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DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 13th Edition

Chapter 36: Chronic Coronary Disease

Paul P. Dobesh; Robert J. DiDomenico; Kelly C. Rogers

KEY CONCEPTS

KEY CONCEPTS

Chronic coronary disease (CCD) is caused by an obstructive atherosclerotic plaque in one or more epicardial coronary arteries. Increases in
myocardial oxygen demand in the setting of a fixed decrease in myocardial oxygen supply result in myocardial ischemia. Some patients with CCD
may have a component of vasospasm that requires a slightly different pharmacologic approach.

Chest pain (angina) from exertion is the cardinal symptom of myocardial ischemia in patients with CCD. Using the PQRST pneumonic can help
distinguish between chest pain of cardiac and noncardiac origin.

Assessment of successful treatment of angina includes reducing the number of episodes, enabling patients to participate in activities that
provide a high­level quality of life (eg, Canadian Cardiovascular Society Classification [CCS], Seattle Angina Questionnaire), and decreasing
mortality by using guideline­directed medical therapy (GDMT).

Evaluation of patients with or suspected of having CCD should include an assessment of medical history, including medications, vital signs,
and laboratory values (eg, high­sensitivity cardiac troponin [hs­cTn], fasting lipid profile). For patients with new or worsening symptoms, an
electrocardiogram (ECG), stress testing, and/or imaging studies (eg, coronary angiogram) may be performed to detect coronary atherosclerosis.

Revascularization procedures may provide a survival advantage over GDMT in select CCD patients with more extensive atherosclerotic
disease but have not demonstrated a clear advantage over GDMT in those with less extensive disease. Antithrombotic therapy is necessary after
revascularization for a variable duration of time.

Management of modifiable atherosclerotic risk factors is key to reducing mortality and improving quality of life in patients with CCD.

Aspirin, angiotensin­converting enzyme inhibitors, and statins play an important role in preventing adverse cardiovascular events in patients
with CCD.

β­Blockers, calcium channel blockers, and long­acting nitrates are recommended for the management and control of angina in patients with
CCD and are often used in combination.

Ranolazine is recommended as adjunctive therapy for those who remain symptomatic. Calcium channel blockers and nitrates are first­line
therapies in vasospastic disease.

All patients with CCD should receive sublingual nitroglycerin for acute symptomatic treatment and should receive education regarding its
proper use.

BEYOND THE BOOK

BEYOND THE BOOK

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To better understand the normal physiology of the heart and the pathophysiology of coronary artery disease (CAD), please watch the following
Chapter 36: Chronic Coronary Disease, Paul P. Dobesh; Robert J. DiDomenico; Kelly C. Rogers Page 1 / 44
videos.McGraw
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1. Pathophysiology of CAD—What Is Coronary Artery Disease? Khan Academy: https://tinyurl.com/y3cjyb8v (Duration: 13:38 minutes)
 proper use.
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BEYOND THE BOOK

BEYOND THE BOOK

To better understand the normal physiology of the heart and the pathophysiology of coronary artery disease (CAD), please watch the following
videos. These videos are useful to enhance learner’s understanding regarding the COLLECT and ASSESS steps in the Patient Care Process.

1. Pathophysiology of CAD—What Is Coronary Artery Disease? Khan Academy: https://tinyurl.com/y3cjyb8v (Duration: 13:38 minutes)

2. Myocardial oxygen supply—University of British Columbia, UBC Anesthesiology: https://tinyurl.com/yxjouoh3 (Duration: 4:59 minutes)

3. Myocardial oxygen demand—University of British Columbia, UBC Anesthesiology: https://tinyurl.com/y5488brm (Duration: 4:37 minutes)

INTRODUCTION
Coronary artery disease (CAD) is the leading cause of ischemic heart disease and is typically the result of atherosclerotic plaques in the epicardial
arteries. The process of atherosclerosis begins early in life, with fatty steaks developing in many people in their teenage years or early twenties. These
plaques grow over decades and often become pathologic in a person’s fifth decade of life and beyond. Less common causes include microvascular
angina, which is due to atherosclerosis in endocardial instead of epicardial vessels, and coronary vasospasm, caused by an increase in coronary vascular
tone in either normal or diseased vessels. These pathophysiologic changes reduce coronary blood flow, can precipitate ischemia, and often progress in
a dynamic fashion. Therefore, patient manifestations range from asymptomatic CAD to acute coronary syndrome (Chapter 37, “Acute Coronary
Syndromes”), which includes unstable angina, non­ST­segment elevation myocardial infarction (MI), or ST­segment elevation MI. Chronic coronary
disease (CCD) refers to the more stable presentations of CAD, including (1) stabilized patients discharged from the hospital following an acute coronary
syndrome (ACS) event or coronary revascularization, (2) those with reduced left ventricular function that is caused by CAD, (3) patients with stable angina
symptoms, (4) vasospastic or microvascular angina, and (5) asymptomatic CAD detected solely through screening tests. In addition to CAD,
atherosclerosis can also occur in other vascular beds, leading to cerebrovascular disease (Chapter 42, “Stroke”) and peripheral arterial disease (Chapter
e38, “Peripheral Arterial Disease”). Inappropriate, insufficient, or untreated CCD can lead not only to MI and cardiac death, but also to the development
of heart failure (HF), arrhythmias, and valvular disease. American and European societies have published guidelines for the diagnosis and management
of CCD.

EPIDEMIOLOGY
In 2020, an estimated 128 million (49%) adult Americans had at least one form of cardiovascular (CV) disease, which includes CAD, HF, stroke, and
hypertension (HTN). Between 2017 and 2020, approximately 20.5 million adult Americans had CAD, corresponding to an estimated prevalence of 7.1%.
The prevalence of CAD increases with age and is higher in men, particularly White men. Approximately 11 million Americans have chronic stable angina
pectoris (3.9% prevalence) while the prevalence of MI among adult Americans exceeds 9 million (3.2% prevalence). Chest pain, the classic symptom of
angina, is the second most common reason for adults presenting to the emergency department, accounting for more than 6.5 million visits annually. In
patients with CCD, up to one­third report having angina symptoms within the previous month, nearly one­fourth reporting daily or weekly symptoms.
Subclinical CAD is also common. One study in asymptomatic adults in the United States found nearly half had detectable CAD via coronary computed
tomography (CT) angiography, with significantly higher rates observed among men and individuals 55 years and older. Another study demonstrated that
CAD was detected in 53% of individuals without previously detectable CAD (eg, coronary artery calcium score = 0), 8% of these individuals had
significantly elevated coronary artery calcium scores consistent with increased risk of future ischemic events.

The mortality and costs associated with CAD are enormous. In 2021, CV disease was the number one cause of death in the United States with CAD being
the most common cause of CV death, accounting for 40% of all CV­related mortality, although age­standardized death rates declined by 13% between
2010 and 2021. Adjusting for age, death rates per 100,000 are highest among Black patients compared to those of White and Hispanic ancestry and
among men compared to women within each racial demographic. Social determinants of health also impact outcomes. Individuals with three or more
social determinants of health have been associated with higher risk of fatal CAD events compared to individuals with no social determinants of health.
CAD, including MI, is among the top 10 most expensive conditions treated in the United States.

The prognosis of patients with CCD is related to the extent of atherosclerotic disease, the presence of left ventricular (LV) dysfunction, and the presence
of other comorbidities. The presence of angina symptoms or ischemia has also been associated with an increased risk of CV death or MI. In addition to
mortality, CAD leads to significant morbidity. Many patients will eventually need to be hospitalized for ACS or coronary revascularization, accounting for
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Chapter 36: Chronic and 600,000
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Disease, Pauldischarges,
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Robert J. DiDomenico; CCD often have a reduced quality of life due to their inability
C. Rogers Pageto2 / 44
perform activities of daily living without chest pain, which can result in time lost from work,
©2025 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility lost productivity, and large indirect costs to patients and
society. In fact, angina symptoms prior to treatment interventions are the factor most strongly associated with improved symptom control and quality of
life following the intervention.
social determinants of health have been associated with higher risk of fatal CAD events compared to individuals with no social determinants of health.
University of New England ­ Maine
CAD, including MI, is among the top 10 most expensive conditions treated in the United States.
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The prognosis of patients with CCD is related to the extent of atherosclerotic disease, the presence of left ventricular (LV) dysfunction, and the presence
of other comorbidities. The presence of angina symptoms or ischemia has also been associated with an increased risk of CV death or MI. In addition to
mortality, CAD leads to significant morbidity. Many patients will eventually need to be hospitalized for ACS or coronary revascularization, accounting for
approximately 1.2 million and 600,000 annual discharges, respectively. Patients with CCD often have a reduced quality of life due to their inability to
perform activities of daily living without chest pain, which can result in time lost from work, lost productivity, and large indirect costs to patients and
society. In fact, angina symptoms prior to treatment interventions are the factor most strongly associated with improved symptom control and quality of
life following the intervention.

ETIOLOGY AND PATHOPHYSIOLOGY

Angina pectoris is most often the result of an imbalance between myocardial oxygen supply and myocardial oxygen demand (MVO2). The process of
maintaining adequate coronary blood flow to meet the metabolic demands of the myocytes is complex. Multiple factors influence the supply/demand
equation.

The pathophysiology of CCD is driven by an increase in MVO2 in the setting of a fixed decrease in myocardial oxygen supply. The etiology of the fixed
decrease in supply is long­standing, well­developed atherosclerotic plaque. These plaques grow over several decades. The extent and rate of growth are
related to risk factors such as smoking, dyslipidemia, HTN, diabetes mellitus (DM), and genetics. The process and development of atherosclerosis are
detailed in Chapter 35, “Dyslipidemia.” Unlike an ACS, the episodes of angina in patients with SIHD are not caused by ruptured atherosclerotic plaque,
which leads to thrombus formation and a rapid reduction in coronary blood flow. Rather, the atherosclerotic plaques are stable, have a reduced lipid
core, and a firm calcified covering. Since the vessel lumen size does not acutely change, the atherosclerotic plaque produces a relatively fixed decrease in
myocardial oxygen supply. The pathophysiology of an ACS is covered in more detail in Chapter 37.

Determinants of Myocardial Oxygen Demand

The major determinants of MVO2 include heart rate (HR), myocardial contractility, and intramyocardial wall tension. A twofold increase in any of these
determinants requires an approximate 50% increase of coronary flow to maintain the myocardial oxygen supply. Intramyocardial wall tension is the
leading contributor to increased MVO2 and is directly related to the radius or size of the ventricular cavity and blood pressure (BP), and indirectly related
to the ventricular muscle mass. The larger the size of the ventricular cavity, the more energy or myocardial work is needed for myocardial contraction
(systole). During early systole, myocardial work peaks as the pressure in the LV overcomes the pressure outside the aortic valve. The aortic valve is then
pushed open and blood is ejected into the systemic circulation. The higher the BP outside the aortic valve, the more MVO2 needed. Increased ventricular
muscle mass should make myocardial work easier and reduce MVO2. For example, some athletes have increased ventricular muscle mass and their heart
works more efficiently. Unfortunately, left ventricular hypertrophy results in dysfunctional myocytes that do not improve MVO2. Left ventricular
hypertrophy can worsen the supply/demand balance because the blood vessel development (supply) is less than the native myocardium.

The rate­pressure product, or double product, is a common noninvasive indirect measure of MVO2. To determine the rate­pressure product, multiply the
HR and systolic BP. However, changes in contractility or volume loading of the LV are not accounted for in this calculation. An increase in MVO2
requirements commonly stems from the release of norepinephrine by adrenergic nerve endings in the myocardium and vascular bed as part of the
physiologic response to exertion, emotion, or mental stress. The rate of increase of MVO2, which correlates to the speed at which a physical task is
carried out, can be as important as the total amount of MVO2. A rapid increase in physical exertion is particularly likely to precipitate angina. Tasks
involving motion of the hands over the head can also provoke chest pain. Mental and emotional stress may precipitate angina, presumably by increasing
adrenergic tone and reducing vagal activity. Sexual activity may precipitate angina due to the combination of physical exertion and emotional
stimulation. Similarly, anger can produce constriction of coronary arteries. Other precipitates of angina include physical exertion after a heavy meal and
excessive metabolic demands imposed by chills, fever, exposure to cold, thyrotoxicosis, hypoglycemia, and other causes of tachycardia.

Determinants of Myocardial Oxygen Supply

Coronary Blood Flow

Meeting the metabolic demands of the myocardium is centered on the ability to maintain adequate coronary blood flow and coronary arterial pressure.
The coronary vasculature is made up of larger epicardial vessels, also referred to as R1 or conductance vessels, and smaller endocardial vessels called R2
or resistance vessels (Fig. 36­1). Resistance to coronary blood flow is the sum of the resistance in the R1 and R2 vessels. The larger epicardial vessels
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Chapter 36: Chronic Coronary Disease, Paul P. Dobesh; Robert J. DiDomenico; Kelly C. Rogers Page 3 / 44
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• Accessibility
vessels. These vessels will contract and dilate to maintain blood flow based on the metabolic demands of the myocardium. When a person is at rest or
not engaged in physical activity, MVO2 is low and endocardial vessels constrict. The need for blood flow is low. When there is physical exertion or
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Meeting the metabolic demands of the myocardium is centered on the ability to maintain adequate coronary blood flow and coronary arterial pressure.
The coronary vasculature is made up of larger epicardial vessels, also referred to as R1 or conductance vessels, and smaller endocardial vessels called R2
or resistance vessels (Fig. 36­1). Resistance to coronary blood flow is the sum of the resistance in the R1 and R2 vessels. The larger epicardial vessels
typically offer little resistance to blood flow and can accommodate large increases in coronary blood flow without producing a significant change in
pressure. These vessels primarily serve a conduit function. In healthy coronary arteries, resistance to flow is controlled by smaller endocardial (R2)
vessels. These vessels will contract and dilate to maintain blood flow based on the metabolic demands of the myocardium. When a person is at rest or
not engaged in physical activity, MVO2 is low and endocardial vessels constrict. The need for blood flow is low. When there is physical exertion or
emotional stress, MVO2 increases and the endocardial vessels dilate to increase myocardial oxygen supply in proportion to the increase in MVO2 (Fig. 36­
1). The process of constricting and dilating the resistance vessels based on MVO2 is called autoregulation. In response to increased MVO2, several
vasodilatory substances (eg, nitric oxide, prostacyclin, and bradykinin) are secreted and this can increase coronary blood flow four­ to fivefold over
normal resting conditions. The increase in coronary flow above resting conditions is the coronary flow reserve.

FIGURE 36­1

Coronary artery blood flow. (Reproduced with permission from Epstein SE, O’Cannon R, Talbot TL. Hemodynamic principles in the control of coronary
blood flow. Am J Cardiol 1985;56(9):4E­10E.)

The four illustrations show coronary blood flow. Panels A and C depict blood flow at rest in the absence (Panel A) and presence (Panel C) of
atherosclerosis. Panels B and D depict flow during exercise in the absence (Panel B) and presence (Panel D) of atherosclerosis.

Coronary atherosclerotic plaques typically develop in the larger epicardial vessels. As plaques grow and cause luminal narrowing, resistance to blood
flow in epicardial vessels transforms from minimal to considerable. This continues to a point where the resistance from the epicardial vessels becomes
dominant. Through autoregulation, the increase in resistance from the R1 or conductance vessels is offset by vasodilation in the R2 or resistance vessels
to maintain flow.

The luminal diameter occupied by the atherosclerotic plaque determines the drop in pressure and blood flow distal to the stenosis. The most important
determinant of resistance for any given level of flow is the minimum stenosis cross­sectional area. Because resistance is inversely proportional to the
square of the cross­sectional area, small dynamic changes in the luminal area caused by atherosclerotic plaque size, thrombus creation, or vasospasm
can lead to large changes in the stenosis pressure­flow relationship and reduce maximal perfusion during vasodilation.

Coronary plaques that occupy less than 50% of the vessel luminal diameter are often referred to as “nonobstructive.” They rarely produce ischemia or
angina. These smaller plaques typically do not produce symptoms, and therefore, the patient and clinician typically have no idea they exist. Cases of
ischemia with nonobstructive atherosclerosis are caused by concurrent vasospasm and/or microvascular disease. Small plaques have a rich lipid core
and thin fibrous cap, they are more prone to rupture and provoke acute thrombus formation, making them potentially lethal (see Chapter 37, “Acute
Coronary Syndrome”).

Once the epicardial vessel is narrowed by 70% or more of the luminal diameter, the endocardial vessels must fully dilate in order to maintain normal
coronary flow. These larger plaques are considered obstructive. At this point, much of the coronary flow reserve has been used to preserve resting
coronary blood flow and minimal physical exertion exhausts any remaining capacity. Further increases in exercise intensity are no longer accompanied
by decreases in endocardial (R2) resistance. Blood flow cannot increase to accommodate the demand and autoregulation has reached its ceiling. The
resulting flow deficit causes myocardial ischemia and, frequently, angina. The amount of exertion a patient can endure is largely based on the extent of
arterial stenosis and the remaining coronary flow reserve. The endocardial flow reserve is exhausted when the epicardial stenosis severity exceeds 90%.
Narrowing of the luminal diameter by 90% or more is called a critical stenosis.

Heart Rate and Systole

Increasing HR not only increases MVO2 but also reduces myocardial oxygen supply. While most tissues and organs are perfused during systole, the heart
is the only organ that is perfused during diastole, the phase of myocardial relaxation. There are two physiologic explanations. First, the pressure created
in the ventricles during systole creates an increase in pressure in the coronary circulation well above the pressure for coronary perfusion (50­60 mm Hg).
Only during diastole does the pressure drop sufficiently to allow coronary flow. Second, the physical compression force of the myocardium that occurs
during systole squeezes the coronary vessels closed, preventing blood flow. During a typical cardiac cycle with a normal resting HR, the myocardium
spends twice as much time in diastole compared to systole. When the HR increases, time spent in diastole is reduced while time in systole remains
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Chapter 36: Chronic Coronary Disease, Paul P. Dobesh; Robert J. DiDomenico; Kelly C. Rogers Page 4 / 44
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Oxygen Extraction and Oxygen Carrying Capacity

Increasing HR not only increases MVO2 but also reduces myocardial oxygen supply. While most tissues and organs are perfused during systole, the heart
University
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in the ventricles during systole creates an increase in pressure in the coronary circulation well above the pressure for coronary perfusion (50­60 mm Hg).
Only during diastole does the pressure drop sufficiently to allow coronary flow. Second, the physical compression force of the myocardium that occurs
during systole squeezes the coronary vessels closed, preventing blood flow. During a typical cardiac cycle with a normal resting HR, the myocardium
spends twice as much time in diastole compared to systole. When the HR increases, time spent in diastole is reduced while time in systole remains
relatively unchanged. During times of exertion and increased HR, the ratio of time spent in diastole to systole is reduced from 2:1 to as little as 1:1. This
reduces the time for myocardial perfusion, and thus, myocardial oxygen supply is significantly diminished.

Oxygen Extraction and Oxygen Carrying Capacity

Two additional determinants of myocardial oxygen supply are myocardial oxygen extraction and oxygen­carrying capacity. The oxygen­carrying capacity
of the coronary arteries is relatively fixed under normal circumstances and not capable of changing in response to increased MVO2. Therefore, during
exertion, the ability to increase oxygen delivery to myocytes is limited mainly through increasing oxygen extraction from the arterial blood. However, this
compensatory mechanism provides little additional oxygen as myocardial arterial oxygen extraction is already approximately 75% under normal
circumstances.

Arterial oxygen content is related to hemoglobin concentration and oxygen saturation. Consequently, patients with anemia (low hemoglobin) or hypoxia
(low oxygen saturation) have lower than normal oxygen­carrying capacity. Anemia is thought to impact total oxygen­carrying capacity to a greater degree
than hypoxia until the oxygen saturation falls below 50% (0.50). This explains why patients with CCD often require transfusions when hemoglobin
concentrations fall below 9 to 10 g/dL (90­100 g/L; 5.59­6.21 mmol/L), whereas patients without CCD can tolerate hemoglobin concentrations as low as 6
g/dL (60 g/L; 3.72 mmol/L). Most patients have arterial oxygen saturation between 95% and 100% (0.95 and 1.0) so oxygen therapy would not improve
oxygen delivery. Therefore, there is little opportunity to improve myocardial oxygen supply by improving myocardial oxygen extraction or oxygen­
carrying capacity, leaving increased myocardial blood flow as the principal mechanism for increasing myocardial oxygen supply.

Coronary Collateral Circulation

Collateral vessels can develop in a process termed arteriogenesis. When coronary stenosis exceeds 70%, endocardial vessel pressure falls due to
maximized autoregulation. This extent of stenosis also contributes to the severity and duration of the episodes of exertion­induced ischemia. The
ischemic episodes stimulate NO synthase and lead to the production of vascular endothelial growth factor and basic fibroblast growth factor. The
combination of altered coronary pressure, growth factors, and endogenous vasodilators (eg, NO and prostacyclin) change native collateral vessels in
existing epicardial anastomoses into mature vessels. While most functional collateral flow develops from the process of arteriogenesis, collateral
perfusion can also occur from the development of new collateral vessels in a process called angiogenesis. The process of angiogenesis is also driven by
physical forces and growth factors but produces smaller, capillary­like vessels. These vessels can provide collateral flow in the border between ischemic
and nonischemic regions of the myocardium. Capillary angiogenesis may also occur within the ischemic region and can reduce the intercapillary
distance for oxygen delivery.

Other Factors

While atherosclerotic coronary stenosis is the leading etiology in the development of CCD and angina, there are additional pathophysiologic
mechanisms that also contribute to disease onset and progression. These mechanisms include endothelial dysfunction, microvascular dysfunction,
vasospasm, platelet activation, coagulation, as well as inflammation. A reduction in NO–mediated vasodilation leads to endothelial dysfunction. This can
be due to impaired NO synthesis or availability. Reduced vasodilator response may lead to ischemia at lower levels of exertion. There can also be
impairments that reduce microvascular response to endogenous vasodilators or exaggerate the response to vasoconstrictors.

