Jayendrakumar S. Patel, Sandeep S. Sodhi, Anuradha Godishala, and Mohammad A. Kizilbash
GENERAL PRINCIPLES
Epidemiology
· Ischemic heart disease (IHD) is the cause of 1 of every 6 deaths in the United States.1
· More than 1 million Americans experience a myocardial infarction (MI) each year.
· IHD does not always produce symptoms; 64% of women and 50% of men who die suddenly from IHD had no previous symptoms.
· After age 40, 49% of men and 32% of women will have an MI during the remainder of their lifetime.1
Risk Factors
· Greater than 90% of patients experiencing acute coronary syndrome (ACS) will have at least one established coronary artery disease (CAD) risk factor.2
· Traditionally, major cardiovascular risk factors have been defined as the following3:
o Increased age
o Diabetes (DM)
o Hypertension (HTN)
o Cigarette smoking
o Elevated low-density lipoprotein (LDL) cholesterol
o Low high-density lipoprotein (HDL) cholesterol
o Family history of premature CAD, defined as first-degree male relative with an MI before age 55 or female relative before age 65
· Risk equivalents for coronary heart disease: Patients with known coronary heart disease (CHD) have a 20% or higher risk for a subsequent CHD event; similarly, some patients without established CHD may also be at high risk if they have3,4:
o Diabetes mellitus (DM)
o Peripheral arterial disease (PAD) or presence of an aortic aneurysm
o Prior cerebrovascular accident (CVA) or transient ischemic attack (TIA)
o Chronic kidney disease (CKD)
o A high global risk score for CHD or cardiovascular disease (CVD)
· Other less potent coronary heart disease risk factors5:
o Obesity, particularly central obesity
o Physical inactivity
o High-fat, high-cholesterol diet
o Systemic autoimmune collagen vascular diseases
o In women, history of preeclampsia or gestational diabetes
· Novel cardiac risk factors
o C-reactive protein (CRP), as compared to other novel CVD risk factors, has gained more acceptance in its role in primary prevention. It is widely available, easily attained, and more often covered by health insurance carriers than other risk biomarkers or indirect measures of atherosclerosis, such as coronary calcium scoring.
§ CRP levels can be affected by various conditions (Table 7-1).6
§ CRP is a component of the Reynolds score, which is one of the available risk calculators for CVD events.
§ CRP has also been studied as part of a protocol to determine patient eligibility for statin therapy, which could supplement or supplant the traditional methods discussed such as the global risk score discussed in the Prevention section. Statin therapy can be considered in men older than 50 years and women older than 60 years with LDL <130 mg/dL and a CRP levels >2 mg/dL.7
§ What is not yet known is whether similar patients with an LDL <130 mg/dL would benefit from statin therapy regardless of their CRP level.
§ Although low levels of CRP are associated with lower rates of cardiovascular events, several studies have failed to demonstrate the incremental utility of CRP testing or have questioned the results of prior studies.7–13
§ For patients with a high global risk score (GRS) or for use in secondary prevention efforts, CRP plays no current role.
o Other biomarkers
§ Other biomarkers such as homocysteine, other lipid parameters (lipoproteins, apolipoproteins, particle size, and density), fibrinogen, B-type natriuretic peptide, and genotyping are not currently recommended for cardiovascular risk assessment in the asymptomatic individual.14
§ Urinalysis evaluation for microalbuminuria may be of benefit in risk assessment.
§ Lipoprotein-associated phospholipase A2 might be reasonable for cardiovascular risk assessment in intermediate-risk individuals.
· Other medical conditions contributing to CVD risk
o A growing body of literature has suggested that autoimmune conditions such as rheumatoid arthritis and lupus are associated with higher rates of MI and other cardiovascular events.15–17 This risk appears to be independent of hypercoagulable states that frequently accompany these disease processes, although chronic inflammation may play a pathogenic role. Paradoxically, chronic steroids and other immunosuppressive drugs may also increase the risk of CAD.
o Infection with human immunodeficiency virus (HIV) may be associated with accelerated atherosclerosis, particularly when treatment includes medications such as protease inhibitors, which promote dyslipidemia and glucose intolerance.18
o Cocaine abuse may dramatically accelerate atherosclerosis in certain individuals, particularly with chronic abuse. Both angina and MI may be precipitated acutely by cocaine-induced vasospasm, thrombosis, and increased myocardial demand from hyperadrenergic tone.19
TABLE 7-1 Variables Associated with CRP Concentration
CRP, C-reactive protein; HDL, high-density lipoprotein cholesterol.
Modified from Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice. Circulation 2003;107:499–511.
Prevention
· Treatment of cardiovascular risk factors has resulted in a 50% decrease in deaths from CHD over the past few decades.20 Despite impressive declines in mortality, CVD, which includes CHD, stroke/TIA, and PAD, remains the leading cause of death in men and women worldwide.21
· The majority of known risk factors for CVD are modifiable by preventive measures, including lifestyle changes and adjunctive pharmacotherapy. The INTERHEART study demonstrated that nine modifiable risk factors account for over 90% of the risk of an initial acute myocardial infarction.22 Importantly, the presence of multiple risk factors confers at least additive risk.23
· Assessment of risk in primary prevention should not be limited to risk for CHD but should also include risk for CVD events. This is of particular concern in women who have a higher stroke burden than men.5
· A GRS can be calculated to determine the absolute risk of an atherosclerotic CVD (ASCVD) event over a specified time period, usually 10 years, based on the presence of major risk factors without known CHD or CHD risk equivalent. Risk calculators include the following:
o The American Heart Association (AHA)/American College of Cardiology (ACC) atherosclerotic CVD (ASCVD) risk calculator based on the Pooled Cohort Equations and lifetime risk prediction tools (http://www.cardiosource.org/science-and-quality/practice-guidelines-and-quality-standards/2013-prevention-guideline-tools.aspx, last accessed December 23, 2014). These risk estimations were derived from large racially and geographically diverse cohort studies and predict so-called hard cardiovascular events, including stroke. The factors included are age, sex, race (non-Hispanic white vs. African American), systolic blood pressure, use of antihypertensive therapy, total and HDL cholesterol, diabetes, and smoking. Formal estimation of 10-year ASCVD risk is recommended beginning at age 40 and should be repeated every 4 to 6 years in adults 40 to 79 years of age who are free from ASCVD. Due to limitations of the data, calculated risks for Hispanics and Asian Americans may be overestimated.14
o The Framingham Risk Score (FRS) for the prediction of CHD events (angina, MI, or coronary death) (http://cvdrisk.nhlbi.nih.gov/calculator.asp, last accessed December 23, 2014). The Framingham Study included only middle-aged Caucasian patients and assesses only the risk of developing CHD. The generalizability of the Framingham Risk Score to other populations remains questionable.
