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Coronary Heart Disease and Stable Angina General Principles Definition Coronary artery disease (CAD) refers to the luminal narrowing of a coronary artery, usually due to atherosclerosis. CAD is the leading contributor to ischemic heart disease (IHD). IHD includes angina pectoris, myocardial infarct...

Coronary Heart Disease and Stable Angina General Principles Definition Coronary artery disease (CAD) refers to the luminal narrowing of a coronary artery, usually due to atherosclerosis. CAD is the leading contributor to ischemic heart disease (IHD). IHD includes angina pectoris, myocardial infarction (MI), and silent myocardial ischemia. Cardiovascular disease (CVD) includes IHD, cardiomyopathy, heart failure (HF), arrhythmia, hypertension, cerebrovascular accident (CVA), diseases of the aorta, peripheral vascular disease (PVD), valvular heart disease, and congenital heart disease. Stable angina is defined as angina symptoms or angina equivalent symptoms that are reproduced by consistent levels of activity and relieved by rest. American Heart Association/American College of Cardiology (AHA/ACC) guidelines provide a more thorough overview of stable IHD.1,2 Freemedicalbooks4download Epidemiology In the United States, IHD is the cause of one of every six deaths.3 The lifetime risk of IHD at age 40 is one in two for men and one in three for women. There are more than 15 million Americans with IHD, 50% of whom have chronic angina. CVD has become an important cause of death worldwide, accounting for nearly 30% of all deaths, and has become increasingly significant in developing nations. Death due to CVD continues to decline in large part because of adherence to current guidelines. Etiology CAD most commonly results from luminal accumulation of atheromatous plaque. Other causes of obstructive CAD include congenital coronary anomalies, myocardial bridging, vasculitis, and prior radiation therapy. Freemedicalbooks4download Pathophysiology Stable angina results from progressive luminal obstruction of angiographically visible epicardial coronary arteries or, less commonly, obstruction of the microvasculature, which results in a mismatch between myocardial oxygen supply and demand. Atherosclerosis is an inflammatory process, initiated by lipid deposition in the arterial intima layer followed by recruitment of inflammatory cells and proliferation of arterial smooth muscle cells to form an atheroma. The coronary lesions responsible for stable angina differ from the vulnerable plaques associated with acute MI. The stable angina lesion is fixed and is less prone to fissuring, hence producing symptoms that are more predictable.4 All coronary lesions are eccentric and do not uniformly alter the inner circumference of the artery. Epicardial coronary lesions causing less than 40% luminal narrowing generally do not significantly impair coronary flow. Moderate angiographic lesions (40%–70% obstruction) may interfere with flow and are routinely underestimated on coronary angiograms given the eccentricity of CAD. Risk Factors Of IHD events, >90% can be attributed to elevations in at least one major risk factor.5 Assessment of traditional CVD risk factors includes: Age. Blood pressure (BP). Blood sugar (note: diabetes is considered an IHD risk equivalent). Lipid profile (low-density lipoprotein [LDL], high-density lipoprotein [HDL], triglycerides); direct LDL for nonfasting samples or very high triglycerides. Tobacco use (note: smoking cessation restores the risk of IHD to that of a nonsmoker within approximately 15 years).6 Family history of premature CAD: Defined as first-degree male relative with IHD before age 55 or female relative before age 65. Measures for obesity, particularly central obesity; body mass index goal is between 18.5 and 24.9 kg/m2; and waist circumference goal is <40 inches for men and <35 inches for women. As of 2013, AHA/ACC guidelines recommend assessing 10-year atherosclerotic cardiovascular disease (ASCVD) risk for patients aged 40–79 years using new race and age- specific pooled cohort equations.7 The ASCVD risk calculator is available online (http://tools.cardiosource.org/ASCVD-Risk-Estimator/). If there remains uncertainty about lower risk estimates, highsensitivity C-reactive protein (≥2 mg/dL), coronary artery calcium score (≥300 Agatston units or ≥75th percentile), or ankle–brachial index (<0.9) may be obtained to revise risk estimates upward. Traditional risk factors noted above should be assessed in patients younger than age 40 and every 4–6 years after 40; 10-year ASCVD risk should be calculated every 4–6 years in patients 40–79 years of age. Lifetime risk can be assessed using the ASCVD risk calculator and may be helpful in the setting of counseling patients about lifestyle modifications. Freemedicalbooks4download Prevention Primary prevention: See Chapter 3, Preventive Cardiology Diagnosis Clinical Presentation History Typical angina has three features: (1) substernal chest discomfort with a characteristic quality and duration that is (2) provoked by stress or exertion and (3) relieved by rest or nitroglycerin. Atypical angina has two of these three characteristics. Noncardiac chest pain meets one or none of these characteristics. Chronic stable angina is reproducibly precipitated in a predictable manner by exertion or emotional stress and relieved within 5–10 minutes by sublingual nitroglycerin or rest. The severity of angina may be quantified using the Canadian Cardiovascular Society (CCS) classification system (Table 4-1). Associated symptoms may include dyspnea, diaphoresis, nausea, vomiting, dizziness, jaw pain, and left arm pain. Female patients and those with diabetes or chronic kidney disease (CKD) may have minimal or atypical symptoms that serve as anginal equivalents. Such symptoms include dyspnea (most common), epigastric pain, and nausea. The clinician’s assessment of the pretest probability of IHD is the important driver for further diagnostic testing in patients without known CAD and is largely ascertained from the clinical history (Table 42). Patients with a low pretest probability (<5%) of CAD are unlikely to benefit from further diagnostic testing aimed at detecting CAD. TABLE 4-1 Canadian Cardiovascular Society (CCS) Classification System Class Definition CCS 1 Angina with strenuous or prolonged activity CCS 2 Angina with moderate activity (walking greater than two level blocks or one flight of stairs) CCS 3 Angina with mild activity (walking less than two level blocks or one flight of stairs) CCS 4 Angina that occurs with any activity or at rest Data from Sangareddi V, Chockalingam A, Gnanavelu G, Subramaniam T, Jagannathan V, Elangovan S. Canadian Cardiovascular Society classification of effort angina: an angiographic correlation. Coron Artery Dis. 2004;15(2):111-114. Freemedicalbooks4download Anginal symptoms may include typical chest discomfort or anginal equivalents. TABLE 4-2 Pretest Probability of Coronary Artery Disease by Age, Gender, and Symptoms Nonanginal Atypical/Probable Typical/Definite Angina Chest Pain Angina Pectoris Pectoris Gender Women Men Women Men Women Men Women Men 30–39 <5 <5 2 4 12 34 26 76 40–49 <5 <10 3 13 22 51 55 87 50–59 <5 <10 7 20 31 65 73 93 60–69 <5 <5 14 27 51 72 86 94 Very Low <5% Low <10% Intermediate 10%–80% High >80% Data from Gibbons RJ, Balady GJ, Timothy Bricker J. et al. (Committee Members) ACC/AHA 2002 guideline update for exercise testing: summary article: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee to update the 1997 exercise testing guidelines). Circulation. 