Larisa H. Cavallari and Robert J. DiDomenico
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Identify risk factors for the development of ischemic heart disease (IHD).
2. Differentiate between the pathophysiology of chronic stable angina and acute coronary syndromes (ACSs).
3. Recognize the symptoms and diagnostic criteria of IHD in a specific patient.
4. Identify the treatment goals of IHD and appropriate lifestyle modifications and pharmacologic therapy to address each goal.
5. Design an appropriate therapeutic regimen for the management of IHD based on patient-specific information.
6. Formulate a monitoring plan to assess effectiveness and adverse effects of an IHD drug regimen.
KEY CONCEPTS
Ischemic heart disease (IHD) results from an imbalance between myocardial oxygen demand and oxygen supply that is most often due to coronary atherosclerosis. Common clinical manifestations of IHD include chronic stable angina and the acute coronary syndromes (ACSs) of unstable angina, non-ST-segment elevation myocardial infarction (MI), and ST-segment elevation MI.
Early detection and aggressive modification of risk factors is one of the primary strategies for delaying IHD progression and preventing IHD-related events including death.
Patients with chest pressure or heaviness that is provoked by activity and relieved with rest should be assessed for IHD. Sharp pain is not a typical symptom of IHD. Some patients may experience discomfort in the neck, jaw, shoulder, or arm rather than, or in addition to, the chest. Pain may be accompanied by nausea, vomiting, or diaphoresis.
The major goals for the treatment of IHD are to prevent ACSs and death, alleviate acute symptoms of myocardial ischemia, prevent recurrent symptoms of myocardial ischemia, and avoid or minimize adverse treatment effects.
Both 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and angiotensin-converting enzyme (ACE) inhibitors are believed to provide vasculoprotective effects, and in addition to antiplatelet agents, have been shown to reduce the risk of acute coronary events and death in patients with IHD. Angiotensin receptor blockers (ARBs) may be used in patients who cannot tolerate ACE inhibitors because of side effects (e.g., chronic cough). β-Blockers have been shown to decrease morbidity and improve survival in patients who have suffered a MI.
Antiplatelet therapy with aspirin should be considered for all patients without contraindications, particularly in patients with a history of MI. Clopidogrel may be considered in patients with allergies or intolerance to aspirin. In some patients, combination antiplatelet therapy with aspirin and clopidogrel may be used.
To control risk factors and prevent major adverse cardiac events, statin therapy should be considered in all patients with IHD, particularly in those with elevated low-density lipoprotein cholesterol. In the absence of contraindications, ACE inhibitors should be considered in IHD patients who also have diabetes mellitus, left ventricular dysfunction, history of MI, or any combination of these. Angiotensin receptor blockers maybe used in patients who cannot tolerate ACE inhibitors because of side effects.
All patients with a history of angina should have sublingual nitroglycerin tablets or spray to relieve acute ischemic symptoms. Patients should be instructed to use one dose (tablet or spray) every 5 minutes until pain is relieved and to call 911 if pain is unimproved or worsens 5 minutes after the first dose.
β-Blockers are first-line therapy for preventing ischemic symptoms, particularly in patients with a history of Ml Long-acting calcium channel blockers and long-acting nitrates maybe added for refractory symptoms or substituted if a β-blocker is not tolerated.
Patients should be monitored to assess for drug effectiveness, adverse drug reactions, and potential drug-drug interactions. Patients should be assessed for adherence to their pharmacotherapeutic regimens and lifestyle modifications.
INTRODUCTION
Ischemic heart disease (IHD) is also called coronary heart disease (CHD) or coronary artery disease. The term “ischemic” refers to a decreased supply of oxygenated blood, in this case to the heart muscle. IHD is caused by the narrowing of one or more of the major coronary arteries that supply blood to the heart, most commonly by atherosclerotic plaques. Atherosclerotic plaques may impede coronary blood flow to the extent that cardiac tissue distal to the site of the coronary artery narrowing is deprived of sufficient oxygen in the face of increased oxygen demand. IHD results from an imbalance between myocardial oxygen supply and oxygen demand (Fig. 7–1). Common clinical manifestations of IHD include chronic stable angina and the acute coronary syndromes (ACSs) of unstable angina, non-ST-segment elevation myocardial infarction (MI), and ST-segment elevation MI.
Angina pectoris, or simply angina, is the most common symptom of IHD. Angina is discomfort in the chest that occurs when the blood supply to the myocardium is compromised. Chronic stable angina is defined as a chronic and predictable occurrence of chest discomfort due to transient myocardial ischemia with physical exertion or other conditions that increase oxygen demand. The primary focus of this chapter is on the management of chronic stable angina. However, some information is also provided related to ACS, given the overlap between the two disease states. The American College of Cardiology and the American Heart Association have jointly published practice guidelines for the management of patients with chronic stable angina, and the reader is referred to these guidelines for further information.1,2
EPIDEMIOLOGY AND ETIOLOGY
IHD affects over 16 million Americans and is the leading cause of death for both men and women in the United States.3 The incidence of IHD is higher in middle-aged men compared to women. However, the rate of IHD increases two-to threefold in women after menopause. Chronic stable angina is the initial manifestation of IHD in about 50% of patients, whereas unstable angina or MI is the first sign of IHD in other patients. Chronic stable angina is associated with considerable patient morbidity, with many affected patients eventually requiring hospitalization for ACS. In addition, chronic stable angina has a major negative impact on health-related quality of life. Thus, in patients with chronic stable angina, it is important to optimize pharmacotherapy to reduce symptoms, improve quality of life, slow disease progression, and prevent ACS.
FIGURE 7–1. This illustration depicts the balance between myocardial oxygen supply and demand and the various factors that affect each. It should be noted that diastolic filling time is not an independent predictor of myocardial oxygen supply per se, but rather a determinant of coronary blood flow. On the left is myocardial oxygen supply and demand under normal circumstances. On the right is the mismatch between oxygen supply and demand in patients with IHD. In patients without IHD, coronary blood flow increases in response to increases in myocardial oxygen demand. However, in patients with IHD, coronary blood flow cannot sufficiently increase (and may decrease) in response to increased oxygen demand resulting in angina. (IHD, ischemic heart disease; Po2, partial pressure of oxygen.)
Conditions Associated With Angina
Figure 7–2 shows the anatomy of the coronary arteries. The major epicardial coronary arteries are the left main, left anterior descending, left circumflex, and right coronary arteries. Atherosclerosis involving one or more of the major coronary arteries or their principal branches is the major cause of angina. Vasospasm at the site of an atherosclerotic plaque may contribute to angina by further restricting blood supply to the distal myocardium. Less commonly, vasospasm in coronary arteries with no or minimal atherosclerotic disease can produce angina and even precipitate ACS. This type of vasospasm is referred to as variant or Prinzmetal angina. Other nonatherosclerotic conditions that can cause angina-like symptoms are listed in Table 7–1. It is important to differentiate the etiology of chest discomfort since treatment varies depending on the underlying disease process.
FIGURE 7–2. Coronary artery anatomy with sternocostal and diaphragmatic views. (Reproduced from Talbert RL Ischemic heart disease. In: DiPiro JT, Talbert RL, Yee GC, et al. (eds.) Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York: McGraw-Hill; 2005: 263, with permission.)
Risk Factors
Factors that predispose an individual to IHD are listed in Table 7–2. Hypertension, diabetes, dyslipidemia, and cigarette smoking are associated with endothelial dysfunction and potentiate atherosclerosis of the coronary arteries. The risk for IHD increases twofold for every 20 mm Hg increment in systolic blood pressure and up to eightfold in the presence of diabetes.4,5 Physical inactivity and obesity independently increase the risk for IHD, in addition to predisposing individuals to other cardiovascular risk factors, namely hypertension, dyslipidemia, and diabetes.
Table 7–1 Nonatherosclerotic Conditions That Can Cause Angina-Like Symptoms
Table 7–2 Major Risk Factors for Ischemic Heart Disease
Patients with multiple risk factors, particularly those with diabetes, are at the greatest risk for IHD. While there are alternative definitions for metabolic syndrome, it is generally considered as a constellation of cardiovascular risk factors related to hypertension, abdominal obesity, dyslipidemia, and insulin resistance. Metabolic syndrome increases the risk of developing IHD and related complications by twofold.6According to the American Heart Association, patients must meet at least three of the following criteria for the diagnosis of metabolic syndrome7:
• Increased waist circumference (more than or equal to 40 inches or 102 centimeters in males and more than or equal to 35 inches or 89 centimeters in females).
• Triglycerides of 150 mg/dL (1.70 mmol/L) or greater or active treatment to lower triglycerides.
• Low high-density lipoprotein (HDL) cholesterol (less than 40 mg/dL or 1.04 mmol/L in males and less than 50 mg/dL or 1.3 mmol/L in females) or active treatment to raise HDL cholesterol.
• Systolic blood pressure of 130 mm Hg or greater, diastolic blood pressure of 85 mm Hg or greater, or active treatment with antihypertensive therapy.
• Fasting blood glucose of 100 mg/dL (5.55 mmol/L) or greater or active treatment for diabetes.
Early detection and aggressive modification of risk factors are among the primary strategies for delaying IHD progression and preventing IHD-related events including death.
PATHOPHYSIOLOGY
The determinants of oxygen supply and demand are shown in Figure 7–1. Increases in heart rate, cardiac contractility, and left ventricular wall tension increase the rate of myocardial oxygen consumption (MVO2). Ventricular wall tension is a function of blood pressure, left ventricular end-diastolic volume, and ventricular wall thickness. Physical exertion increases MVO2 and commonly precipitates symptoms of angina in patients with significant coronary atherosclerosis. Medications that reduce heart rate, cardiac contractility, and/or ventricular wall tension are commonly prescribed to prevent ischemic symptoms in chronic stable angina.
