CORONARY ARTERY DISEASE (CAD)

• ACRONYMS AND DEFINITIONS

• ABI - Ankle-brachial index. SBP in ankle/SBP in arm. ABI < 0.90 is associated with CVD.
• ACS - Acute coronary syndrome defined as myocardial infarction or unstable angina
• AHA - American Heart Association
• ASA - Acetylsalicylic acid, abbreviation for aspirin
• CABG - Coronary artery bypass grafting
• CAC - Coronary artery calcium scoring
• CAD - Coronary artery disease
• CCTA - Coronary CT angiography
• CKD - Chronic kidney disease
• CP - Chest pain
• CVD - Cardiovascular disease
• DAPT - Dual antiplatelet therapy
• DBP - Diastolic blood pressure
• DM - Diabetes mellitus
• DOAC - Direct-acting oral anticoagulant (factor Xa inhibitor or dabigatran)
• EF - Ejection fraction
• ESC - European Society of Cardiology
• EST - Exercise stress testing
• HFrEF - Heart failure with reduced ejection fraction
• LMD - Left main disease
• MPI - Myocardial perfusion imaging (general term for studies that evaluate coronary blood flow using noninvasive radiological techniques)
• MT - Medical therapy (antiplatelet therapy, statins, aggressive blood pressure and diabetes treatment)
• MVD - Multivessel disease
• NCGC - National Clinical Guideline Center for Acute and Chronic Conditions
• NSTEMI - Non-ST Elevation Myocardial Infarction
• PCI - Percutaneous coronary intervention (heart cath and associated procedures - stents, etc.)
• RCT - Randomized controlled trial
• SBP - Systolic blood pressure
• STEMI - ST-elevation myocardial infarction
• USPSTF - United States Preventive Services Task Force

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• EPIDEMIOLOGY

• Heart disease is the number one cause of death in the United States for men and women, and coronary artery disease (CAD) is the most common cause of heart disease. In the U.S. alone, CAD accounts for 109 billion dollars in healthcare spending each year.
• Every year about 785,000 Americans have their first heart attack, while another 470,000 have a recurrent heart attack. The average age for a first heart attack is 65.8 years for men and 70.4 years for women. [1,2]

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• PHYSIOLOGY

• Coronary artery disease is a condition where the arteries that supply blood to the heart muscle become narrowed
• Narrowed arteries may not be able to supply enough blood to the heart muscle under certain conditions (ex. exertion)
• When heart muscle does not receive enough blood flow, symptoms of chest pain (angina) may occur
• If insufficient blood flow persists, heart muscle may die
• Narrowed arteries may also become occluded when plaques from upstream arterial disease (atherosclerosis) break off and become lodged in the narrowing
• When this occurs, chest pain and death may occur suddenly without warning
• Illustration of coronary artery disease
• Illustration of main coronary arteries

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• VESSEL-DISEASE CATEGORIES

• Main arteries
• There are four main coronary arteries that are evaluated during a heart cath:
• Left Anterior Descending (LAD)
• The circumflex artery
• Right coronary artery (RCA)
• Left main artery
• Illustration of Main Coronary Arteries


• Significant stenosis
• Significant stenosis is defined differently depending on the artery:
• LAD, circumflex, and RCA - stenosis of ≥ 70% of the diameter of the artery is considered significant
• Left main Artery - stenosis of ≥ 50% of the diameter of the artery is considered significant


• Vessel disease
• 1-vessel disease - one artery has significant stenosis
• 2-vessel disease - two arteries have significant stenosis
• 3-vessel disease - three arteries have significant stenosis
• Left main disease - Left main artery has significant stenosis
• Left main equivalent disease - combined stenosis of ≥ 70% in the proximal LAD and ≥ 70% in the proximal circumflex
• Unprotected left main disease - term that means there is no perfusion supplied distal to the left main occlusion from a collateral artery or an intact CABG graft


• Prognosis
• The degree of disease can help predict survival
• The CASS study was a study that followed the survival of a large group of patients who had undergone coronary angiography
• Patients were stratified into four groups based on their angiography findings: zero-vessel disease, 1-vessel disease, 2-vessel disease, or 3-vessel disease
• It's important to note that the CASS study was performed in the 1970s and 80s when statins, aspirin, ace inhibitors, and other meds were not routinely used to treat CAD and heart failure. Today, survival for patients treated with optimal medical therapy would undoubtedly be much better.
• For patients who did not undergo CABG, survival rates were as follows:
• Zero-vessel disease - 88% (12-year survival)
• 1-vessel disease - 74% (12-year survival)
• 2-vessel disease - 59% (12-year survival)
• 3-vessel disease - 40% (12-year survival) [14]
• Left main disease - 27% (15-year survival) [15]
• Left main equivalent disease - 31% (15-year survival) [16]

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• RISK FACTORS

• Known risk factors for CAD
• Diabetes
• High blood pressure
• High cholesterol
• Family history of early-onset CAD (defined as CAD in a first-degree male relative < 55 years old, or CAD in a first-degree female relative < 65 years old)
• Smoking
• In one study, quitting smoking lowered CVD risk within 5 years of quitting. CVD risk returned to that of someone who never smoked at 10 - 15 years after quitting. [PMID 31429895]
• Physical inactivity
• Obesity (see weight loss)
• Male sex
• History of stroke or peripheral artery disease
• Age (men > 45 years old, women > 55 years) [3]
• Short stature [38]

• Possible risk factors for CAD
• Elevated homocysteine levels
• Elevated fibrinogen levels
• Elevated C-reactive protein [3]
• Calcium supplement intake (supplement dose does not appear to be a factor) [4]
• Breast arterial calcification seen on a mammogram [5]
• Radiation treatment for breast cancer (left-sided breast cancer may have higher risk than right) [6, 27]
• Severe Psoriasis [7]

• Risk calculators
• A number of risk calculators are available to estimate a person's risk of heart attack. Most calculators quantify a 10-year risk of stroke or heart attack.
• The Framingham risk calculator has been around for a number of years and is widely used. The Framingham calculator is not applicable to patients with diabetes. In 2013, the AHA introduced another calculator, and it can be used with diabetics.
• Some studies have found that risk calculators often overestimate risk. A study published in the Annals of Internal Medicine found that 4 different risk calculators (AHA calculator and 3 Framingham-based calculators) overestimated cardiovascular events by 37 - 154% in men, and 8 - 67% in women. [PMID 25686167]
• Framingham risk calculator (nondiabetic only)
• AHA risk calculator

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• SCREENING FOR CAD

• Guidelines on screening patients for CAD risk factors can be found on these pages
• Diabetes screening
• High blood pressure screening
• Cholesterol screening

• American College of Physicians (ACP) recommendations
• In 2015, the ACP recommended that healthcare providers not screen asymptomatic patients who are at low-risk for CAD events
• Low-risk is defined as having a 10-year risk of heart attack of < 10% (see risk calculators above)
• Screening tests they recommend against include resting and exercise ECG, stress echocardiography, and stress myocardial perfusion scanning [34]
• STUDY: A study (N=46,611 | median follow-up 5.6 years) published in 2022 found that screening men aged 65 to 74 with CT calcium scoring and ABI had no effect on overall mortality compared to no screening. [PMID 36027560]

• AHA recommendations
• The AHA published guidelines on CAD screening in asymptomatic adults in 2010. The recommendations are presented in the table below, and most are considered "soft," meaning they are based on little or no evidence.
• STUDY: A study (N=46,611 | median follow-up 5.6 years) published in 2022 found that screening men aged 65 to 74 with CT calcium scoring and ABI had no effect on overall mortality compared to no screening. [PMID 36027560]

