History

• Most commonly reported symptom is chest pain that is typically associated with exertion or emotional stress ^c1c2
  • Characteristically described as a retrosternal chest pain, tightness, heaviness, or pressure ^c3c4c5c6
    • Pain may radiate to the left arm or shoulder, the lower jaw and teeth, the back between the shoulder blades, or the epigastrium ^{c7c8c9c10c11c12c13}
    • May be associated with symptoms such as pain, squeezing, or pressure in the arm, neck, or jaw ^c14c15c16c17
  • Chest pain may be accompanied by shortness of breath or nonspecific symptoms (eg, fatigue, syncope, nausea, vomiting, restlessness, a sense of impending doom) ^{r7c18c19c20c21c22c23c24}
    • These nonspecific symptoms in the absence of classic chest pain symptoms may represent anginal equivalents
  • Common precipitants include walking a certain distance (variable), stair climbing, emotional distress, sexual activity, heavy meal, exposure to cold, or waking up in the morning ^c25
    • Symptoms appear or become more severe with increased levels of exertion ^r7
    • Angina threshold may vary from day to day and even during the same day
  • Onset is gradual with increasing intensity over several minutes ^c26
  • Duration of discomfort is brief; less than 10 minutes in most cases ^r7c27
    • Resolves quickly (usually within 5 minutes) with rest or administration of nitroglycerin
    • May be reduced with further exercise (walk-through angina) or on subsequent exertion (warm-up angina)
• Note any history of prior episodes of chest pain or risk factors for or known coronary artery disease ^c28c29c30
• Any change in pattern of usual chest pain symptoms, level of exertion required to elicit anginal symptoms, or response to medications used may indicate disease progression

Physical examination

• Physical examination findings may be unremarkable, particularly if patient is asymptomatic at the time ^c31
• Signs of associated conditions may be present, such as:
  • Anemia ^c32
  • Hypertension ^c33
  • Decreased peripheral pulses ^c34
  • Carotid, femoral, or renal artery bruits ^c35c36c37
  • Elevated jugular vein pressure ^c38
  • Xanthelasma or xanthoma ^c39
  • Arrhythmia ^c40
  • Obesity ^c41
  • Peripheral edema ^c42
  • Pulmonary rales ^c43
• Cardiac examination findings are often normal ^c44
  • Signs of underlying cardiac disease may be present (eg, cardiac enlargement or murmur) ^c45c46
  • During or immediately after an episode of myocardial ischemia, a third (S₃) or fourth (S₄) heart sound may be heard. A systolic murmur of mitral insufficiency may be apparent; however, these signs are rare and nonspecific ^r3c47c48c49
• Palpation of the chest does not typically reproduce symptoms.^r3Reproducible chest wall pain suggests a musculoskeletal cause^r5c50

Causes

Risk factors and/or associations

Primary diagnostic tools

• Diagnosis is based on history, physical examination, 12-lead ECG, measurement of serum biochemical markers, and noninvasive testing ^c118
• Obtain detailed history regarding location, character, and duration of chest pain; its relationship to exertion and other exacerbating or relieving factors; and presence of cardiovascular risk factors ^r5r7
• Obtain resting ECG in all patients at presentation ^r8c119
• Laboratory tests should be obtained to identify possible causes of ischemia, cardiovascular risk factors, and associated conditions, as well as to determine prognosis ^r7
  • CBC, fasting blood glucose level, hemoglobin A1C level, fasting lipid profile, and baseline renal function tests ^c120c121c122
  • Thyroid function tests, if clinically suspicious for thyroid disease ^c123
  • Cardiac-specific troponin (T or I) levels, if there is concern for unstable angina (eg, prolonged periods of angina, angina at rest, new-onset moderate to severe angina) or if previously stable ischemic heart disease with rapidly increasing or crescendo angina is suspected ^c124
    • If troponin level is elevated, proceed with management for non–ST segment elevation acute coronary syndrome ^d1
  • Brain natriuretic peptide/N-terminal pro–B-type natriuretic peptide in patients with suspected heart failure
• Chest radiography is not routinely indicated in initial work-up as it does not provide specific diagnostic or prognostic information ^c125
  • Occasionally useful for assessing patients with suspected heart failure or comorbid pulmonary disease, or to exclude another cause of chest pain in atypical presentations
• Echocardiography is recommended in most patients to exclude alternative causes of angina, identify regional wall motion abnormalities suggestive of coronary artery disease, measure left ventricular ejection fraction for risk stratification purposes, evaluate diastolic function, and assess for valvular disease ^r7
• In patients without a known history of ischemic heart disease, proceed with risk stratification to determine whether pretest probability of ischemic heart disease is sufficient to recommend further testing ^r5
  • Predictive models have been developed for this purpose based on historic and demographic patient features

    • Pretest likelihood of coronary artery disease in symptomatic patients.

      Table shows a combination of Diamond-Forrester and Coronary Artery Surgery Study (CASS) data. The values represent the percentage of patients with significant coronary artery disease on catheterization.

