Stable Ischemic Heart Disease

Gharibyan Rosie Jasper

James C. Blankenship

INTRODUCTION

Epidemiology

Coronary artery disease (CAD) remains the leading cause of death and morbidity worldwide. Cardiovascular disease (CVD) remains the number one cause of death in the United States, accounting for one in three deaths, and it claims more lives than all cancers and pulmonary diseases combined.¹ The overall CAD prevalence is 6.7% (18.2 million) in US adults over 20 years of age and is higher in men (7.4%) than in women (6.2%). Over the past two decades, the incidence of CAD declined from 3.9 to 2.2 per 1000 person-years in people without diabetes and from 11.1 to 5.4 per 1000 person-years among those with diabetes.² The lifetime risk of developing CAD in 40-year-old persons is greater than 40% in men and greater than 30% in women. Of note, the incidence of angina rises continuously with age in women. Stable angina or stable ischemic heart disease (SIHD) is the most common presentation of CAD in women, compared to acute myocardial infarction (MI) and sudden coronary death in men. The direct and indirect costs of heart disease in 2014 to 2015 were estimated at $219 billion in the United States, 42% of which was spent on persons over 60 years of age. Chronic CAD and MI were two of the 10 most expensive conditions treated in US hospitals and accounted for 14% of total health expenditures in 2014 to 2015.²

Risk Factors

The traditional risk factors for atherosclerosis include age, sex, smoking, hypertension, hyperlipidemia, obesity, metabolic syndrome, diabetes mellitus, sedentary lifestyle, and family history. Nontraditional risk factors include socioeconomic and psychosocial stress, autoimmune diseases, malignancy and its therapies, infections, sleep apnea, and pregnancy-related complications.

PATHOGENESIS

Angina pectoris is the result of myocardial ischemia caused by an imbalance between myocardial blood supply and oxygen demand. Myocardial ischemia typically results from a reduction of coronary blood flow caused by fixed and/or dynamic epicardial coronary artery stenosis. Less commonly, it may be due to abnormal constriction (or deficient relaxation) of coronary microcirculation, markedly increased myocardial oxygen demands (ie, malignant hypertension, severe aortic stenosis), or reduced oxygen-carrying capacity of the blood (ie, severe anemia, carboxyhemoglobin).

Coronary stenosis is typically caused by atherosclerosis, affecting large and medium size arteries. Atherosclerosis begins in young adulthood, as demonstrated by an incidence of coronary atherosclerosis of 45% to 75% in soldiers killed in combat.³ The disease progresses in an indolent fashion and is usually clinically silent for many decades.

CLINICAL PRESENTATION

Common Signs and Symptoms

Identifying individuals with cardiac chest pain or SIHD requires careful evaluation of the patient’s history, examination, testing, and risk. Traditionally, “typical angina” is described as substernal chest discomfort with: (1) ischemic quality and duration; (2) exacerbation by exercise and/or emotional stress; and (3) relief by rest and/or nitrates. “Atypical angina” meets two of the above three characteristics, whereas “non-anginal chest pain” meets only one or none. It is generally safe to assume symptoms are noncardiac if the symptoms meet criteria for “non-anginal” and an alternative diagnosis is readily apparent (eg, chest pain reproducible by palpation in a trauma patient). A diagnosis of “non-anginal chest pain,” with only one of the three characteristics present, carries intermediate risk for CAD in women older than 60 years and men older than 40 years.

Angina pectoris is characterized by pain in the retrosternal and/or surrounding areas, often radiating to the jaw, epigastrium, and left shoulder and arm. It is often described as a pressure-like, constricting, burning, or squeezing sensation. It may be accompanied by dyspnea, fatigue, and nausea. The Canadian Cardiovascular Society classification is widely used to grade the severity of typical angina (Table 4.1).⁴

Diabetic patients with coronary disease are more likely to have “noncardiac” chest pain compared to nondiabetics. However, diabetics and nondiabetics have similar ratios of “typical” to “atypical” angina, and most diabetics have typical angina when they present with symptomatic SIHD.