AHA 2010 CAD Screening Recommendations
Step 1 - Categorize person into one of three groups: Low risk - Risk of a heart attack is ≤ 10% over the next 10 years Intermediate risk - Risk of a heart attack is > 10% and < 20% over the next 10 years High risk - Risk of a heart attack is ≥ 20% over the next 10 years See risk calculators above
Step 2 - screening tests and recommendations from the AHA Resting electrocardiogram (ECG) Resting ECG is "reasonable" in adults with hypertension or diabetes Findings on ECG that have been linked to cardiovascular risk in cohort studies include left ventricular hypertrophy, QRS prolongation, ST-segment depression, T-wave inversion, and pathological Q waves Resting echocardiography Resting echocardiography may be considered in adults with hypertension Resting echocardiography is not recommended in adults without hypertension Exercise stress testing Exercise stress testing may be considered in patients with intermediate risk While ST segment depression is historically considered the main marker of heart disease, other non-ECG measures have been found to be just as, or even more predictive than ST changes for predicting heart disease Non-ECG measures include exercise capacity (amount of exercise person can perform before stopping), failure of heart rate to rise appropriately with exercise, failure of heart rate to fall appropriately after exercise, and frequent ventricular ectopy during recovery For more information, see exercise Stress Testing Myocardial Perfusion Imaging (MPI) Myocardial perfusion imaging involves giving the patient a radioactive isotope and then stressing the heart with exercise or medications. Coronary blood flow is then observed on X-rays MPI may be considered in high risk patients with diabetes, a strong family history of heart disease, or coronary artery calcium score > 400 MPI is not recommended in patients with low to intermediate risk For more information, see myocardial perfusion imaging Carotid Intima-Media Thickness on Ultrasound (CIMT) CIMT is reasonable in adults at intermediate risk for heart attack Ankle-Brachial Index (ABI) Ankle-brachial index is reasonable in adults at intermediate risk C-reactive protein (CRP) C-reactive protein is a nonspecific marker of inflammation that is measured with a blood test The AHA makes the following recommendations for CRP: CRP can be useful when considering statin therapy in the following patients: men ≥ 50 years and women ≥ 60 years with LDL cholesterol levels < 130 mg/dl who are not on lipid-lowering drugs, hormone replacement, or immunosuppressant therapy; and who have not been diagnosed with heart disease, diabetes, chronic kidney disease, or severe inflammatory conditions. CRP is not helpful in high-risk patients In intermediate risk men ≤ 50 years or women ≤ 60 years, measurement of CRP may be reasonable for cardiovascular risk assessment In low risk men < 50 years of age or women < 60 years of age, measurement of CRP is not recommended for cardiovascular risk assessment Coronary Artery Calcium (CAC) Coronary artery calcium is a special type of CAT scan that detects and quantifies the amount of calcium within the coronary arteries The amount of calcium in the coronary arteries is directly proportional to the amount of atherosclerosis present The AHA states that CAC is reasonable in patients at intermediate risk (10-20%) CAC may be reasonable in patients at low-to-intermediate risk (6-10%) Patients at low risk should not undergo CAC For a full discussion of CAC screening in asymptomatic patients see CAC screening
Tests that are not recommended Gene testing Advanced cholesterol panels (lipoproteins, apolipoproteins, particle density and size) Beta natriuretic peptide (BNP) Stress Echocardiography CT angiography MRI for detection of vascular plaque

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• EVALUATING CHEST PAIN IN A CLINIC SETTING

• Overview
• Chest pain is a common complaint in patients of all ages, and most cases have a benign cause. However, serious life-threatening etiologies exist, and most providers err on the side of caution when evaluating chest pain.
• The recommendations presented below are for assessing stable chest pain in a clinic setting in patients without known CAD. They are derived from AHA and ESC guidelines and are helpful in determining which patients should receive further testing. Given the litigious and consequential nature of missing cardiac ischemia, many providers refer all patients with chest pain for further evaluation. These practical and easy-to-follow steps provide an evidence- and guideline-based tool that can help alleviate the anxiety and excessive testing associated with these patients.

• Step 1 - Categorize chest pain into one of the following:
• Typical angina
• Atypical angina
• Non-anginal pain


• Typical angina has the following three qualities:
• 1. Described as a "constricting," "squeezing," "heavy," or "tight" pain in the front of the chest, neck, shoulders, jaw, or arms
• 2. Pain occurs with physical exertion
• 3. Pain is relieved with rest or nitroglycerin within 5 minutes [8,9,51]


• Typical angina - all three of the above features are present
• Atypical angina - two of the above symptoms are present
• Non-anginal chest pain - one or none of the three symptoms are present [9,51]


• Other features consistent with obstructive CAD:
• Pain described as dull, aching, pressure, or gripping
• Pain that is central, left-sided, or retrosternal
• Features that are inconsistent with obstructive CAD:
• Pain described as sharp, stabbing, tearing, ripping, or burning
• Pain that is right-sided, shifting, or positional
• Pain that is unrelated to activity and/or occurs at rest
• Pain that is exacerbated by deep breaths or coughing [8,9,51,52]

• Step 2 - Obtain a resting ECG
• Most patients with chest pain should have a resting ECG
• ECG may not be necessary in young patients (< 30 years old) with atypical symptoms or when there is an obvious noncardiac cause
• Changes on resting ECG associated with a higher risk of CAD include:
• Left bundle branch block
• ST-T wave changes
• Pathologic Q waves

• Step 3 - Assess the pretest probability of obstructive CAD
• The table below gives the pretest probability of obstructive CAD based on age, sex, and chest pain type. A separate category for dyspnea is also included. Table data is derived from 3 large studies that encompassed 15,815 patients with chest pain. Using the table, patients are divided into the following categories:
• Very low-risk - pretest probability ≤ 5%
• Low-risk - pretest probability of 6 - 15%. For patients with a pretest probability of < 15%, the annual rate of cardiovascular death or MI is < 1%.
• Intermediate-high risk - pretest probability ≥ 15%

• Step 4 - Order diagnostic tests if indicated
• Once the pretest probability has been determined, testing can be performed based on the recommendations below

• References [51,52]

Very low-risk patients (pretest probability ≤ 5%) No testing is indicated unless another compelling reason is present

Low-risk patients (pretest probability of 6 - 15%) Decision for further testing should be individualized Factors that favor further testing include: (1) strong CVD risk factors (e.g. diabetes, smoking, strong family history), (2) resting ECG changes associated with CAD (e.g. left bundle branch block, ST-T wave changes, pathologic Q waves) The AHA recommends the following tests in low-risk patients: Coronary artery calcium (CAC) scoring Score of 0: less than 5% chance of obstructive CAD and a less than 1% annual risk of death or non-fatal MI Score < 100: less than 2% chance of having an abnormal myocardial perfusion scan, and a less than 3% chance of having significant obstruction on a heart cath Score ≥ 100: accuracy of CAC is limited with high sensitivity and marginal to low specificity (many false positives) [12,51] Exercise stress testing (EST) - EST without imaging is reasonable to perform in low-risk individuals to exclude myocardial ischemia and assess functional capacity

Intermediate-high risk patients (pretest probability > 15%) The AHA recommends the following tests in intermediate-high risk patients: Coronary CT angiography (CCTA) - CCTA is effective for diagnosing CAD, risk stratification, and guiding treatment decisions. CCTA may be preferred in patients < 65 years old who are not on optimal preventive therapy. Stress imaging - Stress imaging includes stress ECHO, stress myocardial perfusion imaging with SPECT or PET scan, and stress CMRI. Stress imaging may be favored in those > 65 years old because they have a higher prevalence of obstructive CAD.

