Chronic Coronary Disease

History

• Most commonly reported symptom is chest pain or discomfort that occurs with exertion or emotional stress and is relieved with rest or nitroglycerin ^r8c1c2
  • 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
    • 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 ^c25
  • 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) ^c28
• Note any history of prior episodes of chest pain or risk factors for or known coronary artery disease ^c29c30c31
• 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 ^c32
• Signs of associated conditions may be present, such as:
  • Anemia ^c33
  • Hypertension ^c34
  • Decreased peripheral pulses ^c35
  • Carotid, femoral, or renal artery bruits ^c36c37c38
  • Elevated jugular vein pressure ^c39
  • Xanthelasma or xanthoma ^c40
  • Arrhythmia ^c41
  • Obesity ^c42
  • Peripheral edema ^c43
  • Pulmonary rales ^c44
• Cardiac examination findings are often normal ^c45
  • Signs of underlying cardiac disease may be present (eg, cardiac enlargement or murmur) ^c46c47
  • 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 ^r3c48c49c50
• Palpation of the chest does not typically reproduce symptoms.^r3Reproducible chest wall pain suggests a musculoskeletal cause^r9c51

Causes

Risk factors and/or associations

Primary diagnostic tools

• Diagnosis is based on history, physical examination findings, 12-lead ECG, measurement of serum biochemical markers, and noninvasive test results ^c119c120
• 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 ^r7r9
• ECG ^c121
  • A 12-lead ECG is recommended for all patients presenting with symptoms of chest pain concerning for angina or possible anginal equivalent ^r7r8
  • 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
  • Dynamic ST-segment changes may be present in the setting of active chest pain due to ischemia
  • Can be diagnostic for 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, and conduction defects
• 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 ^{c122c123c124c125c126c127}
  • Thyroid function tests, if thyroid disease is suspected on clinical examination ^c128
  • 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 ^c129
    • 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 workup, as it does not provide specific diagnostic or prognostic information ^c130
  • 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 for 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
• For 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 ^r9
  • Predictive models have been developed for this purpose based on data that correlate presence of obstructive coronary artery lesions to patient age, sex, and nature of patient symptoms ^r7

    • Pretest probability of obstructive coronary artery disease in symptomatic patients

      Table shows a pooled analysis of three contemporary study cohorts of patients evaluated for suspected CAD; produced probabilities are approximately one-third that of previously published data. The values represent the percentage of patients with significant coronary artery disease by invasive coronary artery angiography or coronary CT angiography

      Knuuti J et al: 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J. 41(3):407-77, 2020.

      Age (y)	Nonanginal chest pain: men (%)	Nonanginal chest pain: women (%)	Atypical angina: men (%)	Atypical angina: women (%)	Typical angina: men (%)	Typical angina: women (%)	Dyspnea: men (%)	Dyspnea: women (%)
      30 to 39	1	1	4	3	3	5	0	3
      40 to 49	3	2	10	6	22	10	12	3
      50 to 59	11	3	17	6	32	13	20	9
      60 to 69	22	6	26	11	44	16	27	14
      70+	24	10	34	19	52	27	32	12