      Data from Fihn et al: 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation. 126(25):e354-471, 2012; Diamond GA et al: Analysis of probability as an aid in the clinical diagnosis of coronary-artery disease. N Engl J Med. 300:1350-8, 1979; and Chaitman BR et al: Angiographic prevalence of high-risk coronary artery disease in patient subsets (CASS). Circulation. 64:360-7, 1981.

      Age (y)	Nonanginal chest pain: men (%)	Nonanginal chest pain: women (%)	Atypical angina: men (%)	Atypical angina: women (%)	Typical angina: men (%)	Typical angina: women (%)
      30 to 39	4	2	34	12	76	26
      40 to 49	13	3	51	22	87	55
      50 to 59	20	7	65	31	93	73
      60 to 69	27	14	72	51	94	86

  • Consultation with a cardiologist is recommended to determine pretest risk probability
  • Further testing is most useful in patients for whom the cause of chest pain is truly uncertain; that is, pretest probability of ischemic heart disease is intermediate (variably defined as a probability of ischemic heart disease between 20% and 70% or 15% and 85%^r3) ^r5
  • Other factors may be involved in the decision to refer a patient for further testing, such as degree of uncertainty acceptable to physician and patient, likelihood of alternative diagnosis, cost, potential risks of further testing, and benefits and risks of treatment in the absence of additional testing ^r5
• If pretest probability of ischemic heart disease is intermediate or greater, consider noninvasive testing (eg, exercise ECG testing, pharmacologic or exercise imaging stress testing)
  • European guidelines recommend the use of either noninvasive functional imaging or anatomical imaging (cardiac CT angiography) as the initial test for diagnosing coronary artery disease; exercise ECG may be considered if imaging tests are not available ^r7
• For patients with a low to intermediate pretest probability (variably defined as less than 10% or less than 20%) of obstructive ischemic heart disease, consider cardiac CT angiography; stress testing is less likely to be indicated
• Coronary angiography is the gold standard for evaluating the presence of coronary artery disease; however, this invasive procedure is not routinely indicated to establish a diagnosis of ischemic heart disease in patients with stable angina ^r7
  • Early angiography without previous noninvasive testing may be indicated in patients who have a high pretest probability of ischemic heart disease and: ^r7
    • Symptoms that are severe, unresponsive to medical therapy, or occur at a low level of exercise, or
    • Clinical evaluation suggesting high risk for a cardiac event
  • May have a role in patients with reduced left ventricular ejection fraction less than 50% and typical angina, in those who cannot undergo stress imaging techniques, or people in certain professions, such as pilots (regulatory requirement)
  • Indicated after risk stratification with noninvasive testing to determine options for revascularization if noninvasive testing suggests presence of high-risk coronary lesions and if a revascularization procedure is reasonable based on patient comorbidities and preferences ^r5
• Fractional flow reserve, which may be measured as part of coronary angiography or derived via CT angiography, may be used to determine need for percutaneous coronary intervention by measuring pressure difference across stenosis to assess hemodynamic significance ^r9