• Differential
• The differential for chest pain is broad, and studies have found that no specific cause is identified in over half of patients, regardless of age. The table below lists some select causes of chest pain and their associated features.

• Reference [52]

Causes of chest pain and their associated symptoms
Cardiac
Aortic dissection History of connective tissue disorder (e.g. Marfan syndrome) Abrupt onset of severe, "tearing" pain that radiates to the back Widened mediastinum on chest X-ray
Heart valve disease Aortic stenosis: exertional dyspnea and fatigue, syncope, systolic murmur Aortic regurgitation: exertional dyspnea, holodiastolic murmur
Pericarditis Fever with pleuritic chest pain that increases in the supine position
Myocarditis Viral syndrome with fever Chest pain and dyspnea Arrhythmias
Pulmonary
Pulmonary embolism Tachycardia, shortness of breath, pleuritic chest pain
Pneumonia Fever and cough Tachycardia and shortness of breath Chest pain is often localized and pleuritic
Pneumothorax Sharp chest pain that is worse with inspiration Tachypnea and tachycardia
Gastrointestinal
Esophagitis Dysphagia, chest pain, heartburn, belching, regurgitation, food stuck in chest
Peptic ulcers Bloating, heartburn, nausea, burning, epigastric pain/discomfort
Gallbladder disease Colicky pain after eating, particularly fatty foods Right upper quadrant tenderness/pain
Esophageal tear/rupture Preceded by violent emesis or coughing Hematemesis Tachypnea
Other
Panic attack Chest pain precipitated by fear or anxiety Palpitations, sweating, tachycardia, tingling, dizziness
Costochondritis Sharp chest pain around the sternum that is worse with inspiration, coughing, and/or chest wall movement

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• DIAGNOSTIC TESTS

• Overview
• A variety of diagnostic tests are available to diagnose CAD
• A summary of the available tests and their diagnostic accuracy is detailed below

• Exercise stress testing (EST)
• Procedure
• During EST, a person walks/runs on a treadmill while their ECG is continuously monitored
• In a Bruce protocol (most widely used), there are 7 stages of exercise, and each stage is 3 minutes long. Each successive stage increases in speed and incline.
• The goal of the test is for the patient to reach 85% of their maximum predicted heart rate (Maximum predicted heart rate = 220 (210 for women) - age). Completion of 9 - 12 minutes or exercise may also be adequate. [10]
• After completion of exercise, the ECG is monitored for up to 15 minutes
• Contraindications
• Resting ECG abnormalities
• Left Ventricular Hypertrophy - may make test uninterpretable
• Left Bundle Branch Block
• Wolff-Parkinson-White pattern
• Digoxin therapy (may produce false positive)
• Resting ST-segment depression ≥ 0.5mm [8,10]
• Unstable angina
• Uncontrolled heart failure
• Uncontrolled hypertension (SBP > 20 mmHg, DBP > 110 mmHg)
• Unable to achieve ≥ 5 METs
• Severe aortic stenosis [10]
• Accuracy
• Sensitivity: 78%
• Specificity: 70%
• Both are lower in women [8,10]
• Preparation
• Beta blockers should be stopped 24 - 48 hours before the test
• Digoxin should be stopped 1 week before the test
• Certain calcium channel blockers (diltiazem and verapamil) may also need to be stopped prior to the test
• Positive test
• A positive test is defined by the following:
• ST segment depression of ≥ 1 mm at 80 ms after the J point
• ST segment down-sloping at 80 ms after the J point
• ST segment elevation in a non-Q wave lead [8]
• Normal ECG changes with exercise
• P wave increases in height
• R wave decreases in height
• J point becomes depressed
• ST segment becomes sharply upsloping
• Q-T interval shortens
• T wave decreases in height [10]
• Reasons to stop the test
• Severe ST depression ( > 3 mm )
• ST elevation > 1 mm in non-Q wave lead
• Ventricular ectopy (Frequent Premature Ventricular Contractions (PVCs), V tach)
• Supraventricular arrhythmia (atrial fibrillation, supraventricular tachycardia)
• Development of new bundle branch block
• Development of new heart block (second and third degree)
• Fall in systolic blood pressure of > 20 mmHg
• Extreme rise in blood pressure - SBP > 300 mmHg, DBP > 130 mmHg
• Patient fatigue, chest pain, dizziness, etc. [10]

• Myocardial perfusion imaging (MPI)
Terminology
• Exercise stress - patient's heart rate is increased through exercise as opposed to pharmacological stress where drugs are used to increase the heart rate
• Gated SPECT - imaging technique that combines information from SPECT images and ECG readings to evaluate left ventricular function during a SPECT scan. Ejection fraction, stroke volume, and wall motion abnormalities can be evaluated using gated SPECT.
• Myocardial Perfusion Imaging (MPI) - general term for studies that evaluate coronary blood flow using noninvasive radiologic techniques
• Pharmacological stress - patient's heart rate is increased with medications
• Radioisotope - an unstable compound that emits radiation. The emitted radiation can then be detected by external equipment.
• Scintigraphy - term used to describe the process where radioisotopes are taken internally and then detected externally with radiologic equipment
• SPECT imaging - stands for single photon emission computed tomography. SPECT is the most common method used to detect radioactive isotopes during MPI studies.
• Technetium-99m - Technetium-99m is the radioisotope most commonly administered during MPI
• Procedure
• In MPI, the patient's heart is stressed either through exercise (treadmill) or with medications (adenosine, dobutamine, dipyridamole)
• A radioisotope (Technetium-99m) is injected during peak stress
• Fifteen minutes to two hours later, SPECT images are obtained
• Resting images that require a second injection of radioisotope are also performed
• Protocols for obtaining rest/stress images differ, with some requiring one day and others two
• Accuracy
• Sensitivity: with exercise stress 82 - 88%, with pharmacological stress 88 - 91%
• Specificity: with exercise stress 70 - 88%, with pharmacological stress 75 - 90% [8]
• Precautions/limitations
• For exercise stress, beta blockers and certain calcium channel blockers (diltiazem and verapamil) may need to be stopped prior to the study being done
• In patients with severe or uncontrolled COPD or asthma, dobutamine may be the preferred agent because it does not induce bronchospasm
• Caffeine may interfere with the effects of dipyridamole and adenosine. Caffeine should be stopped 24 - 48 hrs before a study with these agents.
• Adenosine should not be given to patients with second or third degree AV block
• Images may be suboptimal in obese patients and patients with large breasts
• Patients are exposed to radiation during study

• Stress echocardiography (Stress ECHO)
• Terminology
• Exercise stress - patient's heart rate is increased with exercise on a treadmill
• Pharmacological stress - patient's heart rate is increased with medications
• Procedure
• Patient's heart is stressed through exercise or with medications (dobutamine)
• Cardiac echocardiography is performed during or immediately after stress
• Positive test
• New or worsening wall motion abnormalities and/or changes in global left ventricular function during or immediately after stress
• Accuracy
• Sensitivity: with exercise stress 70 - 85%, with pharmacological stress 85 - 90%
• Specificity: with exercise stress 77 - 89%, with pharmacological stress 79 - 90% [8]
• Precautions
• Reduced image quality may be seen in obese patients and patients with significant lung disease (COPD and emphysema)