Patients with an ACS event have ruptured atherosclerotic plaque with platelet accumulation and coagulation response, producing an acute reduction in
myocardial oxygen supply. In contrast, patients with CCD may have smaller plaques (30%­50% stenosis) rupture and produce a limited platelet and
coagulation response that does not produce an acute compromise in myocardial oxygen supply. Instead, the thrombotic process is arrested, and the
thrombus undergoes re­endothelialization. This greatly accelerates plaque accumulation. Finally, inflammation plays a role in the pathophysiology of
CCD. Macrophages and T lymphocytes produce and secrete cytokines, chemokines, and growth factors that activate endothelial cells, increase
vasoreactivity, and proliferation of vascular smooth muscle cells. Elevations in C­reactive protein, a marker of inflammation, and lipoprotein (a) have
been shown to be elevated in patients with CCD and are associated with adverse CV events but are not routinely measured. While an obstructive
atherosclerotic plaque contributes to ischemia and angina in patients with CCD, the pathophysiology involves multiple mechanisms that can be used as
therapeutic targets.

Coronary Vasospasm

Vasospasm
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of exertion needed to provoke chest pain differs from day­to­day.
An example would be the patient who could walk six blocks before experiencing angina yesterday, but today can only walk one block before becoming
symptomatic. Some patients may have an obstructing atherosclerotic plaque leading to a fixed decrease in myocardial oxygen supply, but also have
been shown to be elevated in patients with CCD and are associated with adverse CV events but are not routinely measured. While an obstructive
atherosclerotic plaque contributes to ischemia and angina in patients with CCD, the pathophysiology involves multiple mechanisms
University of NewthatEngland
can be used as
­ Maine
therapeutic targets. Access Provided by:

Coronary Vasospasm

Vasospasm can occur in patients with obstructive or nonobstructive CCD. Patients without vasospasm typically have what is called fixed­threshold
angina. For example, the patient knows that working in the garden for 20 minutes or walking five blocks at a certain pace will produce chest pain. In
patients with vasospasm, the threshold of angina varies. In these patients, the amount of exertion needed to provoke chest pain differs from day­to­day.
An example would be the patient who could walk six blocks before experiencing angina yesterday, but today can only walk one block before becoming
symptomatic. Some patients may have an obstructing atherosclerotic plaque leading to a fixed decrease in myocardial oxygen supply, but also have
transient vasospasm superimposed at the site of the obstructing plaque. The vasospasm at or distal to the location of atherosclerotic plaque is typically
induced by endothelial damage. Damaged endothelial cells produce less than normal amounts of vasodilator substances such as endothelium­derived
relaxing factor and often have an exaggerated response to vasoconstrictors during exercise. Symptoms will differ based on the extent of the underlying
fixed obstruction and the degree of dynamic change in coronary arterial tone. The changing pattern of ischemia in these patients reflects varying
amounts of vasospasm.

CLINICAL PRESENTATION

CLINICAL PRESENTATION: Chronic Coronary Disease (CCD)

General

The patient is not typically in acute distress; however, careful assessment to identify features consistent with ACS is important.

Symptoms

The classic symptom of CCD is substernal chest pain or discomfort often described as a squeezing, heaviness, or tightness (Table 36­1).
Symptoms may radiate to the arms, shoulders, back, abdomen, or jaw. Nausea, vomiting, diaphoresis, or shortness of breath may also be
present.

The PQRST pneumonic (Table 36­2) is useful for structuring the patient interview to assess the history of chest pain.

Evaluation of symptoms should include an evaluation of the limitations in daily activities due to angina (eg, Canadian Cardiovascular Society
[CCS] classification system, Seattle Angina Questionnaire, see Table 36­3).

Signs

BP or HR may be elevated in patients with CCD

No physical findings are specific for CCD.

Patients with CCD may present with signs of HF, including jugular venous distention, pulmonary edema, and an S3 on auscultation.

Laboratory Tests

High­sensitivity cardiac troponin (hs­cTn) is not typically elevated in patients with CCD.

A fasting lipid panel should be evaluated to assess for the presence of dyslipidemia.

Blood chemistry tests (eg, potassium [K+], serum creatinine [SCr]), liver function tests, and blood glucose should be evaluated to assess for the
presence of CCD risk factors (eg, diabetes), risk for adverse drug events, and/or the need for dosage adjustments.

Complete blood count (eg, hemoglobin [Hgb], platelets) to determine risk of adverse drug events

Other Diagnostic Tests

A 12­lead ECG should be obtained in a patient with new or worsening symptoms of CCD. However, it is often normal in patients with CCD.

Exercise stress testing is a noninvasive test to detect CAD in patients presenting with symptoms of CCD.

To detect the presence and extent of CAD, coronary angiography may be performed in patients with a high likelihood of CCD (eg, “positive”
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Chapter 36: Chronic Coronary Disease, Paul P. Dobesh; Robert J. DiDomenico; Kelly C. Rogers Page 6 / 44
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progression of disease and include positron emission
tomography/single photon emission computed tomography myocardial perfusion imaging, cardiac magnetic resonance imaging, coronary
computed tomography (CT), and coronary CT angiography.
fixed obstruction and the degree of dynamic change in coronary arterial tone. The changing pattern of ischemia in these patients reflects varying
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CLINICAL PRESENTATION

CLINICAL PRESENTATION: Chronic Coronary Disease (CCD)

General

The patient is not typically in acute distress; however, careful assessment to identify features consistent with ACS is important.

Symptoms

The classic symptom of CCD is substernal chest pain or discomfort often described as a squeezing, heaviness, or tightness (Table 36­1).
Symptoms may radiate to the arms, shoulders, back, abdomen, or jaw. Nausea, vomiting, diaphoresis, or shortness of breath may also be
present.

The PQRST pneumonic (Table 36­2) is useful for structuring the patient interview to assess the history of chest pain.

Evaluation of symptoms should include an evaluation of the limitations in daily activities due to angina (eg, Canadian Cardiovascular Society
[CCS] classification system, Seattle Angina Questionnaire, see Table 36­3).

Signs

BP or HR may be elevated in patients with CCD

No physical findings are specific for CCD.

Patients with CCD may present with signs of HF, including jugular venous distention, pulmonary edema, and an S3 on auscultation.

Laboratory Tests

High­sensitivity cardiac troponin (hs­cTn) is not typically elevated in patients with CCD.

A fasting lipid panel should be evaluated to assess for the presence of dyslipidemia.

Blood chemistry tests (eg, potassium [K+], serum creatinine [SCr]), liver function tests, and blood glucose should be evaluated to assess for the
presence of CCD risk factors (eg, diabetes), risk for adverse drug events, and/or the need for dosage adjustments.

Complete blood count (eg, hemoglobin [Hgb], platelets) to determine risk of adverse drug events

Other Diagnostic Tests

A 12­lead ECG should be obtained in a patient with new or worsening symptoms of CCD. However, it is often normal in patients with CCD.

Exercise stress testing is a noninvasive test to detect CAD in patients presenting with symptoms of CCD.

To detect the presence and extent of CAD, coronary angiography may be performed in patients with a high likelihood of CCD (eg, “positive”
exercise stress test) to detect the presence and extent of CAD.

Other diagnostic tests may be used in select patients to detect CAD or assess for progression of disease and include positron emission
tomography/single photon emission computed tomography myocardial perfusion imaging, cardiac magnetic resonance imaging, coronary
computed tomography (CT), and coronary CT angiography.

A thorough patient history is key to the clinical assessment of a patient with CCD. Exertional chest pain is the classic presenting symptom of
patients with CCD. The differential diagnosis of “chest pain” is broad (Table 36­1). Therefore, it is important to determine if symptoms are due to cardiac
or noncardiac pathology. The patient’s description of chest pain can be helpful in determining if the pain is more likely CCD or ACS. The PQRST
pneumonic is commonly used when conducting the patient interview to gather important aspects of the chest pain story (Table 36­2).

TABLE 36­1
Differential Diagnosis of Episodic Chest Pain Resembling Angina Pectoris
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Duration Quality Provocation Relief Location Comment
 A thorough patient history is key to the clinical assessment of a patient with CCD. Exertional chest pain is the classic presenting symptom of
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patients with CCD. The differential diagnosis of “chest pain” is broad (Table 36­1). Therefore, it is important to determine if symptoms are due to cardiac
Access Provided by:
or noncardiac pathology. The patient’s description of chest pain can be helpful in determining if the pain is more likely CCD or ACS. The PQRST
pneumonic is commonly used when conducting the patient interview to gather important aspects of the chest pain story (Table 36­2).

TABLE 36­1
Differential Diagnosis of Episodic Chest Pain Resembling Angina Pectoris

Duration Quality Provocation Relief Location Comment

Effort angina 5­15 minutes Visceral During effort or emotion Rest, nitroglycerin Substernal, First
(pressure) radiates episode
vivid

Rest angina 5­15 minutes Visceral Spontaneous Nitroglycerin Substernal, Often

(pressure) radiates nocturnal

Mitral valve Minutes to Superficial Spontaneous (no pattern) Time Left No pattern,
prolapse hours (rarely anterior variable
visceral)

Esophageal 10 minutes to 1 Visceral Spontaneous, cold liquids, Foods, antacids, H2 blockers, proton Substernal, Mimics
reflux hour exercise, lying down pump inhibitors, nitroglycerin radiates angina

Peptic ulcer Hours Visceral, Lack of food, “acid” foods Foods, antacids, H2 blockers, proton Epigastric,
burning pump inhibitors substernal

Biliary disease Hours Visceral (wax Spontaneous, food Time, analgesia Epigastric, Colic
and wane) radiates

Cervical spine Variable Superficial Spontaneous, food Time, analgesia Arm, neck Not
disorders (gradually relieved by
subsides) rest

Hyperventilation 2­3 minutes Visceral Emotion, tachypnea Stimulus removed Substernal Facial
paresthesia

Musculoskeletal Variable Superficial Movement, palpation Time, analgesia Multiple Tenderness

Pulmonary Minutes to Visceral Often spontaneous Rest, time bronchodilator Substernal Dyspneic
hours (pressure)

H2, histamine receptor­2

TABLE 36­2
PQRST Approach to Assessment of a Patient’s Chest Pain

Factor Presentation in Chronic Coronary Disease Questions to Ask

Precipitating Typically brought on by some level of exercise or What were you doing when the pain started? What brought on this chest pain?
factors exertion

Palliative Relieved by rest with or without sublingual Is there anything that helps the pain go away? If you rest, does the pain get
measures nitroglycerin in 5­10 minutes better? Does your sublingual nitroglycerin help?

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a continuous squeezing, heaviness, or How would you describe the pain? Does the pain change when you breathe in
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Region Substernal Where is the pain located? Can you point to where the pain seems to originate?
 Pulmonary Minutes to Visceral Often spontaneous Rest, time bronchodilator Substernal Dyspneic
hours (pressure) University of New England ­ Maine
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H2, histamine receptor­2

TABLE 36­2
PQRST Approach to Assessment of a Patient’s Chest Pain

Factor Presentation in Chronic Coronary Disease Questions to Ask

Precipitating Typically brought on by some level of exercise or What were you doing when the pain started? What brought on this chest pain?
factors exertion

Palliative Relieved by rest with or without sublingual Is there anything that helps the pain go away? If you rest, does the pain get
measures nitroglycerin in 5­10 minutes better? Does your sublingual nitroglycerin help?

Quality of the Described as a continuous squeezing, heaviness, or How would you describe the pain? Does the pain change when you breathe in
pain tightness and out?

Region Substernal Where is the pain located? Can you point to where the pain seems to originate?

Radiation Left or right arm, back, down into the abdomen, up Does the pain seem to radiate or go to other locations?
into the neck

Severity While pain is subjective, those who have pain report On a scale from 1 to 10, with 1 being no pain, and 10 being the worst pain you
a 5 or higher on a 10­point scale have ever had, how would you rate this pain?

T emporal Pain lasts less than 20 minutes and is usually How long did the pain last? How long before the pain went away? After you
pattern relieved in 5­10 minutes started to rest, how long before the pain went away?
(timing)

Chest pain in a patient with CCD is often precipitated by exertion, such as walking, gardening, sexual activity, or activities of daily living such as
showering, cleaning the house, or doing laundry. In this setting, the exertion produces an increase in MVO2 that exceeds what can be provided by the
fixed decrease in myocardial oxygen supply from the obstructive atherosclerotic plaque. Typically, rest or the use of sublingual (SL) nitroglycerin relieves
the symptoms. As the patient rests for a few minutes, the HR and BP come down, reestablishing a balance between myocardial oxygen supply and
demand, relieving their chest pain. The use of SL nitroglycerin provides acute relief by increasing myocardial oxygen supply through vasodilation of
epicardial vessels and a reduction in preload.

Cardiac chest pain is often described as squeezing, crushing, heaviness, or tightness in the chest. It can also be described as numbness or burning in the
chest. Chest pain that is described as sharp, increases with inspiration or expiration, or is reproducible with palpation is less likely to be cardiac in origin.
The pain is often substernal and may radiate to the right or left shoulder, right or left arm (left more commonly than right), neck, back, or abdomen.
Cardiac chest pain rarely radiates above the mandible (jaw) or below the umbilicus (belly button). The severity of cardiac chest pain can be difficult to
quantify since pain is subjective, but most patients will state the pain is severe and rate it five or higher on a 10­point scale. The duration of chest pain is
less than 20 minutes, usually no more than 5 to 10 minutes. Other symptoms that may be present during times of ischemia include diaphoresis, nausea,
vomiting, and dyspnea.

It is helpful to connect the pathophysiology with the clinical presentation. In CCD, ischemia is produced by an increase in MVO2 in the setting of a fixed
decrease in supply. The exertion exhausts autoregulation and coronary flow reserve and the patient experiences chest pain. When the patient rests for 5
to 10 minutes or uses an SL nitroglycerin, the MVO2 decreases to a point in which myocardial supply and demand are back in balance—the pain and
other symptoms go away. The major differences between the pain with CCD compared to ACS would be the precipitating factors and the duration of the
chest pain. The patient with an ACS typically has angina at rest that lasts longer than 20 minutes. The pathophysiology in a patient with an ACS is an
abrupt decrease in myocardial oxygen supply typically precipitated by a plaque rupture.

The severity of chest pain and its impact on daily activities may be evaluated using the Canadian Cardiovascular Society (CCS) classification system
(Table 36­3). The CCS system evaluates the level of activity needed to produce angina. All the current severity scores are limited by the subjective nature
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as theAreliability
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and reproducibility of patient observations. Newer recommendations advocate for the use of patient­
Chapter 36: Chronic Coronary Disease, Paul P. Dobesh; Robert J. DiDomenico; Kelly C. Rogers Page 9 / 44
centered,
©2025 McGraw Hill. All Rights Reserved. Terms(eg,
disease­specific health status measures Seattle
of Use AnginaPolicy
• Privacy Questionnaire)
• Notice •toAccessibility
assess angina symptoms and their impact on patients’ quality of
life.

TABLE 36­3
other symptoms go away. The major differences between the pain with CCD compared to ACS would be the precipitating factors and the duration of the
University of New England ­ Maine
chest pain. The patient with an ACS typically has angina at rest that lasts longer than 20 minutes. The pathophysiology in a patient with an ACS is an
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abrupt decrease in myocardial oxygen supply typically precipitated by a plaque rupture.

The severity of chest pain and its impact on daily activities may be evaluated using the Canadian Cardiovascular Society (CCS) classification system
(Table 36­3). The CCS system evaluates the level of activity needed to produce angina. All the current severity scores are limited by the subjective nature
of a patient’s pain as well as the reliability and reproducibility of patient observations. Newer recommendations advocate for the use of patient­
centered, disease­specific health status measures (eg, Seattle Angina Questionnaire) to assess angina symptoms and their impact on patients’ quality of
life.

TABLE 36­3
Grading of Angina Pectoris by the Canadian Cardiovascular Society Classification System

Canadian Cardiovascular Society Classification System Seattle Angina Questionnaire­7

Class I Ordinary physical activity does not cause angina, such as walking and climbing stairs. Angina Activity Indicate how much
occurs with strenuous, rapid, or prolonged exertion at work or recreation. limitation you have had
due to chest pain, chest
tightness, or angina
over the past 4 weeks
(Likert scale for each
question below)
Walking indoors
on level ground
Gardening,
vacuuming or
carrying groceries
Lifting or moving
heavy objects (eg,
furniture,
children)

Class Slight limitation or ordinary activity. Angina occurs on walking or climbing stairs rapidly, on an Symptoms Over the past 4 weeks,
II incline, after meals, in the cold, or into the wind. Angina may occur under emotional stress or on average, how many
only during the few hours after awakening. Walking more than two blocks on the level and times have you had
climbing more than one flight of ordinary stairs at a normal pace and in normal condition may chest pain, chest
also precipitate angina. tightness, or angina?
4 or more
times/day
1­3 times/day
3 or more
times/week, but
not every day
1­2 times/week
Less than
once/week
None over the
past 4 weeks

Class Marked limitations of ordinary physical activity. Angina occurs on walking one to two blocks on Nitroglycerin Over the past 4 weeks,
III the level and climbing one flight of stairs in normal conditions and at a normal pace may use on average, how many
precipitate angina. times have you had to
take nitroglycerin
(nitroglycerin tablets or

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pain, chest tightness, 10 / 44
©2025 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility angina?
4 or more
times/day
 Class Marked limitations of ordinary physical activity. Angina occurs on walking one to two blocks on Nitroglycerin Over the past 4 weeks,
III the level and climbing one flight of stairs in normal conditions and at a normal pace may use
University of New England ­ Maine
on average, how many
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precipitate angina. times have you had to
take nitroglycerin
(nitroglycerin tablets or
spray) for your chest
pain, chest tightness, or
angina?
4 or more
times/day
1­3 times/day
3 or more
times/week, but
not every day
1­2 times/week
Less than
once/week
None over the
past 4 weeks

Class Inability to carry on any physical activity without discomfort—anginal symptoms may be present Quality of (Likert scale for each
IV at rest. life question below)
Over the past 4 weeks,
how much has your
chest pain, chest
tightness, or angina
limited your enjoyment
of life?
If you had to spend the
rest of your life with
your chest pain, chest
tightness, or angina the
way it is right now, how
would you feel about
this?

Reproduced with permission from Campeau L. Grading of angina pectoris. Circulation 1976;54(3):522­3.

Not all patients have a classical chest pain presentation of substernal chest discomfort with a characteristic quality and duration provoked by exertion or
emotional stress and relieved by rest or nitroglycerin (Table 36­1). Symptoms of patients presenting this way may be classified as cardiac in origin. Less
common symptoms of angina (eg, angina equivalents) include midepigastric discomfort, effort intolerance, dyspnea, and excessive fatigue. Certain
patient groups (women, older adults, patients with DM) may experience one or more less common angina symptoms or angina equivalents. The
symptoms of patients who present with a mix of classical and less common features may be classified as possible cardiac origin. Patients who present
with minimal features of classical angina may be classified as having noncardiac chest pain.

After a description of the chest pain has been obtained, a review of the patient’s CAD risk factors should be performed with an estimation of annual
cardiovascular risk using a validated risk prediction model (eg, https://professional.heart.org/en/guidelines­and­statements/prevent­calculator).
Nonmodifiable risk factors include the patient’s age, sex, and a family history of premature atherosclerotic cardiovascular disease (ASCVD) in first­
degree relatives (onset in a male before the age of 55 years or a female before the age of 65 years). Modifiable risk factors including HTN, DM,
dyslipidemia, and cigarette smoking should also be explored. This includes a thorough medication history assessing for the use of medications that may
provoke angina (eg, prescription, over­the­counter, and illicit stimulants). Although not routinely measured, markers of inflammation, such as high­
sensitivity C­reactive protein, and lipoprotein (a) may also be obtained to assess ASCVD risk but their value in guiding therapy in the setting of
established CAD (secondary prevention) is less certain.

The physical examination

Downloaded of a patient
2025­6­30 9:58 A Yourwith
IP isCCD usually produces nonspecific findings. At the time of an anginal episode, patients may have tachycardia,
185.80.143.8
Chapter 36: and
diaphoresis, Chronic Coronary
shortness Disease,
of breath. Paulmay
Patients P. Dobesh;
also haveRobert J. DiDomenico;
symptoms Kelly C. Rogers
of nausea, vomiting, Pagerelate
and lightheadedness. Other physical findings may 11 / 44
to
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cardiovascular Hill. All Rights
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including TermsBPoforUse
an increased • Privacy
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long­standing HTN. Other findings may include pulmonary
crackles, peripheral edema, elevated jugular venous pulsation, a displaced point of maximal impulse, or a third heart sound in patients with HF. Due to
the systemic nature of ASCVD, patients with CAD may also have atherosclerotic disease in their cerebrovascular and/or peripheral arteries and the
degree relatives (onset in a male before the age of 55 years or a female before the age of 65 years). Modifiable risk factors including HTN, DM,
dyslipidemia, and cigarette smoking should also be explored. This includes a thorough medication history assessing for the use of
University of medications
New Englandthat may
­ Maine
provoke angina (eg, prescription, over­the­counter, and illicit stimulants). Although not routinely measured, markersAccess
of inflammation,
Provided by:
such as high­
sensitivity C­reactive protein, and lipoprotein (a) may also be obtained to assess ASCVD risk but their value in guiding therapy in the setting of
established CAD (secondary prevention) is less certain.

The physical examination of a patient with CCD usually produces nonspecific findings. At the time of an anginal episode, patients may have tachycardia,
diaphoresis, and shortness of breath. Patients may also have symptoms of nausea, vomiting, and lightheadedness. Other physical findings may relate to
cardiovascular risk factors including an increased BP or a fourth heart sound reflecting long­standing HTN. Other findings may include pulmonary
crackles, peripheral edema, elevated jugular venous pulsation, a displaced point of maximal impulse, or a third heart sound in patients with HF. Due to
the systemic nature of ASCVD, patients with CAD may also have atherosclerotic disease in their cerebrovascular and/or peripheral arteries and the
history and physical examination should assess for the presence of both.

Diagnostic and Prognostic Testing

Several noninvasive and invasive testing can be done to assist in the diagnosis and evaluation of patients with CCD. A detailed discussion of these
tests and when they should be used can be found in the CCD guidelines. More information on how each test is performed is available in Chapter e32,
“Evaluation of Cardiovascular Function.”

