Angina Pectoris

Juan A. Escarfuller, M.D.
Claudia Serrano, M.D.

Basic Information

Definition

Angina pectoris is a term used to describe a clinical syndrome, typically characterized by chest, jaw, shoulder, back or arm discomfort that is caused by myocardial ischemia. This is most commonly related to atheromatous plaque in one or more than one large epicardial coronary artery; however, myocardial ischemia may occur in the absence of obstructive coronary artery disease (CAD), such as uncontrolled hypertension, valvular heart disease, hypertrophic cardiomyopathy, coronary spasm, or endothelial dysfunction. Any situation that causes an imbalance in myocardial oxygen supply and demand can cause an angina syndrome. Angina can be classified as follows:

1.
Chronic stable ischemic heart disease (SIHD):
1. ○
  
  Predictable. Usually follows a precipitating event (e.g., climbing stairs, sexual intercourse, a heavy meal, emotional stress, cold weather).
2. ○
  
  Generally has the same severity as previous attacks; relieved by rest or by the customary dose of sublingual nitroglycerin.
3. ○
  
  Caused by a fixed coronary artery obstruction secondary to atherosclerosis. The presence of one or more obstructions in major coronary arteries is likely; the severity of stenosis is usually >70%.
2.
Unstable (rest, recent onset, crescendo, acute coronary syndrome; will be reviewed under Acute Coronary Syndrome):
1. ○
  
  Rest angina: Angina occurring at rest and usually prolonged >20 min, occurring within 1 week of presentation
2. ○
  
  Recent onset. Angina of at least CCS Class III severity occurring less than 2 months after the onset of the symptoms
3. ○
  
  Crescendo angina: Previously diagnosed angina that is distinctly more frequent, longer in duration, or lower in threshold (i.e., increased by >1 CCS class within 2 months of initial presentation to at least CCS Class III severity)
3.
Prinzmetal’s variant:
1. ○
  
  Occurs at rest.
2. ○
  
  Cyclical in nature.
3. ○
  
  EKG finding of episodic ST-segment elevations.
4. ○
  
  Caused by coronary artery spasm with or without superimposed CAD.
5. ○
  
  Patients are more likely to develop ventricular arrhythmias.
4.
Microvascular angina (syndrome X):
1. ○
  
  Refers to patients with angina symptoms, positive exercise test, normal coronary angiograms and no coronary spasm. Defective endothelium-dependent dilation in the coronary microcirculation contributes to the altered regulation of myocardial perfusion and the ischemic manifestations in these patients.
2. ○
  
  Patients with chest pain and normal or nonobstructive coronary angiograms are predominantly women, and many have a prognosis that is not as benign as commonly thought (2% risk of death or myocardial infarction [MI] at 30 days of follow-up).
5.
Refractory angina:
1. ○
  
  Refers to patients whom, despite optimal medical therapy with at least maximal doses, or as tolerated of 2 antianginal medications, in addition to aspirin, aggressive risk factor modification, such as smoking cessation, adequate control of hypertension, diabetes, and hyperlipidemia, still have both angina and objective evidence of ischemia.
6.
Other:
1. ○
  
  Angina due to aortic stenosis and idiopathic hypertrophic subaortic stenosis, cocaine-induced coronary vasoconstriction.

Functional Classification

Stable angina should be classified using a grading system. The most commonly adopted is that of the Canadian Cardiovascular Society:

•

Class I: Ordinary physical activity, such as walking or climbing stairs, does not cause angina. Angina occurs with strenuous, rapid, or prolonged exertion at work or recreation.
•

Class II: Slight limitation of ordinary activity. Angina occurs on walking or climbing stairs rapidly; walking uphill; walking or stair climbing after meals, in cold, in wind, or under emotional stress; or only during the few hours after awakening. Angina occurs on walking more than two level blocks and climbing more than one flight of ordinary stairs at a normal pace and in normal conditions.
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Class III: Marked limitations of ordinary physical activity. Angina occurs on walking one to two level blocks and climbing one flight of stairs in normal conditions and at a normal pace.
•

Class IV: Inability to carry on any physical activity without discomfort; anginal symptoms may be present at rest.