Reductions in coronary blood flow (secondary to atherosclerotic plaques, vasospasm, or thrombus formation) and arterial oxygen content (secondary to hypoxia) decrease myocardial oxygen supply. Because the coronary arteries fill during diastole, decreases in diastolic filling time (e.g., tachycardia) can also reduce coronary perfusion and myocardial oxygen supply. In chronic stable angina, atherosclerotic plaques are the most common cause of coronary artery narrowing and reductions in coronary blood flow. In contrast, in ACS, disruption of an atherosclerotic plaque with subsequent thrombus (blood clot) formation causes abrupt reductions in coronary blood flow and oxygen supply. Anemia, carbon monoxide poisoning, and cyanotic congenital heart disease are examples of conditions that reduce the oxygen-carrying capacity of the blood, potentially causing ischemia in the face of adequate coronary perfusion. Interventional procedures to compress, cut away, or bypass atherosclerotic plaques are effective methods of improving myocardial oxygen supply in patients with IHD.
Coronary Atherosclerosis
The normal arterial wall is illustrated in Figure 7–3A. The intima consists of a layer of endothelial cells that line the lumen of the artery and form a selective barrier between the vessel wall and blood contents. Vascular smooth muscle cells are found in the media. The vascular adventitia comprises the artery’s outer layer. Atherosclerotic lesions form in the subendothelial space in the intimal layer.
Endothelial dysfunction allows low-density lipoprotein (LDL) cholesterol and inflammatory cells (e.g., monocytes and T lymphocytes) to migrate from the plasma to the subendothelial space, as illustrated in Figure 12–5 in the Dyslipidemias chapter. Monocyte-derived macrophages ingest lipoproteins to form foam cells. Macrophages also secrete growth factors that promote smooth muscle cell migration from the media to the intima. A fatty streak consisting of lipid-laden macrophages and smooth muscle cells is formed. The fatty streak is the earliest type of atherosclerotic lesion.
The fatty streak enlarges as foam cells, smooth muscle cells, and necrotic debris accumulate in the subendothelial space. A collagen matrix forms a fibrous cap that covers the lipid core of the lesion to establish an atherosclerotic plaque. The atherosclerotic plaque may progress until it protrudes into the artery lumen and impedes blood flow. When the plaque occludes 70% or more of a major coronary artery or 50% or more of the left main coronary artery, the patient may experience angina during activities that increase myocardial oxygen demand.
Stable Versus Unstable Atherosclerotic Plaques
The hallmark feature in the pathophysiology of chronic stable angina is an established atherosclerotic plaque that impedes coronary blood flow to the extent that myocardial oxygen supply can no longer meet increases in myocardial oxygen demand. In contrast, the hallmark feature in the pathophysiology of ACS is atherosclerotic plaque rupture with subsequent thrombus formation. Plaque rupture refers to Assuring of the fibrous cap and exposure of the plaque contents to elements in the blood. Plaque composition, rather than the degree of coronary stenosis, determines the stability of the plaque and the likelihood of rupture and ACS. As depicted in Figure 7–3B, a stable lesion characteristic of chronic stable angina consists of a small lipid core that is surrounded by a thick fibrous cap that protects the lesion from the shear stress of blood flow. In contrast, an unstable plaque consists of a thin, weak cap in combination with a large, rich lipid core that renders the plaque vulnerable to rupture (Fig. 7–3C). The transformation of a stable plaque into an unstable plaque involves the degradation of the fibrous cap by substances released from macrophages and other inflammatory cells. Following plaque rupture, platelets adhere to the site of rupture, aggregate, and generate thrombin and a fibrin clot (Fig. 7–3D–F). Coronary thrombi extend into the vessel lumen, where they either partially or completely occlude blood flow, resulting in unstable angina or ML.
FIGURE 7–3. Pathophysiology of chronic stable angina versus acute coronary syndromes. A depicts the cross section of a normal coronary artery. B depicts the cross section of a coronary artery with a stable atherosclerotic plaque. Note that the lipid core is relatively small in size and the fibrous cap is made up of several layers of smooth muscle cells. C depicts an unstable atherosclerotic plaque with a larger lipid core, and a thin fibrous cap comprised of a single layer of smooth muscle cells with a fissure or rupture. D depicts platelet adhesion in response to the fissured plaque. Platelet activation may ensue leading to platelet aggregation as fibrinogen binds platelets to one another to form a meshlike occlusion in the coronary lumen (E). At this stage, patients may experience symptoms of acute coronary syndrome. If endogenous anticoagulant proteins fail to halt this process, platelet aggregation continues and fibrinogen is converted to fibrin, resulting in an occlusive thrombus (F).
An unstable plaque often produces minimal occlusion of the coronary vessel, and the patient remains asymptomatic until the plaque ruptures. In fact, the majority of MIs arise from vulnerable plaques that occlude less than 50% of the coronary lumen.8 As a result, unstable angina or MI is the initial manifestation of IHD in about one-half of affected patients.
Coronary Artery Vasospasm
Prinzmetal or variant angina results from spasm (or contraction) of a coronary artery in the absence of significant atherosclerosis. Variant angina usually occurs at rest, especially in the early morning hours. While vasospasm is generally transient, in some instances vasospasm may persist long enough to infarct the myocardium. Patients with variant angina are typically younger than those with chronic stable angina and often do not possess the classic risk factors for IHD. The cause of variant angina is unclear but appears to involve endothelial dysfunction and paradoxical response to agents that normally cause vasodilation. Precipitants of variant angina include cigarette smoking, cocaine use, hyperventilation, and exposure to cold temperatures. The management of variant angina differs from that of classic angina, and thus it is important to distinguish between the two.
CLINICAL PRESENTATION AND DIAGNOSIS
History
The evaluation of a patient with suspected IHD begins with a detailed history of symptoms. The classic presentation of angina is described in the Clinical Presentation and Diagnosis box. Chronic stable angina should be distinguished from unstable angina since the latter is associated with a greater risk for MI and death and requires more aggressive treatment. Because the pathophysiology of chronic stable angina is due primarily to increases in oxygen demand, rather than acute changes in oxygen supply, symptoms are typically reproducible. Specifically, a patient with angina secondary to significant coronary atherosclerosis will generally experience a similar pattern of discomfort (i.e., same quality, location, and accompanying symptoms) with a similar level of exertion with each angina attack. The exception maybe a patient with coronary artery vasospasm, in whom symptoms maybe more variable and unpredictable. In contrast to chronic stable angina, ACS is due to an acute decrease in coronary blood flow leading to insufficient oxygen supply. Consequently, ACS is marked by prolonged symptoms, symptoms that occur at rest, or an escalation in the frequency or severity of angina over a short period of time. The presentation of unstable angina is described in Table 7–3.9
Clinical Presentation and Diagnosis of Ischemic Heart Disease
General
• Patients with chronic stable angina will generally be in no acute distress. In patients presenting in acute distress, the clinician should be suspicious of ACS.
Symptoms of Angina Pectoris
• The five components commonly used to characterize chest pain are quality, location, and duration of pain; factors that provoke pain; and factors that relieve pain.
• Patients typically describe pain as a sensation of pressure, heaviness, or squeezing in the anterior chest area. Sharp pain is not a typical symptom of IHD.
• Pain may radiate to the neck, jaw, shoulder, back, or arm.
• Pain may be accompanied by dyspnea, nausea, vomiting, or diaphoresis.
• Symptoms are often provoked by exertion (e.g., walking, climbing stairs, and doing yard-or housework) or emotional stress and relieved within minutes by rest or sublingual nitroglycerin. Other precipitating factors include exposure to cold temperatures and heavy meals. Pain that occurs at rest (without provocation) or that is prolonged and unrelieved by sublingual nitroglycerin is indicative of an ACS.
• Some patients, most commonly women and patients with diabetes, may present with atypical symptoms including indigestion, gastric fullness, and shortness of breath. Patients with diabetes may experience associated symptoms, such as dyspnea and diaphoresis, without having any of the classic chest pain symptoms
• In some cases, ischemia may not produce any symptoms and is termed “silent ischemia.”
Signs
• Findings on the physical exam are often normal in patients with chronic stable angina. However, during episodes of ischemia, patients may present with abnormal heart sounds, such as paradoxical splitting of the second heart sound, a third heart sound, or a loud fourth heart sound.
Laboratory Tests
• Cardiac enzymes (creatine kinase [CK], CK-MB fraction, troponin I and troponin T) are elevated in Ml (ST-segment elevation Ml and non-ST-segment elevation Ml), but normal in chronic stable angina and unstable angina.
• Hemoglobin, fasting glucose, and fasting lipid profile should be determined for assessing cardiovascular risk factors and establishing the differential diagnosis.
Other Diagnostic Tests
• A 12-lead ECG recorded during rest is often normal in patients with chronic stable angina in the absence of active ischemia. Significant Q waves indicate prior Ml. ST-segment or T-wave changes in two or more contiguous leads during symptoms of angina support the diagnosis of IHD. ST-segment depression or T-wave inversion is typically observed in chronic stable angina, unstable angina, and non-ST-segment elevation Ml, whereas ST-segment elevation occurs with ST-segment elevation Ml and Prinzmetal (variant) angina.
• Treadmill or bicycle exercise ECG, commonly referred to as a “stress test,” is considered positive for IHD if the ECG shows at least a 1 mm deviation of the ST-segment (depression or elevation).
• Wall motion abnormalities or left ventricular dilation with stress echocardiography are indicative of IHD.
• Stress myocardial perfusion imaging with the radionuclides technetium-99m sestamibi or thallium-201 allows for the identification of multivessel disease and assessment of myocardial viability.
• Coronary angiography detects the location and degree of coronary atherosclerosis and is used to evaluate the potential benefit from revascularization procedures. Stenosis of at least 70% of the diameter of at least one of the major epicardial arteries on coronary angiography is indicative of significant IHD.
The Canadian Cardiovascular Society Classification System
The Canadian Cardiovascular Society Classification System (Table 7–4) is commonly used to assess the degree of disability resulting from IHD.10 Patients are categorized into one of four classes depending on the extent of activity that produces angina. Grouping patients according to this or a similar method is commonly used to assess changes in IHD severity over time and the effectiveness of pharmacologic therapy.