2002;106(14):1883-1892. Age (y) Asymptomatic Physical Examination Clinical examination should include measurement of BP, heart rate, and arterial pulses. Examination findings of a mitral regurgitation (MR) murmur or aortic stenosis murmur can alert the clinician to additional CVD that may be contributing to symptoms of angina. Stigmata of hyperlipidemia such as corneal arcus and xanthelasmas should be noted. Signs of HF, such as an S3 gallop, inspiratory crackles on lung examination, elevated jugular venous pulsation, and peripheral edema, are also high-risk examination findings. Vascular examination should include palpitation of radial, femoral, popliteal, posterior tibial, and dorsalis pedis pulses bilaterally to compare differences. Auscultation with the bell of the stethoscope should be performed to evaluate for femoral or carotid bruits. Pain that is reproducible on physical examination suggests a musculoskeletal cause of chest pain but does not exclude the presence of CAD. Freemedicalbooks4download Differential Diagnosis A wide range of disorders may manifest with chest discomfort and may include both cardiovascular and noncardiovascular etiologies (Table 4-3). A careful history focused on cardiac risk factors, physical examination, and initial laboratory evaluation usually narrows the differential diagnosis. In patients with established IHD, always look for exacerbating factors that contribute to ischemia. Any process that reduces myocardial oxygen supply or increases demand can cause or exacerbate angina (Table 4-4). TABLE 4-3 Differential Diagnosis of Chest Pain Excluding Epicardial Atherosclerosis Diagnosis Cardiovascular Aortic stenosis HCM Prinzmetal angina Pericarditis Comments Anginal episodes can occur with severe aortic stenosis. Subendocardial ischemia may occur with exercise and/or exertion. Coronary vasospasm that may be elicited by exertion or emotional stress. Pleuritic chest pain associated with pericardial inflammation from infectious or autoimmune disease. Aortic dissection May mimic anginal pain and/or involve the coronary arteries. Cocaine use Results in coronary vasospasm and/or thrombus formation. Other Anemia Marked anemia can result in a myocardial O2 supply–demand mismatch. Thyrotoxicosis Increase in myocardial demand may result in an O2 supply–demand mismatch. Esophageal GERD and esophageal spasm can mimic angina (responsive to NTG). disease Biliary colic Gallstones can usually be visualized on abdominal sonography. Respiratory Pneumonia with pleuritic pain, pulmonary embolism, pulmonary hypertension. diseases Musculoskeletal Costochondritis, cervical radiculopathy. GERD, gastroesophageal reflux disease; HCM, hypertrophic cardiomyopathy; NTG, nitroglycerin. TABLE 4-4 Conditions That May Provoke or Exacerbate Ischemia/Angina Independent of Worsening Atherosclerosis Increased Oxygen Demand Noncardiac Decreased Oxygen Supply Hyperthermia Hyperthyroidism Sympathomimetic toxicity cocaine use) Hypertension Anxiety (i.e., Anemia Sickle cell disease Hypoxemia Pneumonia Asthma exacerbation Chronic obstructive pulmonary disease Pulmonary hypertension Pulmonary fibrosis Obstructive sleep apnea Pulmonary embolus Sympathomimetic toxicity (i.e., cocaine use, pheochromocytoma) Hyperviscosity Polycythemia Leukemia Thrombocytosis Hypergammaglobulinemia Cardiac Hypertrophic cardiomyopathy Aortic stenosis Dilated cardiomyopathy Tachycardia Ventricular Supraventricular Aortic stenosis Elevated left ventricular end-diastolic pressure Hypertrophic cardiomyopathy Microvascular disease Data from AHA/ACC Guidelines on Stable Ischemic Heart Disease; 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; Fihn SD, Blankenship JC, Alexander KP, et al. 2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association task force on practice guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2014;64(18):1929-1949. Freemedicalbooks4download Diagnostic Testing General diagnostic testing A resting ECG can be helpful in determining the presence of prior infarcts or conduction system disease and may alert the clinician to the possibility of CAD in patients with chest pain. Chest radiography can be used to evaluate for cardiomegaly, HF, or vascular disease (pulmonary and aortic) that can be important in the management of patients with chest pain or IHD. A transthoracic echocardiogram (TTE) can be useful in determining the presence of left ventricular (LV) dysfunction or valvular heart disease that may affect the management and diagnosis of IHD. TTE can also be used to assess for resting wall motion abnormalities that may be the result of prior MI. Evidence of vascular disease or prior MI on the diagnostic testing modalities noted above should raise the pretest probability of IHD in patients presenting with chest pain. Stress testing overview All stress testing requires (1) a cardiovascular stress and (2) a way of evaluating cardiac changes consistent with ischemia. The latter is always done with continuous ECG; however, it can be done either with or without an imaging modality. The stress and imaging methods are chosen by the clinician to meet the diagnostic needs of the patient. Many stress testing modalities provide not only detection of ischemia/CAD but also prognostic information based on the burden of ischemia. Table 4-5 provides an overview of the sensitivity and specificity for each stress and imaging modality along with advantages and disadvantages for the clinician to consider. Stress testing indications See the ACCF 2013 Multimodality Appropriate Use Criteria for the Detection and Risk Assessment of Stable Ischemic Heart Disease for a comprehensive list of the indications for stress testing.8 The following are some of the more common indications: Patients without known CAD: Patients with anginal symptoms who are intermediate risk Asymptomatic intermediate-risk patients who plan on beginning a vigorous exercise program or working in a high-risk occupation (e.g., airline pilot) Atypical symptoms in patients with a high risk of IHD (i.e., diabetes or vascular disease patients) Patients with known CAD: Post-MI risk stratification (see section on ST-segment elevation MI) Preoperative risk assessment if it will change management before surgery Recurrent anginal symptoms despite medical therapy or revascularization Contraindications to stress testing Acute MI within 2 days Unstable angina (UA) not previously stabilized by medical therapy Cardiac arrhythmias causing symptoms or hemodynamic compromise Symptomatic severe aortic stenosis Symptomatic HF Acute pulmonary embolus, myocarditis, pericarditis, or aortic dissection Stress Modalities Exercise stress testing The stress modality of choice for evaluating most patients of intermediate risk for CAD (see Table 4-2). Bruce protocol: Consists of 3-minute stages of increasing treadmill speed and incline. BP, heart rate, and ECG are monitored throughout the study and the recovery