Manual of Cardiovascular Medicine

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 pectoris (often abbreviated to angina) is characterized as stable or unstable based on 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.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 coronary flow during the initial episode of ischemia.

b.“Decubitus angina,” which is a less common manifestation, occurs with a change in posture believed to be caused by a shift in blood volume. Nocturnal angina, which occurs at night, is frequently associated with nightmares 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 [GI], 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, and so on.

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.

Women may present with symptom constellations that may be different in location or quality in comparison to the symptoms described by men or may have ischemia manifest as anginal equivalents, such as nausea or dyspnea.

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 fewer of the previously mentioned criteria.

5.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 (Table 6.1). Other classification systems include the Specific Activity Scale, the Duke Activity Status Index, and the Braunwald classification.

TABLE 6.1 Classification of Angina
CCS Class	Definition	Comment
I	Ordinary physical activity does not cause angina	Angina only with extraordinary exertion at work or recreation
II	Slight limitation of ordinary activity	Angina with walking more than two blocks on a level surface or climbing more than one flight of stairs at a normal pace
III	Marked limitation of ordinary physical activity	Walking one to two blocks on a level surface or climbing one flight of stairs at a normal pace
IV	Inability to carry on any activity without discomfort	Angina at rest or with minimal activity or stress

CCS, Canadian Cardiovascular Society.

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.

2.Physical examination performed during an episode of chest pain may reveal rales, tachycardia, hypertension, 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 the majority of patients with chest pain have a normal ECG. Presence of pathologic Q-waves 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; however, a normal ECG does not exclude ischemia as being the etiology of chest pain.

III.DIAGNOSTIC TESTING. For a patient with stable symptomatic 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 modalities 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 dedicated chapters 46, 47.

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 minus 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 to an adequate heart rate.

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, ventricular pacing, left bundle branch block (LBBB), or intraventricular conduction disturbance and among patients taking digitalis or other medications that affect conduction and depolarization. Ischemic electrocardiographic changes during vasodilator testing 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 territories. This is assessed by the induction of regional wall motion abnormalities with stress or dilation of the LV cavity with stress (which may indicate global ischemia). Exercise is preferred in patients with intermediate or high pretest probability who are able to exercise. If the patient is unable to exercise, a dobutamine stress test can be performed. A biphasic response with dobutamine, in which contractility 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 hypertensive 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. In addition, PET enables quantification of coronary blood flow and assessment of coronary flow reserve. Injection of fluorine 18–labeled deoxyglucose allows assessment of myocardial viability in patients with resting perfusion defects. The sensitivity and specificity of SPECT nuclear testing are decreased among patients with severe obesity, balanced three-vessel disease, and LBBB.

B.Resting echocardiography provides useful information in the overall assessment of suspected 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/or presence of substantial mitral regurgitation are associated with heightened clinical risk and poorer 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 be used 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 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 of MRI include high cost, lack of portability, and unsuitability for use in many patients with pacemakers and defibrillators.

D.Electron beam computed tomography (EBCT)

1.EBCT is a noninvasive method that 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 because of 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.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 64-slice technology. 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 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 morphologic 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

Class I (general agreement among cardiologists)

Severe anginal symptoms (CCS class III or IV) with OMT (LOE C)

Noninvasive testing indicates high risk of coronary disease (LOE C)

Survivors of sudden cardiac death or potentially fatal ventricular tachyarrhythmia (LOE B)

Symptoms of congestive heart failure with angina (LOE B)

Class II (frequently used but controversial)

Symptoms of angina and an LV ejection fraction <50% with intermediate risk/demonstrable ischemia (IIa, LOE C)

Symptoms of angina and positive stress test (IIa, LOE C)

Inadequate information from noninvasive testing (IIa, LOE C)

Severe angina with preserved ventricular function and intermediate risk noninvasive testing (IIa, LOE C)

Patients who are unable to be evaluated noninvasively (IIa, LOE C)

Patients who cannot undergo stress testing with a high pretest probability of coronary disease (IIa, LOE C)

Suspicion of left main or three-vessel coronary disease (IIa, LOE C)

Class III (unjustified use of angiography)

Low-risk patients who have not had noninvasive testing (LOE C)

Patients with a preserved LV ejection fraction (>50%) and low risk (LOE B)

Mild symptoms that resolve with medical therapy (LOE C)

Patients who would not or cannot undergo revascularization (LOE B)

CCS, Canadian Cardiovascular Society; LOE, level of evidence; LV, left ventricular; OMT, optimal medical therapy.