Physical Findings and Laboratory Analysis
A thorough medical history, physical exam, and laboratory analysis are necessary to ascertain cardiovascular risk factors and to exclude nonischemic and noncardiac conditions that could cause angina-like symptoms. Laboratory analyses should assess for glycemic control (i.e., fasting glucose, glycosylated hemoglobin), fasting lipids, hemoglobin, and organ function (i.e., blood urea nitrogen, creatinine, liver function tests, thyroid function tests). Additionally, serial measurements of cardiac enzymes (usually three measurements within 24 hours) are used to exclude the diagnosis of MI. Cardiac findings on the physical exam are often normal in patients with chronic stable angina. However, findings such as carotid bruits or abnormal peripheral pulses would indicate atherosclerosis in other vessel systems and raise the suspicion for IHD.
Table 7–3 Presentations of Acute Coronary Syndromes
|
• Angina at rest that is prolonged in duration, usually lasting over 20 minutes |
|
• Angina of recent onset (within 2 months) that markedly limits usual activity |
|
• Angina that increases in severity (i.e., by Canadian Cardiovascular Society Classification System of one level or more), frequency, or duration, or that occurs with less provocation over a short time period (i.e., within 2 months) |
From Ref. 9.
Table 7–4 The Canadian Cardiovascular Society Classification System of Angina
Patient Encounter, Part 1
RJ is a 47-year-old man with a history of hypertension who presents to your clinic complaining of chest pain that occurred several times over the past few weeks. RJ describes his chest pain as “a heaviness.” He states that it first occurred while he was mowing the grass. He later felt the same heavy sensation while raking leaves and again while carrying some boxes. The pain was located in the substernal area and radiated to his neck. The pain resolved after about 5 minutes of rest.
What information is suggestive of angina?
What tests would be beneficial in establishing a diagnosis?
What additional information do you need to create a treatment plan for this patient?
Diagnostic Tests
A resting ECG is indicated in all patients with angina-like symptoms. A 12-lead ECG should be done within 10 minutes of presentation to the emergency department in patients with symptoms of ischemia. Patients with ST-segment elevation are at the highest risk of death and need interventions to restore blood flow to the myocardium as quickly as possible. In patients without ST-segment elevation, biochemical markers are used to distinguish between unstable angina and non-ST-segment elevation MI.
“Stress” testing with either exercise or pharmacologic stressors increases myocardial oxygen demand and is commonly used to evaluate the patient with suspected IHD. Approximately 50% of patients with IHD who have a normal ECG at rest will develop ECG changes with exercise on a treadmill (most commonly) or bicycle ergometer. Dobutamine is a pharmacologic stressor used in patients who are unable to exercise. Dobutamine increases oxygen demand by stimulating the β1-receptor, leading to increases in heart rate and contractility. Dobutamine is commonly used with echocardiography (referred to as dobutamine stress echocardiography) to identify stress-induced wall motion abnormalities indicative of coronary disease.
Adenosine and dipyridamole are coronary vasodilators commonly combined with radionuclide myocardial perfusion imaging (nuclear imaging studies). These agents increase coronary blood flow in vessels free of disease, but not in diseased vessels. An IV radioactive tracer is used to detect areas of the heart that receive less blood after adenosine or dipyridamole infusion, indicating a myocardial perfusion defect and coronary disease.
Coronary artery calcium scoring via CT, also known as electron beam CT (EBCT) or “ultra-fast CT,” may be performed as a noninvasive means to assess for IHD. Calcium deposits within the coronary arteries which are indicative of IHD are detected on CT. A calcium score is calculated, and the risk for IHD-related events is estimated.
Coronary angiography (also referred to as a cardiac catheterization or “cardiac cath”) is considered the gold standard for the diagnosis of IHD. Coronary angiography is indicated when stress testing results are abnormal or symptoms of angina are poorly controlled. Angiography involves catheter insertion, usually into the femoral artery, and advancement into the aorta and into the coronary arteries. Contrast medium is injected through the catheter into the coronary arteries allowing visualization of the coronary anatomy by fluoroscopy. Contrast medium must be used cautiously with adequate hydration in patients with pre-existing renal disease (especially in those with diabetes) to avoid contrast-induced nephropathy.
TREATMENT
Desired Outcomes
Once the diagnosis of IHD is established in a patient, the clinician should provide counseling on lifestyle modifications, institute appropriate pharmacologic therapy, and evaluate the need for surgical revascularization. The major goals for the treatment of IHD are to:
• Prevent ACSs and death
• Alleviate acute symptoms of myocardial ischemia
• Prevent recurrent symptoms of myocardial ischemia
• Avoid or minimize adverse treatment effects
The treatment approach to address these goals is illustrated in Figure 7–4.
Patient Encounter, Part 2: Medical History, Physical Exam, and Diagnostic Tests
PMH: Hypertension, diagnosed 7 years ago
FH: Father with coronary artery disease, had a myocardial infarction at age 50 years; mother alive and well
SH: Smokes half a pack to a pack per day; denies alcohol and illicit drug use; no regular exercise program
Allergies: NKDA
Meds: Hydrochlorothiazide 25 mg orally once daily; nifedipine XL 60 mg orally once daily
PE:
VS: BP 154/90 mm Hg, HR 84 bpm, RR 16 per minute, T 37°C (98.6°F), Ht 5’10” (178 cm), wt 105 kg (230 lb)
CV: RRR, normal S1 and S2, no S3 or S4; no murmurs, rubs, gallops
Lungs: Clear to auscultation and percussion
Abd: Nontender, nondistended, + bowel sounds
Labs: Fasting lipid profile: total cholesterol 233 mg/dL (6.03 mmol/L), HDL cholesterol 30 mg/dL (0.78 mmol/L), LDL cholesterol 165 mg/dL (4.27 mmol/L), triglycerides 188 mg/dL (2.12 mmol/L); other labs within normal limits
Exercise treadmill test: Positive for ischemia
Identify RJ’s risk factors for ischemic heart disease.
How might RJ’s current drug regimen adversely affect his ischemic heart disease?
What therapeutic alternatives are available to manage RJ’s IHD?
General Approach to Treatment
The primary strategies for preventing ACS and death are to:
• Modify cardiovascular risk factors
• Slow the progression of coronary atherosclerosis
• Stabilize existing atherosclerotic plaques
The treatment algorithm in Figure 7–5 summarizes the appropriate management of IHD. Risk factor modification is accomplished through lifestyle changes and pharmacologic therapy. Both 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMG-CoA reductase inhibitors or statins) and angiotensin-converting enzyme (ACE) inhibitors are believed to provide vasculoprotective effects (properties that are generally protective of the vasculature, which may include anti-inflammatory effects, antiplatelet effects, improvement in endothelial function, and improvement in arterial compliance and tone), and in addition to aspirin, have been shown to reduce the risk of acute coronary events as well as mortality in patients with IHD. Angiotensin receptor blockers (ARBs) may be used in patients who cannot tolerate ACE inhibitors because of side effects (e.g., chronic cough). β-Blockers have been shown to decrease morbidity and improve survival in patients who have suffered an MI.
FIGURE 7–4. General treatment strategies for angina follow in clockwise fashion from the top center. (ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker.)
Therapies to alleviate and prevent angina are aimed at improving the balance between myocardial oxygen demand and supply. Since angina usually results from increased myocardial oxygen demand in the face of a relatively fixed reduction in oxygen supply, drug treatment is primarily aimed at reducing oxygen demand. Short-acting nitrates are indicated to acutely relieve angina. β-Blockers, calcium channel blockers (CCBs), and long-acting nitrates are traditionally used to reduce the frequency of angina and improve exercise tolerance. In most patients with IHD, the most effective treatments to improve myocardial oxygen supply are invasive mechanical interventions, percutaneous coronary intervention (PCI), and coronary artery bypass graft (CABG) surgery, which are described later in the chapter in the section on interventional approaches.
Adverse treatment effects can largely be averted by avoiding drug interactions and the use of drugs that may have unfavorable effects on comorbid diseases. For example, β-blockers may exacerbate pre-existing bronchospasm. β-Blockers are not absolutely contraindicated in broncho-spastic disease, but should be avoided in patients with poorly controlled symptoms. While patients often require combination antianginal therapy, there is a potential pharmacodynamic drug interaction with the concurrent use of β-blockers and nondihydropyridine CCBs. Since both drug classes slow electrical conduction through the atrioventricular (AV) node, serious bradycardia or heart block may result with their concomitant use. Appropriate drug dosing and monitoring also reduces the risk for adverse treatment effects. Drugs should be initiated in low doses, with careful up-titration as necessary to control symptoms of angina and cardiovascular risk factors.
Lifestyle Modifications
Lifestyle modifications, including smoking cessation, avoidance of second-hand smoke, dietary modifications, increased physical activity, and weight loss, reduce cardiovascular risk factors, slow the progression of IHD, and decrease the risk for IHD-related complications. Cigarette smoking is the single most preventable cause of IHD and IHD-related death. Smoking may also attenuate the antianginal effects of drug therapy. The clinician should ascertain smoking status for the patient and family members on the patient s initial clinic visit. For patients and/or family members who smoke, clinicians should provide counseling on the importance of smoking cessation at each subsequent visit and referral to special smoking cessation programs. There are several pharmacologic aids for smoking cessation. Transdermal nicotine replacement therapy and bupropion have been studied in patients with IHD and appear safe.8,11
Weight loss, through caloric restriction and increased physical activity, should be encouraged in patients who have a body mass index greater than 25 kg/m2. Dietary modification is important for risk factor management, and dietary counseling should be provided to all patients with newly diagnosed angina regardless of weight. The American Heart Association recommends a diet that includes a variety of fruits, vegetables, grains, low-fat or nonfat dairy products, fish, legumes, poultry, and lean meats.12 Fatty fish, such as salmon and herring, are high in omega-3 fatty acids, which have been shown to reduce triglyceride concentrations and slow atherosclerotic plaque progression.12Specific dietary recommendations for patients with IHD should include the following2,12:
• Limit fat intake to less than 30% of total caloric consumption.
• Limit cholesterol intake to less than 200 mg/day.