Imaging

• Echocardiography ^c126c127
  • A resting transthoracic echocardiogram is recommended in all patients to exclude alternative causes of angina, identify regional wall motion abnormalities suggestive of coronary artery disease, measure left ventricular ejection fraction for risk stratification purposes, evaluate diastolic function, and evaluate presence of significant valvular disease ^r7
    • Consider in patients with a cardiac murmur on examination, previous myocardial infarction, or symptoms/signs of heart failure
    • May be omitted in very young and healthy patients with a high suspicion of an extracardiac cause of chest pain and in multimorbid patients in whom the result of echocardiography will not influence patient management
• Noninvasive functional imaging tests
  • Stress test with functional imaging is superior to conventional exercise ECG testing owing to its increased sensitivity in detecting obstructive coronary disease, its ability to quantify and localize areas of ischemia, and its ability to provide diagnostic information in the presence of an abnormal baseline resting electrocardiogram ^r7
  • Recommended as the initial test in patients with intermediate to high pretest probability of ischemic heart disease and in patients without typical angina symptoms who have a left ventricular ejection fraction less than 50%, if local expertise and availability permit ^r5r7
    • Also recommended in patients with abnormal baseline ECG findings that prevent accurate interpretation of ECG changes during stress ECG testing
    • Consider in symptomatic patients with previous percutaneous coronary intervention or coronary artery bypass grafting, particularly if evaluating for changes over time in size and location of ischemia
    • Screen patients of childbearing age for possibility of pregnancy or breastfeeding status when considering any testing modality involving possible radiation exposure
  • Exercise stress testing is recommended over pharmacologic testing when possible as it provides a physiologic environment and provides additional physiologic data (ie, exercise time, workload achieved) as well as information about changes in heart rate, blood pressure, and ECG results ^r3
  • Stress imaging using a pharmacologic stress agent (eg, adenosine, dipyridamole, dobutamine, regadenoson) can be performed in patients who have an inadequate ability to exercise
  • Stress imaging modalities ^r3
    • Exercise stress echocardiography ^c128
    • Exercise stress myocardial perfusion imaging (with single photon emission CT) ^c129
    • Dobutamine stress echocardiography ^c130c131
    • Dobutamine stress MRI ^c132c133
    • Vasodilator stress echocardiography ^c134
    • Vasodilator stress myocardial perfusion imaging (with single photon emission CT) ^c135
    • Vasodilator stress MRI ^c136
    • Vasodilator stress myocardial perfusion PET scan ^c137
• Cardiac CT angiography and coronary artery calcium scoring ^c138c139c140
  • Consider CT angiography as an alternative to stress imaging techniques for ruling out ischemic heart disease in patients with low to intermediate pretest probability for ischemic heart disease in whom good image quality can be anticipated ^r5r7
    • Also consider in patients with an inconclusive exercise ECG or stress imaging test result, those having continued symptoms despite normal exercise ECG findings or stress imaging test results, those with contraindications to stress testing, or those patients who should avoid invasive coronary angiography owing to increased risk ^r5r7
    • Prescreening is recommended to confirm patients have adequate breath-holding capabilities, have a favorable calcium score and distribution, are not severely obese, and are preferably in sinus rhythm with a heart rate of 65 beats per minute or less (preferably 60 beats per minute or less) ^r7
    • Cardiac CT angiography techniques and modeling may be used as noninvasive means to derive fractional flow reserve and determine if coronary artery stenosis is hemodynamically significant ^r10
  • CT also provides measurement of coronary artery calcium score; however, this is not recommended as a standalone test to evaluate ischemia in symptomatic patients
    • Calcium score correlates roughly to total amount of atherosclerosis present in coronary arteries ^r3
    • Correlation with actual extent of luminal narrowing, or stenosis, is poor
    • A "zero" calcium score does not rule out coronary artery stenosis in symptomatic patients

Functional testing

• ECG ^c141
  • A 12-lead ECG is recommended in all patients presenting with symptoms of chest pain concerning for angina or possible anginal equivalent ^r7
  • Establishes baseline for comparison and has a role in risk stratification
  • Resting ECG findings may be normal, even in patients with a history of severe angina, and do not rule out a diagnosis of ischemia
  • Note findings consistent with ischemic heart disease (eg, prior myocardial infarction, abnormal repolarization pattern)
    • Presence of Q waves, chronic ST segment depression (or other ST-T–wave abnormalities), or poor R-wave progression in the precordial leads may suggest prior myocardial infarction ^r5
  • Dynamic ST segment changes may be present in the setting of active chest pain due to ischemia
  • Can be diagnostic in patients with coronary vasospasm if characteristic transient ST segment changes are noted at the time of chest pain event and resolve with resolution of pain
  • Associated ECG abnormalities include left ventricular hypertrophy, left or right bundle branch block, preexcitation, arrhythmias, or conduction defects
• Exercise stress testing ^c142
  • Exercise ECG is recommended as an alternative to noninvasive imaging tests for establishing a diagnosis in patients with angina symptoms and intermediate pretest probability of coronary artery disease who are able to exercise and have no abnormalities on resting ECG ^r7
    • Preferred modality; provides additional information about symptoms, heart rate and blood pressure response, presence of arrhythmias, exercise tolerance, and workload achieved, all of which have both diagnostic and prognostic relevance ^r7
    • Can be used when noninvasive imaging tests are unavailable
    • Less sensitive and specific in female patients ^r3
    • Performed on treadmill or bicycle using 12-lead ECG monitoring
    • An ECG exercise stress test is considered positive for ischemia when there is greater than or equal to 1 mm (0.1 mV) of horizontal or down-sloping ST segment depression, persisting for at least 0.06 to 0.08 seconds after the J point, in 1 or more ECG leads ^r3r8r11
    • Inconclusive results can be followed up using alternative stress testing with noninvasive imaging ^r3
    • Nondiagnostic in patients with resting ECG abnormalities that prevent interpretation of ST segment changes during stress ^r7
    • Contraindications to exercise stress testing: ^r12
      • Inability to exercise
      • Ongoing unstable angina
      • Recent (acute) myocardial infarction (less than 48 hours)
      • Decompensated heart failure
      • Acute myocarditis/pericarditis
      • Acute aortic dissection
      • Active endocarditis

