Stable Angina
Amar Krishnaswamy
Samir R. Kapadia
I. INTRODUCTION.
Angina pectoris, derived from the Greek “ankhon” (strangling) and the Latin “pectus” (chest), is the term used to describe the syndrome of chest discomfort resulting from myocardial ischemia. Angina is characterized as stable or unstable on the basis of symptom pattern.
A. Anginal symptoms are defined as stable if there is no substantial change in symptoms over several weeks. Symptoms of stable angina can fluctuate from time to time, depending on myocardial oxygen consumption, emotional stress, or change in ambient temperature. In general, the clinical definition of stable angina pectoris closely correlates with the stability or quiescence of an atherosclerotic plaque and decreased clinical risk.
B. Angina is said to be unstable when the symptom pattern worsens abruptly (increase in frequency and duration) without an obvious cause of increased myocardial oxygen consumption. Similarly, the onset of rest angina in a patient for whom angina was previously provoked by some degree of exertion may signal an unstable syndrome.
C. For some patients with new-onset angina that has been stable over a few weeks, clear distinction between stable and unstable angina is not possible. These patients can be considered to be in an intermediate stage between unstable and stable angina.
II. CLINICAL PRESENTATION.
For most patients with chest pain, the diagnosis of angina pectoris can be made with careful history taking. The presence of risk factors for coronary artery disease (CAD), such as hypertension, diabetes mellitus, smoking, family history, hyperlipidemia, claudication, and advanced age, increases the likelihood that the chest pain is being caused by myocardial ischemia.
A. Signs and symptoms.
The constellation of symptoms characteristic of angina pectoris includes the following four cardinal features.
1. Location. Discomfort is commonly located in the retrosternal area with radiation to the neck, shoulders, arms, jaws, epigastrium, or back. In some instances, it involves these areas without affecting the retrosternal area.
2. Relation to a trigger. Symptoms are typically triggered by physical activity, emotional stress, exposure to cold, consumption of a heavy meal, or smoking.
a. Some patients will experience the resolution of angina despite continued exertion, which is known as the walk-through phenomenon. Others may experience the warm-up phenomenon, in which an initial exertion produces angina but a similar second exertion does not reproduce anginal symptoms. These circumstances probably result from the recruitment of collateral coro nary flow during the initial episode of ischemia.
b. Decubitus angina, which is a less common manifestation, occurs with a change in posture and is believed to be caused by a shift in blood volume. Nocturnal angina, which occurs at night, is frequently associated with night mares and tachyarrhythmias.
3. Character. Most patients describe angina as a vague chest discomfort. They describe it as a squeezing, burning, tight, choking, heavy, and occasionally hot or cold sensation. Many patients do not perceive angina as pain per se. Some patients may experience dyspnea, profound fatigue, weakness, lightheadedness, nausea, diaphoresis, altered mental status, or syncope in the absence of any chest discomfort. These symptoms are often referred to as anginal equivalents. Noncardiac causes of chest pain (gastrointestinal, respiratory, musculoskeletal, etc.) may be indicated by fleeting chest pain, unrelenting chest pain not affected by activity, antecedent chest trauma, association with food intake, location inferior to the umbilicus, pleurisy, etc.
4. Duration. The chest pain associated with ischemia typically lasts 3 to 5 minutes. Ischemic pain usually does not last more than 30 minutes without causing myocardial infarction (MI). Chest pain triggered by emotional distress tends to last longer than that triggered by exercise. Chest pain that lasts < 1 minute is unlikely to be of cardiac origin, especially when it is not associated with other typical symptoms or findings.
5. It should be stressed that women may present with symptom constellations that may be atypical in location or quality in comparison to the symptoms described by men or manifest as anginal equivalents such as nausea or dyspnea.
6. Chest pain is defined as “typical angina” if it consists of characteristic substernal discomfort, is provoked by stress, and is relieved by rest or nitroglycerin. It is considered “atypical” if it involves two or less of the previously mentioned criteria.
7. Classification. Various classifications are available to assess the severity and to predict the outcome among patients with angina. The Canadian Cardiovascular Society classification is the most popular one (Table 6.1). Other classification systems include the Specific Activity Scale, the Duke Activity Status Index, and the Braunwald classification.
B. Physical findings.
For patients with a history of chest pain, physical examination helps identify risk factors for CAD and occult cardiac abnormalities.
1. The signs associated with a high risk for CAD include elevated blood pressure or manifestations of hypertensive vascular disease such as retinal arteriopathy, signs of hyperlipidemic conditions including corneal arcus or xanthelasma, and evidence of carotid or other peripheral vascular disease.