• Limit consumption of saturated fat and trans unsaturated fat found in fatty meats, full-fat dairy products, and hydrogenated vegetable oils to less than 7% of total calories.
• Consume at least two servings of fish per week. Alternatively patients may take omega-3 fatty acid supplements (1 g/day).
• Consume at least six servings of grains, five servings of fruits and vegetables, and two servings of nonfat or low-fat dairy products per day.
• Consider adding plant stanol/sterols (2 g/day) and/or viscous fiber (over 10 g/day) to lower LDL cholesterol. It is recommended that patients with diabetes consume 14 g of fiber for every 1,000 kcal consumed.
• Limit daily sodium intake to 2.4 g (6 g of salt) for blood pressure control.
Exercise facilitates both weight loss and blood pressure reduction. In addition, regular exercise improves functional capacity and symptoms in chronic stable angina.1 Recent guidelines recommend moderate intensity aerobic activity, such as brisk walking, ideally for 30 to 60 minutes every day.2 Medically supervised cardiac rehabilitation programs are recommended for high-risk patients.
FIGURE 7–5. The treatment algorithm for ischemic heart disease. It begins at the top (blue section), which suggests risk factor modifications as the first treatment modality. Moving down to the green section, appropriate antiplatelet therapy is selected. The purple section identifies patients at high risk for major adverse cardiac events and suggests appropriate drug therapy to decrease cardiovascular risk. The yellow section at the bottom recommends appropriate antianginal therapy. The minimum duration of clopidogrel therapy following intracoronary stent placement is as follows: at least 1 month for bare metal stents and at least 12 months for drug-eluting stents. (ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BMS, bare metal stent; BP, blood pressure; CABG, coronary artery bypass graft; CCB, calcium channel blocker; DES, drug-eluting stent; IR, immediate-release; LA, long-acting; LDL, low-density lipoprotein; LV, left ventricular; NTG, nitroglycerin; PCI, percutaneous coronary intervention; SL, sublingual.)
Interventional Approaches
Percutaneous Coronary Intervention
When drug therapy fails or if extensive coronary atherosclerosis is present, PCI is often performed to restore coronary blood flow, relieve symptoms, and prevent major adverse cardiac events. Patients with one or more critical coronary stenoses (i.e., greater than 70% occlusion of the coronary lumen) detected during coronary angiography may be candidates for PCI. Several catheter-based interventions may be used during PCI, including:
• Percutaneous transluminal coronary angioplasty (PTCA)
• Intracoronary bare metal stent placement
• Intracoronary drug-eluting stent placement
• Rotational atherectomy
During PCI, a catheter is advanced into the blocked coronary artery, as described for cardiac catheterization. If PTCA (i.e., balloon angioplasty) is performed, a balloon at the end of the catheter is inflated inside the artery at the site of the critical stenosis. When inflated, this balloon catheter displaces the atherosclerotic plaque out of the lumen of the artery, restoring normal myocardial blood flow. Most PCI procedures involve the placement of a small wire stent (similar in size and shape to the spring at the tip of a ball point pen) at the site of angioplasty. Coronary stenting involves use of a special balloon catheter containing the stent. When the balloon is inflated, the stent is deployed in the wall of the coronary artery, forming a sort of bridge or scaffold to maintain normal coronary blood flow. Either a bare metal stent or a drug-eluting stent may be used. Drug-eluting stents are impregnated with low concentrations of an antiproliferative drug (either paclitaxel or sirolimus), which is released locally over a period of weeks to inhibit restenosis or renarrowing of the coronary artery after PCI. A recent observational study demonstrated a significant reduction in all-cause mortality over a 4.5-year interval among patients who received a drug-eluting stent compared to those with a bare metal stent.13 Stents themselves are thrombogenic, especially until they become endothelialized (covered in endothelial cells like a normal coronary artery). As such, dual antiplatelet therapy (discussed later) is required until the stent becomes endothelialized and perhaps indefinitely following stent placement to reduce the risk for stent thrombosis, MI, or death. Lastly, rotational atherectomy may be performed wherein a special catheter is used to essentially cut away the atherosclerotic plaque, restoring coronary blood flow.
Coronary Artery Bypass Graft Surgery
As an alternative to PCI, CABG surgery, or open-heart surgery, may be performed if the patient is found to have extensive coronary atherosclerosis (generally greater than 70% occlusion of three or more coronary arteries) or is refractory to medical treatment. In the former case, CABG surgery has been shown to reduce mortality from IHD. During CABG surgery, veins from the leg (i.e., saphenous veins) or arteries from the arm (i.e., radial artery) or chest wall (i.e., internal mammary arteries) are surgically removed. In the case of venous or radial artery conduits, one end of the removed blood vessel is attached to the aorta, and the other end is attached to the coronary artery distal to the atherosclerotic plaque. However, when internal mammary arteries are used, the distal end of the artery is detached from the chest wall and anastomosed to the coronary artery distal to the plaque. A median sternotomy, in which an incision the length of the sternum is made, is commonly required to gain access to the thoracic cavity and expose the heart. As the “new” blood vessels are being engrafted, the patient is typically placed on cardiopulmonary bypass (i.e., heart-lung machine) to maintain appropriate myocardial and systemic perfusion. Alternative surgical approaches for advanced IHD may be used in some settings including “off-pump” CABG (cardiopulmonary bypass is not required) and minimally invasive CABG (i.e., thorascopic surgery), although these techniques are not the norm. Because of the extremely invasive nature of this surgery, CABG surgery is generally reserved for patients with extensive coronary disease or as a treatment of last resort in patients with symptoms refractory to medical therapy.
Pharmacologic Therapy
Pharmacotherapy to Prevent ACSs and Death
Control of Risk Factors
A major component of any IHD treatment plan is control of modifiable risk factors, including dyslipidemia, hypertension, and diabetes. In addition, although not discussed in detail in this chapter, mental depression is common among patients with IHD and increases the risk for cardiac events and death. Thus, patients with IHD should be assessed for depression, and if present, appropriate management of depression should ensue.
Treatment strategies for dyslipidemia and hypertension in the patient with IHD are summarized in the following paragraphs. Visit chapters in this textbook on the management of hypertension and dyslipidemia for further information.
Because lipoprotein metabolism and the pathophysiology of atherosclerosis are closely linked, treatment of dyslipidemias is critical for both primary and secondary prevention of IHD-related cardiac events. In 2001, the Adult Treatment Panel III of the National Cholesterol Education Program issued guidelines for the management of dyslipidemia and recommended an LDL cholesterol goal of less than 100 mg/dL (2.59 mmol/L) for patients with documented IHD or IHD-risk equivalents such as diabetes or other vascular disease.14 Since the publication of these guidelines, new evidence from several primary and secondary prevention trials suggests that there are additional clinical benefits from further reduction in LDL cholesterol.15 In response to this evidence, more aggressive cholesterol-lowering goals were established for patients at high risk for developing IHD-related events, including those with diabetes or known cardiovascular disease. The following modifications were made to national treatment guidelines15,16:
• Statin or other LDL-lowering therapy is indicated along with lifestyle modifications in patients with cardiovascular disease or diabetes and multiple cardiovascular risk factors, regardless of baseline LDL cholesterol.
• Intensity of LDL-lowering therapy should be sufficient to decrease LDL cholesterol by 30% to 40%.
• Goal LDL cholesterol in patients with known clinical cardiovascular disease or diabetes plus one or more cardiovascular risk factors is less than 70 mg/dL (1.81 mmol/L).
Like dyslipidemia, hypertension is a major, modifiable risk factor for the development of IHD and related complications. Unfortunately, awareness, treatment, and control of blood pressure are suboptimal.17Aggressive identification and control of hypertension is warranted in patients with IHD to minimize the risk of major adverse cardiac events. Goal blood pressure in patients with IHD is less than 130/80 mm Hg with consideration of reducing blood pressure to less than 120/80 mm Hg in patients with left ventricular dysfunction or heart failure.18 Because of their cardioprotective benefits, β-blockers and ACE inhibitors (or ARBs in ACE-inhibitor-intolerant patients), either alone or in combination, are appropriate for most patients with both hypertension and IHD.
Antiplatelet Agents
Platelets play a major role in the pathophysiology of ACS. Specifically, platelets adhere to the site of atherosclerotic plaque rupture where they become activated, aggregate, and stimulate thrombus formation and ACS. Thromboxane is a potent platelet activator. Aspirin inhibits cyclooxygenase, an enzyme responsible for the production of thromboxane, thereby inhibiting platelet activation and aggregation. In patients with stable or unstable angina, aspirin has been consistently shown to reduce the risk of major adverse cardiac events, particularly MI.19 Antiplatelet therapy with aspirin should be considered for all patients without contraindications, particularly in patients with a history of MI. Aspirin doses of 75 to 162 mg daily are recommended in patients with or at risk for IHD.2,20 If aspirin is contraindicated (e.g., aspirin allergy) or is not tolerated by the patient, other antiplatelet agents such as clopidogrel should be considered.
Dual antiplatelet therapy with aspirin and a thienopyridine is recommended following PCI with stent placement to prevent stent thrombosis prior to stent endothelialization. Historically, ticlopidine was the thienopyridine agent used in combination with aspirin. However, clopidogrel has essentially replaced ticlopidine due to hematologic toxicity (leukopenia) of ticlopidine and the growing body of evidence supporting the use of clopidogrel. Antiproliferative drugs in drug eluting stents delay endothelialization, and thus a longer period of combination antiplatelet therapy is recommended for drug-eluting stents compared to bare metal stents to prevent thrombosis. Recent guidelines advocate combination antiplatelet therapy for at least 1 month after a bare metal stent and at least 12 months after a drug-eluting stent, although there are some data to support indefinite use of combination antiplatelet therapy after stent placement.21 Because of the risk for stent thrombosis with premature discontinuation of dual antiplatelet therapy, it is imperative for clinicians to educate patients on this risk and the need for continuation of combination antiplatelet therapy for the recommended duration.