3.Limitations. Coronary angiography underestimates plaque burden, possibly because of vascular remodeling and the diffuse nature of the disease. Coronary angiography is insensitive to intraluminal plaque burden and does not show coronary flow reserve. Adjunctive imaging and functional testing facilitates the investigation of hazy areas on coronary angiograms, which may be caused by calcium, thrombus, severe eccentric lesion, or dissection.

G.Intravascular ultrasound 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 and morphology 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 defined role in routine evaluation of patients with stable angina, because of the invasive nature of the test.

H.Optical coherence tomography (OCT) is an intracoronary imaging modality that has better resolution than intravascular ultrasound (IVUS) but provides less depth. Benefits of OCT include visualization of thrombus and thin-cap atheroma, 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 8 to 15 cc per run) and is relatively contraindicated 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 stenosis:

(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 [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 outcomes.

IV.THERAPY. The goals of therapy in stable CAD 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 had 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 therapy. 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. There is general support in the literature for limiting the dose of ASA to 75 to 81 mg daily, and the most recent ACC/AHA guidelines assign a class I, level of evidence (LOE) A, recommendation to aspirin therapy.

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.

c.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 dual antiplatelet therapy (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.

d.The benefits of prolonged DAPT in secondary prevention observed in CHARISMA were confirmed in the Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction (TIMI) 54 trial. In patients who had an MI 1 to 3 years prior, both ticagrelor dosages at 90 and 60 mg twice daily with aspirin reduced the risk of death, MI, and stroke by approximately 15% compared with low-dose aspirin alone. This strategy came with a significantly increased risk (p < 0.001) of TIMI major bleeding (2.6% and 2.3% with ticagrelor 90 and 60 mg, respectively, compared with 1.06% with aspirin alone).

e.Patients with stable CAD who undergo stenting with a bare-metal stent (BMS) should receive DAPT (aspirin + clopidogrel) for at least 1 month; when a drug-eluting stent (DES) is utilized, the treatment should be extended for at least 6 months. Patients who tolerate DAPT without significant bleeding concerns should be considered for longer duration DAPT treatment. This is best achieved on a patient-by-patient basis by reviewing the potential bleeding risk of the patient against the anticipated ischemic risk. A number of clinical and procedural variables need to be considered in this decision and risk scores like the DAPT score are useful in making this decision.

2.Antithrombotic therapy: Historically only stable CAD patients with a primary indication for long-term anticoagulation like atrial fibrillation or mechanical prosthetic valve have been treated with this class of agents. The Cardiovascular Outcomes for People Using Anticoagulation Strategies trial evaluated the of role rivaroxaban (2.5 mg twice) with low-dose aspirin, compared to rivaroxaban 5 mg twice daily and aspirin alone in 27,936 subjects with stable atherosclerotic disease. Over 23 months of follow-up, the combination of low-dose rivaroxaban and aspirin was associated with a 24% risk reduction in the composite cardiovascular death, stroke, and MI (4.1% vs. 5.4%, p < 0.001), but was associated with increased major bleeding events (3.1% vs. 1.9%, p < 0.01). Consequently, these agents will have a role in stable CAD patients at high ischemic risk who are felt to have a low or acceptable risk of bleeding.

3.Lipid-lowering agents. 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. 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 messenger ribonucleic acid, improve platelet function, and decrease production of detrimental free radicals; all of these promote normal endothelial function.

a.Indications. The Scandinavian Simvastatin Survival Study, Cholesterol and Recurrent Events, Long-term Intervention with Pravastatin in Ischemic Disease, and Heart Protection Study 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.

b.Effectiveness. Studies have shown that in patients with stable CAD (treating to new targets trial) or post-acute coronary syndrome (ACS) evaluation and infection therapy–thrombolysis in myocardial infarction 22 (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. Recent trials with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors and ezetimibe have confirmed further reduction in cardiovascular events when LDL is reduced to 30 mg/dL. Achieving very low LDL levels <25 mg/dL in this population has not been associated with any noted side effects.