  • Current US and European guidelines classify patients as either low risk (pretest probability of 15% or less) or intermediate to high risk (pretest probability of more than 15%) of having obstructive coronary artery disease ^r7r8
  • For an individual patient, the pretest probability score from the table should be interpreted in light of other available information such as risk factors (family history, comorbid conditions, lifestyle) and abnormalities on baseline testing (ECG, echocardiogram) ^r8
  • Other elements relevant to the decision to refer a patient for further testing may include the 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
  • Consultation with a cardiologist is recommended to determine pretest risk probability
• For patients with stable chest pain and no known cardiac disease, who are characterized as low risk, additional testing can be deferred ^r7r8
  • Alternatively, coronary artery calcium scan is a reasonable first line test to exclude calcified plaque and determine a low likelihood of obstructive coronary artery disease ^r8
  • Exercise testing without imaging to exclude myocardial ischemia and determine functional capacity is also a reasonable first line test ^r8
• If pretest probability of ischemic heart disease is intermediate or greater, consider noninvasive anatomical or functional tests to establish the diagnosis of obstructive coronary artery disease, for major event risk stratification, and to guide treatment decisions ^r7r8
  • Coronary CT angiography is preferable for patients younger than 65 years or when suspicion for severe obstruction is low, while stress testing (stress echocardiography, stress PET/SPECT [single-photon emission computed tomography] myocardial perfusion imaging, stress cardiac MRI) is recommended for those aged 65 years and older or when suspicion of more severe obstruction is high ^r7r8
    • Exercise electrocardiography is a reasonable choice for patients with an interpretable ECG who can achieve maximum levels of exercise or when the aforementioned tests are not available ^r7r8
• Invasive coronary angiography is the gold standard for evaluating the presence of coronary artery disease; however, this procedure is not routinely indicated to establish a diagnosis of ischemic heart disease for patients with stable angina ^r7
  • Early angiography without previous noninvasive testing may be indicated for patients who have a high pretest probability of ischemic heart disease and: ^r7r8
    • Symptoms that are severe, unresponsive to medical therapy, or occur at a low level of exercise, or
    • Clinical evaluation suggesting high risk for a major adverse cardiovascular event
  • May have a role for patients with reduced left ventricular ejection fraction less than 40% and typical angina, those who cannot undergo stress imaging techniques, or people in certain professions, such as pilots (regulatory requirement) ^r8
  • Indicated after major event risk stratification with noninvasive testing to determine options for revascularization if results suggest presence of high-risk coronary lesions and if a revascularization procedure is reasonable based on patient comorbidities and preferences ^r8
• Fractional flow reserve, which may be measured as part of invasive coronary angiography or derived via CT angiography, may be used to determine need for percutaneous coronary intervention (ie, angioplasty with stent) by measuring pressure difference across stenosis to assess hemodynamic significance ^r11
• Exercise stress testing ^c131
  • Exercise ECG is recommended as an alternative to noninvasive imaging tests for establishing a diagnosis in patients with angina symptoms who are able to exercise and have no abnormalities on resting ECG ^r7
    • Provides 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
    • Diagnostic accuracy is lower with exercise ECG than with stress imaging but may be used when noninvasive imaging tests are unavailable ^r7r8
    • Can be used for patients who are receiving treatment to evaluate control of symptoms and ischemia ^r7
    • Performed on treadmill or bicycle using 12-lead ECG monitoring
    • An ECG exercise stress test is considered positive for ischemia when horizontal or down-sloping ST-segment depression is greater than or equal to 1 mm (0.1 mV) and persists for at least 0.06 to 0.08 second after the J point in 1 or more ECG leads ^r7
    • Inconclusive results can be followed up using alternative stress testing with noninvasive imaging ^r8
    • Nondiagnostic for patients with resting ECG abnormalities that prevent interpretation of ST-segment changes during stress ^r7
    • Contraindications to exercise stress testing: ^r8
      • Inability to exercise
      • Ongoing unstable angina
      • Recent (acute) myocardial infarction (less than 48 hours)
      • Decompensated heart failure
      • Severe hypertension (eg, 200/110 mm Hg or higher)
      • Severe aortic stenosis
      • Acute myocarditis/pericarditis
      • Acute aortic dissection
      • Active endocarditis