• Coronary CT angiography (CCTA)
• Procedure
• Patient is placed in CT scanner
• Heart rate is slowed if necessary with a beta blocker to a target of < 65 beats per minute
• IV contrast is injected and CT images of the coronary arteries and heart are obtained
• Some machines are capable of calculating fractional flow reserve across lesions using computer modeling
• Accuracy
• Sensitivity: 93 - 97%
• Specificity: 80 - 90% [8]
• There can be high variability in the accuracy of the test depending on machine used, testing center, and interpreter experience [11]
• Precautions/limitations
• Accuracy may be reduced in obese patients and patients with extensive coronary calcification
• Patients must be able to hold breath for 20 seconds and lie completely still
• Lesions detected on CCTA may not cause clinically significant ischemia [8]
• Exposure to IV contrast and radiation
• Studies
• DISCHARGE Trial
• The DISCHARGE Trial published in 2022 compared CCTA to invasive coronary angiography as an initial diagnostic strategy in patients with an intermediate pretest probability of obstructive CAD. The primary outcome was major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) over 3.5 years. At the end of the study, the primary outcome occurred in 2.1% of the CT group and 3% of the angiography group (p=0.10). [PMID 35240010]
• SCOT-HEART study
• The SCOT-HEART study published in 2018 compared standard care to standard care + CTA in patients referred to a cardiologist for chest pain
• The primary outcome was death from coronary heart disease or nonfatal myocardial infarction at 5 years
• The 5-year rate of the primary endpoint was lower in the CTA group than in the standard-care group (2.3% vs 3.9%; HR 0.59, 95%CI [0.41 to 0.84] p=0.004)
• The main weakness of the study is that the outcome measures were based on ICD-10 codes collected from a database [PMID 30145934 ]
• PROMISE study
• The PROMISE study published in 2015 compared initial evaluation with CCTA to functional testing (EST, exercise or pharmacologic nuclear stress testing, and stress echocardiography) in symptomatic patients (N=10,003) with suspected CAD
• The primary outcome of the study was death, heart attack, hospitalization for unstable angina, or major procedural complication. The median follow-up period was 25 months.
• There was no significant difference in the primary outcome between patients randomized to CCTA or functional testing (CCTA 3.3%, functional testing 3%, HR 1.04, p=0.75)
• CCTA was associated with fewer catheterizations showing no obstructive CAD than was functional testing (3.4% vs. 4.3%,p=0.02), although more patients in the CCTA group underwent catheterization within 90 days after randomization (12.2% vs. 8.1%) [PMID 25773919 ]
• CCTA vs MPI study
• A study published in the Annals of Internal Medicine in 2015 compared initial evaluation with CCTA to MPI in 400 patients with acute chest pain
• The primary outcome of the study was cardiac catheterization not leading to revascularization within 1 year (false positive)
• There was no significant difference in the primary outcome between patients randomized to CCTA or MPI (CCTA 7.5%, MPI 10%, HR 0.77, 95%CI [0.40 to 1.49] p=0.44) [PMID 26052677]

• Coronary artery calcium (CAC) scoring
• Procedure
• Atherosclerotic plaques calcify over time, making calcification, which is easily detected on a CT scan, a marker of coronary artery disease. Coronary artery calcium scoring, commonly abbreviated CAC, is a procedure where a CT scan quantifies the amount of calcium in coronary arteries. The results are then converted into a score using a standardized system, with higher values indicating more atherosclerosis .
• CAC scores
• Low risk: < 100
• Intermediate risk: 100 - 399
• High risk: ≥ 400
• Precautions/limitations
• Low CAC scores (< 100) are most useful because they are associated with a very low risk of significant CAD. Scores greater than 100 are not as helpful because the presence of coronary calcium is a weak predictor of obstructive CAD.
• In asymptomatic patients, it is unclear how to proceed with intermediate-to-high CAC scores [8,12,51]
• Accuracy (symptomatic patients)
• Score of 0: less than 5% chance of obstructive CAD and a less than 1% annual risk of death or non-fatal MI
• Score < 100: less than 2% chance of having an abnormal myocardial perfusion scan, and a less than 3% chance of having significant obstruction on a heart cath
• Score ≥ 100: accuracy of CAC is limited with high sensitivity and marginal to low specificity (many false positives) [12,51]
• Accuracy (asymptomatic patients)
• The table below shows the estimated annual risk of CAD death or MI based on CAC scores in asymptomatic patients at intermediate risk (Framingham risk of 10 - 20% over ten years) for a heart attack

• Definition of intermediate risk varied slightly between studies but was typically considered 10 - 20% on the Framingham risk calculator
• Reference [12]

CAC score in asymptomatic intermediate-risk individuals	Annual risk of heart disease death or MI
0 - 99	0.4%
100 - 399	1.3%
≥ 400	2.4%

• MESA study
• CAC scores can be combined with other risk factors to improve heart attack risk estimates
• A popular risk calculator for heart disease is the Framingham risk calculator, which estimates a person's 10-year risk of heart attack based on seven common risk factors. The MESA study evaluated the utility of adding a CAC score to the Framingham risk calculation. MESA found that adding CAC scores to risk factors in the Framingham tool improved the 5-year risk estimation of a heart attack compared to the Framingham risk factors alone. For people who went on to have a coronary event during follow-up (median 5.8 years), adding CAC scores to the risk prediction model correctly reclassified 23% of patients. For patients who did not have a coronary event during follow-up, adding CAC scores to the model correctly reclassified 2% of patients. [PMID 20424251]
• The NHLBI has a website with a calculator that incorporates the CAC score with Framingham risk factors to estimate a person's 10-year heart attack risk based on data from the MESA study. See MESA CAC risk calculator.

• Professional guidelines
• The USPSTF does not recommend CAC screening in asymptomatic individuals
• The AHA states that CAC screening is reasonable in patients with intermediate risk (defined as a Framingham risk score of 10 - 20%), and may be reasonable in patients at low-intermediate risk (6 - 10%). CAC screening is not useful in patients at low risk (< 6%), and in patients at high risk.
• The AHA 2018 lipid treatment guidelines offer some guidance on using CAC scores in decisions regarding statin therapy (see CAC scoring in lipid therapy management)
• Summary
• Most providers by now have had an asymptomatic patient bring in a CAC study and ask them what to do with the results. Unfortunately, there are no good studies at this time to guide decision-making.
• Given the available evidence, the following guidance seems reasonable:
• CAC score < 100: no intervention needed
• CAC score 101 - 399: patients with risk factors for heart disease should have them managed aggressively
• CAC score ≥ 400: heart disease risk factors should be managed aggressively. It is reasonable to consider some type of stress testing, although objective evidence that this improves outcomes does not exist.