c.Choice of agents. Statins should be the first line of therapy in patients with established CAD. Provision of statin therapy in this population carries a class I, LOE A, recommendation in the absence of contraindications. Ezetimibe may be added to statins to further reduce LDL levels. PCSK9 inhibitors have been shown to reduce LDL dramatically in those intolerant to statins and in others unable to reach target LDL levels on maximum tolerated statin therapy. Fibric acid derivatives and ω-3 fatty acids may be considered to treat residual hypertriglyceridemia following maximal statin treatment. Although low high-density lipoprotein (HDL) levels are associated with increased cardiovascular risk, it is not a target for intervention because agents that increase HDL have not been shown to improve outcome.

d.Guidelines. Current guidelines support aggressive lowering of LDL cholesterol levels in patients with established coronary disease with moderate- (if over age 75) or high-intensity (if under 75 years old) statin therapy with a goal of ≥50% LDL cholesterol reduction. Recent evidence, however, supports intensive LDL reduction to achieve LDL levels <70 mg/dL in this population because trails that achieved lower LDL levels are associated with additional clinical benefit. As a result, addition of nonstatin agents (PCSK9 inhibitors or ezetimibe) to further drive down LDL levels may be considered. This decision can be guided by additional LDL cholesterol reduction desired, patient choice, cost, and drug tolerability. Patients at highest risk to develop clinical events include older individuals aged 65 years, patients with prior MI or nonhemorrhagic stroke, active smokers, presence of symptomatic peripheral artery disease with prior MI or stroke, history of non-MI–related coronary revascularization, presence of residual CAD with >40% stenosis in two major epicardial vessels, HDL cholesterol <40 mg/dL for men and <50 mg/dL for women, high-sensitivity C-reactive protein >2 mg/L, or presence of metabolic syndrome.

4.Nitrates (Table 6.3)

TABLE 6.3 Nitrates

Medication

Route of Administration

Each Dose

Frequency

Nitroglycerin (glyceryl trinitrate, Nitro-Bid, Nitrostat, and Nitro-Dur)

Sublingual tablet

Sublingual spray

Sustained-release capsule

Ointment (topical)

Disk (patch)

Intravenous

Buccal tablet

0.15–0.6 mg

0.4 mg

2.5–9.0 mg

0.5″–2″ (1.25–5 cm)

1 disk (2.5–15 mg)

5–400 µg/min

1 mg

As needed

Every 6–12 h

Every 4–8 h

Every 24 h

Continuous

Every 3–5 h

Isosorbide dinitrate (Isordil, Sorbitrate, and Dilatrate SR)

Sublingual tablet

Chewable tablet

Oral tablet

Sustained-release tablet

2.5–10 mg

5–10 mg

10–40 mg

40–80 mg

Every 2–3 h

Every 6 h

Every 8–12 h

Isosorbide-5-mononitrate (Imdur and Ismo)

Sublingual tablet

Sustained release

10–40 mg

60 mg

Every 12 h

Every 24 h

Erythrityl tetranitrate (Cardilate)

Sublingual tablet

5–10 mg

10 mg

As needed

Every 8 h

a.Mechanism of action. Nitrates decrease cardiac workload and oxygen demand by means of reducing preload and afterload of the left ventricle. They also redistribute blood flow to the ischemic subendocardium by means of decreasing LV end-diastolic pressure, vasodilation of epicardial vessels, and improvement of collateral blood flow to ischemic tissue. Nitrates may also be weak inhibitors of platelet aggregation, although the clinical relevance of this is unclear.

b.Evidence for effectiveness. Nitrates can decrease exercise-induced myocardial ischemia, alleviate symptoms, and increase exercise tolerance in patients with stable angina.

(1)Adding nitrates to an optimal β-blocker regimen does not improve frequency of anginal episodes, glyceryl trinitrate consumption, exercise duration, or duration of silent ischemia.

(2)In some small studies, the efficacy of nitrates in reducing anginal episodes was increased with concomitant use of angiotensin-converting enzyme (ACE) inhibitors.

(3)No study has shown survival benefit with the use of nitrates to treat patients with chronic stable angina.

c.Selection of preparations. Because nitrates have a fast onset of action, a sublingual tablet or oral spray offers immediate relief of an anginal episode. For short-term prophylaxis (up to 30 minutes), nitroglycerin tablets can be used when activities known to precipitate angina are anticipated. Timing and frequency of the doses can be individualized according to the diurnal rhythm of anginal episodes. A nitrate-free interval of about 8 hours is adequate for preventing tolerance. Use of long-acting medications and transcutaneous delivery systems improves compliance but still necessitates a nitrate-free interval.

d.Side effects. Oral nitrates should be taken with meals to prevent heartburn.