Procedures

Other diagnostic tools

• Risk stratification ^r7c145
  • Identifies patients at high risk for cardiovascular death and myocardial infarction who will benefit from revascularization
  • Conducted in a stepwise fashion based on clinical evaluation, assessment of ventricular function, results of noninvasive testing, and delineation of coronary anatomy
  • Ventricular function
    • Cardiovascular mortality increases as left ventricular ejection fraction declines
      • Left ventricular ejection fraction less than 50% is associated with high risk for cardiovascular death (annual mortality greater than 3%), even without accounting for additional event risk factors ^r3
  • Exercise stress ECG
    • Duke Treadmill Score combines duration of exercise, severity of ST segment depression or elevation, and development of angina to stratify patients into risk groups ^r16
      • High risk: cardiovascular mortality greater than 3% per year
      • Intermediate risk: cardiovascular mortality from 1% to 3% per year
      • Low risk: cardiovascular mortality less than 1% per year
  • Cardiovascular imaging findings
    • High risk: ^r7
      • Area of ischemia greater than 10% on single photon emission CT scan
      • 2 or more segments out of 16 with new perfusion defects or 3 or more dobutamine-induced dysfunctional segments on cardiac MRI
      • 3 or more segments of left ventricle with stress-induced hypokinesia or akinesia on stress echocardiography
    • Intermediate risk: area of ischemia from 1% to 10% or any ischemia less than high risk by cardiovascular magnetic resonance or stress echocardiogram ^r17
    • Low risk: no ischemia
  • Coronary CT angiography findings ^r18
    • High risk: significant high-risk lesions (ie, 3-vessel disease with proximal stenosis, left main disease, proximal anterior descending disease)
    • Intermediate risk: significant lesions in large and proximal coronary arteries but not high-risk category
    • Low risk: normal coronary artery or plaques only
  • Invasive coronary angiography findings ^r11
    • Classified into 1-, 2-, or 3-vessel or left main coronary artery disease on basis of angiography
      • Probability of survival declines progressively with increased number of occluded coronary arteries and presence of severe proximal left anterior descending coronary artery disease ^r11

Most common

• Cardiovascular conditions
  • Acute coronary syndromes ^d1
    • Include unstable or crescendo angina, non–ST elevation myocardial infarction, and ST elevation myocardial infarction ^c146c147c148
      • Typically present as retrosternal chest pain that may radiate to arms, neck, or lower jaw; may be accompanied by dyspnea, diaphoresis, nausea, syncope, or fatigue
    • Diagnosis is based on history, physical examination, ECG findings, and serum cardiac troponin levels
      • Consider acute coronary syndrome in patients presenting with anginal pain lasting more than 15 minutes ^r4
      • New ST segment elevation at the J point in 2 contiguous leads, persisting for 20 minutes or longer, suggests ST elevation myocardial infarction and is a medical emergency ^r19
      • New horizontal or down-sloping ST segment depression and T wave changes suggest non–ST elevation acute coronary syndrome
      • Unstable or crescendo angina lacks the ECG and biochemical evidence for acute myocardial necrosis but has at least 1 of the following features:
        • Occurs at rest or with minimal exertion
        • Lasts at least 20 minutes if not treated with nitroglycerin
        • Severe and new onset (within the past month)
        • Occurs in a crescendo pattern that has progressed and is more severe, prolonged, or frequent than before
  • Pulmonary embolism ^c149d2
    • Sudden obstruction of a portion of the pulmonary arterial vasculature, usually by embolization of a lower extremity or pelvic thrombus
    • Presents with chest pain, dyspnea, tachypnea, and hypoxia. Tachycardia and ST abnormalities on ECG, as well as an elevated cardiac troponin level, may be present
    • Chest pain is usually pleuritic; dyspnea is usually prominent and may be overwhelming; edema, tenderness, or a palpable "cord" may be present in 1 or both lower extremities, which should raise suspicion for deep vein thrombosis
    • Multidetector-row CT angiography is diagnostic for pulmonary embolism; identifies thrombus or thrombi in pulmonary vessels
  • Thoracic aortic dissection ^c150
    • Presents with sudden, severe chest pain that may radiate to the back. May be associated with hypotension or diaphoresis; nonspecific ECG changes and elevated cardiac troponin levels may be present
    • Pain may be characterized as tearing or ripping
    • A murmur of aortic insufficiency may be audible when the dissection extends into the aortic root; brachial or radial pulses may be asymmetrical
    • CT with contrast enhancement is diagnostic for thoracic aortic dissection. Alternate imaging modalities include MRI and transesophageal echocardiogram
  • Pericarditis (acute) ^c151d3
    • Inflammation of the pericardium with or without pericardial effusion
    • Typically presents as pleuritic precordial or retrosternal pain that may radiate to the back, neck, left shoulder, or arm
    • ECG often shows PR segment depression and diffuse ST segment elevation; troponin levels may be elevated
    • Pain is worse on inspiration, when supine, during swallowing, and during movement; pain is improved when seated and leaning forward
    • A pericardial friction rub is sometimes heard on auscultation
    • Echocardiography is the initial diagnostic study of choice, frequently demonstrating pericardial effusion with or without pericardial thickening
• Noncardiac conditions
  • Cholecystitis (acute) ^c152d4
    • Inflammation of the gallbladder; most commonly resulting from obstruction of cystic duct by an impacted gallstone
    • Presents with epigastric pain that may be poorly localized at first, mimicking anginal pain
    • Nausea and vomiting are often prominent, and there is tenderness to palpation in the right upper quadrant
    • Right upper quadrant ultrasonography is usually diagnostic, showing an inflamed gallbladder; stones and ductal dilation may be evident
  • Pancreatitis (acute) ^c153d5
    • Sudden onset of pancreatic parenchymal inflammation with a disease course that can range from mild to severe
    • Presents with epigastric pain, often with radiation to the back; pain may be severe
    • Tenderness to palpation of the upper abdomen, sometimes with rebound tenderness
    • Abdominal CT or ultrasonography shows inflammation of pancreas; lipase and amylase levels are elevated
  • Peptic ulcer disease ^c154d6
    • Development of ulcerations in the stomach or duodenum owing to an imbalance between mucosal protective factors and various mucosal-damaging mechanisms
    • Presents with recurrent chest or epigastric pain
    • Pain is rarely related to exertion and may be improved by eating
    • May have tenderness to palpation of the upper abdomen
    • Diagnosis is confirmed on upper gastrointestinal endoscopy
  • Esophageal spasm ^c155
    • May present with epigastric pain or tightness, which may be relieved by sublingual nitroglycerin
    • May be precipitated by swallowing; associated with dysphagia
    • Pain is rarely related to exertion
    • Sublingual nitroglycerin and certain calcium channel blockers used to treat angina can occasionally alleviate pain due to esophageal reflux or spasm
    • Diagnosis is confirmed by manometry, which reveals premature rapid contractions, or by appearance of "corkscrew" esophagus on barium swallow
  • Costochondritis ^c156
    • Inflammation of costochondral junctions of ribs or chondrosternal joints
    • May present with severe pain in the sternal area
    • Characterized by exacerbation with chest motion (eg, respiration, rotation of the torso)
    • Differentiated by characteristic exacerbation with physical maneuvers and absence of ECG abnormalities