There are also data to support use of dual antiplatelet therapy in patients with ACS regardless of whether PCI with stent implantation is performed. In this population, the combination of aspirin and clopidogrel was more effective than aspirin alone in decreasing the risk of death, MI, and stroke.22,23 For more information regarding the use of dual antiplatelet therapy in the setting of ACS, the reader is referred to the Acute Coronary Syndromes Chapter.
Statins
Statins are the preferred drugs to achieve LDL cholesterol goals based on their potency in lowering LDL cholesterol and efficacy in preventing cardiac events. Specifically, over the last decade, several studies in tens of thousands of patients have revealed that lowering cholesterol with statins is effective for both primary and secondary prevention of IHD-related events.15 Statins shown to decrease morbidity and mortality associated with IHD include lovastatin, simvastatin, pravastatin, and atorvastatin. A recent meta-analysis showed that the risk of major adverse cardiac events is reduced by 21% with the use of statins in patients at high risk for IHD-related events.24
Several studies have investigated whether statins possess pharmacologic properties in addition to their LDL cholesterol-lowering effect that may confer additional benefits in IHD.25 These studies were prompted by evidence that patients with “normal” LDL cholesterol derived benefit from statins. Statins have been shown to modulate the following characteristics thought to stabilize atherosclerotic plaques and contribute to the cardiovascular risk reduction seen with these drugs:
• Shift LDL cholesterol particle size from predominantly small, dense, highly atherogenic particles to larger, less atherogenic particles.
• Improve endothelial function leading to more effective vasoactive response of the coronary arteries.
• Prevent or inhibit inflammation by lowering C-reactive protein and other inflammatory mediators thought to be involved in atherosclerosis.
• Possibly improving atherosclerotic plaque stability.
In summary, to control risk factors and prevent major adverse cardiac events, statin therapy should be considered in all patients with IHD, particularly in those with elevated low-density lipoprotein cholesterol or diabetes. Statins are potent lipid-lowering agents, possess non-lipid-lowering effects that may provide additional benefit to patients with IHD, and have been shown to reduce morbidity and mortality in patients with IHD. Based on these benefits, statins are generally considered the drugs of choice in patients with dyslipidemias. Moreover, based on evidence that statins improve outcomes in patients with IHD and “normal” LDL cholesterol concentration, statins should be considered in all patients with IHD at high risk of major adverse cardiac events, regardless of baseline LDL cholesterol.
ACE-ls and ARBs
Angiotensin II is a neurohormone produced primarily in the kidney. It is a potent vasoconstrictor and stimulates the production of aldosterone. Together, angiotensin II and aldosterone increase blood pressure and sodium and water retention (increasing ventricular wall tension), cause endothelial dysfunction, promote blood clot formation, and cause myocardial fibrosis.
ACE inhibitors decrease angiotensin II production and have consistently been shown to decrease morbidity and mortality in patients with heart failure or a history of MI.26,27 A meta-analysis of 22 clinical trials with ACE inhibitors in post-MI patients found that ACE inhibitors reduced 1-year mortality by 16% to 32%, and the mortality-reducing effects were sustained for up to 4 years.27 In addition, there is evidence that ACE inhibitors reduce the risk of vascular events in patients with chronic stable angina or risk factors for IHD.28,29 Specifically, in nearly 10,000 patients with vascular disease (including IHD) or risk factors for vascular disease, such as diabetes, ramipril reduced the risk of death, acute MI, and stroke by 22% compared to placebo after an average of 5 years of treatment.28 Similar results have been demonstrated with perindopril in patients with IHD.29
In the absence of contraindications, ACE inhibitors should be considered in all patients with IHD, particularly those who also have hypertension, diabetes mellitus, chronic kidney disease, left ventricular dysfunction, history of MI, or any combination of these.2 Additionally, ACE inhibitors should also be considered in patients at high risk for developing IHD based on findings from the studies summarized above. ARBs may be used in patients with indications for ACE inhibitors but who cannot tolerate them due to side effects (e.g., chronic cough). ARBs also antagonize the effects of angiotensin II. In one large trial, valsartan was as effective as captopril at reducing morbidity and mortality in post-MI patients.26 However, there are far more data supporting the use of ACE inhibitors in IHD. Therefore, ACE inhibitors should remain first-line in patients with a history of MI, diabetes, chronic kidney disease, or left ventricular dysfunction. The ACE inhibitors and ARBs with indications for patients with or at risk for IHD or IHD-related complications are listed in Table 7–5.
Side effects with ACE inhibitors and ARBs include hyperkalemia, deterioration in renal function, and rarely, angioedema. Serum potassium increases are secondary to aldosterone inhibition and are more likely in the presence of pre-existing renal impairment, diabetes, or concomitant therapy with nonsteroidal anti-inflammatory drugs (NSAIDs), potassium supplements, or potassium-sparing diuretics. Reductions in glomerular filtration may occur during ACE inhibitor or ARB initiation or up-titration due to inhibition of angiotensin II-mediated vasoconstriction of the efferent arteriole. This type of renal impairment is usually temporary and is more common in patients with pre-existing renal dysfunction or unilateral renal artery stenosis. Bilateral renal artery stenosis is a contraindication for ACE inhibitors and ARBs because of the risk for overt renal failure. Angioedema is a potentially life-threatening adverse effect that occurs in less than 1% of ACE inhibitor-treated patients and may also occur with ARBs. Substitution of an ARB for an ACE inhibitor is appropriate for patients who develop a persistent cough with ACE inhibitor therapy, as this cough is believed to be due to accumulation of bradykinin secondary to ACE inhibition. Both ACE inhibitors and ARBs can cause fetal injury and death and are contraindicated in pregnancy.
Table 7–5 Doses of ACE Inhibitors and ARBs Indicated in IHD
Nitroglycerin to Relieve Acute Symptoms
Short-acting nitrates are first-line treatment to terminate acute episodes of angina. All patients with a history of angina should have sublingual nitroglycerin tablets or spray to relieve acute ischemic symptoms. Nitrates undergo biotransformation to nitric oxide. Nitric oxide activates soluble guanylate cyclase and leads to increased intracellular concentrations of cyclic guanosine monophosphate, and ultimately, to smooth muscle relaxation. Nitrates primarily cause venodilation, leading to reductions in preload. The resultant decrease in ventricular volume and wall tension leads to a reduction in myocardial oxygen demand. In higher doses, nitrates may also cause arterial dilation and reduce after-load. In addition to reducing oxygen demand, nitrates increase myocardial oxygen supply by dilating the epicardial coronary arteries and collateral vessels, as well as relieving vasospasm.
Short-acting nitrates are available in tablet and spray formulations for sublingual administration. Sublingual nitroglycerin tablets are most commonly used to alleviate angina and are less expensive than the spray. However, the spray is preferred for patients who have difficulty opening the tablet container or produce insufficient saliva for rapid dissolution of sublingual tablets. At the onset of an angina attack, a 0.3 to 0.4 mg dose of nitroglycerin (tablet or spray) should be administered sublingually, and repeated every 5 minutes until symptoms resolve. Sitting or standing enhances venous pooling and the effectiveness of nitroglycerin. Sublingual nitroglycerin can also be used to prevent effort-induced angina (i.e., angina that occurs with exertion). In this case, the patient should use sublingual nitroglycerin 2 to 5 minutes prior to an activity known to cause angina, with the effects persisting for approximately 30 minutes. Isosorbide dinitrate, also available in a sublingual form, has a longer half-life with antianginal effects lasting up to 2 hours. The use of short-acting nitrates alone, without concomitant long-acting antianginal therapy, may be acceptable for patients who experience angina symptoms once every few days. However, for patients with more frequent attacks, long-acting antianginal therapy with β-blockers, CCBs, or long-acting nitrates is recommended.
The use of nitrates with phosphodiesterase type 5 inhibitors (e.g., sildenafil, vardenafil, and tadalafil), commonly prescribed for erectile dysfunction, is contraindicated. Phosphodiesterase degrades cyclic guanosine monophosphate (GMP), which is responsible for the vasodilatory effects of nitrates. Concomitant use of nitrates and phosphodiesterase type 5 inhibitors enhances cyclic GMP-mediated vasodilation and can result in serious hypotension and even death. All patients with IHD should receive a prescription for sublingual nitrates and education regarding their use. Points to emphasize when counseling a patient on nitroglycerin use include:
• The seated position is generally preferred when using nitroglycerin because the drug may cause dizziness.
• Call 911 if symptoms are unimproved or worsen 5 minutes after the first dose.
• Keep nitroglycerin tablets in the original glass container and close the cap tightly after use.
• Nitroglycerin should not be stored in the same container as other medications since this may reduce nitroglycerin’s effectiveness.
• Repeated use of nitroglycerin is not harmful or addictive and does not result in any long-term side effects. Patients should not hesitate to use nitroglycerin whenever needed.
• Nitroglycerin should not be used within 24 hours of taking sildenafil or vardenafil or within 48 hours of taking tadalafil because of the potential for life-threatening hypotension.
Pharmacotherapy to Prevent Recurrent Ischemic Symptoms
The overall goal of antianginal therapy is to allow patients with IHD to resume normal activities without symptoms of angina and to experience minimal to no adverse drug effects. The drugs traditionally used to prevent ischemic symptoms are β-blockers, CCBs, and nitrates. These drugs exert their antianginal effects by improving the balance between myocardial oxygen supply and demand, with specific effects listed in Table 7–6. β-Blockers, CCBs, and nitrates decrease the frequency of angina and delay the onset of angina during exercise. However, there is no evidence that any of these agents prevent ACS or improve survival in patients with chronic stable angina. Ranolazine is a newer molecular entity indicated for the treatment of chronic stable angina in patients unresponsive to traditional antianginal medications. Combination therapy with two or three antianginal drugs is often needed.
β-Blockers
Stimulation of the β1-and β2-adrenergic receptors in the heart increases heart rate and cardiac contractility. β-Blockers antagonize these effects and decrease myocardial oxygen demand. β-Blockers may also reduce oxygen demand by lowering blood pressure and ventricular wall tension through blockade of plasma renin release. However, with marked reductions in heart rate, β-blockers may actually increase ventricular wall tension. This is because slower heart rates allow the ventricle more time to fill during diastole, leading to increased left ventricular volume, end-diastolic pressure, and wall tension. However, the net effect of β-blockade is usually a reduction in myocardial oxygen demand. β-Blockers do not improve myocardial oxygen supply.