Imaging

• Echocardiography ^c132c133
  • A resting transthoracic echocardiogram is recommended for 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 ^r7r8
    • Consider for patients with a cardiac murmur on examination, previous myocardial infarction, or symptoms/signs of heart failure
    • May be omitted for very young and healthy patients when an extracardiac cause of chest pain is likely and for those with multiple comorbidities for whom the result of echocardiography will not influence management
• Noninvasive functional imaging tests
  • Ischemia can be provoked by exercise or by pharmacologic stressors, via increased myocardial work and oxygen demand, or by heterogeneity in myocardial perfusion by vasodilation ^r7
  • 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 ECG ^r7r8c134
  • Exercise stress testing is recommended over pharmacologic testing when possible, as it improves the diagnostic and prognostic information of the test ^r8
  • Stress imaging using a pharmacologic stress agent (eg, adenosine, dipyridamole, dobutamine, regadenoson) can be performed with patients who have an inadequate ability to exercise
  • Recommended as the initial test for patients with intermediate to high pretest probability of ischemic heart disease aged 65 years or older and for those suspected of having more severe obstruction ^r7r8
    • Also recommended as an alternative to stress ECG testing for patients with abnormal baseline ECG findings that prevent accurate interpretation of ECG changes during a stress challenge
    • Consider for symptomatic patients with history of 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
  • Stress imaging modalities ^r3
    • Exercise stress echocardiography ^c135
    • Exercise stress myocardial perfusion imaging (with single photon emission CT) ^c136
    • Dobutamine stress echocardiography ^c137c138
    • Dobutamine stress MRI ^c139c140c141
    • Vasodilator stress echocardiography ^c142
    • Vasodilator stress myocardial perfusion imaging (with single photon emission computed tomography) ^c143
    • Vasodilator stress MRI ^c144
    • Vasodilator stress myocardial perfusion PET scan ^c145
• Noninvasive anatomical imaging tests
  • Coronary CT angiography ^c146c147c148
    • Recommended as the initial test for patients with intermediate to high pretest probability of ischemic heart disease younger than 65 years or when suspicion for severe obstruction is low, providing that good image quality can be anticipated ^r7r8
      • Also consider for 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 who should avoid invasive coronary angiography owing to increased risk ^r7
      • May be considered for high-risk asymptomatic adults (eg, with diabetes, strong family history of coronary artery disease) for cardiovascular risk assessment ^r7
      • Prescreening is recommended to confirm patients have adequate breath-holding capability, 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 ^r12
      • Estimated stenoses of 50% to 90% are not always functionally significant and would require subsequent invasive or noninvasive functional testing ^r7
      • May fail to diagnose disease in patients with coronary microvascular dysfunction or vasospastic angina ^r13
  • Coronary artery calcium scan
    • CT can yield a coronary artery calcium score; however, this is not recommended as a standalone test to evaluate ischemia in symptomatic patients ^r7
      • Calcium score correlates roughly to total amount of atherosclerosis present in coronary arteries
      • Correlation with actual extent of luminal narrowing, or stenosis, is poor
      • Can be used to improve estimation of pretest probability of obstructive coronary artery disease
      • Coronary calcium imaging does not exclude coronary stenosis due to a noncalcified atherosclerotic lesion, though a score of zero is associated with low prevalence of obstructive coronary artery disease (less than 5%) and low risk of death or nonfatal myocardial infarction (less than 1% annual risk) ^r7

Procedures

Other diagnostic tools

• Event risk stratification ^r7c151
  • Identifies level of risk for major adverse cardiovascular event, usually defined as nonfatal stroke, nonfatal myocardial infarction, or cardiovascular death; various scores with different end points and time frames exist
  • Recommended for all patients being evaluated for suspected coronary artery disease, as it has major impact on therapeutic decisions ^r7
  • Conducted in stepwise fashion based on clinical evaluation, assessment of ventricular function, results of noninvasive testing, and delineation of coronary anatomy, that is, the same assessments used to make the diagnosis of coronary artery disease ^r7
  • Recommended that patients be classified as having a low (less than 1%), intermediate (1%-3%), or high (more than 3%) yearly risk for cardiovascular death or nonfatal myocardial infarction ^r5
  • 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 ^r18
  • Cardiovascular imaging findings
    • High risk: ^r7
      • Area of ischemia of left ventricular myocardium greater than 10% on SPECT (single photon emission CT) scan or PET perfusion imaging
      • 2 or more segments of 16 with stress perfusion defects or 3 or more dobutamine-induced dysfunctional segments on cardiac MRI
      • 3 or more segments of 16 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 MRI or stress echocardiogram ^r19
    • Low risk: no ischemia
  • Coronary CT angiography findings ^r20
    • 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 ^r21
    • 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 ^r21
  • Invasive functional testing
    • High risk: fractional flow reserve of 0.8 or less, instantaneous wave-free ratio (instant flow reserve) of 0.89 or less

Most common

• Cardiovascular conditions
  • Acute coronary syndromes ^d1
    • Include unstable or crescendo angina, non–ST elevation myocardial infarction, and ST elevation myocardial infarction ^c152c153c154
      • 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 and ECG findings, and serum cardiac troponin levels
      • Consider acute coronary syndrome in patients presenting with anginal pain lasting more than 15 minutes ^r4c155
      • 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 ^r22
      • 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 one 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 ^c156d2
    • Sudden obstruction of a portion of the pulmonary arterial vasculature, usually by embolization from 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 one 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 ^c157
    • 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) ^c158d3
    • 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 reduced 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) ^c159d4
    • 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) ^c160d5
    • 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 ^c161d6
    • 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 ^c162
    • 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 ^c163
    • 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