o Other GRS include SCORE (Systematic Coronary Risk Evaluation) for CVD death, the Reynolds Risk Score for major CVD events, and the JBS3 (Joint British Societies) risk calculator for estimating both CVD risk and the impact of beneficial interventions (http://www.jbs3risk.com, last accessed December 23, 2014).
· Based on the GRS, patients are categorized as low or elevated risk for the development of ASCVD over the next 10 years.
o Low (<7.5%) ASCVD risk patients generally do not need further testing or aggressive risk factor modification with pharmacotherapy, but therapeutic lifestyle interventions are strongly encouraged. Statin therapy may be considered in select patients 21 to 75 years of age (see Lipids below). In patients 20 to 59 years old, it may also be useful to calculate the 30-year or lifetime risk of ASCVD.24
o Elevated (≥7.5%) ASCVD risk patients require intensive risk factor modification, typically through a combination of lifestyle changes and drug therapy, particularly statin medications. Further testing with labs, imaging, or ischemic evaluation is not routinely recommended, but may be indicated based on clinical context. Frequent retesting to determine achievement of specific numeric treatment goals has been discouraged in favor of intermittent assessments of global risk.
· The concept of matching the intensity of risk factor management to the estimated risk of CVD is well established and has resulted in an increased emphasis on the accuracy and reliability of risk assessment. The desire to improve existing risk estimation tools has stimulated interest in finding new risk markers for CVD. On the basis of current, albeit limited, evidence, several novel biomarkers have been identified that show promise for clinical utility. Assessment of one or more of the following may be considered when a risk-based treatment decision is uncertain even after formal risk estimation:
o Family history of premature CVD (first-degree male relative <55 years or female relative <65 years) confers greater risk and supports revising risk assessment upward.
o Coronary artery calcium (CAC) score by computed tomography. A score ≥300 Agatston units suggests higher risk.
o Ankle-brachial index (ABI) ratios <0.9 or >1.3 imply the presence of peripheral vascular disease and thus elevate global CVD risk.
o High-sensitivity C-reactive protein (hs-CRP) levels ≥2 mg/L have been associated with significantly higher rates of CVD events.
o Carotid intima-media thickness (CIMT) assessed by ultrasound. CIMT is a measure of arterial wall thickness used to detect subclinical atherosclerosis. At this time, routine measurement of CIMT is not recommended since the added value in risk prediction is small and unlikely to be of clinical importance.25
· Age
o The incidence of MI increases continuously with age, and >83% of people who die from CHD are in the geriatric population.7
o In the FRS, age is the most heavily weighted risk factor; hence, a common critique is that it underestimates risk in younger individuals.
· Lipids
o Lipid management is discussed in detail in Chapter 11.
o A fasting lipid profile is the preferred screening test and should be first obtained at age 21 and then reassessed every 4 to 6 years along with other traditional ASCVD risk factors (i.e., age, sex, race, blood pressure, diabetes, and smoking).
o Total cholesterol (TC), high-density lipoprotein (HDL), and triglyceride (TG) levels are measured directly. Very low-density lipoprotein (VLDL) level is estimated by dividing the triglyceride concentration by five.
o LDL may be calculated from the following formula:
o This method is accurate only when triglyceride levels are <400 mg/dL.
o Direct measurement of LDL is possible and necessary if triglycerides levels exceed this threshold.
o HDL is the only nonatherogenic subtype of cholesterol, and elevated HDL levels are considered protective or a negative risk factor. Despite an inverse association between HDL levels and CVD risk, therapies to raise HDL have failed to demonstrate improved outcomes. This is consistent with recent trial data suggesting that low HDL is more likely a biomarker for CHD risk rather than causative of it.26
o Specific numeric therapeutic targets are no longer recommended (e.g., LDL <100 mg/dL). Instead, the emphasis is on moderate- or high-intensity statin treatment in appropriate individuals. The four clear statin benefit groups are24
§ Patients ≥21 years old with LDL ≥190 mg/dL
§ Patients 40 to 75 years old with DM and LDL of 70 to 189 mg/dL
§ Patients 40 to 75 years old without clinical ASCVD or DM but with ≥7.5% 10-year risk of ASCVD (ACC/AHA Pooled Cohort Equations)
§ Patients with clinical ASCVD (secondary prevention)
· Hypertension
o Blood pressure is directly related to the incidence of cardiovascular events, starting from a systolic BP of 115 mm Hg.27 However, intensive blood pressure regimens with systolic goals <140/90 mm Hg have not been shown to reduce CVD risk in all populations, including diabetics and the elderly.28
o The recently released report of the Eighth Joint National Committee (JNC 8) recommends a treatment goal of <140/90 for all patients, except those patients ≥60 years old without DM or CKD, for whom a goal of <150/90 is recommended.29
o One notable exception is in those with systolic dysfunction where the aim is to achieve adequate doses of angiotensin-converting enzyme (ACE) inhibitors and β-blockers based on tolerability rather than blood pressure levels.
o HTN management is discussed in further detail in Chapter 6.