• Cardiac magnetic resonance imaging (CMRI)
• Procedure
• An MRI machine is used to evaluate heart motion and anatomy
• Contrast can be given to the patient to evaluate coronary blood flow and artery disease
• Accuracy
• Sensitivity: 87 - 88%
• Specificity: 56 - 70% [8]
• Precautions/limitations
• Not widely available
• High variability in accuracy due to lack of experience and nonuniformity of techniques
• Studies
• A study that compared CMRI to angiography with fractional flow reserve found that CMRI led to a lower rate of revascularization and was noninferior for a composite outcome of death, nonfatal myocardial infarction, or target-vessel revascularization within 1 year. [PMID 31216398]

• Myocardial positron emission tomography (PET) scans
• Procedure
• During myocardial PET scanning, a radioactive compound called a tracer is injected into the patient during pharmacological stress. As the tracer decays, photons are detected by the PET scanner, and an image of the heart is formed. Common tracers used in myocardial PET imaging include Oxygen-15-labeled water(H₂¹⁵O), 13 N-labeled ammonia (¹³NH₃), and ⁸²rubidium (⁸²Rb). In recent years, PET scanners have been combined with CT scanners to create a hybrid device that provides more accurate and comprehensive anatomical and functional information.
• Tracers decay rapidly, so patients are injected while they are lying in the scanner, and cardiac stressing is done with pharmacological agents (e.g. adenosine)
• Accuracy
• Sensitivity: 84 - 93%
• Specificity: 81 - 88%
• Advantages
• Image quality is superior to SPECT and obesity does not affect quality
• Radiation exposure is lower than SPECT
• PET scans have higher resolution so smaller perfusion defects can be detected
• Perfusion can be quantified (ml/min/gram of tissue)
• Precautions/limitations
• Onsite cyclotron or generator is required to make the tracers
• Expensive and not widely available
• Current tracers decay rapidly so exercise stressing is not plausible [45,46]

• Coronary angiography (heart cath)
• Terminology
• Coronary angiography - coronary angiography is a procedure where a cardiologist inserts a catheter into the femoral or radial artery. The catheter is advanced to the heart, where it is used to inject contrast into the coronary arteries, allowing their anatomy to be observed on X-rays. Other techniques that allow for intravascular assessment of arterial stenosis, including ultrasonography and optical coherence tomography, have also been developed.
• Angioplasty - angioplasty is a procedure where a narrowed coronary artery is opened with an inflatable balloon, and a stent is placed to keep it open
• Coronary artery bypass grafting (CABG) - surgery where vessels grafted from other parts of the body, typically the leg and chest wall, are used to bypass narrowed arteries in the heart
• Percutaneous Coronary Intervention (PCI) - term for heart catheterization with angioplasty
• Percutaneous transluminal coronary angioplasty (PTCA) - term for heart catheterization with angioplasty
• Procedure
• Patient is taken to a cath lab where coronary angiography is performed, and stenotic vessels are treated with PCI
• Accuracy
• Coronary angiography allows for direct visualization of arterial anatomy and is considered the gold standard for assessing coronary artery disease
• Precautions/limitations
• It is not uncommon for interpretations of stenosis to vary between observers
• Significant stenosis seen on heart cath may not cause clinically significant ischemia (decreased blood flow)
• Angiography cannot determine which plaques are likely to break off and cause an infarction
• Patient is exposed to radiation and contrast [8]
• Studies
• A study published in 2023 found that intravascular imaging-guided PCI was superior to angiography-guided PCI in patients with complex coronary-artery lesions. [PMID 36876735]

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• ACUTE HEART ATTACK

• Acute heart attacks are typically divided into two categories:
• Non-ST Elevation Myocardial Infarction (NSTEMI)
• ST Elevation Myocardial Infarction (STEMI)

• Non-ST elevation myocardial infarction (NSTEMI)
• Pathology
• NSTEMI is thought to be caused by the disruption or erosion of atherosclerotic plaques in the coronary blood vessels. The defect initiates a pathological process that leads to decreased blood flow (ischemia). This is in contrast to STEMI, where blood flow is entirely occluded (infarction).
• Treatment
• Antiplatelet therapy
• Unless contraindicated, all patients with suspected heart attack should receive a dose of nonenteric-coated aspirin (162 - 325 mg). The aspirin may be chewed or swallowed.
• See AHA dual antiplatelet therapy (DAPT) recommendations for more on antiplatelet therapy in acute heart attack
• Coronary angiography followed by PCI/CABG as indicated
• Early angiography with intent to perform revascularization should be performed in patients with refractory angina, hemodynamic instability, or electrical instability
• Early angiography with intent to perform revascularization should be performed in patients with an elevated risk for clinical events
• Elevated risk for clinical events is defined as
• Recurrent angina or ischemia at rest or with low-level activities despite intensive medical therapy
• Elevated cardiac biomarkers (TnT or TnI)
• New or presumably new ST-segment depression
• Signs or symptoms of heart failure or new or worsening mitral regurgitation
• High-risk findings from noninvasive testing
• Hemodynamic instability
• Sustained ventricular tachycardia
• PCI within 6 months
• Prior CABG
• High risk score (e.g., TIMI, GRACE)
• Reduced left ventricular function (LVEF less than 40%) [1, 30]
• Medical therapy (noninvasive)
• Medical therapy should be used in patients with extensive comorbidities (ex. liver or lung failure, cancer) where the risks of revascularization outweigh the benefits
• Medical therapy may be used in patients with a low risk of clinical events (ex. low TIMI, GRACE score) [1]
• Fibrinolysis
• Fibrinolysis is not effective in patients with NSTEMI and should not be used [1]

• ST-elevation myocardial infarction (STEMI)
• Pathology
• STEMI occurs when a thrombi lodges in a coronary artery and blood flow is totally occluded (infarction). This is in contrast to NSTEMI, where blood flow is only partially occluded (ischemia).
• Treatment
• Antiplatelet therapy
• Unless contraindicated, all patients with suspected heart attack should receive a dose of nonenteric-coated aspirin (162 - 325 mg). The aspirin may be chewed or swallowed.
• See AHA dual antiplatelet therapy (DAPT) recommendations for more on antiplatelet therapy in acute heart attack
• Coronary angiography followed by PCI/CABG as indicated
• All patients with STEMI and symptom onset within the last 12 hours should receive angiography followed by PCI/CABG as indicated
• The goal is for patients with STEMI to undergo angiography within 90 minutes of their first contact with medical personnel
• If a patient is taken to a hospital that does not have angiography/PCI capabilities, the goal is to transfer the patient to a hospital with PCI, and for the patient to undergo angiography/PCI within 120 minutes of first contact with medical personnel [31]
• Fibrinolysis
• If it is not possible for the patient to undergo angiography/PCI within 120 minutes of first contact with medical personnel, then fibrinolytic therapy should be administered [31]
• Ideally, fibrinolytic therapy should be administered within 30 minutes of arrival to a non-PCI-capable hospital
• Definitions
• Fibrinolysis - Fibrinolysis is the dissolution of blood clots with medications. rt-PA is the most common medication used to dissolve clots.
• Recombinant tissue plasminogen activator (rt-PA) - Tissue plasminogen activator (t-PA) is a naturally occurring protein that acts by enhancing the conversion of plasminogen to plasmin. Plasmin causes dissolution and lysis of blood clots. Recombinant tissue plasminogen activator (rt-PA) is a synthetic version of (t-PA). It is available in several medications (ex. Alteplase®, Reteplase®, Tenecteplase®). rt-PA is selective for plasminogen that is bound to fibrin, and therefore it is more selective for blood clots. First generation tissue plasminogen activators (ex. streptokinase, urokinase) are not selective for plasminogen bound to fibrin and may lead to higher bleeding rates.
• Fibrinolysis illustration
• Absolute and relative contraindications for fibrinolytic therapy
• Absolute contraindications
• Any prior Intracranial hemorrhage
• Known structural cerebral vascular lesion (eg, arteriovenous malformation)
• Known malignant intracranial neoplasm (primary or metastatic)
• Ischemic stroke within 3 months (EXCEPT acute ischemic stroke within 4.5 hours)
• Suspected aortic dissection
• Active bleeding or bleeding diathesis (excluding menses)
• Significant closed-head or facial trauma within 3 months
• Intracranial or intraspinal surgery within 2 months
• Severe uncontrolled hypertension (unresponsive to emergency therapy)
• For streptokinase, prior treatment within the previous 6 months
• Relative contraindications
• History of chronic, severe, poorly controlled hypertension
• Significant hypertension on presentation (SBP > 180 mmHg or DBP > 110 mmHg)
• History of prior ischemic stroke > 3 months
• Dementia
• Known intracranial pathology not covered in absolute contraindications
• Traumatic or prolonged (> 10 minutes) CPR
• Major surgery (< 3 weeks)
• Recent (within 2 to 4 weeks) internal bleeding
• Noncompressible vascular punctures
• Pregnancy
• Active peptic ulcer
• Oral anticoagulant therapy [31]

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• TREATMENT (PCI vs CABG vs MT)

• Overview
• There are 3 options for treating stable CAD
• Percutaneous Coronary Intervention (PCI) - angioplasty with stenting
• Coronary Artery Bypass Grafting (CABG)
• Medical Therapy (MT) - typically involves aspirin, statins, and aggressive treatment of risk factors (ex. diabetes, hypertension, cholesterol)
• These options have been compared in a number of studies involving different patient subgroups. Some of the larger trials are detailed below.