period. The ECG portion of the study is considered positive if: New ST-segment depressions of >1 mm in multiple contiguous leads Hypotensive response to exercise Freemedicalbooks4download Sustained ventricular arrhythmias are precipitated by exercise The Duke Treadmill Score provides prognostic information for patients presenting with chronic angina (Table 4-6). When exercise testing is combined with imaging (e.g., echocardiography), and the test is normal at the target heart rate for age, the risk of infarction or death from CVD is <1% annually in patients with no prior history of IHD. In patients who cannot exercise and require pharmacologic testing, the annual risk of infarction or death in a normal study doubles (i.e., 2% per year). This underscores the inability to perform physical activity as a marker of increased cardiovascular risk. Pharmacologic stress testing In patients who are unable to exercise, pharmacologic stress testing may be preferable. Pharmacologic stress testing is preferred in patients with left bundle branch block (LBBB) or a paced rhythm on ECG. This is due to the increased incidence of false-positive stress tests seen with either exercise or dobutamine infusion. Dipyridamole, adenosine, and regadenoson are vasodilators commonly used in conjunction with myocardial perfusion scintigraphy. Technically, these agents do not impose a physiologic stress. Relative ischemia across a coronary vascular bed is elucidated as healthy vessels dilate more than diseased vessels with fixed obstruction. This in turn leads to relative changes in perfusion that are reflected in the post-vasodilator images. Dobutamine is a positive inotrope commonly used with echocardiographic stress tests and may be augmented with atropine to achieve target heart rate for age. Stress testing with imaging Recommended for patients with the following baseline ECG abnormalities: Pre-excitation (Wolf–Parkinson–White syndrome) LVH LBBB or paced rhythm Intraventricular conduction delay Resting ST-segment or T-wave changes Patients unable to exercise or who do not have an interpretable ECG at rest or with exercise May be considered in patients with high pretest probability of IHD who have not met the threshold of invasive angiography Imaging Modalities Myocardial perfusion imaging (MPI): Both PET (positron emission tomography) and SPECT (single-photon emission tomography) use tracers that emit radiation detected by a camera in conjunction with exercise or pharmacologic stress. PET has better contrast and spatial resolution than SPECT, but PET is much more expensive and less widely available. Perfusion imaging compares rest perfusion to stress perfusion images to discern areas of ischemia or infarct. It can be limited by body habitus, breast attenuation, and the quality of the acquisition and processing of images. Severe CAD may cause balanced reduction in perfusion and an underestimation of ischemic burden. Echocardiographic imaging: Exercise or dobutamine stress testing can be performed with echocardiography to aid in the diagnosis of CAD. Echocardiography adds to the sensitivity and specificity of the test by revealing areas with wall motion abnormalities. The technical quality of this study can be limited by imaging quality (i.e., obesity). Magnetic resonance perfusion imaging: MRI sequences obtained with contrast and vasodilator stress testing (and very rarely exercise testing) provides viability assessment without additional testing, as well as evaluation for other causes of myocardial dysfunction that may mimic IHD (i.e., sarcoidosis or infiltrative cardiomyopathies). It can not be performed in certain patients with implanted cardiac devices (i.e., defibrillators and pacemakers). Freemedicalbooks4download TABLE 4-5 Diagnostic Accuracy of Common Stress Testing Modalities in Patients Without Known Ischemic Heart Disease Test Type ECG Exercise Sensitivity Specificity 61% 70%–77% Pharmacologic Echocardiography Exercise — — 70%–85% 77%–89% Pharmacologic 85%–90% (dobutamine) Nuclear Perfusion Imaging Exercise 82%–88% 79%–90% 70%–88% Advantages Disadvantages Easy to perform Inexpensive Less diagnostic accuracy, especially in women No viability assessment Gather other important information on diastolic function, valvular disorders, and pulmonary pressures Can assess viability with pharmacologic stress Limited by image quality Diagnostic accuracy reduced with resting wall motion abnormalities More sensitive for small areas of ischemia/infarct Very accurate ejection fraction assessment Easy to compare to prior studies Significant radiation May underestimate severe balanced ischemia No other valve or other structural information Viability may require separate testing Pharmacologic (adenosine, regadenoson, or dobutamine) Cardiac MRI Exercise 82%–91% 75%–90% — — Excellent assessment of viability Anatomic detail of heart and great vessels is outstanding Expensive Requires closed MRI Exercise option not typically available Pharmacologica 91% 81% All diagnostic accuracies unadjusted for referral bias.1,2 a Vasodilator stress only; dobutamine has sensitivity of 83% and specificity of 86%. TABLE 4-6 Exercise Stress Testing: Duke Treadmill Score Duke Treadmill Score (DTS) = Minutes exercised − [5 × maximum STsegment deviation] − [4 × angina score]. Angina score: 0 = none, 1 = not test limiting, 2 = test limiting DTS 5 Annual Low-risk mortality study 0.25% −10 to 4 Annual Intermediatemortality risk study 1.25% <–10 Annual High-risk mortality study >5% In general, β-blockers, other nodal blocking agents, and nitrates should be discontinued before stress testing.82 Freemedicalbooks4download Diagnostic Procedures Coronary angiography The gold standard for evaluating epicardial coronary anatomy because it quantifies the presence and severity of atherosclerotic lesions, which has prognostic value. Coronary angiography is invasive and associated with a small risk of death, MI, CVA, bleeding, arrhythmia, and vascular complications. Therefore, it is reserved for patients whose risk–benefit ratio favors an invasive approach such as: ST-segment elevation MI (STEMI) patients Most UA/non–ST-segment elevation MI (NSTEMI) patients Symptomatic patients with high-risk stress tests who are expected to benefit from revascularization Class III and IV angina despite medical therapy (see Table 4-1) Survivors of sudden cardiac death or those with serious ventricular arrhythmias Signs or symptoms of HF or decreased LV function Angina that is inadequately controlled with medical therapy for the patient’s lifestyle Previous coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) Suspected/known left main (≥50% stenosis) or severe threevessel CAD To diagnose CAD in patients with angina who have not undergone stress testing because of a high pretest probability of having CAD (see Table 4-2) It can be both diagnostic and therapeutic if PCI is needed. It can be used to evaluate patients who are suspected of having a nonatherosclerotic cause of ischemia (e.g., coronary anomaly, coronary dissection, radiation vasculopathy). Intravascular ultrasound can be used to directly visualize plaque burden and plaque anatomy. Functional significance of intermediate stenotic lesions (50%–70% narrowing) can further be assessed by fractional