· Cigarette smoking
o Smoking is the leading cause of preventable death in the United States, and tobacco cessation reduces the risk of cardiovascular events by 25% to 50%.
o Clinical studies have demonstrated the key role of physician counseling in facilitating an individual’s interest and motivation for quitting.
o Nicotine replacement may be helpful for some patients, but oral medications such as bupropion or varenicline may improve cessation rates.
o Smoking cessation is discussed in Chapter 45.
o Secondhand smoke also increases the risk of cardiovascular events and mortality.
· Aerobic exercise
o The U.S. Department of Health and Human Services recommends goal activity levels of ≥150 minute/week of moderate intensity and/or ≥75 minute/week of vigorous-intensity exercise are recommended for both primary and secondary preventions of heart disease. Individual episodes of aerobic activity should be at least 10 minutes long and spread throughout the week.30
o The ACC/AHA lifestyle management guidelines to reduce cardiovascular risk recommendations are very similar: three to four sessions per week, lasting on average 40 minutes per session, involving moderate- to vigorous-intensity physical activity.31
o Exercise intensity should progress slowly over time. One method to assess intensity, in those not on AV nodal drugs, is to monitor heart rate.
o Heavy exercise is considered more than 80% of the maximal predicted heart rate calculated as 220 minus age.
· Diet
o Dietary modifications can have a powerful and beneficial effect on CVD. In general, a healthy diet emphasizes intake of vegetables, fruits, nuts, beans, high fiber grains, healthy fish at least twice a week (which may exclude tilapia); avoidance of trans fats; minimization of saturated fats in favor of monosaturated fats; and limits intake of red meat, sweets, and sugar-sweetened beverages. Total caloric intake should be appropriate for current weight, and calories should be restricted when necessary.31
o Appropriate dietary plans to achieve these goals include the AHA Diet, the U.S. Department of Agriculture (USDA) Food Pattern, or the DASH (Dietary Approaches to Stop Hypertension) diet.32–35
o Saturated fat intake should be <7% of total energy intake.
o Fiber intake goal is 30 to 45 g/day.
o 200 g/day of fruit and 200 g/day of vegetables should be consumed.
o For those who already drink, alcohol should be limited to 1 drink/day (1 drink = 4 oz of wine or 12 oz of beer or 1 oz of spirits) in women and 1 to 2 drinks/day in men.
· Obesity
o Obesity is the fastest growing cardiovascular risk factor. A calculated body mass index (BMI) >25 kg/m2 is considered overweight, while >30 kg/m2 is considered obese. Central obesity is defined as a waist circumference >40 inches for men and >35 inches for women.36
o Target BMI is between 18.5 and 25 kg/m2, and initial weight loss goals should be 5% to 10% of total weight.
o The metabolic syndrome is correlated with obesity and associated with a higher risk for DM. The diagnostic criteria can be found in Table 7-2.37
o Metabolic syndrome was initially defined to identify patients with insulin resistance at risk for DM and CVD. However, it may not be a unique risk factor whose presence conveys a greater risk than the sum of its parts. Hence, its clinical utility is of uncertain significance. Treatment involves the same lifestyle changes recommended to all patients.38
· Diabetes care in ischemic heart disease
o DM management is important, although intense control is no longer recommended, and it is imperative that therapy does not induce hypoglycemic episodes.28
o Hemoglobin A1c goals of <7% may be considered in those with a short duration of DM and good life expectancy.
o Hemoglobin A1c goals of 7% to 9% may be appropriate in older patients, those with end organ damage from DM, or prior hypoglycemic events.
o Rosiglitazone is contraindicated in patients with IHD/heart failure, although more recent evidence suggests the CVD concerns may have been unjustified.
TABLE 7-2 American Heart Association Criteria for Metabolic Syndrome
aWaist circumference measured horizontally at the iliac crest, at the end of normal expiration; lower cutoffs may be appropriate in Asian Americans (≥90 cm or ≥35 inches for men, ≥80 cm or ≥31 inches for women).
Modified fromGrundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome. Curr Opin Cardiol 2006;21:1–6.
DIAGNOSIS
Clinical Presentation
History
· The most common manifestation of CAD is angina, which is generally described as a substernal pain or discomfort lasting minutes that is crushing, squeezing, pressure, suffocating, and/or heavy. Angina is not usually sharp or stabbing and does not typically change with respiration or position.39
· Some individuals may experience nausea, diaphoresis, epigastric discomfort, or dyspnea as the primary symptom of angina. Atypical symptoms are more common in women and the elderly.39
· Symptoms can be precipitated by emotional or physical stress or illness.
· Symptoms may radiate into the arm, jaw, neck, or back and are frequently associated with a profound sense of discomfort or uneasiness.
· Typical angina has three features: (a) substernal chest discomfort of a characteristic quality and duration that is (b) provoked by stress or exertion, and (c) relieved by rest or nitroglycerin (NTG).39
o Atypical angina has two of these three characteristics.
o Noncardiac chest pain meets one or none of these characteristics.
· Of note, diabetics may not experience chest discomfort despite having significant CAD, and women and elderly patients often experience more atypical forms of chest discomfort.
· Since quality of angina varies significantly among individuals, the Canadian Cardiovascular Society has classified the amount of angina in terms of symptomatic limitations to performing daily activities (Table 7-3). This allows clinicians to titrate medical or surgical therapy to reduce anginal severity.40
· When evaluating patients in the ambulatory setting with symptoms suggestive of CHD, the stability of the symptoms is key in determining which patients need inpatient evaluation and which can be cared for in the ambulatory setting. Patients with angina should first be identified as having stable or unstable angina.
· Chronic stable angina is reproducibly precipitated in a predictable manner by exertion or emotional stress and relieved within 5 minutes by sublingual nitroglycerin or rest. To be considered stable, angina symptoms should be present and unchanged for 2 months or greater. These patients can be safely managed in the ambulatory setting.
· Patients with low-risk unstable angina are those with new-onset exertional angina or worsening existing exertional angina whose onset is between 2 weeks and 2 months of presentation with a normal exam, ECG, and cardiac markers. Other low-risk features include age <70 years, pain after exertion <20 minutes duration, lack of rest pain, and pain that is not rapidly worsening. Ambulatory management of these patients is possible, but treatment and testing should not be delayed and close follow-up should be assured.