TABLE 6.1 Classification of Angina | ||||||||||||||||||
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2. Physical examination performed during an episode of chest pain may reveal rales, an S3 or S4 gallop, or a systolic murmur from ischemic mitral regurgitation, all of which generally disappear with resolution of symptoms.
C. Baseline electrocardiogram (ECG)
1. A baseline ECG is useful for the initial screening of CAD, although about 60% of patients with chest pain have a normal ECG. Presence of a Q wave or persistent ST depression is associated with an unfavorable outcome. The ECG can also demonstrate other abnormalities, such as left ventricular (LV) hypertrophy, bundle branch block, and preexcitation syndromes.
2. Information obtained from the ECG is useful in the assessment of chest pain and helps to stratify patients who are at risk for an adverse event.
3. ECG at the time of chest pain can also help identify the cause of the chest pain. Transient changes in the T-wave, ST-segment, or conduction patterns point toward a cardiac source of the chest pain. A normal ECG does not exclude ischemia as being the etiology of chest pain.
III. DIAGNOSTIC TESTING.
For a patient with stable CAD, investigations are aimed at risk stratification and management of symptoms and unfavorable outcomes.
A. Stress testing.
The basic principle of stress testing is to provoke ischemia or produce coronary vasodilation, followed by functional assessment with different systems to detect ischemia. Stress tests can be categorized according to the methods used to provoke and detect myocardial ischemia. The sensitivity and specificity of each test to identify coronary stenosis vary according to the study population, definition of disease, definition of a positive test result, protocol used for the stress testing, and experience of the interpreter. The following is a brief overview of noninvasive cardiac testing. For a thorough discussion on noninvasive imaging and stress modalities, please refer to the specific chapters.
1. Methods to induce ischemia.
Exercise is the most physiologically sound and useful method for inducing ischemia. An exercise test is considered adequate if 85% or more of age-predicted maximum heart rate (220 — age) is achieved. Exercise testing provides an objective assessment of functional capacity, which provides useful prognostic information. Pharmacologic testing, with dobutamine or adenosine/adenosine derivatives (i.e., dipyridamole), can be used for patients who cannot exercise adequately.
2. Methods to assess ischemia
a. Stress ECG. Exercise ECG provides useful diagnostic information about the patients with normal baseline ECGs who are at intermediate risk for CAD. Stress ECG is also used to create an exercise prescription in patients with stable angina. The sensitivity and specificity of stress ECG are poor among patients with an abnormal baseline ECG, LV hypertrophy, ventricu lar pacing, left bundle branch block (LBBB), or intraventricular conduction disturbance and among patients taking digitalis or other medications that affect conduction and depolarization. Electrocardiographic changes during dipyridamole or adenosine infusion have high specificity but poor sensitivity. Electrocardiographic changes during dobutamine infusion have sensitivity and specificity similar to those of exercise ECG.
b. Echocardiographic imaging. Stress echocardiography is an economical test with good specificity for identifying the location and extent of ischemic terri tories. This is assessed by the induction of regional wall motion abnormalities with stress or dilation of the left LV cavity with stress (which may indicate global ischemia). If the patient is unable to exercise, a dobutamine stress test can be performed. A biphasic response with dobutamine, in which contrac tility initially increases with lower doses of dobutamine and then decreases with higher doses, is diagnostic of ischemia. Augmentation of contractility in hypokinetic segments may indicate the presence of hibernating myocardium in a specific coronary distribution. At some medical centers, dipyridamole and adenosine stress tests are performed with echocardiographic imaging. This method is less sensitive in detecting underlying CAD. Results of stress echocardiography are difficult to interpret in some patients with a hyper tensive response to exercise and in some patients with severe mitral or aortic regurgitation. Preexisting wall motion abnormalities may further complicate image interpretation.
c. Radionuclide imaging. Single-positron emission computed tomography (SPECT) can be performed after injection with thallium 201 or technetium (Tc) 99m—labeled radiopharmaceuticals. Positron emission tomography (PET) can be performed utilizing rubidium 82 or 13N ammonia tracers. PET imaging provides greater spatial resolution and diagnostic accuracy in comparison with SPECT imaging. Injection of fluorine 18—labeled deoxyglucose (FDG) allows assessment of myocardial viability in patients with resting perfusion defects. The sensitivity and specificity of nuclear testing are decreased among patients with severe obesity, balanced three-vessel disease, and LBBB.
B. Echocardiography
provides useful information in the overall assessment of sus pected stable angina.