ICD-10CM CODES
I20.8	Other forms of angina pectoris
I20.9	Angina pectoris, unspecified
I20.1	Angina pectoris with documented spasm
I25.110	Atherosclerotic heart disease of native coronary artery with unstable angina pectoris
I25.111	Atherosclerotic heart disease of native coronary artery with angina pectoris with documented spasm
I25.118	Atherosclerotic heart disease of native coronary artery with other forms of angina pectoris
I25.119	Atherosclerotic heart disease of native coronary artery with unspecified angina pectoris
I25.700	Atherosclerosis of coronary artery bypass graft(s), unspecified, with unstable angina pectoris
I25.790	Atherosclerosis of other coronary artery bypass graft(s) with unstable angina pectoris
I25.791	Atherosclerosis of other coronary artery bypass graft(s) with angina pectoris with documented spasm
I25.798	Atherosclerosis of other coronary artery bypass graft(s) with other forms of angina pectoris
I25.799	Atherosclerosis of other coronary artery bypass graft(s) with unspecified angina pectoris

Epidemiology & Demographics

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It is estimated that 1 in 3 adults in the United States (about 81 million) has some form of cardiovascular disease. Based on the NHANES survey 2007-2010, an estimated 15.4 million have coronary heart disease of which 7.8 million have angina.
•

Angina is most common in middle-aged and elderly men. Among persons 60 to 79 years of age, approximately 25% of men and 16% of women have coronary heart disease, and these figures rise to 37% and 23% among men and women >80 years of age, respectively.
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The incidence of coronary heart disease and angina in women after menopause is similar to that of men.
•

Although the survival rate has steadily improved over time, SIHD remains the number one cause of death in men and women (27% of deaths).
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The initial manifestation of ischemic heart disease is angina pectoris in 50%, and about 50% of patients presenting to the hospital with acute coronary syndrome have preceding angina.
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Two older population-based studies from Olmstead County, MN, and Framingham, MA, showed annual rate of myocardial infarction in patients with symptomatic angina of 3 to 3.5%/year.
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Within 12 months of initial diagnosis, 10% to 20% of patients with diagnosis of stable angina progress to MI or unstable angina.

Physical Findings & Clinical Presentation

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The assessment of chest pain should include quality, location, severity, and duration of pain; radiation; associated symptoms; provocative factors; and alleviating factors. Anginal pain can be described as “squeezing,” “griplike,” “suffocating,” and “heavy,” but it is rarely sharp or stabbing and typically does not vary with position or respiration. The classic Levine’s sign is placing a clenched fist over the precordium to describe the pain. Many patients do not, however, describe angina as frank pain but as tightness, pressure, or discomfort. Other patients, in particular women and older adults, can present with atypical symptoms such as nausea, vomiting, midepigastric discomfort, sharp (atypical) chest pain, dizziness, or syncope.
•

Ischemic pain of more than 20 minutes’ duration should raise concern for possible MI.
•

Women are more likely than men to report atypical chest pain or discomfort (65% reported on Women’s Ischemic Syndrome Evaluation [WISE] study).
•

Elderly and diabetics may report symptoms other than chest pain, such as dyspnea, fatigue, or diaphoresis.

Etiology

Risk Factors

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Advanced age.
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Male sex.
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Genetic predisposition, family history of premature coronary artery disease (CAD) in first-degree relatives (men younger than 55 years of age, and women younger than 65 years of age).
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Smoking (risk of first MI is increased by near threefold).
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Hypertension (risk is double if systolic blood pressure is >180 mm Hg).
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Hyperlipidemia (prevalence remained unchanged from 2002-2008).
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Impaired glucose tolerance or diabetes mellitus (prevalence decreased from 2002-2008).
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History of stroke or peripheral arterial disease.
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Chronic kidney disease (CKD).
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Metabolic syndrome.
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Physical inactivity.
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Obesity (body mass index >30% over ideal). A higher body mass index during childhood is also associated with an increased risk of coronary heart disease (CHD) in adulthood.
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Entities that cause increased oxygen demand include hyperthermia (particularly if accompanied by volume contraction), hyperthyroidism, and cocaine or methamphetamine abuse.
•