· Patients with symptoms suggestive of an ACS or its complications (such as acute heart failure exacerbation) should be referred for prompt inpatient hospital evaluation and management.
TABLE 7-3 Classification of Angina
aUnstable angina is generally considered class IV angina, or progression of classes II–III angina over the preceding 2 months.
Modified from Campeau L. Grading of angina pectoris. Circulation 1976;54:522–523.
Physical Examination
· Physical examination can help identify higher-risk CHD patients or noncardiac causes of chest pain (Table 7-4).
· Concerning physical exam findings include signs of heart failure (edema, rales, S3 heart sound), new or worsening mitral regurgitation murmur, hypotension, and tachycardia or bradycardia.
· Evidence of undiagnosed cardiac risk factors may be noted on examination (e.g., tendon xanthomas in hypercholesterolemia, abnormalities of pulse suggestive of PAD).
· Severe HTN alone may provoke coronary ischemia (hypertensive emergency). In patients with chest discomfort and elevated BP, rapid reduction of systolic BP by approximately one-third—generally in a monitored setting such as an emergency department—with gradual further reduction over the subsequent 48 hours is imperative.
TABLE 7-4 Differential Diagnosis of Chest Pain
Differential Diagnosis
· The differential diagnosis of chest pain is broad (Table 7-4). The diagnosis of obstructive CAD relies heavily on the history and ECG.
· Ischemia from etiologies other than atherosclerotic CAD
o Subendocardial ischemia related to myocardial strain requires management of the underlying cause of strain (i.e., blood pressure control, β-blockers or calcium channel blockers [CCBs] for hypertrophic cardiomyopathy, valve replacement for aortic stenosis).
o Variant angina from coronary vasospasm (an uncommon cause of angina, usually associated with ST-segment elevation on the ECG).
§ Treatment of spasm using CCBs and/or nitrates should be combined with interventions aimed at endothelial stabilization (e.g., tobacco cessation, aspirin therapy, weight loss and exercise, possibly ACE inhibitors). β-Blockers can worsen variant angina and should be avoided.
§ Provocation testing in the catheterization laboratory or 24-hour ECG monitoring to diagnose ST elevations may be necessary for definitive diagnosis.
o Rarely, myocardial bridging (or certain congenital coronary artery anomalies) may also cause angina. This is best relieved by reducing inotropy and improving diastolic flow with β-blockers and possibly CCBs. Surgery for certain coronary anomalies may be necessary.
o Cocaine or other stimulants may provoke ischemia via tachycardia, HTN, and vasoconstriction. Other than cessation of cocaine usage, management is similar to vasospasm, but β-blockers are generally avoided because of the risk of unopposed α-adrenergic stimulation. With acute intoxication, nitrates and benzodiazepines are the mainstay of treatment.
Diagnostic Testing
Laboratories
To identify precipitating causes of chest pain or assess risk, initial tests should include complete blood count, renal function and electrolytes, lipid panel fasting glucose, and an ECG.
Imaging
· Chest radiography may help identify aortopathies, structural heart disease/heart failure, or pulmonary/skeletal etiologies, which can cause chest discomfort.
· Echocardiography (echo) is indicated when chest symptoms or examination findings are potentially related to structural (e.g., valvular heart disease, hypertrophic cardiomyopathy, pericardial disease) or functional abnormalities (systolic or diastolic heart failure) with the heart. Echo may also be obtained in patients with prior MI or an abnormal ECG.
Diagnostic Procedures
Stress Testing
· In patients without established IHD, determining the pretest probability of CAD is very important in deciding which symptomatic patients should undergo stress testing to establish a diagnosis of CAD (Table 7-5).39,41,42
o Stress testing is most clinically useful in patients with symptoms and intermediate pretest probability of CAD (test results will have the least false-positive and false-negative results). Stress testing in low pretest probability patients (<10% likelihood of CAD) will result in more false-positive tests.39,43,44
o Patients with symptoms and high pretest probability of CAD, with severe stable angina (class III/IV despite appropriate medications), and with high-risk unstable angina (stress testing contraindicated) can proceed directly to cardiac catheterization.
· Other situations where stress testing is indicated include the following:
o Assessing change in angina pattern (low-risk unstable angina) in those with prior coronary revascularization on optimal medical therapy should be accompanied by cardiac imaging.
o Assessing the functional significance of a coronary lesion noted at angiography should be considered with imaging.
o Assessing for an ischemic etiology of a new diagnosis of left ventricular (LV) dysfunction in a patient without ischemic symptoms and not at high risk for CHD should be accompanied with cardiac imaging.
o Assessing for an ischemic etiology/myocardial scar in the setting of ventricular tachycardia in a patient without ischemic symptoms and not at high risk for CHD should be accompanied with cardiac imaging.
o Determining prognosis in patients with known symptomatic IHD or in those without known IHD but are at intermediate or higher likelihood of having CAD but invasive interventions are less desirable (with or without cardiac imaging).
o To assess adequacy of medical therapy for symptomatic patients with CAD in whom ongoing symptoms may not be of ischemic origin.
o Prior to starting cardiac rehabilitation, to assess ischemic burden after an ACS where revascularization was not performed, or in previously sedentary patients planning on embarking on vigorous exercise regimens or as part of an exercise prescription, especially in those at high risk for silent ischemia.
o Preoperatively in some circumstances (see Chapter 2).
o Although some guidelines suggest stress testing in some asymptomatic individuals (e.g., coronary calcium score >400 or airline pilots), we do not recommend stress testing in most asymptomatic individuals.
· Contraindications to exercise stress testing are listed in Table 7-6.43
· Generally, β-blockers, nondihydropyridine CCBs, and other antianginals (e.g., nitrates) should be held the day prior to stress testing to permit a normal heart rate/dilatory response in patients without established CAD. In patients with known CAD, these medications may be continued if adequacy of medical therapy is being tested.