Table 7–6 Effects of Antianginal Medications on Myocardial Oxygen Demand and Supply
Table 7–7 Properties and Dosing of β-Blockers in Ischemic Heart Disease
The properties and recommended doses of various β-blockers are summarized in Table 7–7. β-Blockers with intrinsic sympathomimetic activity have partial β-agonist effects and cause lesser reductions in heart rate at rest. As a result, β-blockers with intrinsic sympathomimetic activity may produce lesser reductions in myocardial oxygen demand and should be avoided in patients with IHD. Other β-blockers appear equally effective at controlling symptoms of angina. The frequency of dosing and drug cost should be taken into consideration when choosing a particular drug. Agents that can be dosed once or twice daily are preferred. Most β-blockers are available in inexpensive generic versions. β-Blockers should be initiated in doses at the lower end of the usual dosing range, with titration according to symptom and hemodynamic response. The β-blocker dose is commonly titrated to achieve the following:
• Resting heart rate between 50 and 60 beats per minute (bpm).
• Maximum heart rate with exercise of 100 bpm or less or 20 bpm above the resting heart rate.
β-Blockers are first-line therapy for preventing ischemic symptoms, particularly in patients with a history of MI. In the absence of contraindications, β-blockers are preferred because of their potential cardioprotective effects. Specifically, β-blockers may prevent cardiac arrhythmias by decreasing the rate of spontaneous depolarization of ectopic pacemakers. Second, while the long-term effects of β-blockers on morbidity and mortality in patients with chronic stable angina are largely unknown, certain β-blockers have been shown to decrease the risk for reinfarction and improve survival in patients who have suffered an Ml.30 Specific β-blockers associated with mortality reductions in clinical trials include metoprolol, propranolol, and carvedilol.30,31 In a meta-analysis of 82 clinical trials investigating the use of β-blockers in patients following MI, the relative risk of death was reduced by 23% in patients treated with β-blockers compared to control subjects.30 Long-term therapy (for at least 6 months) was associated with greater mortality benefit compared to short-term β-blockade (6 weeks or less).
β-Blockers are contraindicated in patients with severe bradycardia (heart rate less than 50 bpm) or AV conduction defects in the absence of a pacemaker. β-Blockers should be used with particular caution in combination with other agents that depress AV conduction (e.g., digoxin, verapamil, and diltiazem) because of increased risk for bradycardia and heart block. Relative contraindications include asthma, bronchospastic disease, and severe depression. β1-Selective blockers are preferred in patients with asthma or chronic obstructive pulmonary disease. However, selectivity is dose dependent, and β1-selective agents may induce bronchospasm in higher doses.
There are several precautions to consider with the use of β-blockers in patients with diabetes or heart failure. All β-blockers may mask the tachycardia and tremor (but not sweating) that commonly accompany episodes of hypoglycemiain diabetes. In addition, nonselectiveβ-blockers may alter glucose metabolism and slow recovery from hypoglycemia in insulin-dependent diabetes. β1-Selective agents are preferred because they are less likely to prolong recovery from hypoglycemia. Importantly, β-blockers should not be avoided in patients with IHD and diabetes, particularly in patients with a history of MI who are at a high risk for recurrent cardiovascular events. β-Blockers are negative inotropes (i.e., they decrease cardiac contractility). Cardiac contractility is impaired in patients with left ventricular systolic dysfunction. Therefore, β-blockers may worsen symptoms of heart failure in patients with left ventricular systolic dysfunction (i.e., ejection fraction less than 40%). While certain β-blockers are indicated in patients with heart failure because they have been shown to reduce morbidity and mortality in this population, they must be used cautiously. In particular, when used for management of IHD in a patient with heart failure, β-blockers should be initiated in very low doses with slow up-titration to avoid worsening heart failure symptoms. The initiation of a β-blocker in a patient with acute cardiac decompensation should be delayed until the patient has stabilized.
Other potential adverse effects from β-blockers include fatigue, sleep disturbances, malaise, depression, and sexual dysfunction. Abrupt β-blocker withdrawal may increase the frequency and severity of angina, possibly because of increased receptor sensitivity to catecholamines after long-term β-blockade. If the decision is made to stop β-blocker therapy, the dose should be tapered over several days to weeks to avoid exacerbating angina.
Calcium Channel Blockers
CCBs inhibit calcium entry into vascular smooth muscle and cardiac cells, resulting in the inhibition of the calcium-dependent process leading to muscle contraction. Inhibition of calcium entry into the vascular smooth muscle cells leads to systemic vasodilation and reductions in afterload. Inhibition of calcium entry into the cardiac cells leads to reductions in cardiac contractility. Thus, CCBs reduce myocardial oxygen demand by lowering both wall tension (through reductions in afterload) and cardiac contractility. In addition, the nondihydropyridine CCBs, verapamil and diltiazem, further decrease myocardial oxygen demand by slowing cardiac conduction through the AV node and lowering heart rate. In contrast, dihydropyridine CCBs, nifedipine in particular, are potent vasodilators that can cause baroreflex-mediated increases in sympathetic tone and heart rate. Because of their negative chronotropic effects, verapamil and diltiazem are generally more effective antianginal agents than the dihydropyridine CCBs. In addition to decreasing myocardial oxygen demand, all CCBs increase myocardial oxygen supply by dilating coronary arteries, thus increasing coronary blood flow and relieving vasospasm.
In randomized, controlled, clinical trials, CCBs were as effective as β-blockers at preventing ischemic symptoms. CCBs are recommended as initial treatment in IHD when β-blockers are contraindicated or not tolerated. In addition, CCBs may be used in combination with β-blockers when initial treatment is unsuccessful. However, the combination of a β-blocker with either verapamil or diltiazem should be used with extreme caution since all of these drugs decrease AV nodal conduction, increasing the risk for severe bradycardia or AV block when used together. If combination therapy is warranted, a long-acting dihydropyridine CCB is preferred. β-Blockers will prevent reflex increases in sympathetic tone and heart rate with the use of CCBs with potent vasodilatory effects. For patients with variable and unpredictable occurrences of angina, indicating possible coronary vasospasm, CCBs may be more effective than β-blockers in preventing angina episodes. The dosing of CCBs in IHD is described in Table 7–8.
Verapamil and diltiazem are contraindicated in patients with bradycardia and pre-existing conduction disease in the absence of a pacemaker. As noted above, verapamil and diltiazem should be used with particular caution in combination with other drugs that depress AV nodal conduction (e.g., β-blockers and digoxin). Because of their negative inotropic effects, CCBs may cause or exacerbate heart failure in patients with pre-existing left ventricular systolic dysfunction and should be avoided in this population. The exceptions are amlodipine and felodipine, which have less negative inotropic effects compared to other CCBs and appear to be safe in patients with left ventricular systolic dysfunction.32,33 Finally, there is some evidence that short-acting CCBs (particularly short-acting nifedipine and nicardipine) may increase the risk of cardiovascular events.34 Therefore, short-acting agents should be avoided in the management of IHD.
Table 7–8 Dosing of CCBs in Ischemic Heart Disease
Long-Acting Nitrates
Nitrate products are available in both oral and transdermal formulations for chronic use. Commonly used products are listed in Table 7–9. All nitrate products are equally effective at preventing the recurrence of angina when used appropriately.
The major limitation of nitrate therapy is the development of tolerance with continuous use. The loss of antianginal effects may occur within the first 24 hours of continuous nitrate therapy. While the cause of tolerance is unclear, several mechanisms have been proposed, including the generation of free radicals that degrade nitric oxide. The most effective method to avoid tolerance and maintain the antianginal efficacy of nitrates is to allow a daily nitrate-free interval of at least 8 to 12 hours. Nitrates do not provide protection from ischemia during the nitrate-free period. Therefore, the nitrate-free interval should occur when the patient is least likely to experience angina. Generally, angina is less common during the nighttime hours when the patient is sleeping and myocardial oxygen demand is reduced. Thus, it is common to dose long-acting nitrates so that the nitrate-free interval begins in the evening. For example, isosorbide dinitrate is typically dosed on awakening and again 7 hours later.
Monotherapy with nitrates for the prevention of ischemia should generally be avoided for a couple of reasons. First, reflex increases in sympathetic activity and heart rate, with resultant increases in myocardial oxygen demand, may occur secondary to nitrate-induced venodilation. Second, patients are unprotected from ischemia during the nitrate-free interval. β-Blockers and CCBs are dosed to provide 24-hour protection from ischemia. Treatment with long-acting nitrates should be added to baseline therapy with either a β-blocker or CCB or a combination of the two. β-Blockers attenuate the increase in sympathetic tone and heart rate that occurs during nitrate therapy. In turn, nitrates attenuate the increase in wall tension during β-blocker therapy. As a result, the combination of β-blockers and nitrates is particularly effective at preventing angina and provides greater protection from ischemia than therapy with either agent alone. Monotherapy with nitrates may be appropriate in patients who have low blood pressure at baseline or who experience symptomatic hypotension with low doses of β-blockers or CCBs.
Table 7–9 Nitrate Formulations and Dosing for Chronic Use
Common adverse effects of nitrates include postural hypotension, flushing, and headache secondary to venodilation. Headache often resolves with continued therapy and may be treated with acetaminophen. Hypotension is generally of no serious consequence. However, in patients with hypertrophic obstructive cardiomyopathy or severe aortic valve stenosis, nitroglycerin may cause serious hypotension and syncope. Therefore, long-acting nitrates are relatively contraindicated in these conditions. Because life-threatening hypotension may occur with concomitant use of nitrates and phosphodiesterase type 5 inhibitors, nitrates should not be used within 24 hours of taking sildenafil or vardenafil or within 48 hours of taking tadalafil. Skin erythema and inflammation may occur with transdermal nitroglycerin administration and may be minimized by rotating the application site.