Cocaine is used by >5 million Americans regularly and is responsible for >64,000 emergency department (ED) evaluations yearly to rule out myocardial ischemia. Cocaine causes sympathomimetic toxicity and not only increases myocardial oxygen demand but also induces coronary vasospasm and can cause infarction in young patients. Long-term cocaine use can cause premature development of SIHD.
•

Severe uncontrolled hypertension causes increased myocardial oxygen demand and decreased subendocardial perfusion that increases LV wall tension. Hypertrophic cardiomyopathy and aortic stenosis can induce even more severe LV hypertrophy and resultant wall tension.
•

Other causes of increased myocardial oxygen demand are ventricular or supraventricular tachycardias. Ambulatory monitoring may be required to diagnose these.
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Entities that limit myocardial oxygen supply such as anemia may cause angina when the hemoglobin drops to <9 g/dl, and ST-T-wave changes (depression or inversion) can occur at levels <7 g/dl.
•

Hypoxemia resulting from pulmonary disease (e.g., pneumonia, asthma, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial fibrosis, or obstructive sleep apnea) can also precipitate angina.
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Polycythemia, leukemia, thrombocytosis, and hypergammaglobulinemia.
•

Oral contraceptive and HRT use.
•

Coronary artery calcium is associated with an increased risk of MI.
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Long-term use of nonsteroidal antiinflammatory drugs (NSAIDs).
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Exposure to air pollution from traffic (dilute diesel exhaust) promotes myocardial ischemia and is associated with adverse cardiovascular events.
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Low serum folate levels required for conversion of homocysteine to methionine are associated with an increased risk of fatal CHD. Hyperhomocysteinemia has a toxic effect on vascular endothelium and interferes with proliferation of arterial wall smooth muscle cells. Elevated plasma homocysteine level is a strong and independent risk factor for CHD events, especially in patients with type 2 diabetes mellitus.
•

Elevated levels of highly sensitive C-reactive protein (hs-CRP, cardio CRP). Diseases associated with systemic inflammation can lead to accelerated atherosclerosis.
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Depression.
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Vasculitis.
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Elevated levels of lipoprotein-associated phospholipase A₂.
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Elevated fibrinogen levels.
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Low level of red blood cell glutathione peroxidase-1 activity.
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Radiation therapy.

Diagnosis

Differential Diagnosis

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Nonischemic Cardiovascular: Aortic dissection, pericarditis
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Pulmonary: Pulmonary embolism, pneumothorax, pneumonia, pleuritis
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Gastrointestinal: Esophageal, esophagitis, spasm, reflux, biliary colic, cholecystitis, choledocholithiasis, cholangitis, peptic ulcer, pancreatitis
•

Chest Wall: Costochondritis, fibrositis, rib fracture, sternoclavicular arthritis, herpes zoster (before the rash)
•

Psychiatric: Anxiety disorders, hyperventilation, panic disorder, primary anxiety, affective disorders (i.e., depression), somatoform disorders, thought disorders (i.e., fixed delusions)

Workup

•

In patients with chest pain, the probability of CAD should be estimated on the basis of patient age, sex, cardiovascular risk factors, and pain characteristics.
•

The most important diagnostic element is the history. Chest pain or left arm pain or discomfort occurring with exertion and relieved by rest in a patient with cardiovascular risk factors is consistent with a high likelihood of CAD.
•

In assessing the likelihood of underlying SIHD it is helpful to classify the chest pain as typical angina, atypical angina, and/or noncardiac chest pain.
•

Typical angina, (definite) will have the following three features: (1) substernal chest discomfort with a characteristic quality and duration, (2) provoked by exertion or emotional stress, and (3) relieved by rest and/or sublingual nitroglycerin (NTG).
•

Atypical angina, (probable) will have two of the above listed three features.
•

Noncardiac chest pain will have one or none of the previously listed features.
•

Physical examination may be completely normal in many patients; however, certain findings may be helpful in the assessment of the patient with suspected SIHD. Some findings may identify consequences of ischemia or possible causes of the anginal syndrome other than CAD. The presence of hypertension, arcus senilis, xanthelasma, carotid or peripheral bruits, and a prominent S4 are all physical signs that could raise concern for the presence of CAD. A murmur of mitral regurgitation may be a marker of an ischemic cardiomyopathy or transient ischemia. A murmur suggestive of hypertrophic cardiomyopathy or aortic stenosis may suggest a cause of angina other than CAD.