Admission criteria

Patients with symptoms suggestive of acute coronary syndrome with or without diagnostic ECG changes or elevated troponin levels

Patients with chest pain associated with hemodynamic instability or congestive heart failure

Recommendations for specialist referral

• Consult with cardiologist for patients with symptoms suggestive of myocardial ischemia or abnormal functional testing results ^r4

Drug therapy

• Rapid-acting nitrates ^r11
  • Nitroglycerin sublingual tablets ^c157
    • Nitroglycerin Sublingual tablet; Adults: 300 to 600 mcg SL 5 to 10 minutes before participating in activities that may precipitate an acute attack or at the onset of an attack; may repeat dose every 5 minutes as needed. Max: 3 tablets/15-minute period. If chest pain persists after 3 tablets in a 15-minute period, prompt medical attention should be sought.
  • Nitroglycerin spray ^c158
    • Nitroglycerin Sublingual/Translingual spray; Adults: 400 or 800 mcg on or under the tongue 5 to 10 minutes before participating in activities that may precipitate an acute attack or at the onset of an attack; may repeat 400 mcg every 5 minutes as needed. Max: 1,200 mcg/15-minute period. If chest pain persists after 1,200 mcg in a 15-minute period, prompt medical attention should be sought.
• Short-acting nitrates
  • Isosorbide dinitrate ^c159
    • Isosorbide Dinitrate Oral tablet; Adults: 5 to 20 mg PO 2 to 3 times daily, initially. Increase dose as needed. Usual dose: 10 to 40 mg PO 2 to 3 times daily. Dose range: 10 to 480 mg/day. A daily dose-free interval of 14 hours or more is recommended to minimize tolerance.
  • Nitroglycerin topical ointment (2%) ^c160
    • Nitroglycerin Topical ointment; Adults: 7.5 mg (0.5 inch) topically twice daily every 6 hours, initially. May double dose in persons tolerating but failing to respond. Max: 30 mg/dose.
• Long-acting nitrates ^r11
  • Isosorbide mononitrate ^c161
    • Immediate release
      • Isosorbide Mononitrate Oral tablet; Adults: 20 mg PO twice daily, initially, with doses given 7 hours apart. May consider 5 mg PO twice daily, initially, in persons with small stature; increase dose to at least 10 mg PO twice daily by day 2 to 3.
    • Extended release
      • Isosorbide Mononitrate Oral tablet, extended-release; Adults: 30 or 60 mg PO once daily, initially. May increase dose to 120 mg PO once daily after several days. Max: 240 mg/day, rarely needed.
  • Transdermal patch ^c162
    • Nitroglycerin Transdermal patch - 24 hour; Adults: 0.2 to 0.4 mg/hour transdermally for 12 to 14 hours daily with a 10 to 12 hours daily patch-off period, initially. Adjust dose based on symptoms and adverse effects. Dose range: 0.1 to 0.8 mg/hour.
• β-blockers ^r11
  • Bisoprolol ^c163
    • Bisoprolol Fumarate Oral tablet; Adults: 5 to 20 mg PO once daily.
  • Carvedilol ^c164
    • Carvedilol Oral tablet; Adults: 25 to 50 mg PO twice daily.
  • Metoprolol succinate ^c165
    • Metoprolol Succinate Oral tablet, extended-release; Adults: 100 mg PO once daily, initially. Gradually increase the dose weekly until desired clinical response is achieved or pronounced slowing of heart rate. Max: 400 mg/day. To discontinue, decrease dose gradually over 1 to 2 weeks.
  • Metoprolol tartrate ^c166
    • Metoprolol Tartrate Oral tablet; Adults: 50 mg PO twice daily, initially. Gradually increase the dose weekly until desired clinical response is achieved or pronounced slowing of heart rate. Usual dose: 100 to 400 mg/day.
• Calcium channel blockers ^r11
  • Nondihydropyridine calcium channel blockers
    • Verapamil
      • Verapamil Hydrochloride Oral tablet; Adults: 40 to 120 mg PO 3 times daily. Usual dose: 80 to 120 mg PO 3 times daily. Adjust dose daily or weekly until desired clinical response is achieved.
    • Diltiazem
      • Immediate release
        • Diltiazem Hydrochloride Oral tablet; Adults: 30 mg PO 4 times daily, initially. Gradually increase the dose every 1 to 2 days until desired clinical response is achieved. Usual dose: 180 to 360 mg/day in 3 to 4 divided doses.
      • Extended release
        • Diltiazem Hydrochloride Oral capsule, extended release 24 hour; Adults: 120 to 180 mg PO once daily, initially. Increase the dose every 7 to 14 days until desired clinical response is achieved. Max: 540 mg/day.
  • Dihydropyridine calcium channel blockers
    • Amlodipine
      • Amlodipine Besylate Oral tablet; Adults: 5 to 10 mg PO once daily. Usual dose: 10 mg PO once daily.
    • Nifedipine
      • Nifedipine Oral tablet, extended-release; Adults: 30 or 60 mg PO once daily, initially. Increase the dose every 7 to 14 days until desired clinical response is achieved. Usual Max: 90 mg/day. Max: 120 mg/day.
• Other antianginal agents
  • Ranolazine ^c167
    • Ranolazine Oral tablet, extended-release; Adults: 500 mg PO twice daily. May increase dose to 1,000 mg PO twice daily if needed. Max: 1,000 mg PO twice daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
  • Ivabradine ^c168