1. Regional wall motion abnormalities involving the left ventricle are commonly caused by CAD and may represent resting ischemia or prior MI. Any impairment in LV systolic function, LV hypertrophy, and presence of substantial mitral regurgitation are associated with heightened clinical risk and poor outcome. LV systolic function may guide the choice of medical therapy versus revascularization.
2. Echocardiography is the test of choice to quantify aortic stenosis or the presence of hypertrophic cardiomyopathy.
C. Magnetic resonance imaging (MRI)
1. Ischemic evaluation using pharmacologic stress (dobutamine or adenosine) and cardiovascular magnetic resonance can also be utilized to evaluate myocardium in jeopardy. MRI uses gadolinium as a contrast medium to evaluate regional wall motion abnormalities and ejection fraction, as well as segmental myocardial perfusion (when using adenosine). MRI can also provide direct visualization of the
coronary arteries, although computed tomography (CT) angiography is much better for this application.
coronary arteries, although computed tomography (CT) angiography is much better for this application.
2. Delayed-phase gadolinium imaging also provides information on the location and transmurality of myocardial scar.
3. The weaknesses include increased cost, lack of portability, and unsuitability for use in the growing population of patients with pacemakers and defibrillators.
D. Electron beam computed tomography (EBCT)
1. EBCT is a noninvasive method of obtaining cross-sectional images of the heart and allows quantification of coronary artery calcification. The test is rapid and provides a “calcium score.” This test does not provide sufficient detail to accurately quantify and grade stenosis due to atherosclerotic lesions. An increasing calcium score correlates strongly with heightened risk of cardiovascular events and abnormal findings should lead to further risk factor modification and cardiovascular risk assessment.
E. Multidetector computed tomography
1. Strengths.
Coronary computed tomography angiography (CCTA) allows for the evaluation of the epicardial coronary tree using a noninvasive approach. The sensitivity of CCTA for assessing coronary stenosis approaches 97% with a specificity of 86% when using a 64-slice technology. With technologic advances allowing a greater number of slices to be acquired in current practice, the accuracy of this study is expected to increase. Importantly, the negative predictive value of CCTA is 99%, with an optimal study and appropriate patient selection. Severe coronary artery calcification or previous coronary stent placement may significantly detract from image quality, rendering the evaluation of specific coronary segments uninterpretable. Larger stents may be grossly evaluated for patency but accurate quantification for in-stent restenosis in anatomical locations distal to the left main coronary artery (LMCA) is not always feasible.
F. Coronary angiography
1. Strengths.
Coronary angiography is the standard for anatomic assessment of coronary arterial stenosis and provides important prognostic information.
a. Patients with > 75% stenosis involving at least one coronary artery have a lower survival rate than patients with 25% to 50% or < 25% stenosis. Even for mild stenosis, risk for MI is markedly higher than for no stenosis.
b. The severity of lesions demonstrated with angiography is not predictive of plaque stability; two-thirds of patients with acute MI have stenosis of > 50% diameter at the site of plaque rupture before MI. It is possible, however, to assess plaque instability on the basis of angiographic characteristics or mor phologic features of the lesion.
(1) Eccentric lesions with narrow necks, overhanging edges, or scalloped borders (type II plaques) are more unstable than concentric lesions with smooth borders (type I plaques).
(2) Lesion roughness (i.e., irregular borders) is predictive of plaque instability and heightens the risk of future infarction.
(3) The morphologic characteristics of the plaque help in judging the feasibility and risk of percutaneous or surgical intervention.
c. Ventriculography performed at the time of selective coronary angiography adds an important dimension to risk stratification by providing an index of LV systolic function and regional wall motion characteristics as well as the presence and degree of mitral regurgitation.
2. Indications.
In the management of stable angina, use of angiography is variable. An American College of Cardiology and American Heart Association (ACC/AHA) task force classified the indications for coronary angiography into three categories. The relevant indications in the context of stable angina are presented in Table 6.2.
TABLE 6.2 Indications for Coronary Angiography in Stable Angina | ||||||||||||||||||||||||
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3. Limitations.
Coronary angiography underestimates plaque burden, possibly because of vascular remodeling and the diffuse nature of the disease. Coronary angiography does not depict intraluminal plaque burden and does not show coronary flow reserve. Adjunctive use of intravascular ultrasonography (IVUS) greatly facilitates the investigation of hazy areas on coronary angiograms, which may be caused by calcium, thrombus, severe eccentric lesion, or dissection. The IVUS can also assess positive and negative remodeling, which has been shown to correlate with stable and unstable syndromes.