(1)Headache is common and can be severe. Severity usually decreases with continued use and often can be controlled by decreasing the dose.

(2)Transient episodes of flushing, dizziness, weakness, and postural hypotension can occur, but these effects are usually abrogated by positioning and by other procedures that facilitate venous return.

e. Drug interactions. Hypotension can occur with the use of other vasodilators, such as ACE inhibitors, hydralazine, or calcium channel blockers. Concurrent use of phosphodiesterase type 5 (PDE5) inhibitors like sildenafil (Viagra) and nitrates can lead to severe hypotension and, therefore, is absolutely contraindicated.

f.Controversies

(1)Tolerance. Sustained therapy attenuates the vascular and antiplatelet effects of nitrates. Although the basis for this phenomenon of nitrate tolerance is not completely understood, sulfhydryl depletion, neurohormonal activation, and increased plasma volume are likely involved. Administration of N-acetylcysteine, folic acid, hydralazine, ACE inhibitors, or diuretics does not consistently prevent nitrate tolerance. Intermittent nitrate therapy is the only way to avoid nitrate tolerance.

(2)Rebound angina. Intermittent use of nitrates is not associated with serious rebound of angina among patients taking maintenance therapy with β-blockers. Dosing to allow for a longer nitrate-free interval is also not associated with rebound.

5.β-blockers (Table 6.4)

TABLE 6.4 β-Blockers
Compound	Daily Dose (mg)	Frequency	Excretion	Lipid Solubility	Intrinsic Sympathomimetic Activity	Membrane Stabilization
Selective β-Blockers
Metoprolol
Short acting	50–400	Every 12 h	Liver	Moderate
Long acting		Every 24 h			None	Possible
Atenolol	25–200	Every 24 h	Kidney	None	None	None
Acebutolol	200–600	Every 12 h	Kidney	Moderate	Low	Low
Nebivolol	5–40	Every 24 h	Kidney	High	None
Betaxolol	20–40	Every 24 h	Kidney		Low
Nonselective β (β₁ + β₂)-Blockers
Propranolol	80–320	Every 4–6 h	Liver
Long acting		Every 12 h		High	None	Moderate
Nadolol	80–240	Every 24 h	Kidney	Low	None	None
Timolol	15–45	Every 12 h	Liver	Moderate	None	None
Pindolol	15–45	Every 8–12 h	Kidney	Moderate	Moderate	Possible
Labetalol^a	600–2,400	Every 6–8 h	Liver	None	None	Possible
Carvedilol^a
Short acting	25–50	Every 12 h	Liver	Moderate	None	Possible
Long acting	10–80	Every 24 h

^aAlso a potent α₁-antagonist.

a.Mechanism of action. Blocking the β₁-adrenergic receptors in the heart decreases the rate–pressure product and myocardial oxygen demand. Decreased tension in the LV wall allows favorable redistribution of blood flow from the epicardium to the endocardium.

(1)Coronary vasospasm is rare from the β₂-receptor blocking effect, but use of nonselective β-blockers should be avoided among patients with known, active vasospasm.

(2)β-Blockers have a variable degree of membrane-stabilizing effect.

b.Evidence for effectiveness. β-Blockers decrease mortality after MI. The mortality benefit is not proven among patients with stable angina without prior MI or heart failure, although symptomatic improvement is well documented with multiple agents. Initiation of β-blockers carries a class I, LOE B, recommendation as the initial therapy for relief of symptoms in patients with stable angina.

c.Side effects. The most important side effects are related to blockade of β₂-receptors. However, data show that some of the side effects may occur less frequently than previously believed, and potentially lifesaving therapy should be offered to those at greatest risk for adverse events.

(1)Bronchoconstriction, masking of symptoms caused by hypoglycemic reaction among patients with diabetes, exacerbation of symptoms of peripheral vascular disease, and central nervous system (CNS) side effects such as somnolence, lethargy, depression, and vivid dreaming are well documented. The CNS side effects are thought to be related to the lipid solubility of these compounds.

(2)Symptomatic bradycardia and precipitation of heart failure are concerns for patients with a diseased conduction system and preexisting heart failure, respectively.

(3)Decreased libido, impotence, and reversible alopecia can be a problem for some patients.