TABLE 7-5 Pretest Probability of Coronary Artery Disease on Catheterizationa
aBased on data from Diamond and Forrester and the Coronary Artery Surgery Study.42,43
Modified 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. Circulation2012;129:e354–e471.
TABLE 7-6 Contraindications to Exercise Testing
Modified from Gibbons RJ, Balady GJ, Beasley JW, et al. ACC/AHA guidelines for exercise testing: executive summary. Circulation 1997;96:345–354.
Exercise Treadmill Testing
· Exercise treadmill testing (ETT) with or without cardiac imaging is the preferred method of stress testing and should always be attempted unless it is obvious that the patient cannot exercise or other contraindications to ETT are present.
o ST elevation during stress testing localizes myocardial injury and suggests high-grade obstruction of an epicardial coronary artery. These patients are usually referred urgently for cardiac catheterization.
o Inadequate heart rate response (<85% of the maximum predicted heart rate [MPHR]) can render the stress test nondiagnostic. Upsloping ECG changes may also result in an indeterminate test.
o Downsloping or horizontal ST-segment depression is suggestive of ischemia although it does not necessarily localize the coronary lesion with accuracy.45
o A positive test is defined as ≥1 mm of ST depression in two contiguous ECG leads 60 to 80 ms after the J-point when compared with the PR segment.
o Apart from the ECG, the blood pressure response and heart rate response may be clinically useful. Hypertensive responses may require uptitration of blood pressure medications.
· Prognosis is directly related to exercise stress testing functional capacity, degree of exercise-induced angina, severity of ECG changes, and length of time for ECG changes to revert back to normal in recovery.
o The Duke treadmill score incorporates several prognostic factors from exercise testing into a simple formula (Table 7-7).46
o High-risk patients should be referred for coronary angiography, whereas intermediate-risk patients may be further stratified by either angiography or a repeat stress test with imaging to better assess ischemia.39
TABLE 7-7 Duke Treadmill Scorea and Other Prognostic Factors during Exercise Stress Testing
aDuke treadmill score = minutes of exercise on Bruce protocol – (5 × ST deviation in mm) – (4 × exercise angina score). Exercise angina score: 0 = no angina, 1 = angina during the test, 2 = angina causing test termination.
CAD, coronary artery disease; MET, metabolic equivalent.
Data from Mark DB, Shaw L, Harrell FE, et al. Prognostic value of a treadmill exercise score in outpatients with suspected coronary artery disease. N Engl J Med 1991;325:849–853.
Pharmacologic Stress Testing.
· In patients unable to exercise or attain target heart rate, pharmacologic stress testing should be performed and is always accompanied by cardiac imaging.39
· Pharmacologic stress tests involve redistribution of myocardial blood flow using vasodilators (adenosine or regadenoson) or adrenergic stimulation (dobutamine).
o Adenosine and regadenoson: Adenosine can provoke bronchospasm in patients with severe reactive airway disease. Regadenoson is less likely to cause bronchospasm but should be avoided in these patients. Both agents are contraindicated in advanced AV block, sick sinus syndrome, and those taking oral dipyridamole. All caffeine products need to be withheld for 12 to 18 hours prior to use of these agents since caffeine can block the effect of the vasodilators. Aminophylline can be given to reverse the effects of adenosine or regadenoson.
o Dobutamine may provoke arrhythmias or hypotension and should be avoided in patients with uncontrolled atrial fibrillation, known ventricular tachycardia, or known aortic dissection. β-Blockers can be given to reverse the effects of dobutamine.
Stress Tests with Imaging.
· Echocardiographic imaging, radionuclide myocardial perfusion imaging (MPI), or cardiovascular magnetic resonance (CMR) imaging can be used as imaging adjunct to stress testing and is recommended if the baseline ECG is abnormal (LV hypertrophy with secondary ST-segment changes, resting ST depression >1 mm, digoxin effects, left bundle branch block [LBBB], ventricular pacemaker beats, preexcitation) or in patients who cannot exercise to an adequate heart rate.39
· When LBBB or electronic ventricular pacing is present, exercise stress testing should be avoided in favor of a pharmacologic stress test to prevent a false-positive study due to septal abnormalities. In all other circumstances where stress testing is ordered, ETT with or without imaging is the stress test of choice.
· Sensitivity and specificity are improved with the addition of cardiac imaging as compared to ETT alone.
· High-risk findings during stress testing (Table 7-8) should prompt coronary angiography for prognostic assessment and potential revascularization in appropriate candidates.39
· Each stress imaging modality has its own advantages but similar sensitivities and specificities. In general, indications for stress echo and stress MPI are interchangeable; they are both currently preferred over stress CMR.
o Stress echo allows assessment of both cardiac structure and function with higher specificity, lower cost, and no exposure to radiation, but acquisition and interpretation of stress images require expertise by a dedicated sonographer and echocardiographer. Dobutamine is the preferred pharmacologic agent in those who cannot undergo ETT.
o Guidelines permit more liberal use of stress echo in patients with lower likelihood of CAD, as compared to stress MPI, even if they have a normal baseline ECG.
o Stress radionuclide MPI has a high sensitivity for the detection of CAD and is less technically demanding. In patients with severe cardiomyopathies, stress images can be easier to interpret as compared to stress echo. False-negative studies in the presence of left main or triple vessel disease can occur due to balanced ischemia and should be considered when interpreting results. Exposure to nuclear isotopes that require specialized handling and licensing is a disadvantage of radionuclide MPI.
o Stress CMR is currently limited to a few centers that have the necessary expertise to perform and interpret such studies. Advantages of CMR include the ability to look at cardiac structure/function without exposure to radiation. Additionally, viability of cardiac muscle and infiltrative diseases of the heart may also be assessed. Currently, stress CMR can only be performed as a pharmacologic stress test (vasodilator or dobutamine) and hence should generally not be considered in those who can exercise.
TABLE 7-8 Prognostic Markers from Stress Testing
LV, left ventricle; LVEF, left ventricular ejection fraction; MI, myocardial infarction; VT, ventricular tachycardia; VF, ventricular fibrillation
Modified 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. Circulation2012;129:e354–e471.