The results of cardiac testing can provide prognostic information, may help guide pharmacotherapy, and identify patients who need revascularization.
All patients with angina symptoms should receive a 12­lead electrocardiogram (ECG). In the resting state, the ECG will be normal in ≥50% of patients with
CCD. In patients with CCD and a normal ECG at rest, about 50% will develop ischemic ST­T wave changes during an episode of angina. These changes can
be observed on the ECG conducted during an exercise stress test. Exercise stress testing is a relatively easy and inexpensive method for detecting CAD.
Since many patients cannot physically endure an exercise stress test, the myocardium can also be stressed pharmacologically with adenosine,
regadenoson, dipyridamole, or dobutamine. Stress testing can provide important diagnostic and prognostic information, especially when conducted
with an imaging study to evaluate myocardial perfusion.

Coronary angiography is the most accurate test for the diagnosis and assessment of patients with CAD and is considered the “gold standard.”
Unfortunately, coronary angiography is an invasive procedure that requires arterial access. Coronary angiography detects nonobstructive CAD (<50%
stenosis) in 50% or more of patients who are being evaluated for angina symptoms; obstructive CAD (≥50% stenosis) is present in the remaining
patients.

Additional noninvasive diagnostic tests may be used to establish the diagnosis of CAD or follow the progression of disease in patients with CCD.
Myocardial perfusion imaging (eg, positron emission tomography, single photon emission computed tomography, cardiac magnetic resonance) involves
the administration of an intravenous radioactive tracer before and after a stressor (exercise or pharmacologic). The uptake of the radioactive tracer is
proportional to coronary blood flow in normal myocytes and the resulting images can detect perfusion defects. Cardiac magnetic resonance imaging
combined with physiologic or pharmacologic stressors can also detect the presence of perfusion defects as well as wall motion abnormalities. Cardiac
CT can be used to calculate a coronary artery calcium score and detect CAD. Finally, coronary CT angiography can also be used to detect the presence of
CAD.

Biomarkers

Cardiac troponin is released with myocyte death (infarction) and hence high­sensitivity cTn (hs­cTn) concentrations are not typically elevated in
patients with CCD. However, some patients with CCD have hs­cTn elevations at baseline, increasing their risk of MI and death. While hs­cTn elevations in
patients with CCD may be present and increase the risk of adverse outcomes, routine monitoring of hs­cTn is not recommended in the absence of
unstable symptoms (eg, ACS).

PATIENT CARE PROCESS

Patient Care Process for Chronic Coronary Disease (CCD)

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PATIENT CARE PROCESS University of New England ­ Maine
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Patient Care Process for Chronic Coronary Disease (CCD)

Collect

Patient characteristics (eg, age, sex, pregnancy status)

Description of chest discomfort and/or related symptoms (eg, precipitating factors, palliative measures, quality, location, radiation, and severity)

Patient medical (personal and family) and social histories (eg, tobacco/ethanol use), dietary habits (eg, intake of foods high in sodium,
cholesterol, and/or saturated fat), and physical activity (eg, frequency and duration of moderate­intensity aerobic activity)

Current medications including over­the­counter (OTC) medications (eg, aspirin­containing medications, nonsteroidal anti­inflammatory agents),
herbals/dietary supplements

History of allergy or intolerance to previous medications

Objective data

BP, HR, respiratory rate (RR), height, weight, O2­saturation

Labs: serum creatinine (SCr), potassium (K+), hemoglobin (Hgb), platelets, liver function tests (LFTs), lipid profile, blood glucose, A1c

Diagnostic testing results

Assess

Description of chest discomfort to determine differential diagnosis and classification of angina symptoms (Tables 36­1, 36­2, and 36­3)

Presence of provoking factors (eg, exertion, mental/emotional stress, tachyarrhythmia, high adrenergic state including the use of stimulant
medications, and exposure to cold)

Presence/control of risk factors for CCD (eg, HTN, dyslipidemia, DM, smoking, and obesity)

Presence/control of CCD­related complications (eg, MI, HF, and stroke)

Adverse drug reactions from current/previous medications used to treat/prevent angina symptoms or major adverse cardiac events (MACE)

Previous/recent
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Contraindications to medications to treat/prevent angina symptoms and/or prevent MACE
 Presence/control of risk factors for CCD (eg, HTN, dyslipidemia, DM, smoking, and obesity)
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Presence/control of CCD­related complications (eg, MI, HF, and stroke) Access Provided by:

Adverse drug reactions from current/previous medications used to treat/prevent angina symptoms or major adverse cardiac events (MACE)

Previous/recent revascularization procedures (eg, percutaneous coronary intervention [PCI] with/without stenting, and coronary artery bypass
graft [CABG] surgery)

Contraindications to medications to treat/prevent angina symptoms and/or prevent MACE

Barriers (eg, social determinants of health) that may impair adherence to the care plan

Plan*

Initiate/modify drug therapy to treat and prevent angina symptoms, prevent MACE, and address risk factors for CCD, including specific drug(s),
dose, route, frequency, and duration (see Fig. 36­2, Tables 36­4 and 36­5)

Monitoring parameters: efficacy (eg, signs and symptoms of angina and CCD­related complications) and adverse drug reactions; frequency and
timing of follow­up

Patient education: the purpose of treatment, lifestyle modifications, planned procedures, and drug­specific information (eg, indication, dose,
route, frequency, adverse drug reactions)

Self­monitoring for worsening angina symptoms, signs and symptoms of CCD­related complications, adverse drug reactions, when to seek
emergency medical attention

Address barriers to adherence to medications and lifestyle modification

Referrals to other providers (eg, primary care provider, endocrinologist, dietician, and smoking cessation)

Implement*

Provide patient education regarding all elements of the treatment plan as described above

Use motivational interviewing and coaching strategies to maximize adherence

Schedule follow­up (eg, every 1­2 months until goals achieved, then every 6­12 months)

Follow­up: Monitor and Evaluate

Frequency and severity of chest discomfort, sublingual nitroglycerin use, exercise tolerance, presence/control of CCD risk factors, and
presence/control of CCD­related complications

Presence of adverse drug reactions and drug­drug interactions

Patient adherence to treatment plan using multiple sources of information

* Collaborate with the patient, caregivers, and other healthcare professionals.

TREATMENT
The treatment of patients with CCD typically involves two complementary strategies (see Fig. 36­2). The first strategy is directed toward slowing the
progression of atherosclerosis and preventing complications such as MI, HF, stroke, and death (either sudden cardiac death or progression of
underlying CVD). This strategy focuses on risk­factor modification and providing vasculoprotection therapies (see Table 36­4). While vasculoprotective
therapies have demonstrated the ability to reduce mortality, and therefore, the quantity of life, they have minimal impact on improving symptoms and
the functional limitations caused by angina, or the quality of life. The second strategy is focused on reducing the number of ischemic episodes as well as
increasing the amount of exertion or exercise a patient can accomplish before chest pain occurs (see Table 36­5). Antianginal therapies used to prevent
or decrease ischemic episodes rarely have demonstrated a survival benefit but improve quality of life through symptom reduction. Each of the
antianginal therapies is relatively equivalent in its ability to reduce ischemic episodes. Revascularization procedures may be used to treat patients with
refractory symptoms and may offer a survival advantage over guideline­directed medical therapy (GDMT) in patients with extensive multivessel CAD.
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Treatment algorithm for chronic coronary disease (guideline­directed medical therapy). (ACE, angiotensin­converting enzyme; ARB, angiotensin
therapies have demonstrated the ability to reduce mortality, and therefore, the quantity of life, they have minimal impact on improving symptoms and
University
the functional limitations caused by angina, or the quality of life. The second strategy is focused on reducing the number of New
of ischemic England
episodes ­ Maine
as well as
Access Provided by:
increasing the amount of exertion or exercise a patient can accomplish before chest pain occurs (see Table 36­5). Antianginal therapies used to prevent
or decrease ischemic episodes rarely have demonstrated a survival benefit but improve quality of life through symptom reduction. Each of the
antianginal therapies is relatively equivalent in its ability to reduce ischemic episodes. Revascularization procedures may be used to treat patients with
refractory symptoms and may offer a survival advantage over guideline­directed medical therapy (GDMT) in patients with extensive multivessel CAD.

FIGURE 36­2

Treatment algorithm for chronic coronary disease (guideline­directed medical therapy). (ACE, angiotensin­converting enzyme; ARB, angiotensin
receptor blocker; BP, blood pressure; CCB, calcium channel blocker; CKD, chronic kidney disease; DAPT, dual antiplatelet therapy; DHP, dihydropyridine;
DM, diabetes mellitus; HTN, hypertension; LA, long­acting; LVEF, left ventricular ejection fraction.) aAvoid in patients with significant left ventricular
dysfunction (eg, LVEF ≤40%). bUse of a sodium­glucose cotransporter 2 inhibitor or glucagon­like peptide agonist is recommended. cModerate intensity
statin is recommended for patients with a contraindication or intolerance to high­intensity statins. The Hgb A1c goal of ≤7% (0.07) is equivalent to 53
mmol/mol.

TABLE 36­4
Select Recommendations for Risk Factor Modification

Lipid Managementa

Class 1

1. High­intensity statin therapy is recommended with a goal of achieving a ≥50% decrease in LDL­C to reduce the risk of MACE.
2. In patients with contraindications or intolerant to high­intensity statin therapy, moderate­intensity statins should be used, if tolerated, with a goal of
achieving a 30%­49% decrease in LDL­C to reduce the risk of MACE.
3. Fasting lipid panels should be measured in 4­12 weeks after statin initiation or dose adjustment to assess adherence to lifestyle changes and the effects
of lipid­lowering medications. Fasting lipids should be measured every 3­12 months thereafter based on need to assess response/adherence to therapy.

Class 2a

1. In patients older than 75 years, moderate­ or high­intensity statin therapy should be used after considering the potential benefits (risk reduction) and
risks (adverse drug reactions, drug­drug interactions, patient frailty).
2. For patients with an LDL­C >70 mg/dL (1.81 mmol/L) on maximally tolerated statin therapy and at very high risk for CV events, the addition of ezetimibe is
reasonable.
3. For patients with an LDL­C >70 mg/dL (1.81 mmol/L) or a non­HDL­C level ≥100 mg/dL (2.59 mmol/L) on maximally tolerated LDL­C lowering therapy
(statin plus ezetimibe) and at very high risk for CV events, the addition of a PCSK­9 inhibitor is reasonable depending on benefit, risk, cost, and patient
preference.

Class 3

1. The use of adding niacin, fenofibrate, or dietary supplements containing omega­3 fatty acids to patients receiving statins, is not beneficial in reducing CV
risk.

Blood Pressure Managementb

Class 1

1. Nonpharmacologic strategies are first­line therapy to lower BP in those with an elevated BL (120­129/<80 mm Hg).
2. In patients with HTN a BP target of <130/80 mm Hg is recommended to reduce CVD events and all­cause death.
3. In patients with HTN, the use of nonpharmacologic strategies and GDMT (eg, ACE inhibitors, ARBs, or β­blockers) are recommended first­line for
compelling indications (eg, recent MI or angina)
4. Additional antihypertensive medications (eg, long­acting thiazide diuretics, dihydropyridine calcium channel blockers, or aldosterone antagonists) are
recommended
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A to optimize
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Class 2a
 1. Nonpharmacologic strategies are first­line therapy to lower BP in those with an elevated BL (120­129/<80 mm Hg).
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2. In patients with HTN a BP target of <130/80 mm Hg is recommended to reduce CVD events and all­cause death.
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3. In patients with HTN, the use of nonpharmacologic strategies and GDMT (eg, ACE inhibitors, ARBs, or β­blockers) are recommended first­line for
compelling indications (eg, recent MI or angina)
4. Additional antihypertensive medications (eg, long­acting thiazide diuretics, dihydropyridine calcium channel blockers, or aldosterone antagonists) are
recommended as needed to optimize BP control.

Class 2a

1. For patients who have had an ACS, it is reasonable to continue β­blockers long­term if needed for treatment of HTN.

Diabetes Managementc

Class 1

1. Among patients with type 2 DM the use of either a sodium­glucose cotransporter 2 (SGLT2) inhibitor or glucagon­like peptide 1 (GLP­1) receptor agonist
with proven CV benefit is recommended as part of the glucose­lowering regimen independent of A1c, metformin use, and in consideration of patient­
specific factors to reduce the risk of MACE.
2. In patients with CCD and HF with LVEF ≤40% (0.4), the use of an SGLT2 inhibitor is recommended to reduce the risk of CV death and HF hospitalization
and to improve QOL, irrespective of diabetes status.
3. The ADA recommends a hemoglobin A1c goal <7% (53 mmol/mol) in patients with CCD and type 2 diabetes with a more conservative glycemic target of
<8­8.5% (64­69 mmol/mol) in those >65 years of age or with multiple comorbidities.

Class 2a

1. For selected individual patients, such as those with a short duration of diabetes mellitus and a long life expectancy, a goal A1c of 7% (53 mmol/mol) or
less is reasonable.
2. A goal A1c <8% (64 mmol/mol) is reasonable for certain patients according to age, history of hypoglycemia, the presence of microvascular or
macrovascular complications, or presence of coexisting medical conditions.

Influenza Vaccinationsd

Class 1

1. Annual influenza vaccinations is recommended to reduce CV morbidity, CV death, and all­cause death.
2. Coronavirus disease 2019 (COVID­19) vaccination is recommended per published health guidelines to reduce COVID­19 complications.

Class 2a

1. Pneumococcal vaccine is reasonable to reduce CV morbidity and mortality, and all­cause death.

Physical Activityd

Class 1

1. For patient without contraindications, an exercise regimen including ≥150 min/wk of moderate­intensity or ≥ 75 min/wk of higher­intensity aerobic
activity to improve functional capacity and QOL, reduce hospital admission and mortality.
2. For patient without contraindications, resistance/strength training exercises are recommended ≥2 days/wk to improve muscle strength, functional
capacity, and improve CV risk factors.

Class 2a

1. It is reasonable for the clinician to recommend complementary resistance training at least 2 days/wk.
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Nutrition

Class 1
 2. For patient without contraindications, resistance/strength training exercises are recommended ≥2 days/wk to improve muscle strength, functional
capacity, and improve CV risk factors. University of New England ­ Maine
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Class 2a

1. It is reasonable for the clinician to recommend complementary resistance training at least 2 days/wk.

Nutritiond

Class 1

1. A diet focused on vegetables, fruits, legumes, nuts, whole grains, and lean protein is recommended to reduce CVD events

Class 3

1. The intake of trans fat should be avoided as it is associated with increased morbidity and mortality
2. The use of nonprescription or dietary supplements (including omega­2 fatty acid, vitamins C, D, E, beta­carotene, and calcium) is not beneficial to reduce
the risk of CVD events.

Weight Managementd

Class 1

1. BMI with or without waist circumference should be assessed at every visit.

2. Patients with CCD with overweight or obesity (BMI 25­29.9 kg/m2; waist circumference of 102 cm [40 in.] in men and less than 88 cm [35 in.] in women)
should receive counseling on diet, lifestyle, and goals for weight loss:
Prevent further weight gain
Reduce body weight
Maintain a lower body weight over the long term
3. The initial goal of weight loss therapy should be to reduce body weight by approximately 5%­10% from baseline. With success, further weight loss can be
attempted if indicated.

Class 2a

1. The use of a GLP­1 receptor agonist (reasonable to choose semaglutide over liraglutide) can be beneficial combined with counseling for diet and physical
activity.
2. In patients with severe obesity who have not met weight loss goals with lifestyle and pharmacologic interventions, referral for bariatric surgery is
reasonable for weight loss and CV risk factor reduction.

Class 3

1. The use of sympathomimetic drugs (eg, phentermine, diethylpropion, benzphetamine, phendimetrazine) is potentially harmful as they can increase HR
and BP.

Smoking Cessation Counselingd

Class 1

1. Tobacco use should be assessed at every healthcare visit to identify those who may benefit from behavioral or pharmacologic interventions.
2. Patients who smoke tobacco should be advised to quit at every visit.
3. Patients who smoke tobacco should receive behavioral interventions in combination with pharmacotherapy, including bupropion, varenicline, or
combination NRT.

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Class 3
Chapter 36: Chronic Coronary Disease, Paul P. Dobesh; Robert J. DiDomenico; Kelly C. Rogers Page 17 / 44
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1. Patients with CCD should avoid secondhand smoke exposure to reduce risk of CV events.
 1. Tobacco use should be assessed at every healthcare visit to identify those who may benefit from behavioral or pharmacologic interventions.
University of New England ­ Maine
2. Patients who smoke tobacco should be advised to quit at every visit.
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3. Patients who smoke tobacco should receive behavioral interventions in combination with pharmacotherapy, including bupropion, varenicline, or
combination NRT.

Class 3

1. Patients with CCD should avoid secondhand smoke exposure to reduce risk of CV events.

Alcohol and Substance Used

Class 1

1. Patients should be asked regularly and counseled about substance use to reduce ASCVD events

Class 2a

1. Patients who consume alcohol, should limit intake to ≤1 drink/day for women and ≤2 drinks/day for men to reduce CV and all­cause death. One drink is
equal to 5 ounces (~150 mL) of wine, 12 ounces (355 mL) of beer, or 1.5 ounce (45 mL) of spirits.

ACE, angiotensin converting enzyme; ADA, American Diabetes Association; ARB, angiotensin receptor blocker; ASCVD, atherosclerotic cardiovascular disease; CV,
cardiovascular; CVD, cardiovascular disease; GDMT, guideline directed medical therapy; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; HTN,
hypertension; LVEF, left ventricular ejection fraction; MACE, major adverse cardiovascular events; NRT, nicotine replacement therapy; QOL, quality of life. In brief, Class
1 recommendation refers to conditions for which there is evidence or general agreement that a given procedure or treatment is useful and effective. Class 2 refers to
conditions with conflicting evidence with 2a having a greater weight of evidence/usefulness than 2b and Class 3 is for conditions where there is evidence or general
agreement that treatment or procedures are not useful/effective or may be harmful.

aRefer to Chapter 35, “Dyslipidemia,” for more information.

b Refer to Chapter 33, “Hypertension,” for more information.

cRefer to Chapter 98, “Diabetes Mellitus,” for more information.

dRefer to guideline for the management of patients with chronic coronary disease (Gulati M, Levy PD, Mukherjee D, et al. Circulation 2021;144:e368–454.

DOI:10.1161/CIR.0000000000001029) for more information.

Data summarized from:

1. Virani SS, Newby LK, Arnold SV, et al. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the management of patients with chronic coronary disease. J Am Coll
Cardiol 2023;82(9):833–955. DOI:10.1016/j.jacc.2023.04.003.

2. American Diabetes Association Professional Practice Committee. 6. Glycemic Goals and Hypoglycemia: Standards of Care in Diabetes­2024. Diabetes Care
2024;47(Suppl 1):S111–25.

TABLE 36­5
Pharmacotherapy to Relieve Symptoms

Class 1

1. Antianginal therapy with either a β­blocker, calcium channel blocker, or long­acting nitrate should be prescribed for the relief of angina or equivalent
symptoms.
2. For those who remain symptomatic, the addition of a second antianginal agent from a different therapeutic class is recommended for relive of angina or
equivalent symptoms.
3. Ranolazine is recommended in patients who remain symptomatic despite treatment with β­blockers, calcium channel blockers, or long­acting nitrates.
4. Sublingual nitroglycerin or nitroglycerin spray is recommended for immediate short­term relief of angina or equivalent symptoms.
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1. The use of ivabradine in patients with normal LV function is potentially harmful.

 1. Virani SS, Newby LK, Arnold SV, et al. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the management of patients with chronic coronary disease. J Am Coll
Cardiol 2023;82(9):833–955. DOI:10.1016/j.jacc.2023.04.003. University of New England ­ Maine
Access Provided by:
2. American Diabetes Association Professional Practice Committee. 6. Glycemic Goals and Hypoglycemia: Standards of Care in Diabetes­2024. Diabetes Care
2024;47(Suppl 1):S111–25.

TABLE 36­5
Pharmacotherapy to Relieve Symptoms

Class 1

1. Antianginal therapy with either a β­blocker, calcium channel blocker, or long­acting nitrate should be prescribed for the relief of angina or equivalent
symptoms.
2. For those who remain symptomatic, the addition of a second antianginal agent from a different therapeutic class is recommended for relive of angina or
equivalent symptoms.
3. Ranolazine is recommended in patients who remain symptomatic despite treatment with β­blockers, calcium channel blockers, or long­acting nitrates.
4. Sublingual nitroglycerin or nitroglycerin spray is recommended for immediate short­term relief of angina or equivalent symptoms.

Class 3

1. The use of ivabradine in patients with normal LV function is potentially harmful.

2. Phosphodiesterase type 5 inhibitors should not be used concomitantly with nitrate medications because of risk for severe hypotension.

In brief, Class 1 recommendation refers to conditions for which there is evidence or general agreement that a given procedure or treatment is useful and effective and
Class 3 is for conditions where there is evidence or general agreement that treatment or procedures are not useful/effective or may be harmful.

Data summarized from:

Virani SS, Newby LK, Arnold SV, et al. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the management of patients with chronic coronary disease. J Am Coll Cardiol
2023;82(9):833–955. DOI:10.1016/j.jacc.2023.04.003.

Desired Outcomes

In addition to reducing the risk of CV events and mortality, the CCD guidelines state that a goal of therapy should be the complete, or nearly complete,
elimination of chest pain and return to normal activities with a functional capacity of CCS class I angina.

Nonpharmacologic Therapy (Revascularization)

Coronary revascularization plays a significant role in the treatment of CCD. The most common revascularization procedures are coronary artery
bypass graft (CABG) surgery or percutaneous coronary intervention (PCI) with or without stent placement. In 2017, more than 600,000 PCI procedures
were performed in the United States and approximately a third of these were done electively (eg, in patients with CCD). Stents are placed in over 90% of
patients undergoing PCI, with drug­eluting stents (DES) accounting for 82% of all stents followed by bare metal stents (BMS). In 2021, more than 172,000
CABG surgeries were performed in the United States, including surgeries that also included repair or replacement of one or more heart valves.