G. Intravascular ultrasonography
allows visualization of the cross-sectional image of coronary arteries. This modality helps to quantitate plaque area, artery size, and luminal stenosis; assess hazy areas on coronary angiograms, questionable areas of stenosis, and extent of stenosis; and sometimes determine the calcium content of a plaque. Hypodense areas in a plaque may correlate with high lipid content, which may indicate fast-growing or potentially unstable plaque. This information can help
assess the need for and options of therapy. This modality does not, however, have a role in routine evaluation of patients with stable angina, due to the invasive nature of the test.
assess the need for and options of therapy. This modality does not, however, have a role in routine evaluation of patients with stable angina, due to the invasive nature of the test.
H. Optical coherence tomography (OCT)
is a relatively new intracoronary imaging modality that has better resolution than IVUS but provides less depth. It has been used, thus far, almost exclusively as a research tool, but a number of studies are currently ongoing to establish its clinical utility. Potential contributions of OCT include characterization of plaque, better understanding of stent characteristics (degree of apposition and stent endothelialization, etc.), and arterial remodeling. This technique requires injection of contrast medium during imaging (usually totaling 12 to 20 cc per run) and so may be of limited use in patients with chronic kidney disease.
I. Invasive functional assessment.
Invasive assessment of the functional significance of an intermediate stenosis can be made by means of coronary blood flow measurement with intracoronary Doppler ultrasound and direct measurement of a pressure gradient across a stenosis.
1. With the help of a small transducer mounted on a guidewire, coronary blood flow can be measured by means of a fixed sample volume and pulsed Doppler.
a. In the left coronary artery, most coronary flow occurs during diastole. In normal arteries, a ratio of proximal-to-distal flow velocity approaching 1 is considered normal. In the presence of coronary stenosis, coronary blood flow becomes mainly systolic because the diastolic component of the flow is jeopardized first.
b. Three indices can help identify physiologically important stenoses:
(1) Diastolic-to-systolic average peak coronary flow velocity ratio of < 1.8 distal to the obstruction
(2) A proximal-to-distal average peak coronary flow velocity ratio of > 1.7
(3) Coronary flow reserve (i.e., increase in coronary flow with adenosine, which is administered after intracoronary nitroglycerin) with a less than twofold increase in peak velocity
2. Direct measurement of pressure gradients can be accomplished with a transducer mounted on a catheter. Ratio of mean pressure distal and proximal to the lesion after maximum vasodilation (fraction flow reserve or FFR) of < 0.75 to 0.80 indicates a hemodynamically significant lesion. These techniques supplement angiography in determining the functional significance of an intermediate (30% to 70%) angiographic stenosis. In a group of patients with angiographically intermediate stenosis, the Fractional Flow Reserve versus Angiography for Multivessel Evaluation (FAME) investigators were able to demonstrate lower rates of mortality and MI (8.4% vs. 23.9%, p = 0.02) with less stent placement when a strategy of FFR-guided (vs. angiography-guided alone) percutaneous coronary intervention (PCI) was pursued.
J. Holter monitoring
1. After MI, increased ventricular ectopy is predictive of increased cardiovascular morbidity and mortality. This association is less important among patients with stable angina without prior MI, and routine Holter testing for risk stratification is not indicated. No medical treatment aimed at suppressing ventricular ectopy has been shown to improve outcome.
IV. THERAPY.
The goals of therapy are to prevent cardiovascular morbidity and mortality and to improve quality of life.
A. Therapeutic options.
Medical therapy, PCI, and coronary artery bypass grafting (CABG) have all been shown to control symptoms and improve exercise time to ischemia. In an era of rudimentary medical therapy, CABG has been proven to decrease cardiovascular mortality in specific patient subsets. Although PCI has been shown to improve stable anginal symptoms and improve quality of life, a decrease in mortality has not been proven in randomized controlled trials (RCTs).
B. Pharmacologic therapy
1. Platelet inhibitors
a. The Antiplatelet Trialists’ Collaboration was a meta-analysis that included approximately 100,000 patients from 174 trials involving antiplatelet ther apy. This data set showed that aspirin (acetylsalicylic acid, ASA) reduced the rate of stroke, MI, and death among high-risk patients, including those with stable angina without previous MI. A recent systematic review confirms that, while optimal dosing is controversial, there is general support in the literature for limiting the dose of ASA to 75 to 81 mg daily. Approximately 5% to 10% of patients with CAD have aspirin resistance, defined as a lack of decrease in platelet function associated with aspirin use. Aspirin resistance has been shown to result in higher thrombotic events in people with periph eral vascular disease. Patients who demonstrate increased platelet reactivity despite aspirin therapy have increased risks for stroke, MI, and vascular death compared with aspirin responders.
b. Among patients with true allergy or intolerance to aspirin, clopidogrel has been shown to decrease the frequency of fatal and nonfatal vascular events in peripheral, cerebral, and coronary vessel diseases.