• STUDY
  FAME trial - CABG vs PCI with Fractional Flow Reserve (FFR) in Multivessel Disease, NEJM (2021) [PubMed abstract]
• Design: Randomized controlled trial (N=1500 | length = 1 year) in patients with three-vessel coronary artery disease not involving the left main coronary artery
• Treatment: FFR-guided PCI with zotarolimus-eluting stents vs CABG
• Primary outcome: Occurrence within 1 year of a major adverse cardiac or cerebrovascular event, defined as death from any cause, myocardial infarction, stroke, or repeat revascularization
• Results:
• Primary outcome: PCI - 10.6%, CABG - 6.9% (HR 1.5, 95%CI [1.1 - 2.2])
• Overall mortality: PCI - 1.6%, CABG - 0.9% (HR 1.7, 95%CI [0.7 - 4.3])
• Findings: In patients with three-vessel coronary artery disease, FFR-guided PCI was not found to be noninferior to CABG with respect to the incidence of a composite of death, myocardial infarction, stroke, or repeat revascularization at 1 year

• AHA 2021 recommendations
• Recommendations for revascularization to improve survival in stable CAD compared with medical therapy
• Three vessel disease (with or without proximal LAD) and normal ejection fraction
• CABG may be reasonable to improve survival in patients with suitable anatomy
• The usefulness of PCI to improve survival is uncertain
• Left main disease
• CABG is recommended to improve survival
• In selected patients with stable CAD and significant left main stenosis for whom PCI can provide equivalent revascularization to that possible with CABG, PCI is reasonable to improve survival


• Patients with diabetes
• In patients with diabetes and multivessel CAD with involvement of the LAD, who are appropriate candidates for CABG, CABG (with a LIMA to the LAD) is recommended in preference to PCI to reduce mortality and repeat revascularizations
• In patients with diabetes, who have multivessel CAD amenable to PCI and an indication for revascularization and are poor candidates for surgery, PCI can be useful to reduce long-term ischemic outcomes
• In patients with diabetes, who have left main stenosis and low- or intermediate-complexity CAD in the rest of the coronary anatomy, PCI may be considered an alternative to CABG to reduce major adverse cardiovascular outcomes [50]

• Summary
• The treatment of CAD is constantly evolving as new drugs and procedures are introduced
• Results from the trials detailed above are summarized below
• Medical therapy
• All patients with CAD should receive guideline-recommended medical therapy with aggressive risk factor management
• The ISCHEMIA and ISCHEMIA-CKD trials published in 2020 are the most recent trials to compare MT to an invasive strategy. The trials are superior to previous trials because contemporary medical therapy was used and crossover rates (21%, ISCHEMIA | 19.6%, ISCHEMIA-CKD) were low for revascularization. Medical therapy was found to be noninferior to an invasive strategy in patients with stable CAD. Patients with left main disease and significant heart failure were excluded.
• Medical therapy alone has not been studied in left main disease
• PCI vs CABG
• In trials involving multivessel disease, CABG generally outperformed PCI
• In trials that looked specifically at left main disease, PCI and CABG were equivalent in two trials and CABG was superior in a third. In all three trials, revascularization during follow-up was significantly more frequent in the PCI groups.
• Patients with HFrEF
• In the REVIVED-BCIS2 Trial, PCI + MT did not improve outcomes over MT alone in patients with an EF ≤ 35% and proven myocardial viability. In the STICH trial, CABG + MT was superior to MT in a similar patient population. Entresto®, a drug that improves heart failure outcomes, was used by 35% of participants in the REVIVED-BCIS2 trial, but it was not available when STICH was performed. It's likely that Entresto® would have improved MT results in STICH.

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• ELDERLY PATIENTS

• Overview
• Older patients (> 80 years) are mostly underrepresented in CAD trials. These patients typically have more comorbidities than younger patients which can make determining the most beneficial route of treatment difficult.
• The After Eighty Study was designed to help guide decision-making in elderly patients with NSTEMI or unstable angina. It compared conservative therapy to an early invasive strategy in patients ≥ 80 years old.

• Summary
• The After Eighty Study found that a strategy of early invasive therapy was superior to conservative therapy in patients ≥ 80 years old with NSTEMI or unstable angina
• Although early invasive treatment did not improve overall mortality, it did cut the risk of myocardial infarction in half. The need for urgent revascularization was also significantly reduced, but this was a soft endpoint that was likely susceptible to bias in this open-label study.
• In conclusion, elderly patients with NSTEMI or unstable angina who do not have significant comorbidities will likely benefit from PCI

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• PREVENTIVE PCI

• Overview
• When a patient suffers a heart attack and undergoes angiography, past guidelines recommended that the cardiologist only perform angioplasty (PCI) on the artery that is suspected to have caused the ischemia (culprit-lesion). Several studies have now looked at outcomes when other stenosed arteries (nonculprit lesions) are also treated at or around the same time, an approach referred to as "preventive PCI."
• In the CULPRIT-SHOCK study, preventive PCI was compared to culprit-lesion-only PCI in patients with cardiogenic shock. In the PRAMI and COMPLETE studies, preventive PCI was compared to culprit-lesion-only PCI in stable patients. All three studies are detailed below.

• STUDY
  Immediate vs Staged PCI of Non-culprit Lesions, Lancet (2023) [PubMed abstract]
• Design: Randomized, open-label trial (N=764 | length = 1 year) in patients with STEMI or NSTEMI acute coronary syndrome and multivessel disease with a clearly identifiable culprit lesion
• Treatment: Immediate culprit and nonculprit lesion PCI (Immediate group) vs Immediate culprit PCI and staged nonculprit PCI within 6 weeks (Staged group)
• Primary outcome: Composite of all-cause mortality, myocardial infarction, any unplanned ischemia-driven revascularisation, or cerebrovascular events at 1 year after the index procedure
• Results:
• Primary outcome: Immediate - 7.6%, Staged - 9.4% (p=0.0011 for noninferiority)
• Overall mortality: Immediate - 1.9%, Staged - 1.2% (p=0.30)
• Findings: In patients presenting with acute coronary syndrome and multivessel disease, immediate complete revascularization was non-inferior to staged complete revascularization for the primary composite outcome and was associated with a reduction in myocardial infarction and unplanned ischemia-driven revascularization.

• AHA 2021 recommendations
• In selected hemodynamically stable patients with STEMI and multivessel disease, after successful primary PCI, staged PCI of a significant noninfarct artery stenosis is recommended to reduce the risk of death or MI
• In selected patients with STEMI with complex multivessel noninfarct artery disease, after successful primary PCI, elective CABG is reasonable to reduce the risk of cardiac events
• In selected hemodynamically stable patients with STEMI and low-complexity multivessel disease, PCI of a noninfarct artery stenosis may be considered at the time of primary PCI to reduce cardiac event rates.
• In patients with STEMI complicated by cardiogenic shock, routine PCI of a noninfarct artery at the time of primary PCI should not be performed because of the higher risk of death or renal failure [50]

• Summary
• Preventive PCI appears to be beneficial in stable patients. In the CULPRIT-SHOCK study that only enrolled unstable patients with acute MI, preventive PCI led to worse outcomes.