The primary goal of revascularization is to prolong life and, secondarily, to eliminate or reduce symptoms. Revascularization is recommended over
medical therapy as initial management of CCD in select patients, such as those with significant stenosis of the left main coronary artery, multivessel
disease and LV dysfunction, or refractory angina. Whereas most of the pharmacologic approaches reduce MVO2, revascularization increases myocardial
oxygen supply in vessels with critical stenoses. This is accomplished by opening the vessel (ie, PCI) or using alternative transplanted vessels to bypass a
critical stenosis (ie, CABG surgery). While both procedures are highly effective and have advantages in certain groups of patients over pharmacologic
approaches, both have limitations.

Percutaneous Coronary Intervention

The term PCI encompasses the use of balloon angioplasty with stent placement as well as other less commonly performed intracoronary procedures
such as rotational atherectomy and aspiration thrombectomy. During a PCI, a sheath is placed in either the femoral or radial artery to maintain access
during the procedure. A guide catheter is then introduced through the sheath and advanced to the ostium of the coronary arteries. A guidewire is then
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Chapter 36: theCoronary
Chronic guide catheter and across
Disease, Paul P.the stenosis
Dobesh; in the J.
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DiDomenico; The deflated balloon is then slid along the guidewire toPage
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the coronary lumen by stretching and tearing the atherosclerotic
plaque (see Chapter 37, “Acute Coronary Syndromes,” for detailed review). Most elective PCI procedures are completed in 30 to 60 minutes.
approaches, both have limitations.
University of New England ­ Maine
Percutaneous Coronary Intervention
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The term PCI encompasses the use of balloon angioplasty with stent placement as well as other less commonly performed intracoronary procedures
such as rotational atherectomy and aspiration thrombectomy. During a PCI, a sheath is placed in either the femoral or radial artery to maintain access
during the procedure. A guide catheter is then introduced through the sheath and advanced to the ostium of the coronary arteries. A guidewire is then
advanced through the guide catheter and across the stenosis in the coronary vessel. The deflated balloon is then slid along the guidewire to the site of
the coronary stenosis. The balloon is then inflated. The inflated balloon expands the coronary lumen by stretching and tearing the atherosclerotic
plaque (see Chapter 37, “Acute Coronary Syndromes,” for detailed review). Most elective PCI procedures are completed in 30 to 60 minutes.

Abrupt vessel closure is a potential complication of balloon angioplasty. Abrupt vessel closure is provoked by physical disruption of the plaque on the
vessel walls during the procedure. Another complication from PCI is restenosis, which can lead to recurrent symptoms and the need for another
revascularization procedure. These complications have been dramatically reduced in contemporary practice with the use of antithrombotic therapy and
the evolution of intracoronary stents.

Stents are scaffolds made from stainless steel or other metal alloys placed within coronary arteries that can prevent acute vessel closure and restenosis.
The stent is placed over the deflated balloon and advanced to the area of coronary stenosis. When the balloon is inflated, the stent expands into the
coronary vascular wall. The balloon is then deflated, leaving the expanded stent permanently placed in the diseased coronary vessel. While stents have
had a dramatic effect of reducing restenosis, and therefore repeat revascularization procedures, they do not prevent death or MI more effectively than
balloon angioplasty alone, except perhaps in patients with cardiac allograft vasculopathy.

Restenosis is a phenomenon characterized by a greater than 50% diameter loss in the vessel lumen at the site of the intervention. Restenosis most often
occurs within the first 3 to 6 months following the procedure. The pathophysiology of restenosis differs from atherosclerosis and involves a complex
cascade of various growth factors and cytokines that promote smooth muscle cell proliferation and result in a progressive loss of luminal diameter.

Elastic recoil is a nearly instantaneous phenomenon, occurring during the first hour after the successful dilation of the vessel. As the vessel is stretched
during balloon angioplasty, the endothelium lining in the vessel becomes damaged. In response to the stretching, the fibers begin to recoil back to their
previous size. Balloon­induced injury may also promote late constrictive remodeling, also referred to as negative remodeling, by exposing the adventitia
to the lumen. This triggers cell proliferation and fibrosis, decreasing the cross­sectional area of the artery. The scaffold­like properties of a BMS prevent
restenosis by controlling elastic recoil and negative remodeling. However, stent­induced vessel injury and inflammatory reactions around the stent
struts trigger a set of events that promote neointimal hyperplasia, a normal response to vascular damage. The antiproliferative drugs used in DES target
neointimal hyperplasia. DES are coated with sirolimus, paclitaxel, zotarolimus, or everolimus. These agents interrupt the cell cycle to prevent neointimal
proliferation and reduce restenosis rates to 5% to 10%.

Although stents effectively reduce restenosis, the exposed stent struts can provoke thrombosis. Although stent thrombosis is uncommon (<2% of cases),
it results in a large MI or death in two­thirds of cases; mortality from stent thrombosis ranges from 20% to 45%. Stent thrombosis is driven by the
implantation of the stent into an atherosclerotic plaque, exposing platelet adhering proteins to the stent surface. Patients remain at risk for stent
thrombosis until a thin layer of endothelial tissue can grow around the stent struts. This process is called re­endothelialization and typically occurs in 2
to 4 weeks after BMS deployment. Thus, most cases of stent thrombosis with BMS occur within the first 2 weeks. The process of re­endothelialization is
significantly prolonged with the use of DES. The drugs in a DES prevent smooth muscle, neointimal, and endothelial cell growth. Therefore, while DES
effectively reduces neointimal proliferation and the risk of restenosis, they also increase the period of risk for stent thrombosis. Stent thrombosis can be
largely prevented by using DAPT.

PCI Versus Medical Management

Despite advancements in PCI technique and stent technology, no study to date has demonstrated that PCI in patients with CCD improves survival. This is
most likely due to the advancements in pharmacotherapy and the use of GDMT. While individual trials comparing PCI to optimal medical therapy have
found that PCI lowers the risk of revascularization, hospitalization, and angina frequency, a recent meta­analysis of 15 trials did not find significant
differences in major adverse clinical events (MACE) angina, nor quality of life between PCI and optimal medical therapy. Therefore, current guidelines
recommend PCI to improve symptoms in patients who remain symptomatic despite optimal GDMT, not as an initial management strategy or alternative
to medical therapy.

Coronary Artery Bypass Graft Surgery

While PCI is the most common form of revascularization, CABG surgery is recommended to prolong survival or relieve refractory symptoms of angina in
select patients. In patients with left main coronary artery obstruction (≥50% stenosis) “unprotected” by collateral coronary blood flow or patent bypass
grafts and those with multivessel CAD (≥70% stenosis in three or more major coronary arteries) and severe left ventricular dysfunction (left ventricular
ejection fraction ≤35% [0.35]), CABG surgery is the preferred revascularization strategy (over PCI) because it is associated with prolonged survival.
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In 36: Chronic
the majority of CABG Coronary Disease,
surgeries, Paul P.
a sternotomy, Dobesh;
and divisionRobert J. DiDomenico;
of the sternum Kelly
is done to provide the surgeons with direct access to the heart.Page
C. Rogers Thus,20 / 44
it is
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often referred to as “open­heart surgery.” Once the heart is exposed, vascular conduits surgically harvested from other areas of the body are used to
“bypass” the atherosclerotic plaque. The most commonly used vascular conduits are the saphenous vein grafts from the leg and the left internal
mammary artery from the chest wall. Arterial grafts have better long­term patency than vein grafts while arterial grafts are prone to vasospasm. When a
Coronary Artery Bypass Graft Surgery
University of New England ­ Maine
While PCI is the most common form of revascularization, CABG surgery is recommended to prolong survival or relieveAccess Provided by:
refractory symptoms of angina in
select patients. In patients with left main coronary artery obstruction (≥50% stenosis) “unprotected” by collateral coronary blood flow or patent bypass
grafts and those with multivessel CAD (≥70% stenosis in three or more major coronary arteries) and severe left ventricular dysfunction (left ventricular
ejection fraction ≤35% [0.35]), CABG surgery is the preferred revascularization strategy (over PCI) because it is associated with prolonged survival.

In the majority of CABG surgeries, a sternotomy, and division of the sternum is done to provide the surgeons with direct access to the heart. Thus, it is
often referred to as “open­heart surgery.” Once the heart is exposed, vascular conduits surgically harvested from other areas of the body are used to
“bypass” the atherosclerotic plaque. The most commonly used vascular conduits are the saphenous vein grafts from the leg and the left internal
mammary artery from the chest wall. Arterial grafts have better long­term patency than vein grafts while arterial grafts are prone to vasospasm. When a
left internal mammary artery graft is performed, the distal portion is detached from its insertion point behind the sternum and an anastomosis is made
distal to the atherosclerotic plaque of the diseased coronary artery to restore blood flow beyond the blockage. The other vascular conduits are
considered “free grafts” and are anastomosed distally to atherosclerotic plaques of the other diseased coronary arteries. The proximal ends of the free
grafts are then anastomosed to the aorta restoring blood flow distal to the blockage. Prior to and during the anastomoses of the bypass grafts, patients
are often placed on cardiopulmonary bypass which redirects blood from the heart to a bypass machine. In the bypass machine, venous blood is
oxygenated and then returned to the systemic circulation to maintain myocardial and systemic perfusion during the surgery. The heart is then arrested
allowing the surgeon to perform the surgery without the heart actively beating. After the bypass grafts have been implanted, the patient is weaned from
the cardiopulmonary bypass machine, the heart and lung resume their normal functioning, the cannulas are removed, and the sternum and incisions
are closed.

Despite the advancements in technique and patient care, CABG surgery is associated with several complications. Death, neurological impairment, MI,
major bleeding, acute kidney injury, atrial fibrillation, and surgical wound infections (eg, mediastinitis) are all potential complications following CABG
surgery. Higher rates of complications are observed in patients who are older and have multiple comorbidities. New approaches to CABG surgery,
including off­pump and minimally invasive coronary surgery, have been developed in an attempt to minimize complications. Although used less
commonly, these approaches have been associated with lower rates of adverse neurologic and renal events and shorter recovery time.

Pharmacotherapy to Reduce Cardiovascular Events

Providing GDMT, also referred to as optimal medical therapy, reduces the risk of mortality in patients with CCD. In the absence of proximal CAD,
multivessel CAD, or acute ischemia, GDMT reduces the rate of death and MI similar to revascularization therapy for most patients with CCD. Most of
the evidence­based GDMT target risk­factor modification (Table 36­4), but also include aspirin and angiotensin­converting enzyme (ACE) inhibition.

Antithrombotic Therapy

Aspirin produces an antiplatelet effect by irreversibly blocking cyclooxygenase­1 (COX­1) activity (~95%) for the life of the platelet, thereby inhibiting
thromboxane A2 production. The reduction in thromboxane A2 leads to reduced platelet activation and aggregation. Aspirin doses as small as 30 mg
daily effectively inhibit COX­1. Aspirin doses above 75 to 100 mg provide little additional antiplatelet activity. Aspirin may also provide benefits through
some non­platelet­mediated effects. Higher doses of aspirin (≥325 mg daily) significantly impair endothelial secretion of prostacyclin, which is a natural
vasodilator. Low­dose aspirin does not have this deleterious effect. Although aspirin may inhibit prostacyclin secretion, the effects on the endothelium
are reversible, unlike its effect on platelets. After unbound aspirin has been removed from the circulation (half­life is about 30 minutes), prostacyclin
secretion and its vasodilation effects are restored. Aspirin may also attenuate the synthesis of cytokines such as interleukin­2, interleukin­6, and
interferon in leukocytes as well as prevent leukocyte rolling and macrophage­induced endothelial activation. The extent to which these pharmacologic
properties contribute to the clinical benefits of aspirin is unknown.

Some patients are nonresponsive to the antiplatelet effects of aspirin, and therefore, do not receive a clinical benefit. In patients with CAD, the risk of
recurrent CV events was more than threefold higher in patients with aspirin nonresponsiveness. Fortunately, the occurrence of aspirin
nonresponsiveness is not common, occurring in about 6% of patients and not related to aspirin dose. Therefore, routine laboratory assessment is not
recommended. Given that increasing the dose of aspirin does not impact responsiveness or improve clinical outcomes, the only effective strategy would
be to change to or add an alternative antiplatelet agent.

Aspirin nonresponsiveness may occur because of changes to the COX­1 enzyme, such as changes to the enzyme structure, or temporary blockade of the
active site on the enzyme. Of particular concern is the potential for nonsteroidal anti­inflammatory drug therapy to block the COX­1 enzyme. Naproxen
and ibuprofen have been shown to interfere with aspirin’s antiplatelet effect when coadministered by competing for the site of action. The timing of
coadministration appears to be an important factor. The effect of aspirin on platelet aggregation is impaired when ibuprofen is given 2 hours before
aspirin, but when aspirin is given first, antiplatelet activity is retained.

For patients unable

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significantly reducedRobert J. DiDomenico;
the incidence of stroke, Kelly
MI, orC. Rogers
vascular death in patients with ASCVD comparedPage 21 / 44
to aspirin
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the absolute difference between the two strategies was small (0.5%; number needed to treat = 200). Given the small magnitude of benefit and potential
for nonresponsiveness to clopidogrel, it remains a second­line choice in patients with CAD. When used in patients with CCD, clopidogrel 75mg should be
given daily.
Aspirin nonresponsiveness may occur because of changes to the COX­1 enzyme, such as changes to the enzyme structure, or temporary blockade of the
active site on the enzyme. Of particular concern is the potential for nonsteroidal anti­inflammatory drug therapy to block the COX­1
University enzyme.
of New Naproxen
England ­ Maine
and ibuprofen have been shown to interfere with aspirin’s antiplatelet effect when coadministered by competing for the site of action. The timing of
Access Provided by:
coadministration appears to be an important factor. The effect of aspirin on platelet aggregation is impaired when ibuprofen is given 2 hours before
aspirin, but when aspirin is given first, antiplatelet activity is retained.

For patients unable to take aspirin due to allergy or intolerance, clopidogrel represents a suitable alternative antiplatelet agent to prevent MI and death
in patients with CAD. While clopidogrel significantly reduced the incidence of stroke, MI, or vascular death in patients with ASCVD compared to aspirin
the absolute difference between the two strategies was small (0.5%; number needed to treat = 200). Given the small magnitude of benefit and potential
for nonresponsiveness to clopidogrel, it remains a second­line choice in patients with CAD. When used in patients with CCD, clopidogrel 75mg should be
given daily.

Patient responsiveness to clopidogrel is highly variable and the antiplatelet activity follows a bell­shaped curve. Several tests have been used to evaluate
clopidogrel’s antiplatelet activity and there are different definitions of nonresponsiveness. Thus, estimates of nonresponsiveness to clopidogrel range
from 5% to 44%. Several trials have correlated clopidogrel nonresponsiveness with poor clinical outcomes.

It is unclear what to do if a patient is found to have a lack of appropriate response to clopidogrel. The most common cause of nonresponsiveness is poor
adherence. Even a small number of missed doses will result in an inadequate response to clopidogrel. Data from a large registry provides evidence that
poor adherence is associated with increased ischemic events, as well as important insight into patient predictors of poor adherence. Lack of response
may also be due to polymorphisms in cytochrome P450 (CYP) 2C19, which is responsible for the conversion of clopidogrel into its active compound.
There may also be drug interactions with the CYP2C19, such as proton pump inhibitors, that may alter clopidogrel’s effectiveness. A more detailed
discussion on the clinical impact of these polymorphisms and drug interactions can be found in Chapter 37, “Acute Coronary Syndrome.”

In patients with CCD, but without a history of an ACS event, aspirin therapy has demonstrated the ability to reduce MI or sudden death compared to
patients not receiving aspirin. Autopsy data has revealed that patients with an obstructive atherosclerotic plaque usually have one to two smaller,
nonflow­limiting plaques in their coronary vasculature. Since atherosclerotic plaques producing exertional angina are large and rarely rupture, the
protective benefits of aspirin is by prevention of an ACS from other plaques that are prone to rupture. The use of dual antiplatelet therapy (DAPT) with
aspirin and clopidogrel is not routinely recommended in patients not undergoing PCI and/or without a prior ACS. Studies have demonstrated a small
reduction in CV events with an equal balance of causing an increase in major bleeding.

Rivaroxaban, a direct factor Xa anticoagulant, has demonstrated benefit in patients with CAD when added to aspirin therapy. In a large, randomized trial,
rivaroxaban 2.5 mg twice daily added to low­dose aspirin provided a 24% relative reduction in CV death, MI, and stroke compared to low­dose aspirin
alone. Although there was also a significant increase in major bleeding with patients receiving rivaroxaban, 75% of the major bleeding events would not
have been considered a major bleed by standard bleeding definitions. Patients with polyvascular disease, HF, DM, or at least moderate renal
insufficiency seemed to obtain the most benefit from the addition of rivaroxaban to aspirin therapy. Rivaroxaban should not be added to patients on
DAPT or patients requiring oral anticoagulation therapy and is only considered once the P2Y12 inhibitor has been discontinued.

The physical damage imposed on the atherosclerotic plaque during PCI with stent placement induces platelet recruitment and activation, leading to the
potential for thrombus formation. Therefore, periprocedural antithrombotic therapy with antiplatelet and anticoagulant agents are necessary to
produce a successful outcome. Antiplatelet therapy is also used after the procedure to reduce the risk of stent thrombosis. Patients undergoing
revascularization with PCI for refractory angina (elective PCI), should receive aspirin before PCI. Patients already on chronic aspirin therapy should take
an additional 162 to 325 mg before PCI. Aspirin­naïve patients should be given a dose of 325 mg, preferably at least 2 but up to 24 hours before PCI.
Patients with CCD receiving a stent should also receive a loading dose of a P2Y12 inhibitor at the time of PCI. To reduce the risk of stent thrombosis,
current guidelines suggest DAPT with clopidogrel and aspirin for up to 6 months after the procedure with chronic treatment of aspirin 81 mg daily
thereafter.

The duration of DAPT is influenced by several factors, including stent type, history of ACS, bleeding risk, and concomitant indication for an oral
anticoagulant. For patients who receive a BMS, a minimum of 1 month of DAPT is sufficient. For those at high risk of bleeding, a minimum of 2 weeks of
DAPT may be sufficient, as most re­endothelialization of the stent surface occurs within 2 weeks. Patients with CCD receiving a DES should receive at
least 6 months of DAPT. However, in patients who receive a DES and are at high risk of bleeding, an abbreviated duration of DAPT (1­3 months) may be
considered followed by monotherapy with a P2Y12 inhibitor for at least 12 months. Although several tools to predict bleeding risk following PCI have
been developed, three of the more commonly used tools and the characteristics associated with bleeding risk in each are shown in Table 36­6. For
patients with CCD treated for ACS with PCI, DAPT duration should be at least 12 months following the ACS event. In a select group of ACS patients, the
DAPT score can be used to identify patients who may benefit from prolonged DAPT therapy (up to three years), which has been shown to reduce the risk
of CV adverse events but increases the risk of major bleeding. After the completion of DAPT or P2Y12 inhibitor therapy, consideration can be given to the
addition of rivaroxaban 2.5 mg twice daily to low­dose aspirin for a reduction if CV events as discussed above. In patients with CCD with a concomitant
indication for oral anticoagulation (eg, atrial fibrillation, venous thromboembolism), triple therapy with DAPT and an oral anticoagulant is
recommended for up to 19:58
Downloaded 2025­6­30 to 4 weeks (shorter
A Your durations in patients with low­moderate ischemic events, longer duration in patients with high thrombotic
IP is 185.80.143.8
Chapter 36: Chronic Coronary Disease, Paul P. Dobesh;
risk and low bleeding risk) followed by a combination Robert J.and
of clopidogrel DiDomenico; Kelly C. Rogers
the oral anticoagulant Page 22with
for 6 months. Given the thrombotic risk associated / 44
©2025 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
PCI, bleeding risk associated with antithrombotic therapy, and varying combinations and durations of antithrombotic therapy, it is critical that providers
and patients are properly educated about these risks and the importance of adherence, particularly during transitions of care.
been developed, three of the more commonly used tools and the characteristics associated with bleeding risk in each are shown in Table 36­6. For
patients with CCD treated for ACS with PCI, DAPT duration should be at least 12 months following the ACS event. In a select groupofofNew
University ACS England
patients,­the
Maine
DAPT score can be used to identify patients who may benefit from prolonged DAPT therapy (up to three years), whichAccess
has been shown
Provided by: to reduce the risk
of CV adverse events but increases the risk of major bleeding. After the completion of DAPT or P2Y12 inhibitor therapy, consideration can be given to the
addition of rivaroxaban 2.5 mg twice daily to low­dose aspirin for a reduction if CV events as discussed above. In patients with CCD with a concomitant
indication for oral anticoagulation (eg, atrial fibrillation, venous thromboembolism), triple therapy with DAPT and an oral anticoagulant is
recommended for up to 1 to 4 weeks (shorter durations in patients with low­moderate ischemic events, longer duration in patients with high thrombotic
risk and low bleeding risk) followed by a combination of clopidogrel and the oral anticoagulant for 6 months. Given the thrombotic risk associated with
PCI, bleeding risk associated with antithrombotic therapy, and varying combinations and durations of antithrombotic therapy, it is critical that providers
and patients are properly educated about these risks and the importance of adherence, particularly during transitions of care.

TABLE 36­6
Characteristics Associated with Bleeding Risk Following Percutaneous Coronary Intervention in Validated Tools

Characteristic D A P Ta PARIS PRECISE­DAPT

Age 1.54 (1.34­1.78) per 10­year 1.02 (1.00­1.04) per 1­year 1.34 (1.11­1.48) per 10­year increase
increase increase

Renal impairment 1.66 (1.04­2.66) 1.81 (1.16­2.82) 0.90 (0.82­0.99) per 10 mL/min (0.17 mL/s) increase
SCr ≥2.0 mg/dL [177
µmol/L]
CrCl <60 mL/min (1 mL/s)
CrCl

Anemia 2.72 (1.83­4.04) 0.67 (0.53­0.84) per 1 g/dL (10 g/L; 0.62 mmol/L)
History increase
Hemoglobin

Previous bleeding 4.14 (1.22­14.02)

Peripheral arterial disease 2.16 (1.46­3.20)

Current smoker 1.94 (1.18­3.20)

DAPT + oral anticoagulant 1.93 (1.08­3.43)

Continued P2Y12 inhibitor 1.66 (1.26­2.19)

Body mass index 1.68 (1.09­2.60)

<25 kg/m2
1.79 (1.04­3.08)
≥35 kg/m2

Hypertension 1.45 (1.00­2.11)

White blood cell count 1.06 (0.99­1.13) per 1 × 103 cells/µL (1 × 109 cells/L)

SCr, serum creatinine; CrCl, creatinine clearance; DAPT, dual antiplatelet therapy.

aOnly moderate predictors of bleeding shown; predictors of MI or stent thrombosis not shown.