Coronary CT Angiography
· Coronary CT angiography (CCTA) noninvasively assesses coronary anatomy. CCTA is better suited to ruling out the presence of CAD (e.g., high negative predictive value in populations with lower pretest probability of CAD) and identifying congenital coronary anomalies.47
· Since CCTA is not accompanied by stress testing, the physiologic significance of identified coronary lesions cannot be tested. Thus, an abnormal CCTA may lead to further testing, potentially increasing the cumulative radiation and iodinated contrast exposure. Another disadvantage occurs in patients with coronary stents (especially stents smaller than 3 mm) or significant coronary calcium where image reconstruction artifacts can make quantification of lesion severity less accurate.
· CCTA may be useful for those with persistent symptoms/multiple hospitalizations and inconclusive or normal stress testing results. CCTA can also be useful in assessing graft patency after coronary artery bypass grafting (CABG).
· CCTA should not be used for screening asymptomatic patients to diagnose occult CAD.
· CCTA can be considered a reasonable alternative for the assessment of CAD in symptomatic patients who cannot undergo ETT and are at low to intermediate likelihood risk of CAD.47
Coronary Angiography
· Diagnostic left heart catheterization is the gold standard for assessing the presence of CAD, defining coronary anatomy, lesion severity, and atherosclerotic burden. Cardiac catheterization can also assess LV systolic function and valvular function and can be used to obtain pressure measurements within the heart and vasculature.39,48
· In patients with suspected CAD and angina, coronary angiography is considered an appropriate test in the following scenarios39,49:
o Angina with high-risk criteria by clinical assessment
o Disabling angina (class III to IV) despite medical therapy
o Angina with intermediate-risk stress test findings
o High-risk stress test findings in patients with angina or without angina but stress testing suggests left main or triple vessel disease (Table 7-8)
o Indeterminate stress test results despite high pretest probability of CAD
o Angina or high likelihood of CAD in a patient with new LV systolic dysfunction
o Survivors of sudden cardiac death (SCD) and life-threatening ventricular arrhythmias
o Patients undergoing planned heart valve or other cardiac surgeries if CAD is possible
· Conventional angiography reliably identifies epicardial coronary lesions, but ancillary tools may be needed to determine the significance of some lesions. Interventional techniques such as fractional flow reserve or intravascular ultrasound can quantify the significance of a coronary stenosis by determining if the lesion is flow limiting or if there is greater plaque burden than visually noted.
· Complication rates from diagnostic catheterization are generally <1% to 2%, although higher risks are associated with increasing age, PAD, renal dysfunction, coagulopathy, and extremes of body weight. Mortality risk is approximately 0.1%.
· The transradial approach is an alternative strategy for catheterization as opposed to the more traditional femoral artery technique. The transradial approach is associated with a reduction in vascular access complications as well as lower bleeding rates. The transradial approach should always be considered in patients who cannot accept blood products based on religious or other objections.50
Treatment
· Patient education and adherence to lifestyle modification and medications is of paramount importance for the successful management of IHD. Clinicians must involve patients when formulating a treatment plan.
· Treatment is intended to reduce the risks of cardiovascular mortality and MI, while also reducing symptoms and improving quality of life.
· Outpatient therapies are directed toward increasing coronary blood flow, reducing myocardial oxygen demand, reducing thrombosis, preventing or reversing remodeling of ischemic or infarcted myocardium, and correcting any illness that may precipitate ischemia.
Medications
Antiplatelet Therapy
· Aspirin (ASA) therapy (75 to 100 mg) is the preferred antiplatelet therapy for primary prevention.39,51 The risk-benefit ratio for ASA becomes more favorable as the GRS increases. Hence, bleeding risk and risk for CHD events needs to be weighed. Generally, ASA will be reserved for patients at high GRS. It should be noted that women tend to have higher rates of bleeding on ASA as compared to men.
· Antiplatelet therapy for established CAD consists of ASA and/or platelet P2Y12 receptor blockers (clopidogrel, prasugrel, and ticagrelor).
o Prasugrel has a maintenance dose of 10 mg once daily. It is reserved for patients with ACS who undergo cardiac stenting only. It is contraindicated in patients with a prior TIA or stroke. It should be avoided in those ≥75 years of age or who weigh <60 kg.
o Ticagrelor has a maintenance dose of 90 mg twice daily and is reserved for use in ACS whether stents were placed or not. It must not be used with ASA doses >100 mg. Compliance with twice daily dosing can be a problem.
o Clopidogrel has a maintenance dose of 75 mg once a day. Only clopidogrel can be used in conjunction with warfarin and ASA due to a higher risk of bleeding with the other P2Y12 receptor blockers.
· For patients beyond the first year post-ACS, lifelong single antiplatelet therapy with either aspirin (81 mg) or clopidogrel (in aspirin intolerant patients) is recommended.
o ASA at 81 to 162/day reduces the risk of MI, stroke, and vascular death and reduces all-cause mortality in patients with known CAD.39
o ASA doses of 162 to 325/day or greater are no more protective and are more gastrotoxic compared to lower doses.52
o In surgical patients, aspirin should be continued during the pre- and postoperative period if feasible.
o Enteric coating may not be more protective against GI bleeding risk.53
o Clopidogrel may be substituted for patients with true aspirin allergy (e.g., anaphylaxis). Alternatively, aspirin desensitization may be pursued.
· For patients within 1 year of ACS who did not undergo percutaneous coronary intervention (PCI) or CABG dual antiplatelet therapy [DAPT] with ASA (81 mg) and a platelet P2Y12 receptor blocker is recommended for up to 1 year. Aspirin should be continued indefinitely. Either clopidogrel or ticagrelor may be used.
· For patients within 1 year of ACS who underwent PCI with stenting or CABG, DAPT is recommended for a minimum of 1 year.54–57
o In patients treated with stent placement, any platelet P2Y12 receptor blocker can be employed.
o In patients post-CABG, clopidogrel or ticagrelor may be used along with ASA.