Laboratory Tests

•

Initial laboratory tests in patients with chronic SIHD should include a hemoglobin, fasting glucose, and fasting lipid panel.
•

Cardiovascular screening: Measurement of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and fasting serum triglycerides. Also, measurement of Non–HDL-C, the ratio of total cholesterol to HDL-C, and apolipoprotein fractions (e.g., apolipoprotein B100, apolipoprotein A1).
•

Electrocardiogram should be obtained during pain and when the patient is free of any discomfort. A normal resting electrocardiogram is not unusual in patients with SIHD; in patients who present with chest pain, 1% to 6% who have an acute MI will have a normal or nondiagnostic electrocardiogram.
•

Chest x-ray PA and lateral, to rule out heart failure, valvular disease, pericardial disease, aortic aneurysm/dissection.
•

Cardio-CRP (hs-CRP): Its elevation is a relatively moderate predictor of CHD, and it adds prognostic information to that conveyed by the Framingham risk score.

Exercise Testing and Imaging Studies

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The value of further testing is greatest in patients who have an intermediate risk of CAD (10%-90% pretest likelihood).
•

Exercise testing is used for the purpose of diagnosis as well as prognosis. If the patient is physically capable to perform at least moderate physical exercise, exercise stress testing (Fig. 1) is useful because of the important prognostic information obtained from exercise performance and the hemodynamic response. Patients who have an intermediate risk of CAD, as patients in a low-risk or high-risk category are more likely to have a false-positive or false-negative result, respectively. Risk assessment is also indicated in patients with SIHD who are being considered for revascularization of known coronary stenosis of unclear physiological significance.

FIG.1

Stress test algorithm.

ACS, Acute coronary syndrome; BBB, bundle branch block; DM, diabetes mellitus; ECG, electrocardiogram; echo, echocardiography; ED, emergency department; GTX, graded exercise test; LVH, left ventricular hypertrophy; NSTE, non–ST-segment elevation; NSTEMI, NSTE myocardial infarction; STE, ST-segment elevation; y/o, years old.

From Adams JG et al: Emergency medicine: clinical essentials, ed 2, Philadelphia, 2013, Saunders.
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Stress echocardiography or stress testing with myocardial perfusion imaging may be employed when baseline electrocardiographic abnormalities are present that render the electrocardiographic response to exercise uninterpretable, such as >1 mm ST segment depression, LBBB, preexcitation, paced ventricular rhythm, digoxin treatment with ST segment changes. Stress echocardiography has the advantage of higher specificity and a lower cost. Stress radionuclide perfusion imaging has a higher sensitivity, particularly for single-vessel coronary disease, and has a higher technical success rate. When the patient is unable to exercise adequately, pharmacologic stress testing (i.e., dobutamine, adenosine, regadenoson) may be used with these imaging modalities.
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A good predictor of risk for a patient with stable angina is the Duke treadmill score, which incorporates the patient’s functional status (METS or time in minutes during the Bruce protocol), ST-segment depression in millimeters, and an angina index (yes or no). Patients with favorable Duke scores (>5) have a 5-year survival rate of >97%; this is independent of other factors such as coronary anatomy and LV function.
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Echocardiography is indicated in patients with murmurs suggestive of aortic stenosis, hypertrophic cardiomyopathy, mitral regurgitation, mitral valve prolapse, previous MI, pathological Q waves, complex ventricular arrhythmias, heart failure, hypertension, diabetes, and abnormal EKG.
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Cardiac computed tomography (CCTA; Fig. 2) is useful for the detection of subclinical CAD in asymptomatic patients with an intermediate Framingham 10-year risk estimate of 10% to 20%. Detects and quantifies coronary calcium and evaluates the lumen and wall of the coronary artery. CCTA can be useful as a first-line test for risk assessment in patients with SIHD who are unable to exercise to an adequate workload regardless of interpretability of ECG. Also can be used when a functional test has an indeterminate result and to assess bypass graft patency or patency of previous stents >3 mm diameter. CCTA CT cost and radiation exposure are limiting factors to recommending widespread routine use of this marker.