flow reserve (FFR) or instantaneous wave-free ratio (iFR) Both FFR and iFR are calculated by determining the ratio of pressure distal to the coronary obstruction to that of the aortic pressure (flow) using slightly different methods. An FFR ≤0.8 or iFR ≤0.89 is considered flow limiting, and PCI decreases the need for urgent revascularization for UA or MI, as well as risk of recurrent MI.9 Whether PCI in stable IHD improves cardiovascular outcomes or symptoms compared to medical therapy is controversial.10 Measurement of LV filling pressures (diastolic function) and aortic and mitral valve gradients, assessment of regional wall motion and LV function, and assessment for certain aortopathies can be accomplished by placing a catheter in the LV cavity or aorta directly and making the appropriate pressure measurements and/or injection of contrast. Contrast-induced nephropathy (CIN) occurs after 24–48 hours in up to 5% of patients undergoing coronary angiography. In most patients, creatinine returns to baseline within 7 days. The following are considerations in the prevention of CIN: The volume of contrast media used should be minimized. All patients should receive some CIN prophylactic therapy: oral hydration, IV hydration, held IV diuretics, and statin therapy have proven benefit. We recommend a 3 mL/kg bolus of normal saline at least 6 hours before the procedure with a 1-mg/kg continuous infusion rate until start of procedure. N-Acetyl-l-cysteine has no advantage over simple hydration for prevention of CIN. National Cardiovascular Data Registry Acute Kidney Injury (NCDR AKI) Risk Model is a robust risk stratification tool for acute kidney injury and the need for hemodialysis after cardiac catheterization (Table 4-7).11 Coronary CT Angiography A noninvasive technique used to establish a diagnosis of CAD. Like Freemedicalbooks4download cardiac angiography, it exposes the patient to both radiation and contrast material. Uses arterial phase contrast CT images to evaluate coronary stenosis. Where available, a proprietary software package can calculate intracoronary hemodynamics akin to FFR. CT has a high negative predictive value; it is better suited to rule out diseases for symptomatic patients with a low pretest probability for CAD, such as a patient with repeated emergency room admissions for chest pain or patients with equivocal stress test results. Trials such as PROMISE and SCOT-HEART indicate no advantage to CT over functional stress testing (e.g., MPI) for prediction of major adverse cardiovascular events among patients with an intermediate risk of IHD.12,13 May aid in the identification of congenital anomalies of the coronary arteries. Because of diminished study quality, it is not useful in patients with extensive coronary calcification (e.g., elderly or advanced CKD), coronary stents, or small-caliber vessels. TABLE 4-7 NCDR AKI Risk Model: Risk of AKI and AKI Resulting in HD in Patients Undergoing PCI Points Risk Conversion AKI AKI+HD Variables 5 Age ≤50 50–59 60–69 70–79 80–89 >90 Heart failure within 2 wk GFR ≤30 GFR 31–44 GFR 45–59 Diabetes mellitus Any prior heart failure 0 2 4 6 8 10 11 18 8 3 7 4 2 5 3 1 1 – Points Total 0 2.6 10 15 20 25 30 35 40 45 50 55 >60 Risk AKI (%) 1.9 7 3.6 4.9 6.7 9.2 12.4 16.5 21.7 27.9 35.1 43 51.4 Points Total ≤6 1.5 8 9 10 11 12 13 Risk HD (%) <1 2.6 4.4 7.6 12.6 20.3 31.0 Any prior cerebrovascular 4 – disease/stoke Anemia (Hgb <10 g/dL) 10 – NSTEMI/UA presentation 6 1 STEMI presentation 15 2 Shock before procedure 16 – Cardiac arrest before procedure 8 3 IABP use 11 – Points are determined by the points column and total points are converted to risk in the risk conversion column. AKI, acute kidney injury; GFR, glomerular filtration rate; HD, hemodialysis; Hgb, hemoglobin; IABP, intra-aortic balloon counterpulsation; NCDR, National Cardiovascular Data Registry; NSTEMI, non–STsegment elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction; UA, unstable angina. GFR calculated using the Modification of Diet in Renal Disease (MDRD) formula; AKI defined as at least a ≥0.3 mg/dL increase or ≥1.5-fold relative increase in creatinine after procedure or initiation of dialysis (HD) after procedure. Patients were excluded if on dialysis at the time of the procedure. Freemedicalbooks4download Treatment The major goal of treatment is to reduce symptoms. An absolute reduction in incidence of MI or cardiac death in patients with stable IHD is accomplished mainly through medical therapy and not revascularization. A combination of lifestyle modification, medical therapy, and coronary revascularization can be used. A recommended strategy for the evaluation and management of the patient with stable angina can be found in Figure 4-1. Medical treatment is aimed at improving myocardial oxygen supply, reducing myocardial oxygen demand, controlling exacerbating factors (e.g., anemia), and limiting the development of further atherosclerotic disease. Medical treatment often is sufficient to control anginal symptoms in chronic stable angina. FIGURE 4.1 Approach to the evaluation and management of the patient with stable angina. Patients with clinical heart failure, severe limiting angina, and those with left ventricle (LV) dysfunction should undergo coronary angiography to define underlying coronary artery disease. Patients without these features may undergo further risk stratification with stress testing. Following stress testing, patients may undergo either coronary angiography or empiric medical therapy depending on their risk profile. Patients initially treated with medical therapy who have refractory symptoms should undergo angiography. 1CABG is generally preferred because of known survival advantage over medical therapy alone; however, if the coronary lesions are not complex, PCI may offer similar results to CABG but with a higher need for future Freemedicalbooks4download revascularizations. 2PCI should be reserved for patients who have high-grade lesions, have severe ischemia, and are refractory to medical therapy. CABG, coronary artery bypass grafting; CCS, Canadian Cardiovascular Society Classification (angina); NICM, nonischemic cardiomyopathy; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; WMA, wall motion abnormality. Medications Anti-ischemic therapy β-Adrenergic antagonists (Table 4-8) control anginal symptoms by decreasing heart rate and myocardial work, leading to reduced myocardial oxygen demand. β-Blockers with intrinsic sympathomimetic activity should be avoided. Dosage can be adjusted to result in a resting heart rate of 50– 60 bpm. Use with caution or avoid in patients with active bronchospasm, atrioventricular (AV) block, resting bradycardia, or poorly compensated heart failure (HF). Calcium channel blockers can be used either in conjunction with or in lieu of β-blockers in the presence of contraindications or adverse effects as a second-line agent (Table 4-9). Calcium antagonists are often used in conjunction with βblockers if the latter are not fully effective at relieving anginal symptoms. Both long-acting dihydropyridines and nondihydropyridine agents can be used. Calcium channel blockers are effective agents for the treatment of coronary vasospasm. Nondihydropyridine agents (verapamil/diltiazem) should be avoided