· For patients who underwent PCI with elective stenting (non-ACS indication):
o All patients who receive a cardiac stent on an elective basis should preferably stay on ASA and clopidogrel for 1 year, especially if a drug-eluting stent (DES) was placed.39
o However, therapy beyond 1 month of combined clopidogrel and ASA therapy with bare metal stents (BMS) is less universally accepted and can be sufficient.
· DAPT therapy after PCI with stent placement beyond the first year of therapy57:
o Robust data on the routine use of DAPT beyond 1 year are lacking.
o It is reasonable to continue DAPT beyond 1 year for patients with higher risk for cardiac events (e.g., reduced LV function, complex PCI of bifurcating lesions or heavily calcified lesions, use of multiple stents or long areas of stenting), high-risk sites of stenting (e.g., left main, proximal left anterior descending [LAD]), or suboptimal stenting results in those who are not at high risk of bleeding.39,47
o Risk of late stent thrombosis (beyond 1 year) varies for different DES. Stent-specific data on late thrombosis should be considered and discussed with the patient when considering continuing or stopping platelet P2Y12 receptor blockers after 1 year. There is a lower rate of stent thrombosis associated with use of second-generation DES (everolimus- and zotarolimus-eluting stents) as compared to older DES types.
· For patients who underwent PCI with stent placement who subsequently require nonemergent surgery (see Chapter 2):
o Nonemergent surgery should be delayed a minimum of 6 weeks after ACS, and DAPT therapy should not be interrupted within the first year.
o If the cardiac stent was placed electively, ASA and clopidogrel therapy should be continued for a minimum of 4 weeks for BMS and 6 months for DES, after which ASA alone should be continued.
o All platelet P2Y12 receptor blockers significantly increase bleeding complications during major surgery. Therefore, if therapy needs to be interrupted for surgery, P2Y12 receptor blockers should be withheld for 5 days for clopidogrel or ticagrelor and 7 days for prasugrel.
Antiischemic Therapy
β-Blockers
· β-Blockers (Table 7-9) have been shown to prevent reinfarction and improve survival. They should be the first-line therapy for all patients with prior MI or LV systolic dysfunction (<40%) in the absence of contraindications (hypotension, severe bradycardia or heart block, decompensated heart failure, Prinzmetal angina).39
· β-Blockers should be continued for 3 years in patients post-MI with normal LV function.
· No trials have shown an improvement in survival or reduction in the rate of MI for patients with stable IHD without a history of MI.
· In patients with LV systolic dysfunction, β-blocker therapy should be with carvedilol, metoprolol succinate, or bisoprolol, as these agents have been shown to reduce mortality.39
· Goal heart rate is generally 55 to 60 beats per minute with slow dose titration. The aim when treating stable angina is not to allow the exercise-induced heart rate to exceed 75% of the rate at which ischemia is experienced.
· Agents more selective for β1-receptors at low doses may cause fewer side effects related to β2-antagonism (e.g., bronchospasm).
TABLE 7-9 Commonly Used β-Blockers
CR, controlled release; ISA, intrinsic sympathomimetic activity.
Calcium Channel Blockers
· CCBs may reduce angina by inducing arteriolar vasodilation and reducing myocardial oxygen demand (Table 7-10). They may be added to β-blockers for patients with continued symptoms or used as second-line agents in individuals with contraindications to β-blockers.39
· CCBs, in conjunction with nitrates, are preferable when treating coronary vasospasm.
· Nondihydropyridines may be useful for suppressing atrial arrhythmias or atrioventricular conduction, but given their negative chronotropic and inotropic effects, these agents should be avoided in patients with LV systolic dysfunction.
· Short-acting nifedipine may cause reflex tachycardia, and any CCB may cause peripheral edema, constipation, headaches, or flushing.
TABLE 7-10 Calcium Channel Blockers
CD, continuous duration; LA, long acting; SR, sustained release.
Nitrates
· Nitroglycerin reduces preload (venodilation) and afterload (arterial dilation) in patients with angina and therefore improves both myocardial supply and demand as well as LV wall stress.
· Nitrates should be prescribed for anginal relief when β-blockers cannot be used or as add-on therapy to β-blockers.
· Headaches are common but benign and often treatable with acetaminophen. Hypotension may be precipitated in patients with intravascular depletion, severe aortic stenosis, hypertrophic cardiomyopathy, or concomitant therapy with phosphodiesterase-5-inhibitors (e.g., sildenafil, vardenafil, tadalafil).
· Sublingual nitroglycerin spray or tablets provide rapid relief for many individuals with stable angina, but prolonged discomfort after two to three doses should prompt immediate evaluation in an emergency department.
· Longer-acting nitrates (isosorbide dinitrate and mononitrate, transdermal nitroglycerin patch) may help avoid angina in chronic symptomatic CAD, but all forms require an 8- to 12-hour nitrate-free period to avoid tachyphylaxis.
· These agents have never been demonstrated to improve long-term outcomes, so nitrates should be prescribed for symptom relief in patients with inadequate responses or contraindications to β-blockers or CCBs.39
· As with CCBs, nitrates may help prevent or minimize angina from coronary vasospasm.
Ranolazine
Ranolazine is an anti-ischemic agent with unclear mechanism, which has been shown to reduce angina severity and frequency when added to β-blockers for chronic CAD. Reductions in clinical events have not been demonstrated conclusively to date.39,58–60
Other Medication Therapies
Angiotensin-Converting Enzyme Inhibitors
ACE inhibitors should be added for patients with IHD plus HTN, DM, LV systolic dysfunction (ejection fraction [EF] <40%), or mild-to-moderate renal dysfunction.39 Angiotensin receptor blockers (ARBs) may be reasonable alternatives for patients with intolerance to ACE inhibitors (e.g., significant cough, angioedema).
Aldosterone Antagonists
Eplerenone, an aldosterone antagonist related to spironolactone, improves short- and long-term mortality and cardiovascular outcomes when given to patients with acute MI, LV systolic dysfunction (EF <40%), clinical HF or DM, and no other contraindication to aldosterone blockade (e.g., creatinine >2.5 mg/dL, hyperkalemia).61–63 Therapy should be continued for 2 years after MI.