Physical Examination Findings

The physical examination is often unremarkable in stable CAD. Physical examination findings, which are nonspecific, but may accompany CAD, include the presence of S4, S3, mitral regurgitation murmur, rales, carotid bruit, diminished pedal pulse,
retinal exudates, and xanthomas. Reproducible chest wall pain/pressure in two studies of nontrauma patients significantly correlated with a noncardiac etiology of chest pain. Chest pain that is reproduced by coughing, deep inspiration, lying supine, moving arms and shoulders, rotating the torso, or swallowing is usually not due to myocardial ischemia

TABLE 4.1 Grading of Angina Severity by the Canadian Cardiovascular Society

Class I	Ordinary physical activity does not cause angina, such as walking, climbing stairs, etc. Angina with strenuous or rapid or prolonged exertion at work or with recreation
Class II	Slight limitation of ordinary activity such as walking uphill, walking rapidly, climbing stairs after meals, or cold, or in wind, or under emotional stress or upon first hours after awakening.
Class III	Marked limitation of ordinary physical activity. Angina on walking one or two blocks or one flight of stairs.
Class IV	Inability to carry on any physical activity without discomfort; and may be present at rest
Reprinted from Campeau L. Canadian Cardiovascular Society grading of angina pectoris revisited 30 years later. Can J Cardiol. 2002;18(4):371-379. Copyright © 2002 Elsevier. With permission.

Differential Diagnosis

The majority of patients presenting with chest pain in an outpatient setting have noncardiac etiologies, and these conditions should be considered in the differential diagnosis of chest pain or SIHD (Table 4.2).

DIAGNOSIS

Patient Risk and Recommendations for Further Testing

The diagnosis of CAD starts with the clinical history including assessment of risk factors and comorbidities, physical examination, and the electrocardiogram (ECG). Patient-specific risk can be assessed using probability estimate models, which are derived from basic variables including age, gender, symptom characteristics, presence of risk factors, and ECG findings (Q waves, ST/T waves).⁵ The factors most consistently associated with CAD are the patient’s age and gender.

The limitations of probability estimate models include the following: (1) underrepresentation of the elderly and specific populations; (2) tendency to overestimate risk; (3) poor performance in women because of the lower prevalence of obstructive CAD; and (4) their performance is compared to prevalence of obstructive CAD on imaging (ie, cardiac computed tomography angiography [CCTA] or coronary angiography) and may not necessarily reflect clinical outcomes. The 2014 ACC/AHA/AATS/PCNA/SCAI/STS Focused Update of the Guideline for the Diagnosis and Management of Patients with SIHD references the Diamond-Forrester and Updated Diamond-Forrester estimate models for the determination of pretest probability.⁶ Critical concepts for assessing pretest likelihood include the following:

If the probability of disease is less than 5%, additional testing is not recommended, as false-positive test results are more likely than true-positive test results.
Patients with intermediate probability for CAD (15%-85%) benefit the most from further testing and warrant noninvasive functional or anatomic cardiac evaluation, the results of which should be interpreted with a Bayesian approach. The type of noninvasive stress test employed depends upon patient characteristics, baseline ECG, ability to exercise, physician preference, and test availability. Stress testing with exercise or pharmacologic stress testing is the “gold standard” for provoking cardiac ischemia and for detecting effects of ischemia by ECG changes, perfusion abnormality, or regional wall motion abnormality. In comparison to functional stress testing, CCTA and cardiac magnetic resonance angiography (CMRA) allow anatomic analysis of coronary obstruction similar to invasive coronary angiography. Algorithm 4.1 provides guidance on choice of noninvasive study for the evaluation of newly suspected SIHD or change in clinical status in a patient with SIHD.
If the probability of disease or risk of mortality is high, then early angiography without stress testing is recommended because stress testing has an unacceptably high rate of false-negative results and will not alter the need for invasive evaluation.

Noninvasive Stress (Functional) Testing

Stress testing involves either exercise testing or pharmacologic stress testing with the use of dobutamine or vasodilators (ie, adenosine, regadenoson, or dipyridamole). Exercise testing is preferred. Exercise testing without imaging provides information about prognosis based on threshold for ischemia, reproduction of and correlation with symptoms, and exercise tolerance. Imaging (ie, echocardiography, radionuclide scintigraphy, or magnetic resonance imaging) provides additional sensitivity.