in patients with systolic dysfunction because of their negative inotropic effects. Nitrates, either long-acting formulations for chronic use or sublingual/topical preparations for acute anginal symptoms, are more often used as adjunctive antianginal agents (Table 4-10). Sublingual preparations should be used at the first indication of angina or prophylactically before engaging in activities that are known to precipitate angina. Patients should seek prompt medical attention if angina occurs at rest or fails to respond to the third sublingual dose. Nitrate tolerance resulting in reduced therapeutic response may occur with all nitrate preparations. The institution of a Freemedicalbooks4download nitrate-free period of 10–12 hours (usually at night) can enhance treatment efficacy. For patients with CAD, nitrates have not shown a mortality benefit. Nitrates are contraindicated (even in patients with acute coronary syndrome [ACS]) for use in patients who are on phoshodiesterase-5 inhibitors due to risk of severe hypotension. A washout period of 24 hours for sildenafil and vardenafil and 48 hours for tadalafil is required before nitrate use. Ranolazine is indicated for angina refractory to standard medical therapy and has shown benefit in improving symptoms and quality of life. Ranolazine interacts with simvastatin metabolism and should not be used together. Secondary prevention medications Acetylsalicylic acid (ASA) (75–162 mg/d) reduces cardiovascular events, including repeat revascularization, MI, and cardiac death, by approximately 33%.14,15 ASA 81 mg appears to be sufficient for most patients (primary or secondary prevention for both IHD and CVA). ASA desensitization may be performed in patients with ASA allergy. Clopidogrel (75 mg/d) can be used in those allergic/intolerant of ASA. Angiotensin-converting enzyme inhibitors (ACE Inhibitors) and angiotensin receptor blockers (ARBs) have cardiovascular protective effects that reduce the recurrence of ischemic events. ACE inhibitor therapy, or ARBs in those intolerant to ACE inhibitors, should be used in all patients with an LV ejection fraction (LVEF) <40%, hypertension, diabetes, or CKD. It is reasonable to use ACE inhibitor in all stable angina patients. Statins have a marked effect in secondary prevention, and all patients with IHD who can tolerate therapy should be on a highpotency statin (see Chapter 3, Preventive Cardiology). In secondary prevention of coronary heart disease, statins have the most evidence demonstrating a robust mortality benefit. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors confer a mortality benefit to patients with IHD whose LDL levels remain >70 mg/dL despite high-intensity statins. Currently, expense and insurance coverage limit the use of this class of medications.16 Ezetimibe also improves cardiovascular outcomes among patients with IHD whose LDL remains >100 mg/dL despite high intensity statin therapy.17 Influenza vaccination is recommended for all patients with IHD. TABLE 4-8 β-Blockers Commonly Used for Ischemic Heart Disease Drug β-Receptor Selectivity Propranolol β1 and β2 Metoprolol β1 Atenolol β1 Nebivolol β1 Nadolol β1 and β2 Timolol β1 and β2 a Acebutolol β1 Bisoprolol β1 Esmolol (IV) β1 Labetalol Combined α, β1, β2 a Pindolol β1 and β2 Carvedilol Combined α, β1, β2 a β-blockers with intrinsic sympathomimetic activity. Dose 20–80 mg bid 50–200 mg bid 50–200 mg daily 5–40 mg daily 40–80 mg daily 10–30 mg tid 200–600 mg bid 10–20 mg daily 50–300 µg/kg per minute 200–600 mg bid 2.5–7.5 mg tid 3.125–25 mg bid TABLE 4-9 Calcium Channel Blockers Commonly Used for Ischemic Heart Disease Drug Dihydropyridines Nifedipine Amlodipine Felodipine (SR) Isradipine Nicardipine Nondihydropyridines Diltiazem Immediate release Duration of Action Usual Dosage Long Long Long Medium Short 30–180 mg/d 5–10 mg/d 5–10 mg/d 2.5–10 mg/d 20–40 mg tid Short 30–90 mg qid Freemedicalbooks4download Slow release Verapamil Immediate release Slow release Long 120–360 mg/d Short Long 80–160 mg tid 120–480 mg/d TABLE 4-10 Nitrate Preparations Commonly Used for Ischemic Heart Disease Preparation Sublingual nitroglycerin Aerosol nitroglycerin Oral isosorbide dinitrate Oral isosorbide mononitrate Oral isosorbide mononitrate SR 2% Nitroglycerin ointment Transdermal nitroglycerin patches Intravenous nitroglycerin Dosage 0.3–0.6 mg PRN 0.4 mg PRN 5–40 mg tid 10–20 mg bid 30–120 mg daily 0.5–2.0 in. tid 5–15 mg daily 10–200 µg/min Onset (min) 2–5 2–5 30–60 30–60 30–60 20–60 >60 <2 Duration 10–30 min 10–30 min 4–6 h 6–8 h 12–18 h 3–8 h 12 h During infusion Revascularization In general, medical therapy with at least two classes of antianginal agents should be attempted before medical therapy is considered a failure and coronary revascularization pursued in stable angina. Relief of angina symptoms is the most common objective of all revascularization procedures for stable angina. The indication for all revascularization procedures should consider the acuity of presentation, the extent of ischemia, and the ability to achieve full revascularization. The selection of revascularization should be tailored to the individual patient and, in complex cases, include the use of a multidisciplinary heart team. 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 or diabetes do better with CABG, whereas PCI in select patients with the proper coronary anatomy can provide comparable results as CABG.18 Owing to the more invasive nature of CABG, patient comorbidities often necessitate PCI for revascularization. The Syntax Score is a validated angiographic model that can aid the clinician in determining outcomes after PCI or CABG. In general, patients with a low or intermediate Syntax Score do as well or better with PCI compared to CABG (available at http://www.syntaxscore.com/).19 The Society of Thoracic Surgeons (STS) score can help determine the risk of mortality and morbidity associated with CABG and should be determined for all patients when considering surgical revascularization (available at http://riskcalc.sts.org/). Revascularization is shown to improve survival in the following circumstances as compared to medical therapy: CABG for >50% left main CAD that has not been grafted (unprotected). PCI is a reasonable alternative for patients with left main disease if the patient is a poor surgical candidate (STS score >5) and has a favorable morphology for PCI (low Syntax Score). PCI, in the right clinical context, can offer rates of MI, CVA, or death Freemedicalbooks4download similar to CABG.20 CABG for three-vessel disease or two-vessel disease that includes the proximal left anterior descending (LAD) artery. CABG for patients with two-vessel disease not including the LAD artery if there is extensive ischemia (>20% myocardium at risk) or in patients with isolated proximal LAD artery disease when an internal mammary artery revascularization is performed. CABG, as compared to PCI or medical therapy, in patients with multivessel disease and diabetes, if a left internal mammary artery to the LAD artery can be placed. PCI may offer similar survival outcomes in diabetics with multivessel disease and a low Syntax Score (<22) but does have a higher need for repeat revascularization.21,22 PCI or CABG in patients who have survived sudden