Ranolazine
Ranolazine is an anti-ischemic agent that exerts its effects by inhibiting the late inward sodium current during the plateau phase of the cardiac action potential. Under ischemic conditions, excess sodium may enter the myocardial cell during systole. The resultant intracellular sodium overload leads to intracellular calcium accumulation (calcium overload) though a sodium/calcium exchange mechanism. Calcium overload results in increases in left ventricular wall tension and myocardial oxygen consumption. By reducing intracellular sodium concentrations, ranolazine decreases calcium overload, left ventricular wall tension, and myocardial oxygen consumption.
In clinical trials, ranolazine at a dose of 750 to 1,000 mg twice daily improved angina and increased exercise capacity when added to other antianginal therapy.35,36 Ranolazine has minimal effects on heart rate or blood pressure; however, it has the potential to prolong the QT interval and increase the risk for the life-threatening arrhythmia, torsades de pointes. Therefore, ranolazine should be reserved for patients with angina that is refractory to traditional antianginal medications. Contraindications to ranolazine are shown in Table 7–10. Common adverse effects with ranolazine include dizziness, headache, constipation, and nausea. Syncope may occur infrequently. Ranolazine is a substrate for CYP3A4 and both an inhibitor and substrate of p-glycoprotein. Concomitant use of ranolazine with moderate to potent CYP3A4 inhibitors, including verapamil and diltiazem, is contraindicated. Ranolazine should be used cautiously with p-glycoprotein inhibitors (e.g., cyclosporine) and substrates (e.g., digoxin).
Pharmacotherapy With No Benefit or Potentially Harmful Effects
Hormone Replacement Therapy
Hormone replacement therapy (HRT) has favorable effects on lipoprotein cholesterol concentrations. Data from several observational studies suggested that HRT might reduce the risk of cardiovascular events in women with IHD. However, subsequent randomized, controlled, clinical trials failed to demonstrate a reduction in the risk for IHD or cardiovascular events with HRT in postmenopausal women.37,38 In fact, HRT appeared to be harmful in this patient population, increasing the risk of thromboembolic events and breast cancer. Current guidelines recommend against the use of HRT to reduce cardiovascular risk.1 Furthermore, the clinician should consider discontinuing HRT therapy in women who suffer an acute coronary event while receiving such therapy.
Antioxidants
Oxidization of LDL-cholesterol is believed to play a significant role in the atherosclerotic process. The antioxidant vitamins, vitamin E, vitamin C, and β-carotene, protect LDL cholesterol from oxidation. Evidence from observational and animal studies suggested that increased intake of antioxidant vitamins might inhibit the formation of atherosclerotic lesions and decrease the risk for cardiovascular events.39However, a meta-analysis of several large, randomized, prospective studies found no beneficial effect of vitamin E or β-carotene on cardiovascular outcomes in patients with IHD or IHD risk factors.40,41Similarly disappointing results were demonstrated with vitamin C supplementation.42 Based on this evidence, current guidelines do not recommend supplementation with vitamin E or other antioxidants for the sole purpose of preventing cardiovascular events.
Table 7–10 Contraindications and Precautions With Ranolazine
Folic Acid
Elevated homocysteine concentrations have been associated with an increased risk for cardiovascular disease in both epidemiologic and clinical studies.43 Several studies have evaluated the benefit of lowering homocysteine levels with folic acid, vitamin B6 and/or vitamin B12 supplementation. Despite lowering homocysteine levels, neither folic acid nor other vitamin B supplementation has been shown to reduce cardiovascular events in randomized controlled clinical trials.44,45 Based on available evidence, the use of folate or vitamin B supplementation for the purpose of preventing cardiovascular events in patients with pre-existing IHD or at risk for IHD is not recommended.
Herbal Supplements
Herbal products are widely used for their purported cardiovascular benefits; examples of such products include danshen, dong quai, feverfew, garlic, hawthorn, and hellebore. However, strong evidence supporting their benefits in cardiovascular disease is generally lacking. While small randomized controlled trials have shown benefits with some herbal supplements, the potential for drug interactions and the lack of product standardization limits the products’ usefulness in clinical practice. Safety with herbal supplements in patients with IHD is a major concern. Unlike prescription and OTC medicines, the FDA does not require manufacturers of herbal products to submit proof of safety prior to product marketing. Numerous case reports of adverse cardiovascular events, including stroke, MI, and lethal cardiac arrhythmias with ephedra-based products (e.g., Ma huang) led the FDA to ban ephedra-containing products in 2004. However, other herbal supplements with potentially serious adverse cardiovascular effects remain easily accessible to the consumer (e.g., bitter orange). Some herbal supplements may interact with antiplatelet and antithrombotic therapy and increase bleeding risk (e.g., ginkgo biloba). Others may reduce the effectiveness of antianginal medications. Thus, it is important to assess the use of herbal products in patients with IHD and to counsel patients about the potential for drug interactions and adverse events with herbal therapies.
Cyclooxygenase-2 (COX-2) Inhibitors and NSAIDs
Data suggest that COX-2 inhibitors and nonselective NSAIDs may increase the risk for MI and stroke.46,47 The cardiovascular risk with COX-2 inhibitors and NSAIDs may be greatest in patients with a history of, or with risk factors for, cardiovascular disease. The COX-2 inhibitors rofecoxib and valdecoxib were withdrawn from the market in recent years because of safety concerns. The FDA requested the manufacturers of other COX-2 and nonselective NSAIDs (prescription and OTC) to include information about the potential adverse cardiovascular effects of these drugs in their product labeling. The American Heart Association recommends that the use of COX-2 inhibitors be limited to low-dose, short-term therapy in patients for whom there is no appropriate alternative.46 Patients with cardiovascular disease should consult a clinician before using OTC NSAIDs.
SPECIAL POPULATIONS
Variant Angina
Vasospasm as the sole etiology of angina (Prinzmetal or variant angina) is relatively uncommon. As a result, treatment options are not well studied. Nevertheless, based on the pharmacology of available drugs, several recommendations can be made. First, β-blockers should be avoided in patients with variant angina because of their potential to worsen vasospasm due to unopposed α-adrenergic receptor stimulation. In contrast, both CCBs and nitrates are effective in relieving vasospasm and are preferred in the management of variant angina. Nitrates have several limitations outlined above, most notably the need for an 8-to 12-hour nitrate-free interval. Therefore, the role of monotherapy with long-acting nitrates as prophylaxis for anginal attacks due to vasospasm is limited. However, immediate-release nitroglycerin is effective at terminating acute anginal attacks due to vasospasm. Therefore, all patients diagnosed with variant angina should be prescribed immediate-release nitroglycerin. CCBs are effective for monotherapy of variant angina. Since short-acting CCBs have been associated with increased risk of adverse cardiac events, they should be avoided.34 Long-acting nitrates maybe added to CCB therapy if needed.
Elderly Patients With IHD
Elderly patients are more likely than younger patients to have other comorbidities that may influence drug selection for the treatment of angina. As a result, polypharmacy is more common in elderly patients, increasing the risk of drug-drug interactions, and perhaps decreasing medication adherence. Additionally, elderly patients are often more susceptible to adverse effects of antianginal therapies, particularly the negative chronotropic and inotropic effects of β-blockers and CCBs. Therefore, drugs should be initiated in low doses with close monitoring of elderly patients with IHD.
Patient Encounter, Part 3: Creating a Care Plan
Based on the information presented, create a specific plan for the management of RJ’s ischemic heart disease. Your plan should include:
(1) the goals of therapy;
(2) specific nonpharmacologic and pharmacologic interventions to address these goals; and
(3) a plan for follow-up to assess drug tolerance and whether the therapeutic goals have been achieved.
Acute Coronary Syndrome
The management of ACS is discussed in further detail in the chapter on acute coronary syndromes. It is important to educate patients with IHD on the signs of ACS and what to do if they appear. Importantly, patients should be instructed to seek emergent care if symptoms of angina last longer than 20 to 30 minutes, do not improve after 5 minutes of using sublingual nitroglycerin, or worsen after 5 minutes of using sublingual nitroglycerin. In patients with a history of ACS, it is crucial to select appropriate pharmacotherapy to prevent recurrent ACS and death. Appropriate pharmacotherapy for patients with a history of ACS includes aspirin (perhaps in combination with clopidogrel), ACE inhibitors or ARBs, β-blockers, and statins. In addition, determining appropriate goals and instituting appropriate therapy to meet the goals for cardiovascular risk factors (e.g., dyslipidemia, hypertension, and diabetes) is critical.
OUTCOME EVALUATION
Assessing for Drug Effectiveness and Safety
• Monitor symptoms of angina at baseline and at each clinic visit for patients with IHD to assess the effectiveness of antianginal therapy. In particular, assess the frequency and intensity of anginal symptoms. Determining the frequency of sublingual nitroglycerin use is helpful in making this assessment. If angina is occurring with increasing frequency or intensity, adjust antianginal therapy and refer the patient for additional diagnostic testing (e.g., coronary angiography) and possibly for coronary interventions (e.g., PCI or CABG surgery).
• Assess the patient for IHD-related complications, such as heart failure. The presence of new comorbidities may indicate worsening IHD requiring additional workup or pharmacologic therapy.
• Routinely monitor hemodynamic parameters to assess drug tolerance. Assess blood pressure at baseline, after drug initiation and dose titration, then periodically thereafter in patients treated with β-blockers, CCBs, nitrates, ACE inhibitors, and/or ARBs.
• Blood pressure reduction may be particularly pronounced after initiation and dose titration of β-blockers that also possess α-blocking effects (e.g., labetalol and carvedilol).
• Because of the potential for postural hypotension, warn patients that dizziness, presyncope, and even syncope may result from abrupt changes in body position during initiation or up-titration of drugs with α-blocking effects.
• Closely monitor heart rate in patients treated with drugs that have negative chronotropic effects (e.g., β-blockers, verapamil, or diltiazem) or drugs that may cause reflex tachycardia (e.g., nitrates or dihydropyridine CCBs).
• Treatment with β-blockers, verapamil, or diltiazem can usually be continued in patients with asymptomatic bradycardia. However, reduce or discontinue treatment with these agents in patients who develop symptomatic bradycardia or serious conduction abnormalities.