Data shown are hazard ratio (95% confidence interval) for risk of moderate or severe (DAPT) or major (PARIS) bleeding.

Links to the individual calculators and their interpretation are provided: DAPT score (https://tools.acc.org/daptriskapp/#!/content/calculator/), PARIS
score (http://dx.doi.org/10.1016/j.jacc.2016.02.064,
Downloaded Table 4), PRECISE­DAPT score (http://www.precisedaptscore.com/predapt/).
2025­6­30 9:58 A Your IP is 185.80.143.8
Chapter 36: Chronic Coronary Disease, Paul P. Dobesh; Robert J. DiDomenico; Kelly C. Rogers Page 23 / 44
©2025
Prior to McGraw Hill. All
CABG surgery, Rights Reserved.
attention Terms of Useneeds
to pharmacotherapeutic • Privacy Policy •to
is important Notice • Accessibility
minimize postoperative complications. Patients taking aspirin daily
preoperatively should continue taking aspirin until the time of surgery to reduce ischemic events. However, for patients undergoing elective CABG who
were not taking aspirin preoperatively, aspirin initiation within 24 hours of surgery offers no benefit and is not recommended. To reduce the risk of
 SCr, serum creatinine; CrCl, creatinine clearance; DAPT, dual antiplatelet therapy.
University of New England ­ Maine
aOnly moderate predictors of bleeding shown; predictors of MI or stent thrombosis not shown. Access Provided by:

Data shown are hazard ratio (95% confidence interval) for risk of moderate or severe (DAPT) or major (PARIS) bleeding.

Links to the individual calculators and their interpretation are provided: DAPT score (https://tools.acc.org/daptriskapp/#!/content/calculator/), PARIS
score (http://dx.doi.org/10.1016/j.jacc.2016.02.064, Table 4), PRECISE­DAPT score (http://www.precisedaptscore.com/predapt/).

Prior to CABG surgery, attention to pharmacotherapeutic needs is important to minimize postoperative complications. Patients taking aspirin daily
preoperatively should continue taking aspirin until the time of surgery to reduce ischemic events. However, for patients undergoing elective CABG who
were not taking aspirin preoperatively, aspirin initiation within 24 hours of surgery offers no benefit and is not recommended. To reduce the risk of
CABG­related major bleeding, P2Y12 inhibitors should be discontinued well in advance of an elective CABG surgery (3­5 days for ticagrelor, 5 days for
clopidogrel, 7 days for prasugrel) and at least 24 hours prior to urgent CABG surgery, if possible. Aspirin 81 to 325 mg daily should be resumed or
initiated within 6 hours of CABG surgery and continued indefinitely to reduce the risk of graft closure and acute MI. If patients are allergic to aspirin,
clopidogrel is an acceptable alternative. For patients treated with DAPT following PCI who subsequently undergo CABG surgery, DAPT should be
resumed postoperatively and continued for the initially recommended duration of therapy is completed.

ACE Inhibitors

In the setting of ASCVD, angiotensin converting enzyme (ACE) inhibitors stabilize coronary plaque, provide restoration or improvement in
endothelial function, inhibit vascular smooth muscle cell growth, decrease macrophage migration, and possibly prevent oxidative stress. They may also
possess some antithrombotic properties by inhibiting platelet aggregation and augmenting the endogenous fibrinolytic system. However, ACE inhibitors
have not been shown to improve symptomatic ischemia or chest pain episodes.

The role of ACE inhibitors in patients at high risk for CV events was established in a study comparing ramipril 10 mg daily to placebo in patients with
ASCVD (including ~80% with CAD, most of whom had CCD) or its equivalent (eg, DM with at least one additional risk factor) and normal LV function.
Ramipril significantly reduced the risk of CV death, MI or stroke compared placebo. These impressive benefits were seen despite a minimal reduction in
BP with the use of ramipril. Benefits were consistent across all groups of patients enrolled, regardless of the location of ASCVD. Although subsequent
trials produced conflicting results, a meta­analysis of seven trials demonstrated a significant 14% reduction in mortality in patients with CAD treated with
an ACE inhibitor.

Trials have evaluated the role of angiotensin receptor blockers (ARB) to determine if they provide a similar benefit as ACE inhibitors in the setting of CAD.
A trial in patients with preexisting CVD or DM with end­organ damage treated with either the ACE inhibitor ramipril 10 mg daily or the ARB telmisartan 80
mg daily appeared to have a similar benefit. However, there was no added benefit from combining the two agents. There were significantly more
episodes of hypotension, syncope, and renal dysfunction in patients treated with combination therapy. In a second trial, telmisartan failed to
demonstrate a CV benefit over placebo in patients who were intolerant to ACE inhibitors. Based on these conflicting data, an ARB may be considered if
the patient cannot tolerate ACE inhibitor therapy, and combination therapy should be avoided.

ACE inhibitors are recommended for all patients with CCD who also have HTN, DM, chronic kidney disease (CKD), left ventricular ejection fraction (LVEF)
less than or equal to 40% (0.4), or following an MI unless contraindicated. ARBs are recommended for the same patient populations if they are intolerant
to ACE inhibitors.

The safety and efficacy of initiating ACE inhibitors following CABG surgery are uncertain and may increase the risk of hypotension and acute kidney
injury, particularly if administered during the early postoperative period. However, the continuation of previous ACE inhibitor therapy following CABG
surgery is associated with a significant reduction in nonfatal cardiac, cerebral, and renal events, whereas ACE inhibitor withdrawal following CABG
surgery is associated with increased event rates. Therefore, for patients taking ACE inhibitors or ARBs prior to CABG surgery, these therapies should be
resumed following surgery once patients have demonstrated stable hemodynamics and renal function. For ACE inhibitor­naïve patients, initiation of an
ACE inhibitor should be considered in stable patients with compelling indications (eg, heart failure with reduced ejection fraction [HFrEF], HTN, DM, or
CKD). For symptomatic relief of chest pain episodes, patients need access to SL nitroglycerin after surgery. Smoking cessation is critical to successful
postoperative outcomes and the combination of behavioral and pharmacotherapy interventions is recommended to improve success and reduce MACE.

β­blockers

β­Adrenergic blocking agents are commonly used in the symptomatic management of patients with CCD to reduce both symptomatic and silent episodes
of myocardial ischemia. Data supporting their role in reducing mortality after an MI stem from studies conducted in the 1980s, a time period that did not
include the many clinical advancements utilized for secondary prevention today including PCI, potent antithrombotic regimens, high­intensity statins,
and the use of ACE inhibitors. The use of specific guideline recommended agents (bisoprolol, carvedilol, and metoprolol succinate) has been well
documented in the setting of reduced LVEF in those with and without a prior ACS. Registry data suggest that the use of β­blockers may also be beneficial
Downloaded 2025­6­30 9:58 A Your IP is 185.80.143.8
in those with
Chapter mid­range
36: Chronic LVEF (40%­49%
Coronary Disease,[0.4­0.49]). However,Robert
Paul P. Dobesh; routineJ.use in patients Kelly
DiDomenico; with aC.
history
Rogersof CAD who have preserved ejection fraction
Pagehas
24 been
/ 44
©2025 McGraw
recently Hill.An
challenged. Allobservational
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study evaluating • Privacy
the use Policy •inNotice
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patients with a history of MI, stable CAD without a history of MI, and those
with only risk factors for CAD found no difference in MACE between those treated with and without β­blockers. However, the incidence of hospitalization
for atherothrombotic events or a revascularization procedure was significantly reduced for those receiving a β­blocker with a recent MI within one year.
β­Adrenergic blocking agents are commonly used in the symptomatic management of patients with CCD to reduce both University
symptomaticof New England
and ­ Maine
silent episodes
Access Provided by:
of myocardial ischemia. Data supporting their role in reducing mortality after an MI stem from studies conducted in the 1980s, a time period that did not
include the many clinical advancements utilized for secondary prevention today including PCI, potent antithrombotic regimens, high­intensity statins,
and the use of ACE inhibitors. The use of specific guideline recommended agents (bisoprolol, carvedilol, and metoprolol succinate) has been well
documented in the setting of reduced LVEF in those with and without a prior ACS. Registry data suggest that the use of β­blockers may also be beneficial
in those with mid­range LVEF (40%­49% [0.4­0.49]). However, routine use in patients with a history of CAD who have preserved ejection fraction has been
recently challenged. An observational study evaluating the use of β­blockers in patients with a history of MI, stable CAD without a history of MI, and those
with only risk factors for CAD found no difference in MACE between those treated with and without β­blockers. However, the incidence of hospitalization
for atherothrombotic events or a revascularization procedure was significantly reduced for those receiving a β­blocker with a recent MI within one year.

Therefore, the use of select β­blockers (bisoprolol, carvedilol, or metoprolol succinate) is recommended to reduce the risk of future MACE and CV death
in patients with CCD and LVEF less than or equal to 40% (0.4) regardless of a prior history of MI. It is also recommended to choose one of these three
agents in those with CCD and an LVEF less than 50% (0.5) to reduce CV death and MACE. It is reasonable to use β­blockers in patients with CCD and LVEF
>50% (0.5) to help manage symptoms of angina, arrhythmias, or treat uncontrolled HTN with periodic reassessment to evaluate the need for long­term
use. In the absence of another compelling indication, there is no benefit to routine utilization of β­blockers for CCD in those without a history of prior MI
or LVEF less than or equal to 50% (0.5) to reduce MACE.

Lipid Management

Multiple studies have demonstrated a continuous increase in coronary events with increasing low­density lipoprotein cholesterol (LDL­C) in men and
women with and without CCD. Statin therapy significantly lowers LDL­C and reduces CV event rates. The Cholesterol Treatment Trialist Collaborators
found a 10% reduction in all­cause mortality and a 20% reduction in cardiac mortality for every 40 mg/dL (1.03 mmol/L) reduction in LDL­C. Statin
therapy also reduces the risk of MI, stroke, and the need for coronary revascularization. Higher potency statin regimens are more effective than low­
potency regimens. Due to the accelerated atherosclerotic process in the bypass grafts, high­intensity statin therapy should be resumed or initiated in all
patients following CABG surgery.

Current guidelines recommend that all patients with known ASCVD, such as CCD, should receive high­intensity statin therapy to achieve a 50% or more
reduction in LDL­C. Patients over the age of 75 years and those who cannot tolerate high­intensity statin therapy should receive moderate­intensity
statin therapy to achieve a 30% to 49% reduction in LDL­C. In patients with clinical ASCVD who do not achieve a 50% reduction in LDL­C or who have an
LDL ≥70 mg/dL (1.81 mmol/L) on maximally tolerated high­intensity statin therapy, the additional nonstatin therapies such as ezetimibe, PCSK9­
inhibitors, or bempedoic acid may be considered. In patients considered at very high risk (eg, 2 major ASCVD events [ACS within past 12 month, history of
MI or ischemic stroke, symptomatic PAD] or 1 major ASCVD event plus 2 or more high­risk conditions), targeting an LDL­C less than 55 mg/dL (1.42
mmol/L) or non–high density lipoprotein cholesterol less than 85 mg/dL (2.2 mmol/L) may be considered. High­risk conditions include age 65 years or
older, familial hyperlipidemia, history of coronary revascularization, diabetes, HTN, CKD, current smoker, LDL­C 100 mg/dL or greater, and history of
heart failure. Regular physical activity, dietary changes, and weight management should also be implemented (Table 36­4). Dietary approaches to
lowering LDL­C include replacing saturated and trans fatty acids with dietary carbohydrates or unsaturated fatty acids and reducing dietary cholesterol.
Regular physical exercise improves cardiac fitness and facilitates weight loss but does not reliably lower LDL­C. For more information on the
management of dyslipidemia, refer to Chapter 35.

Blood Pressure Management

A number of observational trials have demonstrated a continuous relationship between BP and the risk of CV events. The risk of vascular death increases
linearly over the BP range of 115/75 mm Hg to 185/115 mm Hg. The risk doubles for every 20 mm Hg increase in systolic BP or 10 mm Hg increase in
diastolic BP. Clinical trials have evaluated when to initiate therapy and attempted to define the target BP goal for patients with HTN. However, the specific
BP target for patients with and without CCD has been debated. Clinical trials and meta­analyses support the current guidelines which recommend
initiating pharmacotherapy in patients with CCD with a BP of 130/80 mm Hg or higher and treating to a BP goal of less than 130/80 mm Hg.

Optimal BP should be achieved using lifestyle modifications as well as pharmacotherapy (Table 36­4). This includes a diet rich in fruits, vegetables, and
low­fat dairy products, regular physical exercise, a reduction in dietary sodium, and limited alcohol consumption. Lifestyle modifications can also
contribute to weight loss. A 10­kg weight loss can reduce systolic BP by 5 to 20 mm Hg.

Drugs used to treat HTN in patients with CCD commonly include agents that can be used to treat the symptoms of the disease. β­Blockers and
dihydropyridine (DHP) calcium channel blockers (CCB) are often used to control angina symptoms and they also lower BP. Patients may also be on ACE
inhibitors to reduce CV risk. If additional therapy is needed and the patient’s angina symptoms are well controlled, thiazide diuretics or
mineralocorticoid receptor antagonists may be considered as add­on therapy for HTN. Refer to Chapter 33, “Hypertension,” for more information on the
management of hypertension.
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Smoking
Chapter Cessation
36: Chronic Coronary Disease, Paul P. Dobesh; Robert J. DiDomenico; Kelly C. Rogers Page 25 / 44
©2025 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
Exposure to tobacco smoke is a leading cause of ASCVD in patients with CCD and is perhaps the most important cause of preventable CVD and death.
Cigarette smoking promotes and accelerates ASCVD through a number of mechanisms including increased platelet adhesion, elevated fibrinogen
Drugs used to treat HTN in patients with CCD commonly include agents that can be used to treat the symptoms of the disease. β­Blockers and
University of New England ­ Maine
dihydropyridine (DHP) calcium channel blockers (CCB) are often used to control angina symptoms and they also lower BP. Patients may also be on ACE
Access Provided by:
inhibitors to reduce CV risk. If additional therapy is needed and the patient’s angina symptoms are well controlled, thiazide diuretics or
mineralocorticoid receptor antagonists may be considered as add­on therapy for HTN. Refer to Chapter 33, “Hypertension,” for more information on the
management of hypertension.

Smoking Cessation

Exposure to tobacco smoke is a leading cause of ASCVD in patients with CCD and is perhaps the most important cause of preventable CVD and death.
Cigarette smoking promotes and accelerates ASCVD through a number of mechanisms including increased platelet adhesion, elevated fibrinogen
concentrations, endothelial dysfunction, altered serum lipids, and vasoconstriction. Compared to those who never smoked, smokers lose approximately
10 years of life expectancy and early cessation is associated with an approximately 90% reduction in mortality and improved quality of life. Therefore,
abstinence and smoking cessation are key components of lifestyle modifications for patients with CCD.

Advice from a clinician recommending and discussing the importance of smoking cessation significantly increases the likelihood that a patient will quit.
Clinicians should approach smoking cessation by using the 6 A’s framework:

1. Ask each patient about tobacco use at every visit.

2. Advise each smoker to quit with clear personalized messages.

3. Assess each smoker’s willingness to make a quit attempt.

4. Assist each smoker in making a quit attempt by offering medication and referral for behavioral interventions.

5. Arrange for follow­up.

6. Avoid exposure to environmental tobacco smoke.

Several pharmacologic agents are available over the counter or with a prescription and are all more effective than placebo. Nicotine replacement therapy
is available in a number of dosage forms without a prescription to fit the patient’s lifestyle, including patches, tablets, gum, lozenges, and nasal spray.
Sustained­release bupropion and the partial agonist of the α4β2 nicotinic receptor, varenicline are also first­line medications to treat tobacco
dependence in adults. All three pharmacotherapies are safe and effective in patients with chronic cardiovascular disease. Nonpharmacologic methods
for smoking cessation are just as important. Self­help programs, telephone counseling, behavioral therapy, and exercise all can be used to help patients
quit smoking.

Diabetes Management

DM is a strong risk factor for the development of CVD. Patients with type 1 DM have a 10­fold increased risk of having a CV event and patients with
type 2 DM have a two­ to sixfold risk of CV death compared to those without DM.

Like HTN, the glycemic target for patients with DM, including those with CCD, has been the subject of considerable debate. Studies have found that
achieving an A1c of less than 7% (53 mmol/mol) reduces microvascular complications from DM such as retinopathy, nephropathy, and neuropathy.
While subgroup analyses of larger trials have suggested lower rates of ischemic events in patients randomized to intensive glycemic control (A1c <7% [53
mmol/mol]), macrovascular events were not significantly reduced in trials comparing intensive to more lenient glycemic control in high­risk patients with
DM, including those with preexisting CVD. In these trials, patients in the intensive glycemic control groups had higher rates of adverse events, including
severe hypoglycemia, CV death, and overall mortality. However, longer­term epidemiological follow­up has shown significant reductions in nonfatal MI,
stroke, or CV death in those with more intensive management compared to less intensive, standard therapy. It is important to understand that these
studies were performed prior to the routine clinical use of glucagon­like peptide 1 (GLP­1) receptor agonists and sodium­glucose­cotransporter­2
(SGLT­2) inhibitors, which have established CV and renal benefits in patients with or without type 2 DM at high risk for complications. In patients with
CCD, a target A1c of less than 7% (53 mmol/mol) is recommended for patients with DM with consideration for a more lenient goal (A1c <8% [64
mmol/mol]) for frail or elderly patients or if the risks and burdens of a more stringent A1c outweigh the potential benefits. (Table 36­4).

Patients at high risk or established ASCVD who have type 2 DM should be treated with pharmacologic agents that reduce CV and CKD risk. Due to its
proven safety and efficacy, metformin has long been the drug of first choice for the treatment of type 2 DM, including patients with CCD. Metformin is
inexpensive and has been shown to reduce CV mortality.

The use of SGLT­2 inhibitors or GLP­1 receptor agonists significantly reduce the risk of CV events, including all­cause mortality. In a meta­analysis, the
risk of death was reduced by 20% in patients treated with SGLT­2 inhibitors and by 12% in patients treated with GLP­1 receptor agonists compared to
Downloaded
patients 2025­6­30
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with standard Your IPinisthe
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control groups. Cardiovascular mortality was also lower in patients treated with either SGLT­2 inhibitors
or GLP­1 agonists compared to control subjects.P.The
Chapter 36: Chronic Coronary Disease, Paul Dobesh; Robert J.
risk of adverse DiDomenico;
event Kelly
rates leading to C. Rogers
discontinuation Page 26 / 44
was higher with GLP­1 agonists compared to
©2025 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
SGLT­2 inhibitors and dipeptidyl peptidase 4 inhibitors. Consequently, for patients with DM, it is recommended to use agents that have been shown to
reduce CV events (eg, empagliflozin, dapagliflozin, semaglutide, and liraglutide) as part of the glucose­lowering regimen, regardless of the patient’s
Patients at high risk or established ASCVD who have type 2 DM should be treated with pharmacologic agents that reduce CV and CKD risk. Due to its
University of New England ­ Maine
proven safety and efficacy, metformin has long been the drug of first choice for the treatment of type 2 DM, including patients with CCD. Metformin is
Access Provided by:
inexpensive and has been shown to reduce CV mortality.

The use of SGLT­2 inhibitors or GLP­1 receptor agonists significantly reduce the risk of CV events, including all­cause mortality. In a meta­analysis, the
risk of death was reduced by 20% in patients treated with SGLT­2 inhibitors and by 12% in patients treated with GLP­1 receptor agonists compared to
patients treated with standard therapies in the control groups. Cardiovascular mortality was also lower in patients treated with either SGLT­2 inhibitors
or GLP­1 agonists compared to control subjects. The risk of adverse event rates leading to discontinuation was higher with GLP­1 agonists compared to
SGLT­2 inhibitors and dipeptidyl peptidase 4 inhibitors. Consequently, for patients with DM, it is recommended to use agents that have been shown to
reduce CV events (eg, empagliflozin, dapagliflozin, semaglutide, and liraglutide) as part of the glucose­lowering regimen, regardless of the patient’s
current glycemic control and these agents should be added to metformin therapy in patients with DM type 2 and ASCVD, HF, CKD or with high­risk
features for ASCVD. Refer to Chapter 98, “Diabetes Mellitus,” for more information on the treatment of diabetes.

Vaccinations

Infections with influenza, COVID­19, and pneumococcal pneumonia increase the risk for death and major cardiovascular events in patients with CCD.
Therefore, all patients with CCD should receive an annual influenza vaccination to prevent morbidity and mortality. There is no outcome data with the
COVID­19 vaccination in those with CCD but considering patients with CCD are at high risk for developing complications and death from COVID­19,
guidelines recommend that the benefits of vaccination outweigh any potential adverse effects of the vaccine. Limited data for pneumococcal vaccination
suggest there is a 22% decrease in all­cause death in those at very high CV risk or with established CCD and therefore it is considered reasonable to
provide a pneumococcal vaccine in this patient population.

Pharmacotherapy to Reduce Symptoms

β­blockers

β­Adrenergic blocking agents competitively inhibit the effects of circulating catecholamines on β­adrenoceptors. The predominant adrenergic
receptor type in the heart is the β1­receptor, and competitive blockade minimizes the influence of endogenous catecholamines on the chronotropic and
inotropic state of the myocardium. β­Blockers also produce a reduction in BP through competitive inhibition of β1­receptors in the kidney, leading to a
reduction in renin release. Their beneficial clinical effects in patients with CCD are related to their ability to reduce MVO2. By reducing HR, myocardial
contractility, and intramyocardial wall tension through BP reduction, β­blockers impact all major contributing factors of MVO2 thereby reducing duration
and frequency of angina. Reductions in HR may also improve myocardial oxygen delivery by prolonging diastole filling time and increasing myocardial
perfusion.