    • Ivabradine Oral tablet; Adults 75 years or more: 2.5 mg PO twice daily, initially. Adjust the dose after 3 to 4 weeks and thereafter as needed based on heart rate and tolerability. Max: 7.5 mg PO twice daily. Discontinue therapy if no improvement in angina symptoms within 3 months and consider discontinuing therapy if there is only limited symptomatic response and no clinically relevant decrease in resting heart rate within 3 months.
    • Ivabradine Oral tablet; Adults 18 to 74 years: 5 mg PO twice daily, initially. Adjust the dose after 3 to 4 weeks and thereafter as needed based on heart rate and tolerability. Max: 7.5 mg PO twice daily. Discontinue therapy if no improvement in angina symptoms within 3 months and consider discontinuing therapy if there is only limited symptomatic response and no clinically relevant decrease in resting heart rate within 3 months.
• Antiplatelet drugs ^r7
  • Aspirin ^c169
    • Aspirin Oral tablet; Adults: 75 to 162 mg PO once daily indefinitely.
  • Clopidogrel ^c170
    • Clopidogrel Bisulfate Oral tablet; Adults: 75 mg PO once daily.
  • Prasugrel ^c171
    • Prasugrel Oral tablet; Adults weighing less than 60 kg: 60 mg PO loading dose, then 5 mg PO once daily in combination with aspirin.
    • Prasugrel Oral tablet; Adults weighing 60 kg or more: 60 mg PO loading dose, then 10 mg PO once daily in combination with aspirin.
  • Ticagrelor ^c172
    • Ticagrelor Oral tablet; Adults: 180 mg PO loading dose, then 90 mg PO twice daily in combination with low-dose aspirin. Reduce dose to 60 mg PO twice daily in combination with low-dose aspirin after 1 year.
• ACE inhibitors
  • Lisinopril ^{c173c174c175c176}
    • Lisinopril Oral tablet; Adults: 10 mg PO once daily, initially. May increase dose if further control is needed. Usual dose range: 10 to 40 mg/day. Max: 80 mg/day.
  • Ramipril ^{c177c178c179c180}
    • Ramipril Oral capsule; Adults: 2.5 mg PO once daily, initially. May increase dose if further control is needed. Usual dose: 2.5 to 20 mg/day in 1 to 2 divided doses.
• Angiotensin II receptor blockers
  • Irbesartan ^{c181c182c183c184}
    • Irbesartan Oral tablet; Adults: 150 mg PO once daily, initially. May increase dose to 300 mg PO once daily if further control is needed.
  • Losartan ^{c185c186c187c188}
    • Losartan Potassium Oral tablet; Adults: 50 mg PO once daily, initially. May increase dose to 100 mg/day in 1 to 2 divided doses if further control is needed.
  • Telmisartan ^{c189c190c191c192}
    • Telmisartan Oral tablet; Adults: 40 mg PO once daily, initially. May increase dose if further control is needed. Dose range: 20 to 80 mg/day.
• Statins
  • Atorvastatin ^c193
    • Atorvastatin Calcium Oral tablet; Adults: 10 to 20 mg PO once daily. May start at 40 mg once daily for greater than 45% LDL-reduction. Range: 10 to 80 mg once daily.
  • Pitavastatin ^c194
    • Pitavastatin Calcium Oral tablet; Adults: 2 mg PO once daily. Analyze lipid concentrations 4 weeks after initiation or dosage titration. Max: 4 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
  • Pravastatin
    • Pravastatin Sodium Oral tablet; Adults: 40 to 80 mg PO once daily. Max: 80 mg/day. Assess LDL-C 4 to 12 weeks after initiation or dose adjustment; adjust dosage as needed. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
  • Rosuvastatin ^c195
    • Rosuvastatin Calcium Oral tablet; Adults: 10 mg PO once daily; 5 mg once daily may be used for less aggressive LDL-reduction, patients with CrCl less than 30 mL/minute, higher risk for myopathy, or for Asian patients. Dose range: 5 to 40 mg once daily. Consider 20 mg once daily for marked hypercholesterolemia (LDL more than 190 mg/dL). Reserve 40 mg/day for insufficient response; 40 mg/day has been associated with higher risk of myopathy. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
  • Simvastatin ^c196
    • Simvastatin Oral tablet; Adults: Initially, 10 to 20 mg PO at bedtime. In patients with CHD, risk factors for CHD, or familial homozygous hypercholesterolemia, starting dose is 40 mg PO once daily in the evening. Usual dosage range: 5 to 40 mg/day PO. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Only use 80 mg in patients who have been taking 80 mg chronically without myopathy.
• Nonstatin lipid-lowering agents
  • Ezetimibe ^r23c197
    • Ezetimibe Oral tablet; Adults: 10 mg PO once daily.
  • Proprotein convertase subtilisin/kexin type 9 (PCSK9) serine protease inhibitors
    • Evolocumab ^r34c198
      • Evolocumab Solution for injection; Adults: 140 mg subcutaneously every 2 weeks or 420 mg subcutaneously once monthly.
    • Alirocumab ^r35c199
      • Alirocumab Solution for injection; Adults: 75 mg subcutaneously every 2 weeks or 300 mg subcutaneously every 4 weeks. Measure LDL-C prior to next dose for persons receiving 300 mg subcutaneously every 4 weeks and otherwise as clinically appropriate. May adjust dose to 150 mg subcutaneously every 2 weeks for inadequate LDL-C response.
• Colchicine
  • Colchicine Oral tablet; Adults: 0.5 mg PO once daily. Optimal duration is not defined.

