasugrel for the treatment of unstable angina?

What is the efficacy of prasugrel for the treatment of unstable angina?

What is the role of ticagrelor in the treatment of unstable angina?

What is the role of glycoprotein IIb/IIIa antagonists (abciximab) (eptifibatide) (tirofiban) in the treatment of unstable angina?

Which glycoprotein IIb/IIIa antagonists have been shown to be beneficial for the treatment of unstable angina in high risk patients?

What is the role of low-molecular-weight heparin (LMWH) in the treatment of unstable angina?

What are is the efficacy of low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH) in the treatment of unstable angina?

What are safe alternatives to low-molecular-weight heparin (LMWH) for the treatment of unstable angina?

Which direct thrombin inhibitors are alternatives to heparin for the treatment of unstable angina?

What is the efficacy of direct thrombin inhibitors for the treatment unstable angina?

What is the role of lepirudin in the treatment of unstable angina?

What is the role of bivalirudin in the treatment of unstable angina?

When are direct thrombin inhibitors used in the treatment of unstable angina?

What is the role of nitrates in the treatment of unstable angina?

Which medications are used in the ongoing management of unstable angina?

What is the role of statin therapy in the treatment of unstable angina?

What is the efficacy of statin therapy for the treatment of unstable angina?

What may improve patient adherence to statin therapy for unstable angina?

What are FDA safety alerts regarding the use of statin therapy for the treatment of unstable angina?

What is the role of ACE inhibitors in the treatment of unstable angina?

Which medications may be beneficial for the treatment of unstable angina?

What are the indications for immediate cardiac catheterization in patients with unstable angina?

What is the prevalence of significant unstable angina?

What is the efficacy of routine catheterization for the treatment of unstable angina?

What is the efficacy of early invasive therapy for the treatment of unstable angina?

What are reported benefits of early invasive strategy in the treatment of unstable angina?

How does the timing of cardiac catheterization affect outcomes for unstable angina?

What is the role of revascularization in the treatment of unstable angina?

What are the benefits of revascularization for the treatment of unstable angina?

What is the cost-to-benefit ratio of an initial invasive approach for the treatment of unstable angina?

What is the role of coronary artery bypass grafting (CABG) in the treatment of unstable angina?

What is the included in patient monitoring following revascularization for unstable angina?

What are the goals of secondary prevention in patients with unstable angina?

What are the goals of smoking cessation in patients with unstable angina?

What is the target lipid levels in patients with unstable angina?

What are the blood pressure targets in patients with unstable angina?

How is diabetes mellitus managed in patients with unstable angina?

What is the target BMI in patients with unstable angina?

What is included in psychosocial management of patients with unstable angina?

Which activity modifications are used in the management of unstable angina?

Which specialist consultations are beneficial in the treatment of unstable angina?

Guidelines

Which organizations have issued treatment guidelines for unstable angina?

What were key changes to the 2014 AHA/ACC revised treatment guidelines for non–ST-elevation acute coronary syndromes (NSTE-ACS)?

What are the AHA/ACC guidelines class I recommendations for the evaluation of acute coronary syndromes (ACSs)?

What are the AHA/ACC class IIa recommendations for the evaluation of suspected acute coronary syndromes (ACSs)?

What are ESC class I recommendations for the evaluation of acute coronary syndromes (ACSs)?

What is the preferred management strategy for the treatment of acute coronary syndromes (ACSs)?

What are the AHA/ACC recommendations for oxygen use in initial hospital care of unstable angina?

What are the AHA/ACC recommendations for nitrate use in initial hospital care of unstable angina?

What are the AHA/ACC recommendations for analgesic therapy in initial hospital care of unstable angina?

What are the AHA/ACC recommendations for beta-adrenergic blockers in initial hospital care of unstable angina?

What are the AHA/ACC recommendations for calcium channel blockers (CCBs) in initial hospital care of unstable angina?

What are the AHA/ACC recommendations for cholesterol management in initial hospital care of unstable angina?

What are the AHA/ACC recommendations for ACE inhibitors (ACEIs) in initial hospital care of unstable angina?

What are the AHA/ACC recommendations for aspirin use in initial antiplatelet/anticoagulation therapy of unstable angina?

What are options for anticoagulation for the treatment of unstable angina?

What are the benefits of dual antiplatelet therapy (DAPT) for the treatment of coronary artery disease (CAD)?

What are the AHA/ACC class I recommendations for dual antiplatelet therapy (DAPT) for non–ST-elevation acute coronary syndromes (NSTE-ACS)?

What are the AHA/ACC class IIa recommendations for dual antiplatelet therapy (DAPT) for non–ST-elevation acute coronary syndromes (NSTE-ACS)?

What are the AHA/ACC class IIb recommendations for dual antiplatelet therapy (DAPT) for non–ST-elevation acute coronary syndromes (NSTE-ACS)?

According to AHA/ACC guidelines, when is prasugrel not recommended?

What are the AHA/ACC recommendations for hospital discharge and follow-up of patients with non–ST-elevation acute coronary syndromes (NSTE-ACS)?

What are the AHA/ACC recommendations for the management of non–ST-elevation acute coronary syndromes (NSTE-ACS) in patients with diabetes?

What are the ESC class I recommendations for the treatment of diabetes in patients with non–ST-elevation acute coronary syndromes (NSTE-ACS)?

What are the ESC class IIa recommendations for the treatment of diabetes in patients with non–ST-elevation acute coronary syndromes (NSTE-ACS)?

Medications

Which medications have been shown to reduce short- or long-term adverse events in patients with unstable angina?

Which medications in the drug class Thrombin inhibitors are used in the treatment of Unstable Angina?

Which medications in the drug class ACE Inhibitors are used in the treatment of Unstable Angina?

Which medications in the drug class Low Molecular Weight Heparins are used in the treatment of Unstable Angina?

Which medications in the drug class Anticoagulant are used in the treatment of Unstable Angina?

Which medications in the drug class Beta-Blockers, Nonselective; Antidysrhythmics, II are used in the treatment of Unstable Angina?

Which medications in the drug class Beta-Blockers, Nonselective are used in the treatment of Unstable Angina?

Which medications in the drug class Beta-Blockers, Beta-1 Selective; Antidysrhythmics, II are used in the treatment of Unstable Angina?

Which medications in the drug class Beta-Blockers, Beta-1 Selective are used in the treatment of Unstable Angina?

Which medications in the drug class Antiplatelet Agent, Cardiovascular are used in the treatment of Unstable Angina?

Which medications in the drug class PCSK9 Inhibitors are used in the treatment of Unstable Angina?

Which medications in the drug class Lipid-Lowering Agents, Statins are used in the treatment of Unstable Angina?

Which medications in the drug class Antiplatelet agents are used in the treatment of Unstable Angina?

Which medications in the drug class Nitrates, Angina are used in the treatment of Unstable Angina?