β1­selectivity does not improve the efficacy of β­blockers for the treatment of CCD and all agents appear equally effective. β1­selective agents would be
preferred in patients with COPD, peripheral arterial disease, DM, dyslipidemias, and sexual dysfunction, where blocking β2­adrenergic receptors may be
problematic. It should be noted that even β1­selective agents lose their selectivity at higher doses. β­Blockers with combined α1 and β­blockade are also
effective in the management of angina. β­Blockers with intrinsic sympathomimetic activity cause a slight­to­moderate activation of the β­receptor, in
addition to competing with endogenous catecholamines. Due to this unique pharmacologic property, they do not affect resting HR but do modestly
lower HR when catecholamine concentrations are increased during exercise. While agents with intrinsic sympathomimetic activity may be useful for
patients with peripheral arterial disease and dyslipidemia, they are not preferred in patients with CAD. The selection of a β­blocker in patients with CCD
should be guided by the presence of anginal symptoms, comorbid diseases, preferred dosing frequency, and cost.

Most adverse drug reactions experienced with the use of β­blockers are an extension of their pharmacologic activity. Patients receiving β­blockers may
experience bradycardia, hypotension, heart block, impaired glucose metabolism, and altered serum lipids. β­Blockers may alter the lipid profile by
increasing triglycerides and decreasing high density lipoprotein cholesterol. They have no impact on LDL­C. Changes in the lipid profile are greater with
nonselective β­blockers and are usually transient. Central nervous system adverse drug reactions such as fatigue, depression, insomnia, and general
malaise are usually mild but among the most common reasons for treatment discontinuation. Impotence has been reported in approximately 1% of men
receiving β­blockers. Patients with a history of airway disease may suffer from bronchospasm and patients with HFrEF may become fluid overloaded
especially if not adequately treated with a diuretic. Patients without these preexisting disease states usually do not suffer from these adverse drug
reactions and it is important to note that even patients at risk for adverse drug reactions receive significant benefit from the use of β­blockers. β­
Blockers are contraindicated in patients with preexisting bradycardia, second­ or third­degree atrioventricular block, a history of uncontrolled reactive
airway disease (asthma), severe peripheral arterial disease (critical limb­threatening ischemia), hypotension, HFrEF with unstable fluid status, and
patients with DM who have frequent episodes of hypoglycemia. A patient with CCD who has never had an ACS, especially acute MI, and who has
concurrent chronic obstructive pulmonary disease (COPD) may be treated with a cardioselective β­blocker if there are compelling reasons to use a β­
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patients with moderate to severe COPD, β­blockers may increase the risk COPD­related hospitalizations.
Chapter 36: Chronic Coronary Disease, Paul P. Dobesh; Robert J. DiDomenico; Kelly C. Rogers Page 27 / 44
©2025
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β­blocker Hill.needs
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to 3 weeks to prevent abrupt withdrawal. During β­blocker therapy, β­
receptors become up­regulated in the myocardium. After an abrupt withdrawal of β­blocker therapy, these new receptors, along with all of the blocked
receptors, are now stimulated by endogenous catecholamines. This can produce a significant increase in MVO2, induce ischemia, and even MI. If for
especially if not adequately treated with a diuretic. Patients without these preexisting disease states usually do not suffer from these adverse drug
University
reactions and it is important to note that even patients at risk for adverse drug reactions receive significant benefit from of β­blockers.
the use of New England β­ ­ Maine
Blockers are contraindicated in patients with preexisting bradycardia, second­ or third­degree atrioventricular block, Access Provided by:
a history of uncontrolled reactive
airway disease (asthma), severe peripheral arterial disease (critical limb­threatening ischemia), hypotension, HFrEF with unstable fluid status, and
patients with DM who have frequent episodes of hypoglycemia. A patient with CCD who has never had an ACS, especially acute MI, and who has
concurrent chronic obstructive pulmonary disease (COPD) may be treated with a cardioselective β­blocker if there are compelling reasons to use a β­
blocker over other antianginals. However, in patients with moderate to severe COPD, β­blockers may increase the risk COPD­related hospitalizations.

If β­blocker therapy needs to be discontinued, doses should be tapered over 2 to 3 weeks to prevent abrupt withdrawal. During β­blocker therapy, β­
receptors become up­regulated in the myocardium. After an abrupt withdrawal of β­blocker therapy, these new receptors, along with all of the blocked
receptors, are now stimulated by endogenous catecholamines. This can produce a significant increase in MVO2, induce ischemia, and even MI. If for
some reason β­blockers cannot be tapered, patients should be instructed to avoid exertion as much as possible and manage angina episodes with SL
nitroglycerin. If β­blockers are contraindicated or must be discontinued (eg, moderate­severe COPD), a non­DHP CCB is the preferred alternative for
patients who require a lower HR.

Calcium Channel Blockers

CCBs effectively reduce the frequency and duration of angina episodes in patients with CCD. All CCBs reduce MVO2 as well as provide some increase
in supply by inducing coronary vasodilation and preventing vasospasm. CCBs modulate calcium entry into the myocardium and vascular smooth muscle,
as well as other tissues. This leads to a reduction in the cytosolic concentration of calcium responsible for activation of the actin­myosin complex leading
to the contraction of vascular smooth muscle and myocardium.

CCBs should be considered as two separate classes of drugs. While all CCBs inhibit the influx of calcium ions, the location of the inhibition differs based
on the chemical structure of the agents. The DHP CCBs, such as nifedipine, amlodipine, isradipine, and felodipine, primarily block calcium receptors in
vascular smooth muscle cells, such as arterioles, with minimal effect on the myocardium. In contrast, the phenylalkylamine (verapamil) and
benzothiazepine (diltiazem) agents, commonly referred to as non­DHP CCBs, block calcium ion entry mostly in the myocardium, with minimal effect on
vascular smooth muscle. Verapamil has the greatest impact on myocardial calcium channels with diltiazem having an intermediate effect.

All CCBs reduce MVO2 by reducing wall tension by lowering arterial BP and to a minor extent, depressing cardiac contractility. Like β­blockers, non­DHP
CCBs also reduce HR and contractility through blockade of myocardial calcium channels. The DHP CCBs slightly reduce cardiac contractility and produce
either a neutral or increase in HR due to potential reflex tachycardia from direct arterial dilation. The effect on contractility and reflex tachycardia is not
uniform across the class of DHP CCBs. Agents such as nifedipine produce more impairment of LV function than amlodipine and felodipine. Due to their
potential to cause reflex tachycardia, short­acting DHP CCBs should be avoided when treating CCD, chronic HTN, hypertensive crisis, or during an ACS
event. Reflex tachycardia from longer­acting DHP CCBs can be prevented with concurrent β­blocker therapy.

Common adverse drug reactions of CCBs vary between the two classes. Patients taking non­DHP CCBs may experience bradycardia, hypotension,
atrioventricular block, and symptoms of LV depression. Non­DHP CCBs should not be used in patients who have contraindications or cannot tolerate the
rate­slowing effects of β­blockers due to their similar pharmacodynamic effects. Non­DHP CCBs should be avoided in patients with concomitant HFrEF
due to their negative inotropic effects but can provide benefit to patients in atrial fibrillation with a rapid ventricular response due to their negative
dromotropic effects. Verapamil has also been reported to cause constipation in up to 8% of patients. Patients taking DHP CCBs may experience reflex
tachycardia, hypotension, headache, gingival hyperplasia, and peripheral edema. While most DHP CCBs are contraindicated in patients with HFrEF,
amlodipine, and felodipine are considered safe options in patients with HFrEF and concomitant CCD or HTN.

CCBs undergo hepatic oxidative biotransformation via the CYP3A4 isoenzyme and other isoenzymes. Verapamil and diltiazem inhibit the clearance of
other substrates for the 3A4 isoenzyme such as carbamazepine, cyclosporine, lovastatin, simvastatin, and benzodiazepines. The DHP CCBs do not
produce a clinically meaningful interaction with these medications. Verapamil, and to a lesser extent diltiazem, also inhibit P­glycoprotein mediated drug
transport. This interaction is partially responsible for increases in serum concentrations of agents such as digoxin and cyclosporine. Because verapamil
decreases digoxin clearance, digoxin levels must be closely monitored if these agents are used together. Agents that induce the P450 3A4 isoenzyme can
reduce the effectiveness of all CCBs. Potential pharmacodynamic interactions also need to be monitored in patients taking CCBs. Patients receiving
verapamil or diltiazem concurrently with other agents that reduce HR and atrioventricular nodal conduction (β­blockers, digoxin, and amiodarone)
should be monitored for the development of bradycardia or heart block.

Nitrates

Organic nitrates were found to have antianginal properties over 100 years ago when Murrell first reported in 1879, the ability of a 1% nitroglycerin
solution administered orally to relieve and prevent angina attacks. Organic nitrates are prodrugs that require biotransformation into the active
compounds. This process leads to denitration of the nitrate and the release of nitric oxide, also known as endothelium­derived relaxing factor. NO
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increases concentrations of cyclic guanosine monophosphate in the vascular endothelium leading to a reduction in cytoplasmic calcium and
Chapter 36: Chronic Coronary Disease, Paul P. Dobesh; Robert J. DiDomenico; Kelly C. Rogers Page 28 / 44
subsequent
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doses are increased, arterial vasodilation also occurs. Arterial vasodilation can produce reflex tachycardia that can negate some of the antianginal
benefits. Patients on adequate doses of β­blockers or non­DHP CCBs will not have reflex tachycardia, making this an effective combination for
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Organic nitrates were found to have antianginal properties over 100 years ago when Murrell first reported in 1879, the ability of a 1% nitroglycerin
solution administered orally to relieve and prevent angina attacks. Organic nitrates are prodrugs that require biotransformation into the active
compounds. This process leads to denitration of the nitrate and the release of nitric oxide, also known as endothelium­derived relaxing factor. NO
increases concentrations of cyclic guanosine monophosphate in the vascular endothelium leading to a reduction in cytoplasmic calcium and
subsequent vasodilation. Vasodilation occurs predominantly in the venous vasculature thereby reducing preload, myocardial wall tension, and MVO2. As
doses are increased, arterial vasodilation also occurs. Arterial vasodilation can produce reflex tachycardia that can negate some of the antianginal
benefits. Patients on adequate doses of β­blockers or non­DHP CCBs will not have reflex tachycardia, making this an effective combination for
controlling a patient’s acute and chronic angina symptoms.

Nitrates also vasodilate stenotic vessels as well as the intracoronary collaterals. Given that blood flow is exponentially related to the degree of stenosis,
small increases in vasodilation in these narrowed vessels can produce significant increases in myocardial oxygen supply to ischemic areas of the
myocardium. Nitrate­induced coronary vasodilation occurs predominately in epicardial vessels, with minimal effect on coronary microcirculation. This
explains why nitrates do not cause coronary steal similar to other vasodilators like dipyridamole or sodium nitroprusside. In coronary steal, there is
vasodilation in coronary vessels without atherosclerotic disease but coronary vessels with disease are not dilated. Therefore, more blood flow is shifted,
or “stolen,” to nondiseased vessels away from atherosclerotic vessels that have reduced blood flow.

Common adverse drug reactions from nitrate therapy include headache, flushing, nausea, postural hypotension, and syncope. While the hypotension is
usually not severe, patients who are volume­depleted may experience paradoxical bradycardia if they attempt to rapidly stand. The headache will usually
resolve after about 2 weeks when nitrates are used for chronic therapy. It is important to note that this does not represent tolerance or loss of
antianginal effectiveness. Acetaminophen is effective in managing nitrate­induced headaches during the initial weeks of therapy. Patients using
transdermal nitroglycerin may experience skin erythema and inflammation. Initiating therapy with smaller doses and rotating the application site can
mitigate some of the adverse drug reactions of transdermal nitroglycerin.

Several formulations of nitrates are available for acute and chronic use (Table 36­7). All patients with CAD should have access to SL nitroglycerin
tablets or spray for the treatment of acute episodes of angina. Patient education is critical to ensure appropriate SL nitroglycerin use (Table 36­8). The SL
route of administration avoids gastrointestinal absorption and hepatic first­pass metabolism. SL nitroglycerin 300 to 400 µg typically provides relief of
angina within 5 minutes of administration. SL nitroglycerin can also relieve symptoms even if the patient is chronically taking long­acting nitrates. The
adverse drug reactions of flushing, headache, and postural hypotension can appear rapidly and the patient should be aware of this potential. SL
nitroglycerin can also be used to prevent acute episodes of angina. When patients want to participate in activities that they know lead to angina, they can
take a dose of SL nitroglycerin 2 to 5 minutes in advance. This prophylactic dose provides up to 30 minutes of protection and allows patients to
participate in activities that they might otherwise be unable.

TABLE 36­7
Nitrate Products

Product Onset (minutes) Duration Initial Dose

Nitroglycerin

IV 1­2 3­5 minutes 5­10 µg/min

Sublinguala 1­3 30­60 minutes 0.3­0.4 mg

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Chapter 36: Chronic Coronary Disease, Paul P. Dobesh; Robert J. DiDomenico; Kelly C. Rogers Page 29 / 44
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adverse drug reactions of flushing, headache, and postural hypotension can appear rapidly and the patient should be aware of this potential. SL
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nitroglycerin can also be used to prevent acute episodes of angina. When patients want to participate in activities that they know lead to angina, they can
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take a dose of SL nitroglycerin 2 to 5 minutes in advance. This prophylactic dose provides up to 30 minutes of protection and allows patients to
participate in activities that they might otherwise be unable.

TABLE 36­7
Nitrate Products

Product Onset (minutes) Duration Initial Dose

Nitroglycerin

IV 1­2 3­5 minutes 5­10 µg/min

Sublinguala 1­3 30­60 minutes 0.3­0.4 mg

Oral 40 3­6 hours 2.5­6.5 mg three times a day

Ointment 20­60 2­8 hours 0.5­1 in. (1.3­2.5 cm)

Patch 40­60 >8 hours 0.2­0.4 mg/h (1 patch)

Isosorbide Dinitrate

Immediate release 20­40 4­6 hours 5­20 mg three times a day

Sustained release 60 8 hours 40 mg once daily

Isosorbide Mononitrate

Immediate release 30­60 6­8 hours 20 mg twice a day

Extended release 30­60 12­24 hours 30­60 mg daily

aSublingual nitroglycerin exists in three different formulations: tablets, spray, and powder packets.

TABLE 36­8
Appropriate Use of Sublingual Nitroglycerin

Education Point Rationale

Keep in original dark glass container SL nitroglycerin will interact with plastic and can lose potency when exposed to light. This is why it is packaged in a
dark glass container.

Do not store in a larger plastic vial During an episode of angina, you do not want the patient struggling to figure out how to open the safety cap.
with a child­resistant safety cap

Do not store in the bathroom SL nitroglycerin will degrade in moisture and tablets will lose their integrity and potency.

Keep SL nitroglycerin close by at all SL nitroglycerin does not do any good to the patient if they do not have it with them at the time of an episode of
times; may need multiple vials angina. The patient should consider having one at home, at work, in the garage, etc.

The patient should be sitting down While the SL nitroglycerin tablets are small, the dose is not. It is likely the patient will have some flushing, may get a
and resting while taking the tablet headache, and even become a little light­headed. They need to know this can happen.

Describe how to use a sublingual The SL nitroglycerin is administered under the tongue in order to provide rapid absorption and avoid first­pass
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tablet metabolism. The patient needs to keep the tablet under the tongue until dissolved. Avoid swallowing the tablet.
Chapter 36: Chronic Coronary Disease, Paul P. Dobesh; Robert J. DiDomenico; Kelly C. Rogers Page 30 / 44
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Once opened, tablets need to be Due to the instability of SL nitroglycerin tablets, they are typically only good for 6 months after the bottle is
refilled every 6 months and spray opened.a Shelf­life of the spray is longer. Patients need to be advised to refill SL nitroglycerin even if all doses have
 Extended release 30­60 12­24 hours 30­60 mg daily University of New England ­ Maine
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aSublingual nitroglycerin exists in three different formulations: tablets, spray, and powder packets.

TABLE 36­8
Appropriate Use of Sublingual Nitroglycerin

Education Point Rationale

Keep in original dark glass container SL nitroglycerin will interact with plastic and can lose potency when exposed to light. This is why it is packaged in a
dark glass container.

Do not store in a larger plastic vial During an episode of angina, you do not want the patient struggling to figure out how to open the safety cap.
with a child­resistant safety cap

Do not store in the bathroom SL nitroglycerin will degrade in moisture and tablets will lose their integrity and potency.

Keep SL nitroglycerin close by at all SL nitroglycerin does not do any good to the patient if they do not have it with them at the time of an episode of
times; may need multiple vials angina. The patient should consider having one at home, at work, in the garage, etc.

The patient should be sitting down While the SL nitroglycerin tablets are small, the dose is not. It is likely the patient will have some flushing, may get a
and resting while taking the tablet headache, and even become a little light­headed. They need to know this can happen.

Describe how to use a sublingual The SL nitroglycerin is administered under the tongue in order to provide rapid absorption and avoid first­pass
tablet metabolism. The patient needs to keep the tablet under the tongue until dissolved. Avoid swallowing the tablet.

Once opened, tablets need to be Due to the instability of SL nitroglycerin tablets, they are typically only good for 6 months after the bottle is
refilled every 6 months and spray opened.a Shelf­life of the spray is longer. Patients need to be advised to refill SL nitroglycerin even if all doses have
every 3 years not been taken.

Remove the cotton plug from the Larger quantity bottles commonly have a cotton plug. During an episode of angina, you do not want the patient to
bottle be struggling with trying to get the cotton plug out of the bottle.

May be taken in advance of events SL nitroglycerin can be used to prevent episodes of angina if taken before partaking in an exertional event known to
known to cause chest pain precipitate angina/chest discomfort.

Contact 911 if first SL nitroglycerin Most episodes of angina are relieved within 5­10 minutes of rest and a single SL nitroglycerin. If pain persists, the
does not relieve anginab episode may be an acute coronary syndrome, not chronic coronary disease. This requires rapid medical attention.

aProduct­specific.

b May be patient­specific based on their experience with SL nitroglycerin and angina episodes.

The development of nitrate tolerance must be considered when chronically using long­acting nitrate therapy for CCD. Several trials have shown that
continuous nitrate therapy for more than 24 hours leads to a reduction or loss of the hemodynamic and antianginal effects of nitrates. In a large study in
patients receiving 24 hours of transdermal nitroglycerin, almost all patients lost control of their angina symptoms within 24 hours to 1 week, which
cannot be overcome with higher doses.

Nitrate tolerance is not an “all or none” phenomenon. Responsiveness is reduced in some patients while others experience a total loss of efficacy.
Despite the continued use of nitrates and a loss of antianginal effect, plasma volume remains expanded and some hemodynamic effects are maintained.
Chronic administration of nitrates produces a state of oxidative stress leading to dysfunction of mitochondrial aldehyde dehydrogenase, the enzyme
responsible for converting nitrates to the active agent NO. Consequentially, the dysfunctional enzyme is unable to produce active NO and the angina
relieving effect of nitrate agents is reduced or lost.

Why nitrate tolerance develops remains unknown, but several pharmacologic approaches have been developed to manage and prevent it. One thought
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that tolerance is due to9:58 A Your IPofissulfhydryl
an exhausting 185.80.143.8
groups needed to use organic nitrates. Based on this hypothesis, acetylcysteine and ACE inhibitors
Chapter 36: Chronic Coronary Disease, Paul P. Dobesh; Robert J. DiDomenico; Kelly C. Rogers Page 31 / 44
such as captopril, which supply sulfhydryl groups, have been investigated as a potential strategy for preventing nitrate tolerance. Unfortunately, both
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agents have provided inconsistent results. ACE inhibitors may prevent nitrate tolerance through other mechanisms. The inhibition of angiotensin II
production can reduce superoxide anion production, leading to reduced nitrate degradation, as well as a reduction in protein kinase C and endothelin
Despite the continued use of nitrates and a loss of antianginal effect, plasma volume remains expanded and some hemodynamic effects are maintained.
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Chronic administration of nitrates produces a state of oxidative stress leading to dysfunction of mitochondrial aldehyde dehydrogenase, the enzyme
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responsible for converting nitrates to the active agent NO. Consequentially, the dysfunctional enzyme is unable to produce active NO and the angina
relieving effect of nitrate agents is reduced or lost.

Why nitrate tolerance develops remains unknown, but several pharmacologic approaches have been developed to manage and prevent it. One thought
is that tolerance is due to an exhausting of sulfhydryl groups needed to use organic nitrates. Based on this hypothesis, acetylcysteine and ACE inhibitors
such as captopril, which supply sulfhydryl groups, have been investigated as a potential strategy for preventing nitrate tolerance. Unfortunately, both
agents have provided inconsistent results. ACE inhibitors may prevent nitrate tolerance through other mechanisms. The inhibition of angiotensin II
production can reduce superoxide anion production, leading to reduced nitrate degradation, as well as a reduction in protein kinase C and endothelin
leading to a reduction in vasoconstriction. Unfortunately, none of these approaches have shown to be effective in maintaining the antianginal effects of
continuous nitrate therapy.

The preferred management of nitrate tolerance for patients with CAD is to ensure a 10­ to 14­hour nitrate­free interval every day. This approach has been
shown to maintain antianginal efficacy with the use of chronic nitrates. The rationale for this approach is based on the observation that although nitrate
tolerance develops rapidly, it is also reversed rapidly. Unfortunately, this approach does not provide the patient with anti­ischemic coverage for a full 24
hours and places the patient at risk for angina episodes. Typically, the nitrate­free interval is provided during the nighttime hours when the patient is
sleeping and, in most cases, has lower MVO2. Several trials have used chronic nitrates with a daily nitrate­free interval and demonstrated increased
exercise time, reduced exercise­induced ischemic events, and reduced need for SL nitroglycerin. Despite these benefits, a nitrate­free interval would not
provide protection to the 20% to 30% of patients with CCD who experience nocturnal episodes of angina. Moreover, it is well documented that angina
episodes and MI commonly occur in the morning hours, immediately before or after awakening. Patients using chronic nitrate therapy are unlikely to
have taken or applied their nitrate therapy for the day during this critical time period. Therefore, nitrates should not be routinely used as monotherapy
in patients with CCD due to the lack of 24­hour coverage, lack of protection against circadian­related ischemic events, and potential for reflex
tachycardia. Trials have demonstrated that patients taking intermittent transdermal nitroglycerin did not experience rebound ischemia during the
nitrate­free interval when β­blockers or diltiazem were concurrently used.