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

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

• Antithrombotic agents ^r7
  • Aspirin ^c164
    • Aspirin Oral tablet; Adults: 75 to 162 mg PO once daily indefinitely.
  • P2Y12 platelet inhibitors
    • Clopidogrel ^c165
      • Clopidogrel Bisulfate Oral tablet; Adults: 75 mg PO once daily.
    • Prasugrel ^c166
      • Prasugrel Oral tablet; Adults 18 to 75 years weighing 60 kg or more: 10 mg PO once daily in combination with low-dose aspirin.
      • Prasugrel Oral tablet; Adults older than 75 years or weighing less than 60 kg: 5 mg PO once daily in combination with low-dose aspirin.
    • Ticagrelor ^c167
      • Ticagrelor Oral tablet; Adults: 60 mg PO twice daily in combination with low-dose aspirin.
  • Factor Xa inhibitors
    • Rivaroxaban
      • Rivaroxaban Oral tablet; Adults: 2.5 mg PO twice daily in combination with low-dose aspirin.
• Statins
  • Atorvastatin ^c168
    • High-intensity therapy
      • Atorvastatin Calcium Oral tablet; Adults: 80 mg PO once daily. May decrease dose to 40 mg PO once daily if unable to tolerate the higher dose.
    • Moderate-intensity therapy
      • Atorvastatin Calcium Oral tablet; Adults: 10 or 20 mg PO once daily.
  • Rosuvastatin ^c169
    • High-intensity therapy
      • Rosuvastatin Calcium Oral tablet; Adults: 20 or 40 mg PO once daily.
    • Moderate-intensity therapy
      • Rosuvastatin Calcium Oral tablet; Adults: 5 or 10 mg PO once daily.
  • Pitavastatin ^c170
    • Moderate-intensity therapy
      • Pitavastatin Calcium Oral tablet; Adults: 1 to 4 mg PO once daily.
  • Pravastatin
    • Moderate-intensity therapy
      • Pravastatin Sodium Oral tablet; Adults: 40 or 80 mg PO once daily.
  • Simvastatin ^c171
    • Moderate-intensity
      • Simvastatin Oral tablet; Adults: 20 or 40 mg PO once daily.
• Nonstatin lipid-lowering agents
  • Ezetimibe ^r32c172
    • Ezetimibe Oral tablet; Adults: 10 mg PO once daily.
  • Proprotein convertase subtilisin/kexin type 9 (PCSK9) serine protease inhibitors
    • Alirocumab ^r33c173
      • 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.
    • Evolocumab ^r34c174
      • Evolocumab Solution for injection; Adults: 140 mg subcutaneously every 2 weeks or 420 mg subcutaneously once monthly.
  • Adenosine triphosphate-citrate lyase inhibitor
    • Bempedoic acid
      • Bempedoic Acid Oral tablet; Adults: 180 mg PO once daily.
  • Small interfering RNA directed to PCSK9 mRNA
    • Inclisiran
      • Inclisiran Solution for injection; Adults: 284 mg subcutaneously every 3 months for 2 doses, then 284 mg subcutaneously every 6 months.
• Colchicine
  • Colchicine Oral tablet; Adults: 0.5 mg PO once daily. Optimal duration is not defined.
• Antihypertensive agents
  • ACE inhibitors
    • Lisinopril ^{c175c176c177c178}
      • 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 ^{c179c180c181c182}
      • 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 ^{c183c184c185c186}
      • 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 ^{c187c188c189c190}
      • 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 ^{c191c192c193c194}
      • 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.
• GLP-1 (glucagon-like peptide 1)
  • Dulaglutide
    • Dulaglutide Solution for injection; Adults: 0.75 mg subcutaneously once weekly, initially. May increase the dose to 1.5 mg subcutaneously once weekly if additional glycemic control is needed. May further increase the dose by 1.5 mg/week after at least 4 weeks if additional glycemic control is needed. Max: 4.5 mg/week.
  • Liraglutide
    • Liraglutide Solution for injection; Adults: 0.6 mg subcutaneously once daily for 1 week, then 1.2 mg subcutaneously once daily, initially. May increase the dose after at least 1 week to 1.8 mg subcutaneously once daily if additional glycemic control is needed.
  • Semaglutide
    • Semaglutide Solution for injection; Adults: 0.25 mg subcutaneously once weekly for 4 weeks, then 0.5 mg subcutaneously once weekly, initially. May increase the dose to 1 mg subcutaneously once weekly after 4 weeks on 0.5 mg/week and 2 mg subcutaneously once weekly after 4 weeks on 1 mg/week if additional glycemic control is needed.
• SGLT2 (sodium-glucose contransporter-2) inhibitors
  • Canagliflozin
    • Canagliflozin Oral tablet; Adults: 100 mg PO once daily, initially. May increase the dose to 300 mg PO once daily if additional glycemic control is needed. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
  • Dapagliflozin
    • Dapagliflozin Oral tablet; Adults: 10 mg PO once daily.
  • Empagliflozin
    • Empagliflozin Oral tablet; Adults: 10 mg PO once daily, initially. May increase dose to 25 mg PO once daily if additional glycemic control is needed.
• Antianginal agents
  • Nitrates
    • Rapid-acting nitrates ^r21
      • Nitroglycerin sublingual tablets ^c195
        • 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 ^c196
        • 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 ^c197
        • 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%) ^c198
        • 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 ^r21
      • Isosorbide mononitrate ^c199
        • 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 ^c200
        • 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 ^r21
    • Bisoprolol ^c201
      • Bisoprolol Fumarate Oral tablet; Adults: 5 to 20 mg PO once daily.
    • Carvedilol ^c202
      • Carvedilol Oral tablet; Adults: 25 to 50 mg PO twice daily.
    • Metoprolol succinate ^c203
      • 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.
    • Metoprolol tartrate ^c204
      • 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 ^r21
    • Nondihydropyridine calcium channel blockers
      • Diltiazem ^c205
        • 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.
      • Verapamil ^c206
        • 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.
    • Dihydropyridine calcium channel blockers
      • Amlodipine ^c207
        • Amlodipine Besylate Oral tablet; Adults: 5 to 10 mg PO once daily. Usual dose: 10 mg PO once daily.
      • Nifedipine ^c208
        • 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
    • Ivabradine ^c209
      • 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.
      • 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.
    • Ranolazine ^c210
      • 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.