Nondrug and supportive care

Smoking cessation ^r36c200d4

Nutrition ^c201

• Modify nutrition counseling based on individual patient factors (eg, lipid profile, blood pressure, required caloric intake, alcohol intake)
• Emphasize intake of vegetables, fruits, nuts, whole grains, lean vegetable or animal protein, and fish ^r37
• Minimize intake of trans fats, red meat and processed red meats, refined carbohydrates, and sweetened beverages ^r37

Weight management ^r36c202

• BMI goal is 18.5 to 24.9 kg/m²; waist circumference goal is less than 89 cm for females and less than 102 cm for males
• If weight loss is required, initial weight loss goal should be 5% to 10% below baseline

Physical activity ^c203

• Before discharge from acute care setting, provide patient with instructions on specific activity recommendations (eg, lifting, stair climbing, housework, yard work, sexual activity)
• Goal is 30 to 60 minutes of moderate intensity aerobic activity for 5 to 7 days per week; supplement with 2 days of resistance training ^r36
• Counsel patients to report exercise-associated symptoms

Prevention of infectious diseases ^r38

• Pneumococcal vaccine is recommended for high-risk patients who have cardiovascular disease and are older than 65 years ^c204
• Yearly influenza vaccine is recommended for patients with cardiovascular disease ^r8c205
  • Influenza vaccination in patients with high-risk coronary heart disease has been shown to lower the risk of all-cause death and cardiovascular death ^r39