(1) Clopidogrel is a second-line therapy in patients unable to tolerate aspirin. In high-risk patients with prior cardiac surgery or ischemic events, the use of clopidogrel as monotherapy, or in addition to aspirin, is beneficial. In patients receiving bare-metal stenting (BMS) for stable coronary disease, at least 1 month of dual antiplatelet therapy (DAPT; aspirin 81 mg plus clopidogrel 75 mg daily) is recommended. The use and duration of DAPT with clopidogrel and aspirin in the setting of drug-eluting stent (DES) implantation are currently under intense review, with concerns of very late stent thrombosis (ST) on one hand and studies questioning the benefit of extended duration DAP on the other. The most recent ACC/AHA PCI guidelines recommend 12 months of DAPT in patients undergoing DES, though longer duration may be considered (class IIb) in specific high-risk patient/stent subsets. Clopidogrel is usually well tolerated and has few side effects.
(2) In the initial analysis of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial, performed on a large group of patients included with either prior cardiovascular events or multiple cardiovascular risk factors, there was no benefit from the use of DAPT over aspirin alone in preventing MI or death. A prespecified analysis of higher risk patients only (such as those with prior MI) did show a decrease in cardiovascular events for the group receiving clopidogrel in addition to aspirin. This suggests that an appropriate group of patients may benefit from prolonged DAPT.
2. Lipid-lowering agents. Among patients with established CAD, secondary prevention with lipid-lowering therapy, specifically statins, has demonstrated marked reduction in risk for subsequent cardiovascular events. Statins are potent inhibitors of 3-hydroxy-3-methylglutaryl coenzyme reductase (HMG-CoA reductase). They are the most effective medical therapy for lowering levels of low-density lipoprotein (LDL) and have also been shown to upregulate nitric oxide (NO) synthase, decrease expression of endothelin-1 mRNA, improve platelet function, and decrease production of detrimental free radicals; all of these promote normal endothelial function.
a. Indications. The Scandinavian Simvastatin Survival Study (4S), Cholesterol and Recurrent Events (CARE), Long-term Intervention with Pravastatin in Ischemic Disease (LIPID), and Heart Protection Study (HPS) trials have provided convincing evidence that in patients with evidence of cardiovascular
disease with normal or elevated cholesterol levels, statins decrease mortality, the rate of MI and stroke, and the need for CABG.
disease with normal or elevated cholesterol levels, statins decrease mortality, the rate of MI and stroke, and the need for CABG.
b. Effectiveness. Recent studies have shown that in patients with stable CAD (treating to new targets [TNT]) or post-acute coronary syndrome (ACS) (PROVE IT-TIMI-22), aggressive lipid lowering to an LDL goal of 70 mg/dL decreases the risks of cardiovascular death, MI, and stroke compared with patients treated to an LDL goal of 100 mg/dL. There is also a suggestion that aggressive statin therapy retards and even results in a mild degree of plaque regression as measured by IVUS.
c. Choice of agents. Statins should be the first line of therapy in patients with CAD. The quantification of lipoprotein(a) [Lp(a)], fibrinogen, apolipoprotein (apo A), and apolipoprotein B100 (apo B100) is investigational. Bile acid sequestrants primarily reduce LDL cholesterol and should not be used in patients with triglyceride levels higher than 300 mg/dL, because these agents may exacerbate hypertriglyceridemia. Nicotinic acid reduces LDL and triglyceride levels and is the most effective of the available lipid-lowering medications at increasing high-density lipoprotein (HDL) level. It is also the only agent that lowers Lp(a). Fibric acid derivatives are most effective against hypertriglyceridemia; they raise HDL level modestly and have little effect on LDL. They are the first line of treatment in patients with triglyceride levels higher than 400 mg/dL. ω-3 Fatty acids may also be used to treat hypertri glyceridemia that is refractory to niacin and fibric acid therapy. Agents to raise HDL cholesterol, cholesteryl ester transfer protein inhibitors, are cur rently undergoing intensive clinical evaluation in RCTs and may provide a beneficial treatment adjunct to statin therapy in the future.