Several nitrate preparations can be used for chronic long­term prevention of angina episodes. Transdermal patches and isosorbide mononitrate are the
most commonly prescribed chronic nitrates. Although isosorbide dinitrate is effective, the three times daily dosing regimen requires patients to take a
dose every 4 to 5 hours in order to provide an adequate nitrate­free interval. Two of the isosorbide mononitrate preparations are dosed twice daily. The
twice­daily preparations should be dosed 7 hours apart, such as 7 am and 2 pm. It is critical to be specific about the times each dose should be taken so
that patients do not take the doses 12 hours apart, thus compromising the nitrate­free interval. One isosorbide mononitrate preparation is dosed once
daily. It is an extended­release preparation that provides 12 hours of nitrate exposure. This should be followed by a 12­hour nitrate­free interval.
Transdermal nitroglycerin patches are typically prescribed as “on in the am and off in the pm.” It is best to provide specific times for application and
remove (eg, apply at 8 am and remove at 8 pm). Patients who work evening or night shifts need to have the timing of their nitrate doses adjusted to
coincide with when they are active during the day.

Ranolazine

Unlike other agents used for angina, ranolazine does not impact HR, BP, the inotropic state, or coronary blood flow. Animal studies have
demonstrated that ranolazine has little affinity for α1, β1, and β2 adrenoreceptors and has minimal calcium channel blocking activity. Ranolazine reduces
ischemic episodes by selective inhibition of late sodium current (INa). Total sodium entry during an action potential is comprised of an early (fast) and
late (slow) component. Under normal conditions, late INa constitutes only 1% of total INa. Several preclinical studies have observed an increase in late INa

in ischemic and failing hearts. It is not fully appreciated if this increase in late INa is due to an increase in the density of the late sodium (Na+) channels or

dysfunction of these channels. The increase in intracellular Na+ triggers an increase in the influx of calcium (Ca2+) through the reverse mode of the
Na+/Ca2+ exchanger, resulting in intracellular Ca2+ overload and eventually myocardial stunning. Therefore, it is not the intracellular Na+ concentration
that produces ischemic damage, but its recognized role in Ca2+ accumulation via Na+/Ca2+ exchange. By inhibiting late INa, ranolazine produces a

reduction in intracellular Na+. The reduction in intracellular Na+ contributes to a reduction in the magnitude of ischemia­induced Ca2+ overload and
improves myocardial function as well as myocardial perfusion.

Ranolazine is available as a sustained­release preparation dosed twice daily. With a half­life of approximately 7 hours, ranolazine achieves a steady­state
within 3 days. Since ranolazine 1,000 mg twice daily significantly improves exercise tolerance more than 500 mg twice daily, titration to 1,000 mg twice
daily should be attempted. When ranolazine was added to atenolol (50 mg daily), diltiazem (180 mg daily), or amlodipine (5 mg or 10 mg daily), there was
an increase in exercise duration, time to angina, time to 1 mm ST­depression, and a reduction in the number of angina episodes and SL nitroglycerin
tablets used per week compared to placebo. In these trials, the magnitude of increase in exercise duration during testing was associated with a 25%
reduction
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angina episodes
IP is and SL nitroglycerin use over placebo and almost a 50% reduction from baseline. The improvement
185.80.143.8
in exercise
Chapter duration
36: Chronicdemonstrated with ranolazine
Coronary Disease, is consistent
Paul P. Dobesh; withJ.results
Robert produced
DiDomenico; withC.β­blockers,
Kelly Rogers CCBs, and chronic nitrates. Page 32 / 44
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Patients should be initiated on ranolazine 500 mg twice daily, with the dose increased to 1,000 mg twice daily within the next 1 to 2 weeks if tolerated.
Ranolazine is primarily metabolized by CYP3A4 (70%­85%) and CYP2D6 (10%­15%) in the liver and is a substrate for P­glycoprotein, making it prone to
Ranolazine is available as a sustained­release preparation dosed twice daily. With a half­life of approximately 7 hours, ranolazine achieves a steady­state
University
within 3 days. Since ranolazine 1,000 mg twice daily significantly improves exercise tolerance more than 500 mg twice daily, of New
titration England
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mg twice
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daily should be attempted. When ranolazine was added to atenolol (50 mg daily), diltiazem (180 mg daily), or amlodipine (5 mg or 10 mg daily), there was
an increase in exercise duration, time to angina, time to 1 mm ST­depression, and a reduction in the number of angina episodes and SL nitroglycerin
tablets used per week compared to placebo. In these trials, the magnitude of increase in exercise duration during testing was associated with a 25%
reduction in the weekly number of angina episodes and SL nitroglycerin use over placebo and almost a 50% reduction from baseline. The improvement
in exercise duration demonstrated with ranolazine is consistent with results produced with β­blockers, CCBs, and chronic nitrates.

Patients should be initiated on ranolazine 500 mg twice daily, with the dose increased to 1,000 mg twice daily within the next 1 to 2 weeks if tolerated.
Ranolazine is primarily metabolized by CYP3A4 (70%­85%) and CYP2D6 (10%­15%) in the liver and is a substrate for P­glycoprotein, making it prone to
several clinically important drug interactions. Potent inhibitors of CYP3A4 and P­glycoprotein, such as ketoconazole, itraconazole, protease inhibitors,
and clarithromycin, will significantly increase ranolazine drug concentrations. Conversely, potent CYP3A4 inducers such as phenytoin, phenobarbital,
carbamazepine, rifampin, rifabutin, rifapentine, and St. John’s wort significantly decrease ranolazine drug concentrations. Concurrent use of these
strong inhibitors and inducers with ranolazine is contraindicated. Moderate inhibitors of CYP3A4, such as diltiazem, verapamil, erythromycin, and
fluconazole, can be used with ranolazine, but the dose should not exceed 500 mg twice daily. Due to inhibition of CYP3A4 by ranolazine, doses of
simvastatin should not exceed 20 mg daily. Ranolazine increases digoxin 1.4­ to 1.6­fold at trough and 2­fold at peak plasma concentrations, likely
through competition for intestinal and renal P­glycoprotein. Digoxin doses may need to be reduced to avoid toxicity. Agents that are potent inhibitors of
P­glycoprotein, such as cyclosporine, may increase ranolazine concentrations and adverse drug reactions. The dose of ranolazine should be reduced.

Ranolazine and metformin compete for renal clearance through the organic cation transporter 2, which has the potential to increase metformin drug
concentrations and increase the risk of lactic acidosis. This interaction is only clinically meaningful when both full­dose ranolazine (1,000 mg twice daily)
and full­dose metformin (1,000 mg twice daily) are used together. In this setting, the metformin dose should be reduced to 850 mg twice daily. Patients
on ranolazine 500 mg twice daily do not need to alter their metformin doses. Ranolazine produces reductions in A1c by 0.6% to 0.7% (7­8 mmol/mol).
Reductions in blood glucose were observed in patients with or without DM, without causing hypoglycemia. While ranolazine is not a treatment for DM,
clinicians may find this property useful.

The most common adverse drug reactions from ranolazine use are constipation, nausea, dizziness, and headache. At therapeutic doses, ranolazine
produces a modest prolongation of QTc (15 ms or less). A linear relationship exists between ranolazine plasma concentration and the QTc interval, but
the effect is modest when used at recommended doses. Patients should not receive doses of more than 1,000 mg twice daily and caution should be used
in patients receiving concomitant QTc­prolonging agents.

While ranolazine is safe and effective for treating angina episodes, it would only be an option as monotherapy in patients with CCD who cannot tolerate
traditional antianginal agents due to hemodynamic or other adverse drug reactions. Ranolazine is recommended as an add­on therapy to traditional
antianginal agents. In patients who have achieved HR and BP targets on maximally tolerated doses of traditional agents but continue to have exertional
angina symptoms, ranolazine is a reasonable choice because it does not impact these hemodynamic parameters.

Management of Angina

Medical management of angina episodes follows a stepwise approach (see Fig. 36­2 and Table 36­5). All patients should have access to SL
nitroglycerin for the treatment of an acute episode of angina. Patients need to be adequately educated on appropriate use and storage, ensuring
consistent access to the tablets or spray (Table 36­8). This may require patients to have multiple vials or canisters that are in areas that they spend time
(eg, home, work, car). While some patients may only need SL nitroglycerin for infrequent attacks, many patients with CCD will need chronic therapy to
prevent angina episodes. Patients experiencing frequent angina episodes or in whom angina is impacting the quality of life should receive chronic
antianginal therapy. The goal of chronic therapy is to provide complete or nearly complete elimination of angina episodes while having the patient take
part in normal activities.

Since increased HR can increase MVO2 and precipitate angina, either a β­blocker or a non­DHP CCB (verapamil or diltiazem) can be used for the initial
chronic management of angina. The goal is to lower the patient’s resting HR to 55 to 60 beats/min and an exercise HR of less than 100 beats/min. Not all
patients, especially older adults, can tolerate an HR in this range; the goal HR should be as low as the patient can tolerate to relieve symptoms without
causing adverse effects. Both β­blockers and non­DHP CCBs can improve exercise duration and reduce the number of weekly angina episodes.

β­Blockers are recommended over CCBs as initial therapy for control of angina episodes in patients with CCD and recent (within 12 months) MI and/or
HFrEF. This recommendation is based on improved survival demonstrated with the use of β­blockers in patients with HFrEF after MI. Only carvedilol,
metoprolol succinate, and bisoprolol should be used in patients with HFrEF, starting with low doses and titrating up in a slow and set regimen. CCBs have
not demonstrated similar benefits in patients following an MI or with HFrEF. Patients with contraindications or intolerable adverse drug reactions to β­
blocker therapy may be treated with a non­DHP CCB in patients needing HR reduction. In patients without a history of MI or HF, the use of β­blocker
therapy does not provide a survival advantage and is used purely for the control of ischemic episodes and symptoms of angina.
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If angina 36:
Chapter symptoms
Chronicare controlled
Coronary once BPPaul
Disease, and P.
HRDobesh;
goals areRobert
achieved, no additional Kelly
J. DiDomenico; antianginal therapy is necessary, and patients are monitored
C. Rogers Page 33 for/ 44
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or non­DHP CCB are selected as initial therapy for HR reduction, many
patients will require combination therapy to attain adequate control of their symptoms. If additional therapy is required, the need for additional
antihypertensive agents should be considered in the next step. Patients with angina symptoms refractory to β­blockers who continue to have elevated
β­Blockers are recommended over CCBs as initial therapy for control of angina episodes in patients with CCD and recent (within 12 months) MI and/or
HFrEF. This recommendation is based on improved survival demonstrated with the use of β­blockers in patients with University
HFrEF afterofMI.
NewOnlyEngland ­ Maine
carvedilol,
metoprolol succinate, and bisoprolol should be used in patients with HFrEF, starting with low doses and titrating up inAccess
a slowProvided by:
and set regimen. CCBs have
not demonstrated similar benefits in patients following an MI or with HFrEF. Patients with contraindications or intolerable adverse drug reactions to β­
blocker therapy may be treated with a non­DHP CCB in patients needing HR reduction. In patients without a history of MI or HF, the use of β­blocker
therapy does not provide a survival advantage and is used purely for the control of ischemic episodes and symptoms of angina.

If angina symptoms are controlled once BP and HR goals are achieved, no additional antianginal therapy is necessary, and patients are monitored for
continued efficacy and adverse drug reactions. Regardless of whether a β­blocker or non­DHP CCB are selected as initial therapy for HR reduction, many
patients will require combination therapy to attain adequate control of their symptoms. If additional therapy is required, the need for additional
antihypertensive agents should be considered in the next step. Patients with angina symptoms refractory to β­blockers who continue to have elevated
BP above the goal of 130/80 mm Hg should be prescribed a DHP CCB. Unlike long­acting nitrates and ranolazine, DHP CCBs decrease BP, thereby reduce
MVO2. While not commonly used together, the combination of a DHP CCB and non­DHP CCB is a reasonable regimen for patients with CCD with
contraindications or intolerance to β­blockers, since each CCB targets different calcium channels. It is important to monitor the patient for peripheral
edema and signs and symptoms of reduced cardiac output.

In patients with continued angina episodes despite achieving BP and HR goals, a long­acting nitrate or ranolazine should be considered. Both
agents have demonstrated efficacy when used in combination with other antianginal medications. While long­acting nitrates are not optimal agents
when used as monotherapy due to reflex tachycardia, this is attenuated in patients who are taking a β­blocker or non­DHP CCB. Ranolazine does not
reduce HR or BP, making it an option in patients who have already achieved their HR and BP goals, but still have exertional angina. The selection of a
long­acting nitrate or ranolazine should be based on patient preferences, tolerability, and cost. Long­acting nitrates do not provide 24­hour angina
protection, but this may not be an issue for all patients. While ranolazine provides 24 hours protection and has a more attractive adverse drug reaction
profile compared to long­acting nitrates, it is associated with numerous drug interactions.

Some patients may have inadequate control of chest pain symptoms despite the use of maximally tolerated therapies, making them unable to fully
participate in the activities that bring them joy in life. Inadequate symptom control in these patients may occur while taking relatively fewer antianginal
medications or lower doses due to intolerances or contraindications. Patients with inadequate control of symptoms despite maximally tolerated medical
therapy may be candidates for revascularization therapy.

In patients where the onset of angina varies, pharmacotherapy that targets vasospasm is needed. While β­blockers are commonly used for treatment of
angina symptoms, they are less useful in patients with vasospasm. Although not all studies report increased chest pain episodes with β­blockers in
patients with vasospasm, they can induce coronary vasoconstriction and prolong ischemia. Worsening angina is most likely due to unopposed α1­
adrenergic receptor stimulation during β­blockade. A similar phenomenon may occur in patients with CCD treated with β­blockers who also abuse
cocaine or methamphetamines.

Both nitrates and CCBs reduce vasospasm. Most patients respond well to SL nitroglycerin for acute attacks. While long­acting nitrates can be used in the
treatment of vasospasm, the high doses typically needed for adequate symptom control are not well tolerated. Therefore, CCBs are often required.
There is no preference to which agent is selected first. DHP CCBs, verapamil, and diltiazem are all equally effective for the initial management of coronary
vasospasm and the choice of agents should be individualized to the patient. Dose titration is important to maximize the response with CCBs. Patients
unresponsive to CCBs alone may add long­acting nitrates.

EVALUATION OF THERAPEUTIC OUTCOMES

The therapeutic goals in the management of patients with CCD are to prolong life, reduce symptoms of angina, and improve quality of life. Improving the
patient’s quality of life requires careful attention to the potential adverse drug reactions from medications. Surrogate endpoints such as BP goal
attainment, use of high­intensity statin, A1c goal attainment, smoking cessation, and achieving a healthy weight should be used to determine progress
toward the ultimate goal—reduced risk of mortality and major cardiovascular events. Patients should be evaluated every 1 to 2 months until goals are
achieved. Follow­up every 6 to 12 months thereafter is appropriate.

Monitoring for improvements in symptoms related to angina should include asking the patients about the number and severity of angina episodes
and weekly SL nitroglycerin use as well as inquiring about exercise capacity or duration of exertion needed to induce angina. It is important to ask the
patient about their ability to engage in activities they want to do. It is not uncommon for patients to report reduced or no episodes of angina because
they have stopped engaging in activities that bring on angina. Patients experiencing worsening angina may complain of increasing frequency and
severity of symptoms, increased SL nitroglycerin use, decreased exercise capacity, or a combination of these. Once patients have received optimal
medical therapy, symptoms should improve in 2 to 4 weeks and remain stable until the disease progresses. Instruments such as the Seattle Angina
Questionnaire and CCS classification system can be used to improve the assessment of symptoms. While objective tests such as an exercise tolerance
test with or without cardiac imaging can be obtained to assess the adequacy of treatment, they are primarily performed in patients who do not achieve
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control. A Your aIPrevascularization
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KEY RESOURCES
patient about their ability to engage in activities they want to do. It is not uncommon for patients to report reduced or no episodes of angina because
they have stopped engaging in activities that bring on angina. Patients experiencing worsening angina may complain University of New
of increasing England
frequency and ­ Maine
Access Provided by:
severity of symptoms, increased SL nitroglycerin use, decreased exercise capacity, or a combination of these. Once patients have received optimal
medical therapy, symptoms should improve in 2 to 4 weeks and remain stable until the disease progresses. Instruments such as the Seattle Angina
Questionnaire and CCS classification system can be used to improve the assessment of symptoms. While objective tests such as an exercise tolerance
test with or without cardiac imaging can be obtained to assess the adequacy of treatment, they are primarily performed in patients who do not achieve
adequate symptom control. Following a revascularization procedure, the patients’ symptoms should be assessed every 6 to 12 months.

KEY RESOURCES

Key Resources

Guidelines

Virani SS, Newby LK, Arnold SV, et al. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the management of patients with chronic coronary disease.
J Am Coll Cardiol 2023;82(9):833–955. DOI:10.1016/j.jacc.2023.04.003.

Comprehensive guideline on evidence­based and patient­centered diagnosis, pharmacologic and non­pharmacologic treatment strategies for
patients with chronic coronary disease. References to supporting literature are provided.

Landmark Research Trials

Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017;377:1319–­30. DOI:
10.1056/NEJMoa1709118.

Pivotal study for managing patients with stable atherosclerotic vascular disease which evaluated the benefits and risks associated with
combining low­dose rivaroxaban and aspirin versus using either agent alone.

Danchin N, Cucherat M, Thuillez C, et al. Angiotensin­converting enzyme inhibitors in patients with coronary artery disease and absence of heart
failure or left ventricular systolic dysfunction: an overview of long­term randomized controlled trials. Arch Intern Med 2006;166:787–96. DOI:
10.1001/archinte.166.7.787.

Meta­analysis of the seven trials that have evaluated ACE inhibitors in patients with coronary artery disease without heart failure. This analysis
demonstrated a significant reduction in all­cause mortality, cardiovascular mortality, myocardial infarction, and stroke in patients receiving an
ACE inhibitor in these patients.

Comprehensive Rreviews

Bertero E, Heusch, Munzel T, Maack C. A pathophysiological compass to personalize antianginal drug treatment. Nat Rev Cardiol 2021;18:838–­52. DOI:
10.1038/s41569­021­00573­w.

In­depth review of the pathophysiology of chronic coronary disease, pharmacology of the antianginal drugs, and their roles in managing this
disease.

Joshi PH, de Lemos JA. Diagnosis and management of stable angina: a review. JAMA 2021;325:1765–­78. DOI: 10.1001/jama.2021.1527.

This is a comprehensive review of the diagnosis and management of stable angina (aka, chronic coronary disease) and includes practical
guidance for clinical management and summaries of the relevant literature.

ABBREVIATIONS

ACE angiotensin­converting enzyme

ACS acute coronary syndrome

ARB angiotensin receptor blocker

ASCVD 2025­6­30 9:58 A atherosclerotic

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©2025BMS
McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
bare­metal stent

BP blood pressure
 ACE angiotensin­converting enzyme

University of New England ­ Maine

ACS acute coronary syndrome
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ARB angiotensin receptor blocker

ASCVD atherosclerotic cardiovascular disease

BMS bare­metal stent

BP blood pressure

Ca2+ calcium

CABG coronary artery bypass graft

CAD coronary artery disease

CCB calcium channel blocker

CCD chronic coronary disease

CCS Canadian Cardiovascular Society

COPD chronic obstructive pulmonary disease

COX cyclooxygenase

CT computer topography

CV cardiovascular

DAPT dual antiplatelet therapy

DES drug­eluting stent

DHP dihydropyridine

DM diabetes mellitus

ECG electrocardiogram

GDMT guideline­directed medical therapy

GLP­1 glucagon­like peptide­1

HF heart failure

HFrEF heart failure with reduced ejection fraction

HR heart rate

hs­cTn High­sensitivity cardiac troponin

HTN hypertension

INa late sodium current

LDL­C low­density lipoprotein cholesterol

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LV 36: Chronic Coronary Disease, Paul P. Dobesh; Robert J. DiDomenico; Kelly C. Rogers
left ventricle Page 36 / 44
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LVEF left ventricular ejection fraction
 HTN hypertension
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INa late sodium current

LDL­C low­density lipoprotein cholesterol

LV left ventricle

LVEF left ventricular ejection fraction

MACE major adverse cardiac events

MI myocardial infarction

MVO2 myocardial oxygen demand

Na+ sodium

NO nitric oxide

PCI percutaneous coronary intervention

SGLT­2 sodium­glucose­cotransporter­2

SL sublingual

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Heart Journal 2018;40:190–4. DOI: 10.1093/eurheartj/ehy504.

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Godoy LC, Farkouh ME, Austin PC, et al. Association of beta­blocker therapy with cardiovascular outcomes in patients with stable ischemic heart
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Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of
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and colorectal cancer: an evidence update for the US Preventive Services Task Force. Evidence Synthesis No. 211. Agency for Healthcare Research and
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Gulati M, Levy PD, Mukherjee D, et al. 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;144:e368–454. DOI:
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Lee CR, Luzum JA, Sangkuhl K, et al. Clinical pharmacogenetics implementation consortium guideline for CYP2C19 genotype and clopidogrel therapy:
2022 update. Clin Pharmacol Ther 2022;112:959–67. DOI: 10.1002/cpt.2526.

Lloyd­Jones DM, Morris PB, Ballantyne CM, et al. 2022 ACC expert consensus decision pathway on the role of nonstatin therapies for LDL­cholesterol
lowering in the management of atherosclerotic cardiovascular disease risk. J Am Coll Cardiol 2022;80:1366–418. DOI: 10.1016/j.jacc.2022.07.006.

Martin SS, Aday AW, Almarzooq ZI, et al. 2024 Heart disease and stroke statistics: a report of US and global data from the American Heart Association.
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Chronic ES, Sacco
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Disease, Banerjee S, Boden
P. Dobesh; WE. Antianginal
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2016;24:177–89.

