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

Epidemiology

• 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.³

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.

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 glucose (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 years or female relative before age 65 years
  • Measures for obesity, particularly central obesity; body mass index goal is between 18.5 and 24.9 kg/m²; waist circumference goal is <40 in for men and <35 in 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, high-sensitivity 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 40 years 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.

Prevention

Primary prevention: See Chapter 3, Preventive Cardiology.

Clinical Presentation

Differential Diagnosis

• A wide range of disorders may manifest with chest discomfort and may include both cardiovascular and noncardiovascular etiologies (Table 4-3 - Differential Diagnosis of Chest Pain Excluding Epicardial Atherosclerosis).
• A careful history focused on cardiac risk factors, physical exam, 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 - Conditions That May Provoke or Exacerbate Ischemia/Angina Independent of Worsening Atherosclerosis).

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.
  • A transthoracic echocardiogram (TTE) can be useful in determining 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.
  • Many stress testing modalities provide not only detection of ischemia/CAD but also prognostic information based on the burden of ischemia.
  • Table 4-5 - Diagnostic Accuracy of Common Stress Testing Modalities in Patients Without Known Ischemic Heart Disease 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 Disease¹⁰ for a comprehensive list of the indications for stress testing.
  • 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 prior to surgery
      • Recurrent anginal symptoms despite medical therapy or revascularization
• Contraindications to stress testing
  • Acute MI within 2 days
  • Unstable angina 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 - Pretest Probability of Coronary Artery Disease by Age, Gender, and Symptoms).
    • 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
      • Sustained ventricular arrhythmias are precipitated by exercise
    • The Duke Treadmill Score provides prognostic information for patients presenting with chronic angina (Table 4-6 - Exercise Stress Testing: Duke Treadmill Score¹¹).
    • 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 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. 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 postvasodilator 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:
    • Preexcitation (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 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). Can be performed in patients with implanted cardiac devices (i.e., defibrillators and pacemakers).

Medications

• Anti-ischemic therapy
  • β-Adrenergic antagonists (Table 4-7 - β-Blockers Commonly Used for Ischemic Heart Disease) 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 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 4-8 - Calcium Channel Blockers Commonly Used for Ischemic Heart Disease).
    • Calcium antagonists are often used in conjunction with β-blockers 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 due to 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 4-9 - Nitrate Preparations Commonly Used for Ischemic Heart Disease).
    • 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 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 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 prior to 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%.²⁰
    • ASA 81 mg appears to be sufficient for most patients.
    • ASA desensitization may be performed in patients with ASA allergy.
    • Clopidogrel (75 mg/d) can be used in those allergic or 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 with ACE inhibitors intolerance, should be used in all patients with an LVEF <40%, hypertension, diabetes, or chronic kidney disease.
  • Statins have a marked effect in secondary prevention, and all patients with IHD who can tolerate therapy should be on a high-potency 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.²¹
  • Ezetimibe also improves cardiovascular outcomes among patients with IHD whose LDL remains >100 mg/dL despite high-intensity statin therapy.²²
  • Influenza vaccination is recommended for all patients with IHD.

Revascularization

• Coronary 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.²³
    • 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 CABG²⁴ (available at http://www.syntaxscore.com/).
    • 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 similar to CABG.²⁵
    • 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.²⁶ 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.²⁷
    • PCI or CABG in patients who have survived sudden cardiac death due to ischemic ventricular tachycardia (VT).
  • Due 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.²⁸
  • 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 is still largely unproven.