Nondrug and supportive care

US Preventive Services Task Force recommends offering or referring adults with cardiovascular disease risk factors to behavioral counselling interventions to promote a healthy diet and physical activity ^r35

Smoking cessation ^r36c211d4

Nutrition ^c212

• 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 ^r36c213

• 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 ^c214

• 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

• Infections with pneumococcus, influenza, and COVID-19 are contributing factors to major adverse cardiovascular events and all-cause mortality for patients with chronic coronary disease ^r5
• Pneumococcal vaccine is recommended for high-risk patients who have cardiovascular disease or who are older than 65 years ^c215
• Yearly influenza vaccine is recommended for patients with cardiovascular disease ^r29c216
  • Influenza vaccination of patients with high-risk coronary heart disease has been shown to lower the risk of all-cause death and cardiovascular death ^r38
• Patients with chronic coronary disease are among those at highest risk for COVID-19 complications and should receive yearly vaccination per public health guidelines ^r5

Comorbidities

• Diabetes ^c225
  • 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 ^r43
  • Sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists are the recommended oral antihyperglycemic agents for patients with type 2 diabetes, as these have been shown to reduce major adverse cardiac events and hospitalization for heart failure ^r7r43
  • Ranolazine has glucose-lowering effect, particularly in patients with poorly controlled type 2 diabetes ^r43
• Heart failure ^c226
  • β-Blockers may simultaneously confer a symptomatic benefit for patients with angina and a mortality benefit for patients with heart failure ^r5
    • Use with caution and only for patients in a compensated state owing to the negative inotropic effect
    • Metoprolol succinate, carvedilol, and bisoprolol have proven efficacy for reducing major adverse cardiovascular events (including death) in patients with left ventricular systolic dysfunction
  • Use of nondihydropyridine calcium channel blockers for angina is not recommended for patients with chronic coronary disease and significant left ventricular dysfunction owing to their negative inotropic effects ^r5
• Hypertension ^r25c227
  • 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 of less 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 ^c228
  • Use of aspirin in combination with oral anticoagulant therapy for atrial fibrillation increases risk for major bleeding compared with either agent alone with no additional reduction in risk of stroke or cardiovascular events for patients with chronic coronary heart disease ^r44r45
  • 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 ^r44r46
• Peripheral vascular disease ^c229
  • Mild peripheral vascular disease: there is no contraindication to 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 ^r7c230
  • Use β-blockers with caution for patients with significant bradyarrhythmias
  • Use diltiazem and verapamil (ie, nondihydropyridine calcium channel blockers) with caution for 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 for older adult patients
• Ischemic dilated cardiomyopathy ^c231
  • Calcium channel blockers may relieve angina, although they have not been found to confer a mortality benefit in this population
  • Nondihydropyridine calcium channel blockers are not recommended for patients with chronic coronary disease and significant left ventricular dysfunction owing to the drugs' negative inotropic effects ^r5
• Asthma ^c232
  • Avoid β-blockers owing to their potential exacerbation of bronchospasm in patients prone to wheezing and bronchoconstriction ^r47r48
• Migraine ^c233