Table 4.3 summarizes the sensitivity and specificity of different stress modalities, including guideline-graded recommendations and specific benefits and pitfalls of each modality. In summary, the guidelines give a Class I recommendation for exercise as an initial stress modality if the patient is able to perform moderate exercise and has an interpretable ECG. For patients with baseline ECG abnormalities, exercise with imaging should be performed. If patients are unable to exercise, then pharmacologic stress testing with imaging is recommended.

Noninvasive Anatomic Imaging

Cardiac Computed Tomography Angiography

The role of CCTA as an initial diagnostic test for CAD has been validated in randomized controlled trials (RCTs).⁷ CT imaging

of the coronary arteries can be performed with or without intravenous iodinated contrast. With noncontrast CT, coronary calcifications as a reflection of atherosclerosis can be detected and quantified using the Agatston coronary artery calcium score.⁸ The extent of coronary calcification correlates with the extent of atherosclerosis but does not imply luminal narrowing of the coronary arteries. Subsequently, the specificity of CCTA decreases with high calcium scores, leading to an overdiagnosis of obstructive CAD if the Agatston score is over 400.

TABLE 4.2 Differential Diagnosis of Chest Pain

Diagnosis	Characteristics of Chest Pain	Typical Physical Findings, if Present
Cardiac
Stable ischemic heart disease	Chronic typical or atypical angina	None
Acute coronary syndrome	Unstable angina (progressive, new onset, or new occurrence of rest angina)	None
Arrhythmias	Palpitations	Irregular heart sounds
Aortic dissection	Sharp or tearing, sudden onset radiating from substernal to intrascapular	Loss of carotid or upper extremity pulses, stroke
Pericarditis	Pleuritic pain relieved by sitting up	Friction rub
Pulmonary
Pulmonary embolus	Pleuritic pain with dyspnea	Pleural friction rub
Pneumothorax	Acute onset, pleuritic, with dyspnea	Diminished breath sounds unilaterally
Pleuritis	Pleuritic pain	Pleural friction rub
Gastrointestinal
Esophageal disease	Substernal pain or pressure, sharp or dull	None
Gastroesophageal reflux	Substernal and/or epigastric burning	None
Biliary	Right upper quadrant pain radiating to back or scapula	Right upper quadrant tenderness
Pancreatitis	Epigastric pain, may be boring, radiating to back	Epigastric tenderness
Musculoskeletal
Costochondritis	Chest wall tenderness	Pain to palpation
Chest trauma	Inspiratory pain, chest wall tenderness	Pain to palpation or with motion of torso and shoulders
Fibrositis	Chest wall pain	Pain to palpation
Dermatologic
Herpes zoster	Radicular pain	Rash
Psychiatric
Anxiety, depression	Nonexertional, related to emotion or stress, may be accompanied by acute anxiety, hyperventilation, palpitations, diaphoresis	Physical signs of anxiety (eg, pressured speech) or depression (eg, flat affect)
Schizophrenia	Atypical pattern	Schizophrenic affect
Factitious (ie, Munchausen)	Atypical pattern	None

ALGORITHM 4.1 Guidelines on noninvasive versus invasive therapy in suspected disease or established disease with new clinical change. CABG, coronary artery bypass graft; CAD, coronary artery disease; GDMT, guideline-directed medical therapy; PCI, percutaneous coronary intervention.

TABLE 4.3 Noninvasive Functional Stress Testing Modalities and Guideline Recommendations