FIG.2

Example of coronary artery calcium scoring in which calcified foci are identified within the left anterior descending (orange; single arrow) and left circumflex (pink outlined in blue; double arrow) coronary arteries. The region’s area (R-Ar) and its average density in Hounsfield units (R-Av) are displayed and used in the area-density calcium scoring calculation.

From Bonow RO et al: Heart disease, ed 9, Philadelphia, 2012, Saunders.
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Coronary artery calcium (CAC) score is a strong predictor of incidence of CAD and provides predictive information in patients with low to intermediate pretest probability of CAD beyond that provided by standard risk factors. A score below 100 indicates low risk, and a score above 400 high risk.
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Cardiac magnetic resonance imaging (CMRA), in addition to its use for diagnosis of arrhythmogenic right ventricular dysplasia, can also be used to assess myocardial perfusion and viability as well as function in patients unable to exercise. Additional studies are needed to determine the cost effectiveness of these studies in patients with ischemic cardiomyopathy.
•

Invasive coronary angiography remains the gold standard for the identification of clinically significant CAD. Angiography is performed to define the location and extent of coronary disease; indicated in selected patients who are candidates for coronary revascularization (either coronary artery bypass graft [CABG] surgery or angioplasty).

Treatment

Five fundamental overlapping strategies are recommended

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Patient education: Support active participation of patients in the decision-making process of their treatment.
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Management of comorbid conditions that contribute or worsen SIHD.
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Aggressive modification of preventable risk factors such as smoking cessation, weight reduction in obese patients, regular aerobic exercise program (at least 30 to 60 min/day), correction of folate deficiency, reduced intake of saturated fats (to <7% of total calories) and trans fatty acids (to <1% of total calories), low-sodium diet (<2 g/day), and teaching importance of medication adherence. Whole grains as the main form of carbohydrates, an abundance of fruits and vegetables, and adequate omega-3 fatty acids are optimal for prevention of SIHD.
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Evidence-based pharmacologic management to improve quality of life and survival.
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Use appropriate revascularization procedures to improve survival and long-term outcomes in selected patients.

Pharmacologic Therapy

Treatment can be classified based on medications that prevent MI and death.