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• THROMBECTOMY

• Overview
• Thrombectomy is a procedure where the occluding thrombus (clot) in the coronary artery is manually removed during PCI. Removing the thrombus before stenting may thereoretcilly prevent distal embolization and improve blood flow
• The TAPAS trial [PMID 18256391] published in 2008 showed improvement in markers of perfusion when thrombectomy was added to PCI. After TAPAS, a number of guidelines began to recommend routine thrombectomy in patients with STEMI.
• In 2015, the TOTAL trial was published that compared PCI alone to PCI with manual thrombectomy in 10,732 patients. Results from 1-year of follow-up were also published, and both are detailed below.

• AHA 2015 recommendations
• The usefulness of selective and bailout aspiration thrombectomy in patients undergoing primary PCI is not well established
• Routine aspiration thrombectomy before primary PCI is not useful [41]

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• PRIMARY PREVENTION WITH ASPIRIN

• Overview
• The most effective way to prevent CVD is to properly manage risk factors like hypertension, dyslipidemia, and diabetes. Antiplatelet therapy with aspirin can also lower the risk of CVD events, but at the same time, it increases the risk of significant bleeding. Whether the risk-benefit ratio of aspirin therapy is favorable in patients without documented CVD is a matter of controversy.
• Five large randomized controlled trials that compared aspirin to placebo or control in various populations are detailed below. None of the trials found a net benefit of aspirin.

• Professional recommendations
• The AHA updated their aspirin recommendations in 2019 after the ARRIVE trial, ASCEND study, and ASPREE study were published
• The USPSTF recommendations were updated in 2021


• AHA 2019 recommendations
• Low-dose aspirin (75-100 mg orally daily) might be considered for the primary prevention of ASCVD among select adults 40 to 70 years of age who are at higher ASCVD risk but not at increased bleeding risk
• Low-dose aspirin (75-100 mg orally daily) should not be administered on a routine basis for the primary prevention of ASCVD among adults > 70 years of age
• Low-dose aspirin (75-100 mg orally daily) should not be administered for the primary prevention of ASCVD among adults of any age who are at increased risk of bleeding
• The AHA does not specifically define "higher ASCVD risk" or "increased risk of bleeding" but states the following:
• Elevated ASCVD risk - as calculated by risk estimators like the AHA risk calculator or based on the presence of specific ASCVD risk factors
• Increased risk of bleeding - A nonexhaustive list of scenarios associated with increased risk of bleeding includes: a history of previous gastrointestinal bleeding or peptic ulcer disease or bleeding from other sites, age >70 years, thrombocytopenia, coagulopathy, CKD, and concurrent use of other medications that increase bleeding risk, such as nonsteroidal anti-inflammatory drugs, steroids, direct oral anticoagulants, and warfarin [47]


• USPSTF 2021 recommendations
• Adults 40 to 59 years with a 10-year CVD risk ≥ 10%: The decision to initiate low-dose aspirin use for the primary prevention of CVD should be an individual one. Evidence indicates that the net benefit of aspirin use in this group is small. Persons who are not at increased risk for bleeding and are willing to take low-dose aspirin daily are more likely to benefit. [Grade C] (AHA 10-year risk calculator)
• Adults ≥ 60 years The USPSTF recommends against initiating low-dose aspirin use for the primary prevention of CVD in adults age 60 years or older. [Grade D]

• Summary
• Five large randomized controlled trials have now been published that found no clear benefit of aspirin for the primary prevention of CVD. Most of the trials only enrolled patients who were at high risk for CVD.
• Aspirin has no proven net benefit in the primary prevention of CVD in any patient population

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• SECONDARY PREVENTION | Antiplatelet therapy

• Overview
• Stable CAD (> 12 months since ACS, PCI, or CABG)
• A number of trials that took place in the 1970s and 1980s found that aspirin reduced the risk of heart attacks and death in patients with cardiovascular disease. Daily low-dose aspirin is universally recommended in patients with established CAD who do not have a contraindication.
• P2Y12 inhibitors have also been studied in stable CAD. Clopidogrel was compared to aspirin in the CAPRIE trial and HOST-EXAM trial detailed below, and dual antiplatelet therapy with a P2Y12 inhibitor and aspirin has been evaluated in several large trials. In the CHARISMA trial, clopidogrel + aspirin was compared to aspirin alone, and in the PEGASUS-TIMI 54 trial and the THEMIS trial, the combination of ticagrelor and aspirin was compared to aspirin alone.
• Acute coronary syndrome and/or PCI
• After ACS, dual antiplatelet therapy (DAPT) is recommended for a period of time in most patients. See antiplatelet therapy in CAD for a review.

• AHA recommendations
• The AHA recommends that all patients with CAD take 75 - 162 mg of aspirin daily in the absence of contraindications
• For patients who cannot take aspirin, clopidogrel (Plavix®) is considered an appropriate alternative
• Clopidogrel + aspirin "might" be reasonable in certain high-risk patients with CAD [8]

• Summary
• In the CAPRIE trial and HOST-EXAM trial, clopidogrel was slightly more effective than aspirin in preventing a composite of cardiovascular outcomes and bleeding events. Overall mortality was not significantly different in either trial. The CAPRIE trial was an international study and the HOST-EXAM trial was performed in South Korea where 50 - 60% of the population have a CYP2C19 loss-of-function allele (see clopidogrel and CYP2C19 poor metabolizers for more). The significance of this and how it relates to other patient populations is unknown.
• In the trials where aspirin was compared to dual antiplatelet therapy, the addition of clopidogrel or ticagrelor to aspirin lowered the overall risk of CVD events but increased the risk of bleeding. There was no significant effect on mortality in any of the trials.

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• SECONDARY PREVENTION | Antiplatelet + Anticoagulant Therapy

• Overview
• Stable CAD (> 12 months since ACS, PCI, or CABG)
• Patients with stable CAD sometimes have an indication for anticoagulation (e.g. A fib, DVT, PE). Whether these patients should receive an antiplatelet agent in addition to their anticoagulant therapy has long been a matter of debate. In 2019, a study was published that finally offered some guidance on the issue. The AFIRE study detailed below compared rivaroxaban alone to rivaroxaban + antiplatelet therapy in patients with stable CAD and A fib.
• Acute coronary syndrome and/or PCI
• Antithrombotic therapy recommendations for patients with ACS and/or PCI who also have A fib or VTE are reviewed here - triple therapy

• ACC 2020 recommendations for antithrombotic therapy in patients with CAD and A fib or VTE
• Patients with A fib or VTE who are > 12 months since ACS, PCI, or CABG
• Patients should receive oral anticoagulant therapy only (DOAC is preferred). Antiplatelet therapy is not recommended.
• Patients with A fib or VTE who are < 12 months since ACS, PCI, or CABG
• See ACC 2020 triple therapy recommendations [49]

• Summary
• The AFIRE study found that adding antiplatelet therapy to an anticoagulant in patients with A fib and stable CAD led to worse outcomes. The ACC 2020 recommendations are in line with these findings.