cardiac death due to ischemic ventricular tachycardia (VT). PCI or CABG in patients with ACS. Owing to the morbidity of a repeat CABG, PCI is often used to improve symptoms in patients with recurrent angina after CABG. The use of internal mammary artery grafts is associated with 90% graft patency at 10 years, compared with 40%–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. The risks of elective PCI include <1% mortality, a 2%–5% rate of nonfatal MI, and <1% need for emergent CABG for an unsuccessful procedure. Patients undergoing PCI have shorter hospitalizations but require more frequent repeat revascularization procedures compared to CABG. Elderly patients represent a unique population when considering revascularization due to comorbidities, frailty, the physiology of aging as it relates to drug metabolism and cardiopulmonary function, and concern over polypharmacy. In general, this population has been underrepresented in most trials but still derives benefit from revascularization to relieve symptoms. Frailty should be heavily considered when considering a procedure or counseling about the benefits of revascularization. It is reasonable to revascularize selected patients with severe LV dysfunction (EF <35%), as evidenced by the long-term mortality benefit seen with CABG in the STICHES trial.23 Viability testing (nuclear perfusion imaging or MRI) may provide some assistance to the clinician when trying to determine the possible benefit of revascularization in patients with prior MI or severe LV dysfunction, but it is still largely unproven. Freemedicalbooks4download Patient Education Compliance with medications, diet, and exercise should be stressed to patients. All patients should be encouraged to participate in cardiac rehab as well as meet with a registered dietician. Patients with known CAD should present for evaluation if any change in chest pain pattern, frequency, or intensity develops. Patients should also be reevaluated if they report the presence of any HF symptoms. Monitoring/Follow-Up Close patient follow-up is a critical component of the treatment of CAD because lifestyle modification and secondary risk factor reduction require serial reassessment and interventions. All patients should be aggressively treated for the traditional risk factors mentioned above. Relatively minor changes in anginal symptoms can be safely treated with titration and/or addition of antianginal medications. Significant changes in anginal complaints (frequency, severity, or time to onset with activity) should be evaluated by either stress testing (usually in conjunction with an imaging modality) or cardiac angiography as warranted. Cardiac rehabilitation or an exercise program should be offered or instituted. Freemedicalbooks4download Acute Coronary Syndromes, Unstable Angina, and Non–ST-Segment Elevation Myocardial Infarction General Principles Definition NSTEMI and UA are closely related conditions whose pathogenesis and clinical presentations are similar but differ in severity. If coronary flow is not severe enough or the occlusion does not persist long enough to cause myocardial necrosis (as indicated by positive cardiac biomarkers), the syndrome is labeled UA. NSTEMI is defined by an elevation of cardiac biomarkers and the absence of ST-segment elevation on the ECG. NSTEMI, like STEMI, can lead to cardiogenic shock. AHA/ACC guidelines provide a more thorough overview of NSTEMI/UA.24 Epidemiology The annual incidence of acute coronary syndrome (ACS) is >780,000 events, with 70% being NSTEMI/UA. Among patients with ACS, approximately 60% have UA and 40% have MI (one-third of MIs present with an acute STEMI). At 1 year, patients with UA/NSTEMI are at considerable risk for death (∼6%), recurrent MI (∼11%), and need for revascularization (∼50%– 60%). It is important to note that although the short-term mortality of STEMI is greater than that of NSTEMI, the long-term mortality is similar.24 Patients with NSTEMI/UA tend to have more comorbidities, both cardiac and noncardiac, than STEMI patients. Women with NSTEMI/UA have worse short-term and long-term outcomes and more complications compared to men. Much of this has been attributed to delays in recognition of symptoms and underutilization of guideline-directed medical therapy and invasive management.25 Freemedicalbooks4download Etiology and Pathophysiology Myocardial ischemia results from decreased myocardial oxygen supply and/or increased demand. In the majority of cases, NSTEMI is due to a sudden decrease in blood supply via partial occlusion of the affected vessel. In some cases, markedly increased myocardial oxygen demand may lead to NSTEMI (demand ischemia), as seen in severe anemia, hypertensive crisis, acute decompensated HF, surgery, or any other significant physiologic stressor. UA/NSTEMI most often represents severe coronary artery narrowing or acute atherosclerotic plaque rupture/erosion and superimposed thrombus formation. Alternatively, it may also be due to progressive mechanical obstruction from advancing atherosclerotic disease, in-stent restenosis, or bypass graft disease. Plaque rupture may be triggered by local and/or systemic inflammation as well as shear stress. Rupture allows exposure of lipid-rich subendothelial components to circulating platelets and inflammatory cells, serving as a potent substrate for thrombus formation. A thin fibrous cap (thin-cap fibroatheroma) is felt to be more vulnerable to rupture and is most frequently represented as only moderate stenosis on angiography. Less common causes include dynamic obstruction of the coronary artery due to vasospasm (Prinzmetal angina, cocaine), coronary artery dissection (more common in women), coronary vasculitis, and embolus. DIAGNOSIS Clinical Presentation History ACS symptoms include all the qualities of typical angina except the episodes are more severe, of longer duration, and may occur at rest. The three principal presentations for UA are rest angina (angina occurring at rest and prolonged, usually >20 minutes), new-onset angina, and progressive angina (previously diagnosed angina that has become more frequent, lasts longer, or occurs with less exertion). New-onset and progressive angina should occur with at least mild to moderate activity, CCS class III severity. Female sex, diabetes, HF, end-stage kidney disease, and older age are traits that have been associated with a greater likelihood of atypical ACS symptoms. However, the most common presentation in these populations is still typical anginal chest pain. Jaw, neck, arm, back, or epigastric pain and/or dyspnea can be anginal equivalents. Pleuritic pain, pain that radiates down the legs or originates in the mid/lower abdomen, pain that can be reproduced by extremity movement or palpation, and pain that lasts seconds in duration are unlikely to be related to ACS. Freemedicalbooks4download Physical Examination Physical examination should be directed at identifying hemodynamic instability, pulmonary congestion, and other causes of acute chest discomfort. Objective evidence of HF including peripheral hypoperfusion, heart murmur (particularly MR murmur), elevated jugular venous pulsation, pulmonary edema, hypotension, and peripheral edema worsens the prognosis. Killip classification