  • β-Blockers and calcium channel blockers may be beneficial ^r49
  • Nitrates may worsen headaches
• Use of amphetamines and/or cocaine ^{r50c234c235d7}
  • 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 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 ^r5
    • Coronary sinus constriction
    • Spinal cord stimulation
• Ischemia with nonobstructive coronary arteries
  • More than one-half of patients with chronic angina have nonobstructive epicardial coronary arteries, defined as stenosis of 50% or less ^r13
  • Myocardial ischemia occurs due to coronary microvascular dysfunction, vasospastic disease, or a combination of the two ^r5
  • Is associated with increased risk of all-cause death and myocardial infarction ^r5
  • May explain lack of benefit seen after many revascularization procedures in patients with stable angina ^r13
  • Both groups have a high prevalence of atherosclerotic plaque and should receive anti-thrombotic and lipid-lowering therapy, management of hypertension and diabetes, and support for lifestyle modification (weight control, healthy diet, exercise, smoking cessation) to prevent progression to obstructive coronary artery disease ^r10
  • Formal diagnostic criteria for both entities are provided in the American Heart Association/American College of Cardiology guidelines ^r5
  • Vasospastic angina
    • Involves spasm of epicardial and/or microvascular coronary arteries ^r5
    • Affects both sexes, more common in persons of Asian ancestry and smokers, generally in younger patients with fewer risk factors ^r7
    • Anginal episodes usually occur at rest, most often at night or during early morning; exercise tolerance usually preserved ^r7
    • Includes Prinzmetal angina: chest pain at rest with ST-segment elevation, sometimes triggered by the cold, stress, or drug use ^r7
    • Detection of episodes may require prolonged ambulatory 12-lead ECG monitoring (longer than 1 week) or provocative tests (eg, acetylcholine) during invasive angiography ^r7
    • Generally responds well to calcium channel blockers and long-acting nitrates ^r7r13
  • Microvascular dysfunction
    • May be caused by impaired microcirculatory conductance or by arteriolar dysregulation ^r7
    • Angina is usually exercise induced but may occur at rest or be triggered by cold ^r7
    • More prevalent in females and those with hypertension or diabetes ^r8
    • May be diagnosed by invasive coronary artery functional testing or by PET or magnetic resonance stress perfusion imaging with measurement of myocardial blood flow reserve ^r8r13
    • Drugs that reduce myocardial oxygen demand (β-blockers, nondihydropyridine calcium-channel blockers, ivabradine) or that optimize myocardial oxygen utilization (ranolazine, trimetazidine) appear most effective ^r5r13

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 ^r32

Screening tests

• Screen to identify candidates who may benefit from lifestyle or pharmacologic interventions (lipid-lowering therapy) aimed at reducing cardiovascular risk ^r32
  • 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) ^c253
    • Total and HDL-C ^c254c255
    • Blood pressure ^c256
    • Question regarding tobacco use ^c257
  • Based on these, estimate 10-year cardiovascular risk using the ASCVD Risk Predictor Plus (arteriosclerotic cardiovascular disease) ^r32r52r53
• Coronary artery calcium score is the best imaging measure of risk for asymptomatic patients ^r54
  • Consider CT coronary artery calcium scoring for asymptomatic patients with an intermediate or high risk for coronary artery disease
  • Not usually indicated in asymptomatic patients with low risk for coronary artery disease
• CT angiogram of the coronary arteries is an alternative for imaging for asymptomatic patients with a high risk for coronary artery disease ^r54