Statin Therapy
· High-intensity statin therapy should be administered to all patients with CAD or CAD risk equivalents. See Prevention above and Chapter 11, Dyslipidemia.24
· Patients with myalgias or other adverse effects on one particular statin should be tried on other statins. Other approaches include using lower doses of an initial statin and/or every-other-day dosing.
· High-dose, high-potency statins may modify plaque composition and reduce atherosclerotic progression over time but may be associated with a higher incidence of DM. Potential benefits regarding cardiovascular events very likely outweigh potential harm.7,64–66
· High-potency statins also have pleiotropic effects beyond lowering of LDL. Thus, all patients with CAD (prior CABG or PCI) should be treated with a statin at a moderate or higher dose irrespective of their baseline LDL.
· Adding niacin, fibrates, or omega-3 fish oil tablets to statin therapy has not shown any clear benefit beyond statin therapy alone. Alternative lipid-lowering agents can be considered in statin-intolerant patients.
Other Risk Reduction Therapy
· Influenza vaccine is recommended annually for patients with known CVD.39
· Discussion with patients about symptoms of depression and stress can help control angina. Treatment of major depressive disorder may be needed.
· Treatments not recommended for IHD include39,49:
o Estrogen
o Dipyridamole
o Supplements with vitamins C, E, B6, and B12, beta carotene, garlic, coenzyme Q10, selenium, and chromium
o Acupuncture
o Chelation therapy
Other Nonpharmacologic Therapies
· Most patients may resume driving, sexual activity, commercial air travel, and return to work approximately 1 to 2 weeks after a myocardial infarction.
· Cardiac rehabilitation in a structured format has been shown to reduce long-term mortality after MI or coronary revascularization procedures by approximately 25%.67
· The initial goal is 50% to 60% of MPHR (estimated as 220 – age) for 10 to 30 minutes at least three times per week followed by a gradual escalation of exercise duration and heart rate to 75% to 85% of maximal predicted.67
· Warm-up and cool-down periods of 5 to 15 minutes are recommended.
· Elderly patients enjoy mortality and morbidity benefits equivalent to younger patients, and referral to cardiac rehabilitation is highly encouraged for this age group. Supervision and hemodynamic surveillance is recommended initially for this group.68
· Enhanced external counterpulsation (EECP) involves sequential inflations and deflations of cuffs on a subject’s limbs, and for patients with refractory angina despite maximal medical and interventional therapy, symptoms may be improved after several weeks of daily therapy.39,69–71
· Spinal cord stimulation and transmyocardial revascularization can also be considered for those with refractory angina.39
· Persistent LV systolic dysfunction after MI (EF ≤35%), despite aggressive medication titration for at least 40 days, should prompt evaluation for an implantable defibrillator (potentially with cardiac resynchronization therapy [CRT] if the QRS is prolonged [LBBB ≥120 ms, non-LBBB QRS ≥150 ms]) in appropriate patients with mild-to- moderate HF symptoms and otherwise good 1-year prognosis.72,73
· Cardiac transplantation can be considered for individuals with medically or surgically refractory angina.
Surgical Management
Coronary Revascularization for Stable Ischemic Heart Disease
· In general, medical therapy with at least two, and preferably three, classes of antianginal agents should be attempted before medical therapy is considered a failure and coronary revascularization pursued.48
· In patients with stable angina, medical therapy results in similar cardiovascular outcomes when compared to PCI except that PCI offers greater short- and long-term relief of anginal symptoms. Patients should be aware, as part of the informed consent, that their risk for MI or death is not altered by PCI if the indication is stable angina.39,48
· However, patients with certain coronary lesions have a survival advantage with revascularization as compared to medical therapy alone.
· The choice between PCI and CABG surgery is dependent on the coronary anatomy, medical comorbidities, and patient preference.
· In general, patients with complex and diffuse disease do better with CABG, while PCI in select patients with the proper coronary anatomy can provide comparable results as CABG. Due to the extensive nature of CABG, patient comorbidities often necessitate PCI for revascularization.
· The decision regarding medical therapy alone, PCI, or CABG should consider whether both symptom and mortality benefits are sought or symptom relief alone is sufficient. PCI and CABG are both effective at symptom relief of angina.39
· Revascularization is shown to improve survival as compared to medical therapy alone in the following circumstances encountered in the outpatient setting:
o CABG for >50 % left main disease or PCI if patient is ineligible for CABG and has left main anatomy suitable for PCI.
o CABG or PCI in survivors of ischemia-mediated SCD.
o CABG for three-vessel disease or disease in the proximal LAD and one other artery, two-vessel disease with extensive ischemia, and multivessel disease with an left ventricular ejection fraction (LVEF) of >35% when either reversible ischemia or viable myocardium is present.
· CABG carries a 1% to 3% mortality rate, 5% to 10% incidence of perioperative MI, and a small risk of perioperative stroke. The use of internal mammary artery grafts is associated with 90% graft patency at 10 years, compared with 40% to 50% for saphenous vein grafts. The long-term patency of a radial artery graft is 80% at 5 years. After 10 years of follow-up, 50% of patients develop recurrent angina or other adverse cardiac events related to late vein graft failure or progression of native CAD.74–76
FOLLOW-UP
· Routine stress testing or angiography is not indicated after revascularization.
o With the current DES and use of internal thoracic artery for bypass surgery, the pretest probability of restenosis is significantly lower than 10 to 20 years ago.39
o Although the practice is not universally accepted, stress testing may be considered for stable or asymptomatic patients in patients with known silent ischemia.
· In patients with recurrent symptoms following PCI, stress MPI is relatively inaccurate for the first 2 months after PCI, resulting in high rates of false-positive studies.44
· Above all else, modification of underlying risk factors is imperative because revascularization does not modify the progression of atherosclerosis. Future angina prevalence and ischemic burden is associated with progression of native CAD rather than with the type of revascularization performed.76
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