can be useful to risk stratify and identify patients with features of cardiogenic shock (Table 4-11). Examination may also give clues to other causes of ischemia such as thyrotoxicosis or aortic dissection (see Table 4-4). TABLE 4-11 Killip Classification Class I II III IV Definition No signs or symptoms of heart failure Heart failure: S 3 gallop, rales, or JVD Severe heart failure: pulmonary edema Cardiogenic shock: SBP <90 mm Hg and signs of hypoperfusion and/or signs of severe heart failure a In-hospital mortality of patients in 1965–1967 with no reperfusion therapy (n = 250).83 JDV, jugular venous distention; SBP, systolic blood pressure. Mortality a 6% 17% 38% 81% Diagnostic Testing Electrocardiography Before or immediately on arrival to the emergency department, a baseline ECG should be obtained in all patients with suspected ACS. A normal tracing does not exclude the presence of disease. The presence of Q waves, ST-segment changes, or T-wave inversions is suggestive of CAD. Isolated Q waves in lead III only are a normal finding. Serial ECGs should be obtained to assess for dynamic ischemic changes. Comparison to prior ECGs is important when evaluating an ECG for dynamic changes. The posterior circulation (i.e., circumflex coronary artery distribution) is poorly assessed with standard ECG lead placement and should always be considered when evaluating patients with ACS. Posterior placed leads or urgent echocardiography may more accurately assess the presence of ischemia when the suspicion is high. Approximately 50% of patients with UA/NSTEMI have significant ECG abnormalities, including transient ST-segment elevations, ST depressions, and T-wave inversions.24 ST-segment depression in two contiguous leads is a sensitive indicator of myocardial ischemia, especially if dynamic and associated with symptoms. The threshold value for abnormal J-point depression should be 0.5 mm in leads V2 and V3 and 1 mm in all other leads. ST-segment depression in multiple leads plus ST-segment elevation in aVR and/or V1 suggests ischemia due to multivessel or left main disease. Biphasic or deeply inverted T waves (>5 mm) with QT prolongation in leads V2 to V4 in the setting of stuttering chest pain within the past 24 hours suggests a critical lesion in the LAD artery distribution (Wellens Syndrome).26 Nonspecific ST-segment changes or T-wave inversions (those that do not meet voltage criteria) are nondiagnostic and unhelpful in the Freemedicalbooks4download management of acute ischemia but are associated with a higher risk for future cardiac events. Laboratories A complete blood count, basic metabolic panel, fasting glucose, and lipid profile should be obtained in all patients with suspected CAD. Other conditions may be found to be contributing to ischemia (e.g., anemia) or mimicking ischemia (e.g., hyperkalemia-related ECG changes) or may alter management (e.g., severe thrombocytopenia). Cardiac biomarkers are essential in the diagnosis of UA/NSTEMI and should be obtained in all patients who present with chest discomfort suggestive of ACS. Troponin is the recommended biomarker for assessment of myocardial necrosis. Troponin T and I assays are highly specific and sensitive markers of myocardial necrosis. Serum troponin levels are usually undetectable in normal individuals, and any elevation is considered abnormal. In patients with troponin below the detectable limit of the assay within 6 hours of the onset of pain, a second sample should be drawn 8–12 hours after symptom onset. MI size and prognosis are directly proportional to the magnitude of increase in troponin.27,28 Creatine kinase (CK)-MB is no longer a recommended marker for the initial diagnosis of NSTEMI. It lacks specificity because it is present in both skeletal and cardiac muscle cells. CK-MB may be a useful assay for detecting postinfarct ischemia because a fall and subsequent rise in enzyme levels suggests reinfarction if accompanied by recurrent ischemic symptoms or ECG changes. Brain natriuretic peptide (BNP) can be a useful biomarker of myocardial stress in patients with ACS, and elevations are associated with worse outcomes. Severe elevations of BNP in the setting of ACS in patients without known HF should raise concern for a large infarction and urgent angiography.29 Freemedicalbooks4download Treatment Acute treatment aims to reduce the symptoms of chest pain and risks of recurrent MI or death. Risk stratification can be helpful in determining the appropriate testing, pharmacologic interventions, and timing or need for coronary angiography. Risk of death or MI progression is elevated with the following highrisk ACS characteristics, which should prompt urgent coronary angiography (<2 hours) with the intent to revascularize: Recurrent/accelerating angina despite adequate medical therapy Signs or symptoms of new HF, pulmonary edema, or shock (high Killip Classification) New or worsening MR New LBBB VT Several clinical tools can estimate a patient’s risk of recurrent MI and cardiac mortality, such as the Thrombolysis in Myocardial Infarction (TIMI) and Global Registry of Acute Coronary Events (GRACE) risk scores. The TIMI risk score can be used to determine the risk of death or nonfatal MI up to 1 year after an ACS event (Figure 4-2). In the stabilized patient, two treatment strategies are available: the ischemia-driven approach (formerly termed conservative) versus the routine invasive approach (early defined as <24 hours of presentation or delayed >24 hours). The planned approach should always be individualized to the patient (Figure 4-3). All patients should receive aggressive antithrombotic, antiplatelet, and ischemic medical therapy no matter the final revascularization strategy. Table 4-12 summarizes the selection approach. In ACS, as opposed to stable IHD, a routine invasive approach with possible PCI has been shown to reduce the incidence of recurrent MI, hospitalizations, and death. In general, patients with ACS should undergo a routine invasive strategy unless it is clear that the risk outweighs the possible benefit in a given patient. In the ischemia-driven approach, if the patient does not develop high-risk ACS features, has normal subsequent cardiac biomarkers, has no dynamic ECG changes, and responds to medical therapy, a noninvasive stress test should be obtained for further risk stratification. Patients should be angina-free for at least 12 hours before stress testing. If a patient with positive cardiac biomarkers is selected for noninvasive testing, a submaximal or pharmacologic stress test 72 hours after the peak value may be performed. Coronary angiography is reserved for patients who develop high-risk ACS features, have a high-risk stress test, develop angina at low levels of stress, or are noted to have an LVEF <40%. In the routine invasive strategy, the patient is planned for a coronary angiography with the intent to revascularize. An early (<24 hours from presentation) invasive approach is recommended for patients with high-risk scores or other high-risk features (see Table 4-12). Refractory chest pain, hemodynamic instability, or serious ventricular arrhythmias are indications for an urgent/emergent invasive strategy similar to STEMI; this is not to be confused with a routine invasive