• Regularly assess control of existing risk factors and the presence of new risk factors for IHD. Routine screening for the presence of metabolic syndrome will help in assessing the control of known major risk factors and identifying new risk factors. If new risk factors are identified and/or the presence of metabolic syndrome is detected, modify the pharmacotherapy regimen, as discussed previously, to control these risk factors and lower the risk of IHD and IHD-related adverse events.
• In patients treated with ACE inhibitors and/or ARBs, routinely monitor renal function and potassium levels at baseline, after drug initiation and dose titration, then periodically thereafter. This is particularly important when using these therapies in patients with pre-existing renal impairment or diabetes as they may be more susceptible to these adverse events.
Duration of Therapy
• Drugs that modify platelet activity, lipoprotein concentrations, and neurohormonal systems reduce the risk for coronary events and death. However, these therapies do not cure IHD.
• Treatment with antiplatelet (aspirin or clopidogrel), lipid-lowering, and neurohormonal-modifying therapy for IHD is generally lifelong. Similarly, antianginal therapy with a β-blocker, CCB, and/or nitrate is usually long term.
• A patient with severe symptoms managed with combination antianginal drugs who undergoes successful coronary revascularization maybe able to reduce antianginal therapy. However, treatment with at least one agent that improves the balance between myocardial oxygen demand and supply is usually warranted.
Patient Care and Monitoring
1. Assess the patient’s symptoms to determine whether the patient should be evaluated by a physician.
• Determine the quality, location, and duration of pain.
• Determine factors that provoke and relieve pain.
• Are symptoms characteristic of angina?
2. Identify risk factors for IHD.
• Are there any modifiable risk factors?
3. Obtain a thorough history of prescription drug, nonprescription drug, and herbal product use.
• Is the patient taking any medications/supplements that may exacerbate angina or interact with antianginal drug therapy?
4. Educate the patient on lifestyle modifications to control risk factors for IHD.
5. Is the patient taking appropriate drug therapy to prevent ACS and death? If not, why?
6. Is the patient taking appropriate antianginal therapy? If not, why?
7. Develop a plan to assess effectiveness of anti-ischemic therapy after 1 to 2 weeks.
8. Evaluate the patient to assess for adverse drug reactions, drug intolerance, and drug interactions.
9. Stress the importance of adherence with the therapeutic regimen, including lifestyle modifications.
10. Provide patient education regarding disease state, lifestyle modifications, and drug therapy:
• What are the consequences of untreated IHD?
• What lifestyle modifications should the patient follow?
• When should the patient take his or her medications?
• What potential adverse drug effects may occur?
• Teach the patient how to monitor heart rate and blood pressure to assess tolerance to antianginal therapy.
• Which drugs may interact with therapy or worsen IHD?
• What should the patient do when chest pain or its equivalent occurs?
• When should the patient seek emergent care?
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
REFERENCES
1. Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina—Summary article: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on the Management of Patients With Chronic Stable Angina). J Am Coll Cardiol 2003;41:159–168.
2. Fraker TD Jr., Fihn SD, Gibbons RJ, et al. Chronic angina focused update of the ACC/AHA 2002 guidelines for the management of patients with chronic stable angina: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 guidelines for the management of patients with chronic stable angina. J Am Coll Cardiol 2007;50:2264–2274.
3. Rosamond W, Flegal K, Furie K, et al. Heart disease and stroke statistics—2008 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2008; 117:e25-e146.
4. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality: A meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903–1913.
5. Grundy SM, Howard B, Smith S Jr, et al. Prevention Conference VI: Diabetes and Cardiovascular Disease: Executive summary: Conference proceeding for healthcare professionals from a special writing group of the American Heart Association. Circulation 2002; 105:2231–2239.
6. Ninomiya JK, L’Italien G, Criqui MH, et al. Association of the metabolic syndrome with history of myocardial infarction and stroke in the Third National Health and Nutrition Examination Survey. Circulation 2004;109:42–46.
7. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005;112:2735–2752.
8. Tzivoni D, Keren A, Meyler S, et al. Cardiovascular safety of transdermal nicotine patches in patients with coronary artery disease who try to quit smoking. Cardiovasc Drugs Ther 1998;12:239–244.
9. Braunwald E, Jones RH, Mark DB, et al. Diagnosing and managing unstable angina. Agency for Health Care Policy and Research. Circulation 1994;90:613–622.
10. Sangareddi V, Chockalingam A, Gnanavelu G, et al. Canadian Cardiovascular Society classification of effort angina: An angiographic correlation. Coron Artery Dis 2004;15:1111–1114.
11. Tonstad S, Farsang C, Klaene G, et al. Bupropion SR for smoking cessation in smokers with cardiovascular disease: A multicentre, randomised study. Eur Heart J 2003;24:946–955.
12. Krauss RM, Eckel RH, Howard B, et al. AHA Dietary Guidelines: Revision 2000: A statement for healthcare professionals from the Nutrition Committee of the American Heart Association. Stroke2000;31:2751–2766.
13. Shishehbor MH, Goel SS, Kapadia SR, et al. Long-term impact of drug-eluting stents versus bare-metal stents on all-cause mortality. J Am Coll Cardiol 2008;52:1041–1048.
14. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood Cholesterol in adults (adult treatment panel III). JAMA 2001;285:2486–2497.
15. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227–239.
16. Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk: Consensus conference report from the American Diabetes Association and the American College of Cardiology Foundation. J Am Coll Cardiol 2008;51:1512–1524.
17. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 2003;42:1206–1252.
18. Rosendorff C, Black HR, Cannon CP, et al. Treatment of hypertension in the prevention and management of ischemic heart disease: A scientific statement from the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention. Circulation 2007;115:2761–2788.
19. Tran H, Anand SS. Oral antiplatelet therapy in cerebrovascular disease, coronary artery disease, and peripheral arterial disease. JAMA 2004;292:1867–1874.
20. Patrono C, Baigent C, Hirsh J, Roth G. Antiplatelet drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133:199S–233S.
21. Grines CL, Bonow RO, Casey DE Jr, et al. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: A science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. Circulation 2007;115:813–818.
22. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494–502.
23. Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: Randomised placebo-controlled trial. Lancet 2005;366:1607–1621.
24. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: Prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267–1278.
25. Liao JK. Effects of statins on 3-hydroxy–3-methylglutaryl coenzyme A reductase inhibition beyond low-density lipoprotein cholesterol. Am J Cardiol 2005;96:24F–33F.
26. Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:1893–1906.
27. Rodrigues EJ, Eisenberg MJ, Pilote L. Effects of early and late administration of angiotensin-converting enzyme inhibitors on mortality after myocardial infarction. Am J Med 2003;115: 473–479.
28. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145–153.
29. Fox KM. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003;362:782–788.
30. Freemantle N, Cleland J, Young P, Mason J, Harrison J. Beta Blockade after myocardial infarction: Systematic review and meta regression analysis. BMJ 1999;318:1730–1737.
31. Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet 2001;357:1385–1390.
32. Packer M, O’Connor CM, GhaliJK, etal. Effect of a mlodi pineonmorbidity and mortality in severe chronic heart failure. Prospective Randomized Amlodipine Survival Evaluation Study Group. N Engl J Med 1996; 335:1107–1114.
33. Cohn JN, Ziesche S, Smith R, et al. Effect of the calcium antagonist felodipine as supplementary vasodilator therapy in patients with chronic heart failure treated with enalapril: V-HeFT III. Vasodilator-Heart Failure Trial (V-HeFT) Study Group. Circulation 1997;96: 856–863.
34. Psaty BM, Smith NL, Siscovick DS, et al. Health outcomes associated with antihypertensive therapies used as first-line agents. A systematic review and meta-analysis. JAMA 1997;277:739–745.
35. Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, et al. Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: The MERLIN-TIMI 36 randomized trial. JAMA 2007;297:1775–1783.
36. Chaitman BR, Pepine CJ, Parker JO, et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: A randomized controlled trial. JAMA 2004;291:309–316.
37. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605–613.
38. Heiss G, Wallace R, Anderson GL, et al. Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA 2008;299:1036–1045.
39. Willcox BJ, Curb JD, Rodriguez BL. Antioxidants in cardiovascular health and disease: key lessons from epidemiologic studies. Am J Cardiol 2008;101:75D–86D.
40. Bleys J, Miller ER, 3rd, Pastor-Barriuso R, Appel LJ, Guallar E. Vitamin-mineral supplementation and the progression of atherosclerosis: A meta-analysis of randomized controlled trials. Am J Clin Nutr 2006; 84:880–887; quiz 954–955.
41. Vivekananthan DP, Penn MS, Sapp SK, Hsu A, Topol EJ. Use of antioxidant vitamins for the prevention of cardiovascular disease: Meta-analysis of randomised trials. Lancet 2003;361:2017–2023.
42. Cook NR, Albert CM, Gaziano JM, et al. A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: Results from the Women’s Antioxidant Cardiovascular Study. Arch Intern Med 2007;167:1610–1618.
43. Malinow MR, Bostom AG, Krauss RM. Homocyst(e)ine, diet, and cardiovascular diseases: A statement for healthcare professionals from the Nutrition Committee, American Heart Association. Circulation 1999;99:178–182.
44. Bazzano LA, Reynolds K, Holder KN, He J. Effect of folic acid supplementation on risk of cardiovascular diseases: A meta-analysis of randomized controlled trials. JAMA 2006;296:2720–2726.
45. Albert CM, Cook NR, Gaziano JM, et al. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: A randomized trial. JAMA 2008;299:2027–2036.
46. Bennett JS, Daugherty A, Herrington D, et al. The use of nonsteroidal antiinflammatory drugs (NSAIDs): A science advisory from the American Heart Association. Circulation 2005;111:1713–1716.
47. Gislason GH, Jacobsen S, Rasmussen JN, et al. Risk of death or reinfarction associated with the use of selective cyclooxygenase–2 inhibitors and nonselective nonsteroidal antiinflammatory drugs after acute myocardial infarction. Circulation 2006;113:2906–2913.