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Aspirin reduces cardiovascular mortality and morbidity rates by 20% to 25% among patients with CAD. Appropriate dose is 75 to 162 mg/day in the absence of contraindications. It inhibits the enzyme cyclooxygenase and synthesis of thromboxane A2 and reduces the risk of adverse cardiovascular events by 33% in patients with unstable angina. Patients intolerant to aspirin can be treated with other antiplatelet agents (see below).
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Clopidogrel irreversibly blocks the P2Y12 adenosine diphosphate receptor on the platelet surface, thereby interrupting platelet activation and aggregation. Clopidogrel can be combined with ASA in high-risk patients with SIHD or can be given alone in patients that are aspirin intolerant. Dose is 75 mg/day. The combination of aspirin and clopidogrel increases bleeding risk, and long-term use is controversial.
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Ticagrelor, the newest CTPT inhibitor (P2Y12 antagonist), in the Pegasus-TIMI-54 reduced the risk of death, cardiovascular MI, or stroke in patients after 1 year of MI. However, it is associated with an increased risk of bleeding when compared to placebo.
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Dipyridamole is not recommended as an antiplatelet therapy for the treatment of patients with SIHD.
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Beta-adrenergic blockers, which prevent MI and death, are first-line therapy in the management of angina pectoris. They achieve their major antianginal effect by decreasing myocardial oxygen demand in reducing heart rate and systolic blood pressure product, AV nodal conduction, and myocardial contractility, in this manner contributing to a reduction in angina onset, with improvement in the ischemic threshold during exercise and during the usual daily activities. Absent contraindications, they should be regarded as initial therapy for stable angina for all patients. Their dose should generally be adjusted to reduce the resting heart rate to 55 to 60 beats/min. Despite the difference among the available beta blockers, they all seem to be equally efficacious in SIHD.
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Nitrates cause venodilation and relaxation of vascular smooth muscle; the decreased venous return from venodilation decreases diastolic ventricular wall tension (preload) and thereby reduces mechanical activity (and myocardial oxygen consumption) during systole. Relaxation of vascular smooth muscle increases coronary blood flow and reduces systemic pressure. Dilatation of the arterial wall will not be affected by plaque, but independent of an intact endothelium, leads to reduced resistance across the obstructed lumen. Nitroglycerin contributes to coronary blood flow redistribution by augmenting collateral flow and lowering ventricular diastolic pressure from areas of normal perfusion to ischemic zones. Nitroglycerin also has demonstrated antithrombotic and antiplatelet effects. Sublingual nitroglycerin or nitroglycerin spray should be prescribed to all patients with SIHD for immediate angina relief. Tolerance to nitrates can be minimized by avoiding sustained blood levels with a daily nitrate-free period (e.g., omission of bedtime dose of oral isosorbide dinitrate or 12 hr on/12 hr off transdermal nitroglycerin therapy). Nitrates are relatively contraindicated in patients with hypertrophic obstructive cardiomyopathy, and should also be avoided in patients with severe aortic stenosis. Nitrates should not be used within 24 hr of sildenafil (Viagra) or vardenafil (Levitra) or within 48 hr of tadalafil (Cialis) because of the potential for hypotension.
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Calcium channel blockers are antiischemic medications that have no proven mortality benefit in SIHD. They improve myocardial oxygen supply by decreasing coronary vascular resistance and augmenting epicardial conduit vessel and systemic arterial blood flow. Myocardial demand is decreased by a reduction in myocardial contractility, systemic vascular resistance, and arterial pressure. They are first-line treatment when beta-blockers are contraindicated. They play a major role in preventing and terminating myocardial ischemia induced by coronary artery spasm. They are particularly effective in treating microvascular angina. All classes of calcium channel blockers reduce anginal episodes, increase exercise duration, and reduce use of sublingual nitroglycerin in patients with effort-induced angina. Short-acting calcium channel blockers should be avoided. Calcium channel blockers (particularly non-dihydropyridine) should generally also be avoided in patients with CHF secondary to systolic dysfunction due to its negative inotropic effect.
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Ranolazine, which has been tested in four different studies with a total of 1737 patients (MARISA, CARISA, RAN080, and ERICA), inhibits the late inward sodium current, indirectly reducing the sodium-dependent calcium current during ischemic conditions and leading to improvement in ventricular diastolic tension and oxygen consumption. It seems to increase the efficiency of energy production in the heart, maintaining cardiac function. Its antianginal and antiischemic effects do not depend on reductions in heart rate or blood pressure. It is indicated for treatment of chronic angina that is inadequately controlled with other antianginals. It represents a new class of drugs known as metabolic modulators and can be useful when prescribed as substitute for beta-blockers or in combination with them for relief of symptoms when initial treatment with beta-blockers is not successful or is contraindicated. Side effects include prolongation of QT interval. Low doses of diltiazem and verapamil should be used with ranolazine. The extended-release preparation reduces the frequency of angina, improves exercise performance, and delays the development of exercise-induced angina and ST-segment depression.
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Angiotensin-converting enzyme (ACE) inhibition through changes in the physiologic balance between angiotensin II and bradykinin could contribute to the reductions in LV and vascular hypertrophy, atherosclerosis progression, plaque rupture, and thrombosis; the favorable changes in cardiac hemodynamics; and the improved myocardial oxygen supply/demand. It has been shown to be effective in reducing cardiovascular death, MI, and stroke in patients who are at risk for or who had vascular disease. They are indicated in patients with hypertension, diabetes, LVEF <40%, and CKD. Angiotensin receptor blockers (ARBs) can be given to patients with SIHD who are intolerant to ACEI and qualify for them.
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Use of high-intensity statin drugs is recommended in all patients with CAD. Among patients who have recently had an acute coronary syndrome, an intensive lipid-lowering statin regimen to reduce LDL cholesterol to <70 mg/dl is a reasonable treatment objective. Statins also decrease the level of the inflammatory marker hs-CRP independently of the magnitude of change in lipid parameters.
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Influenza vaccine is recommended for patients with SIHD on annual basis to prevent all-cause mortality, morbidity, and hospitalization caused by the exacerbation of underlying medical conditions produced by influenza.