strategy. An early invasive strategy is also warranted in low- or intermediaterisk patients with repeated ACS presentations despite appropriate therapy. A routine invasive strategy is not recommended for the following: Patients with severe comorbid illnesses such as advanced CKD, end-stage liver or lung disease, or metastatic/uncontrolled cancer whereby the benefits of the procedure are likely outweighed by the risk from the routine invasive procedure. Freemedicalbooks4download Acute chest pain with a low likelihood of ACS and negative biomarkers, especially in women. FIGURE 4.2 Fourteen-day rates of death, MI, or urgent revascularization from the TIMI 11B and ESSENCE trials based on increasing TIMI risk score. Coronary artery Freemedicalbooks4download disease (CAD) risk factors include family history of CAD, diabetes, hypertension, hyperlipidemia, and tobacco use. ASA, aspirin; LMWH, low–molecular-weight heparin; MI, myocardial infarction; TIMI, Thrombolysis in Myocardial Infarction; UFH, unfractionated heparin.76 Freemedicalbooks4download FIGURE 4.3 Diagnostic and therapeutic approach to patients presenting with acute coronary syndrome (ACS) focusing on antiplatelet and antithrombotic therapy. *Bivalirudin is an appropriate alternative to UFH and LMWH, or at time of PCI, patients on UFH may be switched to bivalirudin. †Choose either clopidogrel, ticagrelor, or prasugrel as the second antiplatelet agent. #Indicators of recurrent ischemia include worsening chest pain, increasing cardiac biomarkers, heart failure signs/symptoms, arrhythmia (VT/VF), and dynamic ECG changes. ASA, aspirin; CABG, coronary artery bypass grafting; CAD, coronary artery disease; EF, ejection fraction; glycoprotein IIb/IIIa inhibitor; LMWH, low–molecular-weight heparin; NSTEMI, non–ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; Rx, treatment; STEMI, ST-segment elevation myocardial infarction; UA, unstable angina; UFH, unfractionated heparin; VT/VF, ventricular tachycardia/ventricular fibrillation; WMA, wall motion abnormality.24,77 TABLE 4-12 Appropriate Selection of Routine Invasive Versus Ischemia-Driven Revascularization Strategy in Patients With NSTEMI/UA Immediate/urgent invasive (within 2 h) Refractory angina Worsening signs or symptoms of heart failure or mitral regurgitation Hemodynamic instability or shock Sustained VT or VF Ischemia-driven Low-risk score (TIMI ≤1 or GRACE <109) Low-risk biomarker-negative female patients Patient or clinician preference in the absence of high-risk features Early invasive (within 24 h) None of the above but a high-risk score (TIMI ≥3 or GRACE >140) Rapid rate of rise in biomarkers New or presumably new ST depressions Delayed invasive (24–72 h) None of the above but presence of diabetes Renal insufficiency (GFR <60) LV ejection fraction <40% Early postinfarction angina Prior PCI within 6 mo Prior CABG TIMI score ≥2 or GRACE score 109–140 and no indication for early invasive strategy CABG, coronary artery bypass graft; GFR, glomerular filtration rate; GRACE, Global Registry of Acute Coronary Events; LV, left ventricular; NSTEMI, non–ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; TIMI, Thrombolysis in Myocardial Infarction; UA, unstable angina; VF, ventricular fibrillation; VT, ventricular tachycardia. Medications Patients presenting with UA/NSTEMI should receive medications that reduce myocardial ischemia through reduction in myocardial oxygen demand, improvement in coronary perfusion, and prevention of further thrombus formation. This approach should include antiplatelet, anticoagulant, and antianginal medications. Supplemental oxygen should be provided if the patient is hypoxemic (<90%) or having difficulty in breathing. Routine use of oxygen is not needed and possibly harmful.30,31 Antiplatelet therapy Table 4-13 summarizes available agents and dosing recommendations for use in ACS. Early dual antiplatelet therapy (DAPT) with aspirin plus a P2Y12 inhibitor is strongly recommended for patients with NSTEMI/UA without a contraindication (e.g., uncontrolled severe bleeding, recent neuraxial surgery or trauma, recent hemorrhagic stroke, or intra-cranial or spinal metastases). DAPT should ideally be continued for 12 months from the index ACS event, regardless of whether revascularization is performed or not. See the 2016 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease for specific recommendations tailored to stent type, bleeding risk, and other considerations.32 Aspirin blocks platelet aggregation within minutes. A chewable 162–325-mg dose of ASA should be administered immediately at symptom onset or at first medical contact, unless a contraindication exists. This should be followed by ASA 81 mg daily indefinitely. If an ASA allergy is present, clopidogrel may be substituted. An allergy consultation should be obtained for possible desensitization, preferably before the need for a coronary stent. After PCI, ASA 81 mg is the current recommended dose in the Freemedicalbooks4download setting of DAPT. Clopidogrel is a prodrug whose metabolite blocks the P2Y12 receptor and inhibits platelet activation and aggregation by blocking the adenosine diphosphate receptor site on platelets. The addition of clopidogrel to ASA reduced cardiovascular mortality and recurrent MI both acutely and at 11 months of follow-up.33 A loading dose of 600 mg should always be given in naïve patients. In patients unable to take oral medications or unable to absorb oral medications because of ileus, rectal administration is unproven but has been reported. Alternatively, parenteral agents (e.g., cangrelor or eptifibatide), may be considered. It can be used as part of the protocol in both the ischemiadriven and routinely invasive strategies. Prasugrel is also a prodrug that blocks the P2Y12 adenosine receptor; its conversion to its active metabolite occurs faster and to a greater extent than clopidogrel. It results in faster, greater, and more uniform platelet inhibition compared to clopidogrel at the expense of higher risk of bleeding.34 It decreases risk of CVD death, MI, CVA, and acute stent thrombosis as compared to clopidogrel in ACS patients, including STEMI patients. It should be used with caution or avoided in patients older than 75 years and who weigh less than 60 kg. It is contraindicated in those with prior stroke or transient ischemic attack. It is used only in the invasive approach of ACS and only after coronary anatomy is known and PCI is planned. There is no benefit over clopidogrel when tested before the initiation of PCI. Ticagrelor is not a prodrug and blocks the P2Y12 adenosine receptor directly. It reduces the risk of death, MI, CVA, and stent thrombosis as compared to clopidogrel in ACS patients, including STEMI patients.35 After the loading dose of ASA, the maintenance dose of ASA must be <100 mg. It can be used as part of the protocol in both the ischemiadriven and early invasive strategies. Barring any contraindication, ticagrelor is the preferred P2Y12 inhibitor of choice because of the mortality advantage over medications in this class. The relative contraindications include baseline bradycardia, severe reactive airways disease, and prior hemorrhagic stroke. Cangrelor is a parenteral, direct, and reversible inhibitor of the P2Y12 adenosine rec