Testing Modality	Sensitivity and Specificity for Obstructive CAD	Benefits and Pitfalls	Guideline Recommendations ACCF/AHA 2012 and ESC 2013
Exercise electrocardiography	Sensitivity: 61%^a Specificity: 70%-77%^b Performs well in low- to intermediate-risk group (risk 10%-60%)	Prognostic findings: exercise duration chronotropic incompetence, HR recovery angina arrhythmias blood pressure drop with exercise extent and duration of ST changes	Class I for intermediate-risk patients Class IIa for low-risk patients Class III—patients unable to exercise, using digitalis or have uninterpretable ECG Rated the same for ACCF and ESC guidelines
Exercise echocardiography	Sensitivity: 70%-85% Specificity: 77%-89%	Assessment of systolic and diastolic left ventricular function and response to stress	Class Ib for intermediate- to high-risk patients and uninterpretable ECG Class IIa (ESC) symptomatic patients with prior revascularization and to assess functional severity of intermediate coronary lesions
Dobutamine echocardiography	Sensitivity: 85%-90% Specificity: 79%-90%	Assesses viability better than exercise, favorable when there is resting wall motion abnormality	Class Ia—intermediate- to high-risk patients and unable to exercise Class III—not recommended if patient is able to exercise and has interpretable ECG
Exercise myocardial perfusion imaging	Sensitivity: 82%-88% Specificity: 70%-88%	Balanced flow reduction may lead to underestimation of extent of ischemia in multivessel or left main coronary disease. Transient ischemic dilation, reduced poststress ejection fraction, and increased uptake in lung field can help identify severe coronary artery disease.	Class Ib for intermediate- to high-risk patients Class IIa for intermediate- to high-risk patients and interpretable ECG Class III—in low-risk patients
Vasodilator^c myocardial perfusion imaging	Sensitivity: 88%-91% Specificity: 75%-90%	Balanced flow reduction may lead to underestimation of extent of ischemia in multivessel or left main coronary disease.	Class Ia—intermediate- to high risk and unable to exercise Class III—not recommended if patient is able to exercise and has interpretable ECG
Cardiac magnetic resonance imaging with dobutamine or perfusion stress	Sensitivity: 88% Specificity: 72% Cardiac magnetic resonance angiography has shown good correlation with FFR measurements.	Not widely used	No recommendations
ACCF, American College of Cardiology Foundation; AHA, American Heart Association; CAD, coronary artery disease; ECG, electrocardiogram; ESC, European Society for Cardiology; FFR, fractional flow reserve; HR, heart rate.
^aValid in patients with normal ECG. ^bLower in women. ^cAdenosine, regadenoson, or dipyridamole.
Compiled with data from Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2012;60(24):e44-e164 and Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the management of stable coronary artery disease: The Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J. 2013;34(38):2949-3003.

Combined Imaging

Combined anatomic and physiologic imaging applications are currently under investigation. The combination of positron emission tomography (PET) or single-photon emission computed tomography (SPECT) and CT, fractional flow reserve (FFR) with CCTA, PET, and CMRA is available in selected centers. The benefit of combined imaging is the availability of hemodynamic assessment of an anatomic lesion. A drawback to this approach is an increase in radiation dosage. The 2012 and 2014 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines do not include recommendations for hybrid imaging.⁶,⁹,¹⁰

Coronary Angiography

The role of coronary angiography in diagnosis of suspected CAD is discussed in detail in the 2014 ACCF/AHA guideline update.⁶ In the majority of patients with suspected CAD, noninvasive stress testing is the initial diagnostic test. However, in high-risk patients in whom a negative stress test would be suspected of being falsely negative, angiography may be reasonable without prior stress testing. A coronary angiogram is performed to evaluate the severity of obstructive CAD, assess cardiovascular risk, and determine an approach for revascularization if indicated. Angiographic data regarding lesion complexity and vessel involvement are used to generate the SYNTAX score—scored from 0 to 60 with a higher score indicating a higher burden and complexity of CAD—and to formulate appropriate revascularization strategies.

Limitations of angiography include inter- and intraobserver variability in assessment of lesion severity and inability to predict hemodynamic significance of intermediate stenotic lesions. The evaluation of FFR is often necessary as an invasive assessment of physiologic significance of intermediate angiographic lesions (defined as 40%-70% luminal diameter narrowing).

MANAGEMENT OF PATIENTS WITH STABLE ISCHEMIC HEART DISEASE

Medical Approach

The treatment goals in stable CAD are to:

(1) reduce premature cardiovascular death; (2) prevent complications (ie, heart failure and MI); (3) maintain optimal functional capacity; (4) eliminate or decrease ischemic symptoms; and (5) minimize health care costs by eliminating unnecessary tests, procedures, and hospitalizations.⁸

Clinicians are obligated to help patients understand their disease etiology, clinical manifestations, and signals of worsening disease. Patients should be empowered to make shared decisions regarding revascularization options and actively participate in risk reduction, behavioral modification, and medication adherence.¹¹

Antianginal Therapies

Nitrates. All patients with stable CAD should be prescribed sublingual nitroglycerin or a nitroglycerin spray for immediate relief of angina (Class Ib).⁹ Long-acting formulations are recommended when an initial anginal therapy with maximum tolerated beta-blocker is not effective in preventing angina. Failure of nitrate therapy is often due to nitrate tolerance. Therefore, depending on nitrate formulation used, a 10- to 14-hour nitrate-free interval is indicated.