New Modalities for the Treatment of Chronic Stable Angina Pectoris

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Although a significant amount of progress has been made in the management of CAD with percutaneous coronary intervention (PCI) and CABG, many patients with the condition require additional therapeutic modalities for relief of symptoms and improvement in quality of life. This group of patients includes those with diffuse CAD who are not suitable for revascularization, patients with previous multiple PCIs or CABG limiting the chances for further revascularization, the lack of vascular conduits for CABG, severe left ventricular systolic dysfunction in patients with previous CABG or PCI, and comorbidities that would render the patients at high risk for revascularization.
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The following pharmacologic agents have been used for the management of stable angina in combination with the standard protocol of nitrates, beta-blockers, calcium channel blockers, and ranolazine: high-dose statin therapy, trimetazidine, perhexiline, nicorandil, allopurinol, ivabradine, fasudil, and testosterone.
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Other, nonpharmacologic modalities that are highly experimental include stem cell therapy, therapeutic angiogenesis, and mechanical therapies like external counterpulsation, spinal cord stimulation, transmyocardial laser revascularization, and coronary sinus reducing device.
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Allopurinol, a xanthine oxidase inhibitor, was shown to reduce myocardial oxygen demand per unit of cardiac output in patients with heart failure in a small crossover study of 65 patients given 600 mg of allopurinol daily for 6 weeks. Allopurinol increased the median time to ST depression from 232 seconds at baseline to 393 seconds. Further and larger studies are necessary to recommend allopurinol as an adjunctive therapy for stable angina.
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Testosterone improves endothelial dysfunction and may be an effective antiangina agent. However, given the potential side effects, additional trials are necessary to recommend testosterone as an adjunctive drug for chronic angina.

The value of enhanced external counterpulsation, or EECP, was assessed with the MUST-EECP trial, which randomly assigned 139 outpatients with angina, documented CAD, and a positive stress test to 35 hours of active EECP. The results indicated the following regarding EECP: (1) was well tolerated; (2) exercise duration increased in both groups; (3) active EECP patients had a significant increase in time to 1-mm ST-segment depression, while there was no change in the inactive group; (4) more patients undergoing active EECP had a decrease in angina episodes, and fewer had an increase in angina symptoms compared with the active group. These data corroborate similar data from multicenter registries. The American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American Thoracic Society, and Society of Thoracic Surgeons focused update states that EECP may be considered for relief of refractory angina.

The following treatments have NOT been shown to be beneficial in reducing cardiovascular risk or improving clinical outcomes: estrogen therapy, vitamin C, vitamin E, and beta-carotene supplementation; treatment of elevated homocysteine with folate or vitamins B₆ and B₁₂; chelation therapy; garlic; coenzyme Q10; selenium; and chromium.

Referral

Revascularization:

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Revascularization methods should be formulated taking into consideration improved survival or improved symptoms. Revascularization includes either percutaneous coronary intervention (balloon angioplasty and stenting) or CABG. However, note that although the role of PCI is unquestionable in the presence of an acute myocardial infarction, its role is not so clear in stable CAD. The utilization of PCI for stable CAD was reduced by 51.7% from 2007 to 2011, and hospitals with higher volumes of PCI had the largest reduction of these procedures.
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To improve survival:
1. 1.
  