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• SECONDARY PREVENTION

• Statins
• All patients who have documented CAD should receive a high-intensity statin unless contraindicated
• See AHA cholesterol treatment recommendations for more

• Beta blockers
• The AHA 2012 CAD guidelines recommend that beta blockers be given for 3 years to all patients with a normal EF after a myocardial infarction or acute coronary syndrome
• Beta blockers should be used indefinitely in all patients with an EF ≤ 40% with heart failure and prior myocardial infarction. Carvedilol, metoprolol succinate, and bisoprolol are the only three beta blockers that should be used [8]
• See beta blockers for more

• ACE inhibitors and ARBs
• The AHA 2012 CAD guidelines recommend that the following patients with stable ischemic heart disease receive an ACE Inhibitor or ARB:
• Patients with an ejection fraction ≤ 40%
• Patients with hypertension
• Patients with chronic kidney disease
• Patients with diabetes [8]

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• AHA RECOMMENDATIONS FOR CABG PATIENTS

• Overview
• In 2015, the AHA published recommendations specifically for CABG patients
• The recommendations are summarized below
• Antiplatelet therapy
• Aspirin should be administered preoperatively and within 6 hours after CABG in doses of 81 to 325 mg daily. It should then be continued indefinitely to reduce graft occlusion and adverse cardiac events. (Clopidogrel 75 mg once daily is a reasonable alternative in patients who cannot take aspirin)
• After off-pump CABG, dual antiplatelet should be administered for 1 year with combined aspirin (81 – 162 mg daily) and clopidogrel 75 mg daily to reduce graft occlusion
• Statin therapy
• All patients should receive a statin
• For patients < 75 years, high-intensity statin therapy (atorvastatin 40–80 mg, rosuvastatin 20–40 mg) should be administered
• Moderate-intensity statin may be appropriate in patients who cannot tolerate high-intensity statins, or in those at higher risk for drug interactions (ex. > 75 years old)
• Beta blockers
• All CABG patients should be prescribed perioperative beta blocker therapy to prevent postoperative atrial fibrillation, ideally starting before surgery, unless contraindicated (e.g. bradycardia, severe reactive airway disease)
• Patients with a history of heart attack should be prescribed a beta blocker
• Patients with heart failure or left ventricular dysfunction should be prescribed a beta blocker (bisoprolol, sustained-release metoprolol succinate, or carvedilol)
• ACE inhibitors/ARBs
• ACE inhibitors should be given to CABG patients with recent heart attack, heart failure, left ventricular dysfunction, diabetes, and/or chronic kidney disease
• ARBs may be used in patients who cannot tolerate ACE inhibitors
• Aldosterone antagonists
• Aldosterone antagonists are reasonable after CABG in patients with EF < 35% and who have NYHA class II - IV heart failure
• Blood pressure goals
• Blood pressure goal of < 140/85 mmHg is reasonable, although the ideal BP goal has not been determined in randomized controlled trials
• Implantable cardioverter-defibrillators (ICDs)
• ICD therapy for the prevention of sudden cardiac death should only be performed after 3 months of post-op medical therapy has been provided and persistent left ventricular dysfunction (EF < 35%) has been confirmed [39]

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• ANGINA (CHEST PAIN) TREATMENT

• Overview
• The AHA recommends beta blockers as first-line treatment for angina in patients with CAD
• Calcium channel blockers and long-acting nitrates are recommended as second-line therapies in patients who cannot tolerate beta blockers and in those who are uncontrolled on beta blockers


• PCI
• A study published in the Lancet in 2018 compared PCI to sham PCI in patients with single vessel disease and stable angina. The study found no significant effect of PCI on difference in exercise time and angina symptoms when compared to the sham procedure. [PMID 29103656]


• Pharmacological treatments for angina are reviewed on these pages:
• Beta Blockers in angina
• Calcium channel blockers in angina
• Nitrates in angina

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• FOLLOW-UP IN CAD

• Patients with CAD should have regular follow-up for risk factor evaluation and treatment, along with monitoring for new or worsening symptoms. Routine noninvasive testing (e.g. ECG, stress testing, ECHO, MPI) in stable patients has not been proven to be beneficial. A study in high-risk patients that compared routine functional testing (nuclear stress testing, EST, or stress echo) one year after PCI to standard care found no benefit of routine testing. [PMID 36036496]
• The AHA makes a soft recommendation that noninvasive testing may be helpful in patients with a prior history of silent ischemia or those at high risk for a recurrent event. The recommendation gives a time interval for testing of every 2 years or more. [8]

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• BIBLIOGRAPHY

• 1 - PMID 21444888 - AHA GL on Unstable angina and NSTEMI
• 2 - PMID CDC website
• 3 - PMID 12485966 - ATP III
• 4 - PMID 21505219
• 5 - PMID 21252734
• 6 - PMID 21251585
• 7 - PMID 21787906
• 8 - PMID 23166211 - AHA GL on CAD
• 9 - PMID 22420013 - NCGC GL
• 10 - PMID 11991917
• 11 - PMID 21403014
• 12 - PMID 17220398 - AHA CAC GL
• 13 - PMID 20424251 - Mesa study
• 14 - PMID 7994804 - CASS study
• 15 - PMID 7729018 - CASS study left main dx
• 16 - PMID 7729019 - CASS study left main equivalent dx
• 17 - PMID 17387127 - Courage trial
• 18 - PMID 19502645 - BARI2 trial
• 19 - PMID 17339566 - MASS trial
• 20 - PMID 21463150 - STICH trial
• 21 - PMID 19228612 - SYNTAX trial
• 22 - PMID 23121323 - FREEDOM trial
• 23 - PMID 22231610 - AIM MA
• 24 - PMID 19482214 - Lancet MA
• 25 - PMID 8918275 - CAPRIE trial
• 26 - PMID 16531616 - CHARISMA trial
• 27 - PMID 23484825
• 28 - PMID 23439102
• 29 - PMID 20197530
• 30 - PMID 22800849
• 31 - PMID 23247304
• 32 - PMID 23991625
• 33 - PMID 25401325
• 34 - PMID 25775317
• 35 - PMID 25773919 PROMISE study
• 36 - PMID 25774645 BEST trial
• 37 - PMID 25853743 TOTAL trial
• 38 - PMID 25853659 Height and CAD
• 39 - PMID 25679302 Post-CABG GL
• 40 - PMID 26052677 CCTA vs MPI
• 41 - PMID 26490017 - AHA 2015 focused update
• 42 - PMID 26559572 - COURAGE follow-up
• 43 - PMID 21463149 - PRECOMBAT trial
• 44 - PMID 30145934 - Coronary CT Angiography and 5-Year Risk of Myocardial Infarction, NJEM (2018)
• 45 - PMID 28188475 - Myocardial perfusion imaging with PET, Int J Cardiovasc Imaging (2017)
• 46 - PMID 30145934 - American Society of Nuclear Cardiology and Society of Nuclear Medicine and Molecular Imaging Joint Position Statement on the Clinical Indications for Myocardial Perfusion PET, The Journal of Nuclear Medicine (2016)
• 47 - PMID 30894319 - 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease
• 48 - PMID 22315257 ACCP GL on thrombosis
• 49 - PMID 33250267 - 2020 ACC Expert Consensus Decision Pathway for Anticoagulant and Antiplatelet Therapy in Patients With Atrial Fibrillation or Venous Thromboembolism Undergoing Percutaneous Coronary Intervention or With Atherosclerotic Cardiovascular Disease, JACC (2020)
• 50 - PMID 34882436 - 2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines, Circulation (2022)
• 51 - PMID 31504439 - 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes, Eur Heart J (2020)
• 52 - PMID 34709879 - 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines, Circulation (2021)