Pelliccia F, Zimarino M, Niccoli G, et al. In­stent restenosis after percutaneous coronary intervention: emerging knowledge on biological pathways. De
Lloyd­Jones DM, Morris PB, Ballantyne CM, et al. 2022 ACC expert consensus decision pathway on the role of nonstatin therapies for LDL­cholesterol
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lowering in the management of atherosclerotic cardiovascular disease risk. J Am Coll Cardiol 2022;80:1366–418. DOI: 10.1016/j.jacc.2022.07.006.
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Martin SS, Aday AW, Almarzooq ZI, et al. 2024 Heart disease and stroke statistics: a report of US and global data from the American Heart Association.
Circulation 2024;149(8). DOI: 10.1161/CIR.0000000000001209.

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Card Rev 2016;24:177–89.

Pelliccia F, Zimarino M, Niccoli G, et al. In­stent restenosis after percutaneous coronary intervention: emerging knowledge on biological pathways. De
Rosa S, ed. Eur Heart J Open 2023;3(5):oead083. DOI: 10.1093/ehjopen/oead083.

Rousan TA, Mathew ST, Thadani U. Drug therapy for stable angina pectoris. Drugs 2017;77:265–84. [PubMed: 28120185]

Sofi F, Marcucci R, Gori AM, Abbate R, Gensini GF. Residual platelet reactivity on aspirin therapy and recurrent cardiovascular events—at meta­analysis.
Int J Cardiol 2008;128:166–71. [PubMed: 18242733]

The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547–59. [PubMed:
18378520]

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Preventive Services Task Force Recommendation Statement. JAMA 2021;325(3):265–79. [PubMed: 33464343]

Virani SS, Newby LK, Arnold SV, et al. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA guideline for the management of patients with chronic coronary disease. J
Am Coll Cardiol 2023;82(9):833–955. DOI: 10.1016/j.jacc.2023.04.003.

Vrints C, Andreotti F, Koskinas KC, et al. 2024 ESC guidelines for the management of chronic coronary syndromes. Eur Heart J 2024;45(36):3415–537.
10.1093/eurheartj/ehae177. PUBMED: 39210710.

Wang ZJ, Zhang LL, Elmariah S, Han HY, Zhou YJ. Prevalence and prognosis of nonobstructive coronary artery disease in patients undergoing
coronary angiography or coronary computed tomography angiography. Mayo Clin Proc 2017;92:329–46. DOI: 10.1016/j.mayocp.2016.11.016.

Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection,
evaluation, and management of high blood pressure in adults—a report of the American College of Cardiology/American Heart Association Task Force
on Clinical Practice Guidelines. J Am Coll Cardiol 2018;71:e127–48. DOI: 10.1016/j.jacc.2017.11.006.

SELF­ASSESSMENT QUESTIONS
1. A 56­year­old patient had coronary artery bypass graft (CABG) surgery performed for refractory symptoms of angina despite maximally tolerated
medical therapy and multiple percutaneous coronary interventions. Which of the following medications should be initiated following CABG surgery
and continued indefinitely to maintain patency of the saphenous vein grafts?

A. Aspirin

B. Prasugrel

C. Rivaroxaban

D. Ticagrelor

2. Which of the following best explains why ischemia does not typically occur with exertion in patients with chronic coronary disease until coronary
stenosis reaches 70% or more of the luminal diameter?

A. Atherosclerotic plaque rupture beyond this degree of coronary stenosis

B. Collateral circulation diminishes as coronary stenosis increases

C. Coronary flow reserve is exhausted as the degree of coronary stenosis increases

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D. Vasospasm
Chapter 36: Chronicoccurs once coronary
Coronary Disease,stenosis
Paul P. exceeds
Dobesh;70% of luminal
Robert diameter Kelly C. Rogers
J. DiDomenico; Page 39 / 44
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3. Which of the following patients with chronic coronary disease is more likely to experience atypical symptoms of angina?
 stenosis reaches 70% or more of the luminal diameter?
University of New England ­ Maine
A. Atherosclerotic plaque rupture beyond this degree of coronary stenosis Access Provided by:

B. Collateral circulation diminishes as coronary stenosis increases

C. Coronary flow reserve is exhausted as the degree of coronary stenosis increases

D. Vasospasm occurs once coronary stenosis exceeds 70% of luminal diameter

3. Which of the following patients with chronic coronary disease is more likely to experience atypical symptoms of angina?

A. 46­year­old with hypertension, dyslipidemia, and obesity

B. 54­year­old with gastroesophageal reflux disease and dyslipidemia

C. 62­year­old with atrial fibrillation, stroke, and chronic kidney disease

D. 76­year­old with hypertension, dyslipidemia, and diabetes

4. A patient with chronic coronary disease is being evaluated for control of angina symptoms. The patient reports experiencing angina symptoms one
to two times weekly, unchanged from baseline. Angina symptoms are typically provoked when walking up a flight of stairs, consistent with baseline.
The chest discomfort is described as 5 out of 10, similar to baseline. The patient reports using 3 to 4 tablets/wk of sublingual nitroglycerin compared
to 1 to 2 tablets/wk at baseline. His blood pressure is 132/84 mm Hg, heart rate is 70 beats/min. Which of the following suggest worsening angina
control?

A. Frequency of angina symptoms

B. Provoking factors

C. The severity of angina symptoms

D. Sublingual nitroglycerin use

5. A 63­year­old female with hypertension, diabetes, dyslipidemia, and obesity is newly diagnosed with chronic coronary disease. Blood pressure is
148/86 mm Hg, heart rate is 64 beats/min. Weight is 104 kg; body mass index is 43.3 kg/m2. LDL cholesterol is 127 mg/dL (3.28 mmol/L) and
hemoglobin A1c is 8.3% (67 mmol/mol). Which of the following risk factor modification goals is appropriate for this patient?

A. Blood pressure <130/80 mm Hg

B. Body mass index <30 kg/m2

C. Hemoglobin A1c <6.5% (48 mmol/mol)

D. LDL cholesterol <70 mg/dL (1.81 mmol/L)

The next two questions (#6 and #7) refer to the following case.

A 68­year­old male presents with complaints of angina when walking two flights of stairs. The pain is relieved with rest and only occasionally
requires a dose of SL nitroglycerin for relief. His PMH includes a history of MI 3 years ago, HTN, and hyperlipidemia. He quit smoking 3 years ago
after his MI. His home medications include aspirin 81 mg daily, metoprolol 25 mg twice daily, and atorvastatin 80 mg daily. Vital signs: BP is
158/92 mm Hg, HR 82 beats/min.

6. Which of the following is most appropriate to treat this patient’s angina?

A. Add lisinopril 10 mg daily

B. Add ranolazine 1,000 mg twice daily

C. Add SL nitroglycerin 1 tablet as needed for angina

D. Increase metoprolol to 50 mg twice daily

7. The patient returns for a cardiology appointment 6 weeks later and states that his angina has improved and he is feeling much better. His laboratory
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findings are 9:58 limits.
within normal A Your IP signs:
Vital is 185.80.143.8
BP is 140/88 mm Hg, HR 68 beats/min. LDL 67 mg/dL (1.73 mmol/L). Which of the following is most
Chapter
appropriate to consider in this patient Paul
36: Chronic Coronary Disease, P. Dobesh;
to reduce Robert J. DiDomenico; Kelly C. Rogers
mortality? Page 40 / 44
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A. Clopidogrel 75 mg daily
 B. Add ranolazine 1,000 mg twice daily
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C. Add SL nitroglycerin 1 tablet as needed for angina Access Provided by:

D. Increase metoprolol to 50 mg twice daily

7. The patient returns for a cardiology appointment 6 weeks later and states that his angina has improved and he is feeling much better. His laboratory
findings are within normal limits. Vital signs: BP is 140/88 mm Hg, HR 68 beats/min. LDL 67 mg/dL (1.73 mmol/L). Which of the following is most
appropriate to consider in this patient to reduce mortality?

A. Clopidogrel 75 mg daily

B. Lisinopril 5 mg daily

C. Ezetimibe 10 mg daily

D. Hydrochlorothiazide 25 mg daily

8. A 74­year­old patient undergoes PCI for stable angina symptoms and receives a drug­eluting stent in the right coronary artery. PMH includes chronic
kidney disease (CrCl 39 mL/min [0.65 mL/s]), anemia, and a history of a gastrointestinal bleed. What is the most appropriate duration of DAPT for this
patient?

A. 3 months

B. 6 months

C. 12 months

D. 36 months

9. A patient presents to his local pharmacy with a new prescription for SL nitroglycerin tablets. Which is not correct patient counseling information to
give the patient?

A. This medication is only for the treatment of acute anginal attacks.

B. Keep the bottle in the original glass bottle as the medication is sensitive to light.

C. Be sure to sit down before taking this medication as it may cause dizziness.

D. It is recommended to replace the bottle every 6 months to ensure optimal potency.

10. A 75­year­old patient with CCD presents with continued angina. His home medications include aspirin 81 mg daily, allopurinol 100 mg daily, lisinopril
20 mg daily, carvedilol 25 mg twice daily, rosuvastatin 20 mg daily, isosorbide mononitrate 60 mg daily, and acetaminophen as needed for pain. His
PMH includes a history of MI, HTN, gout, dyslipidemia, and arthritis. Vital signs: BP 100/60 mm Hg; HR 62 beats/min, weight 90 kg. Laboratory findings
are within normal limits. Which of the following is the most appropriate option to treat this patient’s angina?

A. Change carvedilol 25 mg twice daily to amlodipine 10 mg daily

B. Change isosorbide mononitrate to a nitroglycerin patch

C. Increase carvedilol to 50 mg twice daily

D. Add ranolazine 500 mg twice daily

11. A 65­year­old patient with continued angina presents to the primary care physician. Home medications include aspirin 81 mg daily, ramipril 10 mg
daily, metoprolol 50 mg twice daily, atorvastatin 40 mg daily, nitroglycerin patch 0.8 mg/hr daily, SL nitroglycerin as needed for angina, dofetilide 500
mcg twice daily, and apixaban 5 mg twice daily. PMH includes a history of multiple MI’s, a history of PCI with stents 5 years ago, atrial fibrillation, HTN,
and dyslipidemia. Vital signs: BP 138/85 mm Hg, HR 58 beats/min. LDL 70 mg/dL (1.81 mmol/L). Which of the following is the most appropriate agent
to treat this patient’s angina?

A. Increase metoprolol to 100 mg twice daily

B. Add ranolazine 500 mg twice daily

Downloaded 2025­6­305 mg
C. Add amlodipine 9:58daily
A Your IP is 185.80.143.8
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mg daily

12. A 72­year­old patient is getting ready to be discharged after undergoing a CABG procedure for newly diagnosed CAD with left main disease and left
 to treat this patient’s angina?
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A. Increase metoprolol to 100 mg twice daily

B. Add ranolazine 500 mg twice daily

C. Add amlodipine 5 mg daily

D. Add diltiazem ER 120 mg daily

12. A 72­year­old patient is getting ready to be discharged after undergoing a CABG procedure for newly diagnosed CAD with left main disease and left
ventricular dysfunction (ejection fraction 30% [0.3]). PMH includes HTN and diabetes. Discharge medications include aspirin 81 mg daily, metformin
500 mg twice daily, carvedilol 12.5 mg twice daily, and lisinopril 10 mg daily. Vital signs: BP 120/80 mm Hg, HR 75 beats/min. Hemoglobin A1c is 6.5%
(48 mmol/mol) and LDL is 75 mg/dL (1.94 mmol/L). Which of the following medications should be added to this patient’s regimen?

A. Semaglutide 0.25 mg SC once weekly

B. Rosuvastatin 40 mg daily

C. Prasugrel 10 mg daily

D. Empagliflozin 10 mg daily

13. Which of the following directly affects myocardial oxygen demand?

A. Myocardial wall tension

B. Presence of anemia

C. Large plaque burden

D. Coronary vasospasm

14. A 64­year­old patient is newly diagnosed with CCD. PMH includes dyslipidemia. Blood pressure is 126/74 mm Hg, HR 68 beats/min. LDL is 110 mg/dL
(2.84 mmol/L). The following medications are initiated: aspirin 81 mg daily, atenolol 50 mg daily, atorvastatin 80 mg daily, and ramipril 2.5 mg daily.
Which of the following medications should also be considered?

A. Clopidogrel 75 mg daily

B. Ranolazine 500 mg twice daily

C. Nitroglycerin SL 0.4 mg PRN

D. Verapamil ER 180 mg daily

15. A 69­year­old female with diabetes complains of midepigastric discomfort that radiates to her jaw. Her symptoms are brought on by gardening and
relieved with rest. Which of her symptoms is atypical?

A. Midepigastric discomfort

B. Provocation by gardening

C. Radiation to her jaw

D. Relief by rest

ANSWERS
1. A . The best answer is to initiate and continue aspirin indefinitely as it has been shown to reduce the risk of SVG closure during the first year after
CABG surgery. Low­dose rivaroxaban has been evaluated in patients with both stable ASCVD and ACS undergoing CABG with no statistically
significant differences in graft failure found. Therefore, it is not recommended to maintain graft patency. Ticagrelor as a single antiplatelet agent is
not recommended post­CABG as the antiplatelet agent of choice. It could be used post­CABG in combination with aspirin in patients who have had a
recent stent or an ACS event, but it has not been found to be better than aspirin alone post­CABG in one trial (RKC1). Warfarin would not be indicated
Downloaded
post­CABG2025­6­30
unless the 9:58 A had
patient Youra IP is 185.80.143.8
specific indication for anticoagulation. Thus, A is the best answer. See section “Coronary Artery Bypass Graft
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2. C . When coronary atherosclerotic plaques exceed a critical threshold, typically approximately 70% blockage, the coronary reserve is used at rest to
vasodilate the obstructed coronary artery and maintain coronary blood flow. As a result, the ability to adapt to increases in oxygen demand is
 University
1. A . The best answer is to initiate and continue aspirin indefinitely as it has been shown to reduce the risk of SVG closure ofthe
during New England
first ­ Maine
year after
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CABG surgery. Low­dose rivaroxaban has been evaluated in patients with both stable ASCVD and ACS undergoing CABG with no statistically
significant differences in graft failure found. Therefore, it is not recommended to maintain graft patency. Ticagrelor as a single antiplatelet agent is
not recommended post­CABG as the antiplatelet agent of choice. It could be used post­CABG in combination with aspirin in patients who have had a
recent stent or an ACS event, but it has not been found to be better than aspirin alone post­CABG in one trial (RKC1). Warfarin would not be indicated
post­CABG unless the patient had a specific indication for anticoagulation. Thus, A is the best answer. See section “Coronary Artery Bypass Graft
Surgery.”

2. C . When coronary atherosclerotic plaques exceed a critical threshold, typically approximately 70% blockage, the coronary reserve is used at rest to
vasodilate the obstructed coronary artery and maintain coronary blood flow. As a result, the ability to adapt to increases in oxygen demand is
diminished because coronary flow reserve is exhausted, leading to ischemia. Thus, C is the best answer. See section “Etiology and Pathophysiology.”

3. D . Older patients, females, and those with diabetes are more likely to experience atypical symptoms of angina. Therefore, D is correct (age 76, history
of diabetes). See the “Clinical Presentation” section.

4. D . Successful treatment of angina should reduce the frequency of angina episodes as well as the weekly use of sublingual nitroglycerin. Although the
patient reports no change in provoking factors nor the frequency or severity of episodes, the increased use of sublingual nitroglycerin may indicate
worsening symptoms of angina; D is the best answer. See the “Evaluation of Clinical Outcomes” section.

5. A . Current guidelines recommend a BP goal of <130/80 mm Hg; thus, A is correct. Although LDL goals of <70 mg/dL (1.81 mmol/L) may be targeted in
“very high­risk” patients (such as those with a history of multiple ASCVD events or 1 major event and multiple high­risk comorbidities), current
guidelines recommend the use of high­intensity statins in patients with clinical ASCVD such as this patient or patients who are 40 to 75 years of age
and diabetes to reduce LDL by ≥50%. Diabetes guidelines recommend a hemoglobin A1c of <7% (53 mmol/mol) in select patients and 7% to 9% (53­
75 mmol/mol) in frail or high­risk patients, not <6.5% (48 mmol/mol). While a BMI between 18.5 and 24.9 kg/m2 is ideal to reduce CV risk, the initial
goal of weight management is to lose 5% to 10% of body weight from baseline (Table 36­4).

6. D . The best answer is to increase the β­blocker dose since the patient is experiencing continued angina and is on a low dose of metoprolol.
Additionally, his blood pressure and heart rate are not at target levels and further lowering of BP and HR will improve the myocardial oxygen
mismatch and improve his angina. See the “Pharmacotherapy to Reduce Symptoms” section and “β­blockers” subsection.

7. B . The best answer is to initiate an ACE inhibitor in this patient since he has CCD and is also post MI. The CCD guidelines recommend the use of ACE
inhibitors in all patients with CCD who also have HTN, DM, LV dysfunction, or chronic kidney disease, unless contraindicated as well in patients post­
MI. See “ACE Inhibitors” and “Blood Pressure Management” sections (see Table 36­4).

8. A . Based on this patient’s age, renal function, and history of both anemia and gastrointestinal bleeding, she is at high risk for bleeding on DAPT.
Therefore, the most appropriate duration to minimize bleeding complications is 3 months. Six months would be appropriate if her bleeding risk was
low or moderate whereas 12 months would be appropriate if she had a recent ACS. Select patients at low bleeding risk may continue therapy up to 36
months. See the “Percutaneous Coronary Intervention” section.

9. A . SL nitroglycerin can be used for the treatment of acute angina attacks but also can be used for the prevention or prophylaxis of angina if taken
before partaking in an exertional event known to precipitate angina. See education for clinicians and patients on use of sublingual nitroglycerin
(Table 36­8).

10. D . The correct answer in this patient with continued angina while receiving a β­blocker and chronic nitrate with low blood pressure and heart rate is
to add ranolazine. Ranolazine provides relief of angina without impacting hemodynamics such as HR, BP, the inotropic state, or increase coronary
blood flow. See the “Pharmacotherapy to Reduce Symptoms” section and “Ranolazine” subsection.

11. C . The patient’s blood pressure is not at the goal of <130/80 mm Hg and since he is continuing to experience angina, amlodipine would be the best
agent to add on to his current regimen to control both angina and reduce blood pressure. Ranolazine can be added on to anginal regimens, often as
third­ or fourth­line options but this patient has a drug­drug interaction with the dofetilide and ranolazine; both of which can increase the QTc
interval and predispose this patient to torsades de pointes. In addition, ranolazine will not address this patient’s elevated blood pressure.
Metoprolol is not a good option in this patient due to the low heart rate of 58 beats/min on the current dose. Lastly, diltiazem is not a good option to
add on in this situation since he is already taking another AV nodal blocking agent, metoprolol, and his heart rate is already low. See the
“Pharmacotherapy to Reduce Symptoms” section.

12. B . The addition of a high­intensity statin should be considered in patients with CAD following CABG to reduce the risk of future cardiac events,
including premature graft failure. This patient has diabetes, HTN, and his LDL­C is not at goal. The use of dual antiplatelet therapy (adding prasugrel)
may be considered in some patients post­CABG, such as those with a recent stent ACS presentation. In a patient with chronic coronary disease
Downloaded
undergoing 2025­6­30
CABG, DAPT 9:58 A clopidogrel
with Your IP is 185.80.143.8
or ticagrelor, but not prasugrel, could be an option. There is no need for semaglutide or empagliflozin in
Chapter 36: Chronic Coronary Disease, Paul P. Dobesh; Robert J. DiDomenico; Kelly C. Rogers Page 43 / 44
this patient since his hemoglobin A1c is <7% (53 mmol/mol). See the “Coronary Artery Bypass Graft Surgery” section.
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13. A . The major determinants of MVO2 include heart rate (HR), myocardial contractility, and intramyocardial wall tension. Arterial oxygen content is
 add on in this situation since he is already taking another AV nodal blocking agent, metoprolol, and his heart rate is already low. See the
University of New England ­ Maine
“Pharmacotherapy to Reduce Symptoms” section.
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12. B . The addition of a high­intensity statin should be considered in patients with CAD following CABG to reduce the risk of future cardiac events,
including premature graft failure. This patient has diabetes, HTN, and his LDL­C is not at goal. The use of dual antiplatelet therapy (adding prasugrel)
may be considered in some patients post­CABG, such as those with a recent stent ACS presentation. In a patient with chronic coronary disease
undergoing CABG, DAPT with clopidogrel or ticagrelor, but not prasugrel, could be an option. There is no need for semaglutide or empagliflozin in
this patient since his hemoglobin A1c is <7% (53 mmol/mol). See the “Coronary Artery Bypass Graft Surgery” section.

13. A . The major determinants of MVO2 include heart rate (HR), myocardial contractility, and intramyocardial wall tension. Arterial oxygen content is
related to hemoglobin concentration and oxygen saturation. Consequently, patients with anemia (low hemoglobin) or hypoxia (low oxygen
saturation) have lower than normal oxygen­carrying capacity. Both large atherosclerotic plaque burden inside a coronary artery and coronary
vasospasm affect coronary artery oxygen supply. See the “Etiology and Pathophysiology” section.

14. C . All patients with CCD should be prescribed SL nitroglycerin to treat acute symptoms of angina in the absence of contraindications (C is correct). A
combination of antianginal therapies is not recommended for the initial management of patients with CCD; therefore, neither ranolazine nor
verapamil is indicated. In the case of verapamil, adding this to β­blocker therapy (atenolol) may also increase the risk of bradycardia and should be
avoided. In the absence of an ACS event or PCI within the preceding 6 to 12 months, DAPT is not indicated. Thus, clopidogrel is incorrect. See Fig. 36­2
and section “Antithrombotic Therapy.”

15. A . Atypical symptoms of angina may consist of mid­epigastric discomfort (A is correct), effort intolerance, dyspnea, and/or excessive fatigue.
Radiation to the jaw or left arm (C), provocation by exertion (B), and relief by rest (D) are all typical symptoms of angina and, thus, incorrect. See the
“Clinical Presentation” section.

Downloaded 2025­6­30 9:58 A Your IP is 185.80.143.8

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