Comorbidities

• Diabetes ^c214
  • Use β-blockers with caution
    • Vasodilating β-blockers (carvedilol, labetalol, nebivolol) may be preferable as these have fewer metabolic effects in patients with type 2 diabetes ^r44
  • Sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists are the recommended oral antihyperglycemic agents in patients with type 2 diabetes, as these have been shown to reduce major adverse cardiac events and hospitalization from heart failure ^r7r44
  • Ranolazine has glucose-lowering effect, particularly in patients with poorly controlled type 2 diabetes ^r44
• Heart failure ^r5c215
  • β-blockers may simultaneously confer a symptomatic benefit for patients with angina and a mortality benefit for patients with heart failure
    • Use with caution and only in patients in a compensated state owing to the negative inotropic effect
    • Metoprolol succinate, carvedilol, and bisoprolol are FDA approved for patients with congestive heart failure
  • In general, avoid nondihydropyridine calcium channel blockers in patients with heart failure with reduced ejection fraction owing to the drug's negative inotropic effect
• Hypertension ^r28c216
  • Antihypertensive drug therapy, in addition to lifestyle modification, is recommended for patients with blood pressure of 130/80 mm Hg or higher
  • Aim for blood pressure target lower than 130/80 mm Hg
  • First line therapy should consist of medications such as ACE inhibitors (or angiotensin II receptor blockers) and β-blockers as required for other indications
  • Add thiazide diuretics, dihydropyridine calcium channel blockers, or mineralocorticoid receptor antagonists if first line agents fail to control hypertension
• Atrial fibrillation ^c217
  • Use of aspirin in combination with oral anticoagulant therapy for atrial fibrillation increases risk for major bleeding compared to either agent alone with no additional reduction in risk of stroke or cardiovascular events in patients with stable ischemic heart disease ^r45r46
  • For patients that meet criteria for anticoagulation (CHADS VASc score greater than or equal to 2) monotherapy with either warfarin (INR target of 2-3) or a direct-acting oral anticoagulant is recommended ^r46r47
• Peripheral vascular disease ^c218
  • Mild peripheral vascular disease: there is no contraindication for use of β-blockers or calcium channel blockers
  • Severe peripheral vascular disease and pain during rest: calcium channel blockers are preferred; avoid β-blockers
• Bradyarrhythmias ^r5c219
  • Use β-blockers with caution in patients with significant bradyarrhythmias
  • Use diltiazem and verapamil (ie, nondihydropyridine calcium channel blockers) with caution in patients with significant bradyarrhythmias
  • Exercise caution when using concomitant β-blockers and heart rate–limiting calcium channel blockers (ie, diltiazem, verapamil) owing to their combined effects impairing conduction across the atrioventricular node; this is a frequent cause of hospitalization in older adult patients
• Ischemic dilated cardiomyopathy ^c220
  • Calcium channel blockers may relieve angina, although they have not been found to confer a mortality benefit in this population
  • In general, avoid nondihydropyridine calcium channel blockers in patients with heart failure with reduced ejection fraction owing to the drug's negative inotropic effect ^r5
• Asthma ^c221
  • Avoid β-blockers owing to their potential exacerbation of bronchospasm in patients prone to wheezing and bronchoconstriction ^r48r49
• Migraine ^c222
  • β-blockers and calcium channel blockers may be beneficial ^r50
  • Nitrates may worsen headaches
• Use of amphetamines and/or cocaine ^{r51c223c224d7}
  • β-blockers may allow unopposed α-adrenergic effects of these drugs, which may lead to significant vasospasm
  • Consider using calcium channel blockers

Special populations

• Patients with vasospastic (Prinzmetal) angina ^r7
  • Calcium channel blockers and long-acting nitrates are first line agents for preventive treatment
  • All patients should also achieve optimal coronary risk factor control, in particular through smoking cessation and aspirin
• Patients with refractory angina
  • Defined as symptoms caused by established reversible ischemia that last for at least 3 months and are not controlled by escalating medical therapy, bypass grafting, or percutaneous coronary intervention
  • Certain patients may be candidates for novel treatments such as: ^r7
    • Enhanced external counterpulsation ^r11
    • Coronary sinus constriction
    • Spinal cord stimulation

At-risk populations

• Patients with severe hypercholesterolemia (LDL-C levels of 190 mg/dL or higher), adults with diabetes, and adults aged 40 to 75 years ^r23

Screening tests

• Screen to identify candidates who may benefit from lifestyle or pharmacologic interventions (lipid-lowering therapy) aimed at reducing cardiovascular risk ^r23
  • Evaluate adults without preexisting atherosclerotic cardiovascular disease every 4 to 6 years with tests that measure traditional cardiovascular risk factors
    • Fasting blood glucose (or other assessment of diabetes) ^c248
    • Total and HDL-C ^c249c250
    • Blood pressure ^c251
    • Question regarding tobacco use ^c252
  • Based on these, estimate 10-year cardiovascular risk using the ASCVD Risk Predictor Plus ^r23r54r55
• Coronary artery calcium score is the best imaging measure of risk in asymptomatic patients ^r56
  • Consider CT coronary artery calcium scoring in asymptomatic patients with an intermediate or high risk of coronary artery disease
  • Not usually indicated in asymptomatic patients with low risk of coronary artery disease
• CT angiogram of the coronary arteries is an alternative for imaging asymptomatic patient with a high risk of coronary artery disease ^r56