Beta-blockers. Beta-blockers should be prescribed as a first-line therapy for relief of ischemic symptoms in patients with stable CAD (Class I).⁹ In the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial, patients with stable CAD and coronary stenosis greater than 70% on angiography who received a beta-blocker reported a 22% improvement in symptoms of angina, similar to results following percutaneous coronary intervention (PCI).¹² Similarly, in the Objective Randomized Blinded Investigation with optimal medical Therapy of Angioplasty in stable angina (ORBITA) trial, PCI did not improve exercise angina after medical therapy with beta-blockers was optimized.¹³ All beta-blockers have similar efficacy in patients with angina. The dose of beta-blocker is titrated for a goal heart rate of 55 to 60 beats per minute. An abrupt discontinuation of beta-blockers may be poorly tolerated and is discouraged, as it can worsen angina and precipitate an acute coronary syndrome (ACS) (9).

Calcium Channel Blockers. The calcium channel blockers (CCBs) are as effective as beta-blockers in relieving angina and increasing angina-free exercise time. CCBs can be used alone as antianginal therapy, though their combination with nitrates and beta-blockers exerts a more potent antianginal effect. All CCB classes are equally efficacious in treating angina, and selection of a specific agent should be based on drug interactions and potential side effects. Dihydropyridine (DHP) CCBs or long-acting nitrates should be prescribed in combination with beta-blockers for relief of anginal symptoms (Class Ib).⁹ Alternatively, long-acting non-DHP CCBs (ie, diltiazem or verapamil) can be considered instead of beta-blockers as initial therapy (Class IIa).⁹

Ranolazine. Ranolazine is a selective late sodium channel inhibitor that reduces sodium-dependent calcium currents in ischemic myocardium. It is administered orally in doses of 500 to 2000 mg daily to reduce angina and increase symptom-free exercise capacity. Ranolazine has antianginal efficacy when used as a monotherapy or in combination with first- and second-line antianginal agents and shows a more potent effect in diabetic patients with elevated hemoglobin A1C levels. Ranolazine can be useful as a substitute for beta-blockers for relief of angina in
stable CAD (Class IIb) or in combination with beta-blockers (Class IIa).⁹,¹⁰

Ivabradine. Ivabradine was approved in the United States in 2015 for the treatment of heart failure with reduced ejection fraction (EF). Although it has not been approved in the United States for angina, it has been reported to have antianginal properties. Ivabradine as monotherapy improves treadmill test performance and decreases frequency of angina attacks with efficacy similar to that of beta-blockers and amlodipine.¹⁴

Other Antianginal Therapies. Nicorandil and trimetazidine are antianginal therapies not available in the United States but are used in Europe and other countries.¹⁰

Nonpharmacologic Therapies for Refractory Angina in Stable Ischemic Heart Disease

Individuals with refractory angina constitute approximately 10% of stable CAD patients. Refractory angina is defined as angina despite maximal medical therapy because of CAD that is not amenable to revascularization. Nonpharmacologic therapies may be considered in patients to improve quality of life.⁶ These new therapies attempt to either (1) improve myocardial perfusion or (2) modulate afferent and efferent pain pathways to change perception of ischemic pain.¹⁵

Angiogenesis. Intracoronary or transendocardial injection of autologous cells (CD34⁺, CD133⁺) that activate myocardial angiogenesis can improve exercise capacity. Their therapeutic use for refractory angina is currently under review.¹⁶

Enhanced External Counterpulsation. The Food and Drug Administration (FDA) approved the use of enhanced external counterpulsation (EECP) in 1995 for the treatment of refractory angina. The full treatment course consists of 1-hour treatments, 5 days per week, for 35 sessions. Contraindications include heart failure, severe peripheral arterial disease (PAD), and aortic regurgitation. Studies have shown some benefit of EECP for treatment of refractory angina not responsive to conventional antianginal therapies.¹⁵ EECP has a Class IIb (may be considered for refractory angina) indication for angina therapy per the ACCF/AHA 2014 guidelines.⁶,¹⁵

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Tags: Cardiovascular Medicine and Surgery

May 8, 2022 | Posted by drzezo in CARDIOLOGY | Comments Off

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