  Perform CABG for patients with significant (>50% diameter stenosis) left main coronary artery stenosis, more than 70% diameter stenosis in proximal left anterior descending artery (LAD), or more than 70% diameter stenosis in three major epicardial vessels, >70% diameter stenosis in two major coronary arteries with severe or extensive myocardial ischemia, and in patients with mild to moderate LV systolic dysfunction (EF 35% to 50%) and significant multivessel CAD. Left internal mammary artery (LIMA) graft improves survival when used to bypass a proximal LAD artery stenosis. CABG is recommended in preference to PCI to improve survival in patients with multivessel CAD and diabetes, particularly if a LIMA graft to LAD is used.
2. 2.
  
  PCI is reasonable as an alternative to CABG in selected stable patients with unprotected left main CAD, low risk of PCI procedural complications, and a high likelihood of good long-term outcome and clinical characteristics that predict a significantly increased risk of adverse surgical outcomes (e.g., STS-predicted risk of operative mortality >5).
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To improve symptoms:
1. 1.
  
  CABG or PCI to improve symptoms is beneficial in patients with one or more significant (>70% diameter) coronary artery stenosis amenable to revascularization and unacceptable angina despite maximal medical treatment, or in whom increasing medical therapy cannot be implemented because of medication contraindications, adverse effects, or patient preferences.
2. 2.
  
  Hybrid coronary revascularization: LIMA-to-LAD artery grafting and of >1 non-LAD coronary artery can be used in patients who have an unfavorable aorta, have poor target vessels for CABG, have unsuitable graft conduits, or have unfavorable LAD for PCI.
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Compared with percutaneous coronary intervention (PCI), CABG is more effective in relieving angina and leads to fewer repeated revascularizations but has a higher risk for procedural stroke. Survival to 10 years is similar for both procedures.
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Angioplasty and coronary stents (Fig. E3).

FIG.E3

Coronary angioplasty procedure.

A, Critical stenosis in midsegment of a right coronary artery. B, Inflation of a 3.5-mm-diameter angioplasty balloon. C, Angiographic control after balloon inflation. D, Placement of a 3.5-mm-diameter, 18-mm-long metal stent. E, Inflation of the balloon. F, Final result.

From Vincent JL et al: *Textbook of critical care,* ed 6, Philadelphia, 2011, Saunders.

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PCI has an established place in treating angina but is not superior to intensive medical therapy to prevent MI and death in symptomatic or asymptomatic patients. Patients selected for PCI should also be candidates for CABG. Approximately 80% of patients show immediate benefit after PCI. The development of coronary stents has increased the number of patients who can be treated in the cardiac laboratory. Cardiac stents (Fig. E4) are currently used in nearly 95% of all patients with PCI lesions. The rate of restenosis is reduced by placing a stent electively in primary atheromatous lesions. The major limitations of stenting are subacute thrombosis, restenosis within the stent, bleeding complications when antiplatelets are used after stenting, and higher cost. The combination of aspirin and P2Y12 antagonists is effective in preventing coronary stent thrombosis and the duration of therapy depends on whether bare metal stents (BMS) or drug-eluting stents (DES) are used. Duration of dual antiplatelet therapy can be as short as 4 weeks for BMS, but 12 months of therapy is generally required for DES. This difference in duration is due to the lack of endothelium proliferation in DES initially. New drug-eluting stents with thin struts releasing Limus-family analogs from durable polymers have lowered the risk of stent thrombosis compared with early-generation stents releasing sirolimus or paclitaxel. Current evidence supports the use of drug-eluting stents in most clinical settings without safety concerns (unless there are contraindications to use of dual antiplatelet therapy). Recent data has shown that extending clopidogrel therapy beyond 6 months after stent placement does not reduce death or ischemic events, and it increases the risk of bleeding complications.

FIG.E4

Implantation of a coronary stent.

A, Placement of balloon catheter. B, Predilation

Pearls & Considerations

Comments

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Although nitrate responsiveness is usually an integral part of a diagnostic strategy for SIHD, recent reports question its value and conclude that in a general population admitted for chest pain, relief of pain after nitroglycerin treatment does not predict active CAD and should not be used to guide diagnosis in the acute care setting.
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CABG is associated with higher long-term survival rates and lower rates of repeat revascularization than PCI and stenting; however, patients often prefer stenting because it is less invasive, involves a shorter hospital stay, and has a lower in-hospital mortality rate.

Ferri – Angina Pectoris