(4)β-Blockers adversely alter lipid profile by increasing LDL cholesterol and decreasing HDL cholesterol.

d.Drug interactions. Severe bradycardia and hypotension can occur with concomitant use of some calcium channel blockers.

e.Selection of preparations. Cardioselectivity, lipid solubility, mode of excretion, and frequency of dosing are the main considerations when selecting a particular agent. The major cardiospecific agents (i.e., β₁-blockade) include metoprolol, atenolol, bisoprolol, and nebivolol. Of note, nebivolol also induces the endothelial NO pathway and contributes to vasodilation. Intrinsic sympathomimetic activity (ISA) is not a clinically important factor in the choice of a medication, although benefits in patients with CAD have been decreased with agents having ISA, such as pindolol and acebutolol.

f.Effect on lipids. The clinical significance of lipid abnormalities associated with β-blockers is unclear. β-Blockers have been associated with a decline in HDL level and a rise in triglycerides level. β-Blockers can improve survival among patients in New York Heart Association (NYHA) class I or II heart failure and angina. The condition of a patient with NYHA class III or IV disease should be stabilized before β-blocker therapy is instituted.

6.Calcium channel blockers (Table 6.5)

TABLE 6.5 Calcium Channel Blockers
Compound	Each Dose (mg)	Frequency	Vasodilation	Sinoatrial Node Inhibition	Atrioventricular Node Inhibition	Negative Inotrope
Nifedipine	30–120	Every 8 h	5	1	0	1
Nifedipine (Procardia XL)	30–180	Every 24 h
Diltiazem	30–90	Every 6–8 h	3	5	4	2
Diltiazem (Cardizem CD)	120–300	Every 24 h
Verapamil	40–120	Every 6–8 h	4	5	5	4
Verapamil (Calan SR and Isoptin SR)	120–240	Every 12 h
Amlodipine (Norvasc)	2.5–10	Every 24 h	4	1	0	1
Felodipine (Plendil)	5–20	Every 24 h	5	1	0	0
Bepridil (Vascor)	200–400	Every 24 h	4	4	4	5
Isradipine (DynaCirc)	2.5–10	Every 24 h	4	4	0	0
Nicardipine (Cardene)	10–20	Every 8 h	5	1	0	0

0, no activity; 5, most potent effect. Intermediate numbers suggest intermediate potency of effects.

a.Mechanism of action. These agents block calcium entry into vascular smooth muscle cells and cardiac cells by inhibiting calcium channels, but they do not affect the regulation of intracellular calcium release. The result is decreased contraction of muscle cells.

(1)The four types of calcium channels are L, T, N, and P.

(2)The T-type calcium channels are located in the atria and sinoatrial node and affect the phase I of depolarization.

(3)The L-type channels contribute to entrance of calcium into the cell during phase III of the action potential.

(4)The N and P types of channels are present mainly in the nervous system.

(5)The three main groups of calcium channel blockers are dihydropyridines (e.g., nifedipine), benzothiazepines (e.g., diltiazem), and phenylalkylamines (e.g., verapamil).

The dihydropyridines bind to the extracellular portion of the L channels at a specific site. They do not bind to the T channels and do not have a negative chronotropic effect. Because of their extracellular site of action, dihydropyridines do not inhibit receptor-induced intracellular calcium release.

Verapamil binds to the intracellular part of the L channel and inhibits the T channel. Intracellular calcium release is inhibited by verapamil because of its intracellular binding site and reflex sympathetic activation is less effective. Use dependence occurs with verapamil because open channels are needed for transport of the drug into the intracellular binding site. In stable angina, verapamil helps by improving rate–pressure product and by increasing oxygen delivery from coronary vasodilation.

b.Evidence of effectiveness. Numerous placebo-controlled, double-blind trials have shown that calcium channel blockers decrease the number of anginal attacks and attenuate exercise-induced depression of ST-segments. Calcium channel blockers are either started in patients who are β-blocker intolerant (class I, LOE B) or as an adjunct in those for whom β-blockers have not provided symptomatic relief (class I, LOE B).

(1)Studies comparing the efficacy of β-blockers and calcium channel blockers in the management of stable angina in which death, infarction, and unstable angina were used as end points showed calcium channel blockers to be as effective as β-blockers.

(2)Increased mortality caused by short-acting nifedipine among patients with CAD has been demonstrated. If the use of nifedipine is contemplated, a long-acting preparation in conjunction with β-blocker therapy is the safer approach. The mechanism of increased mortality is unclear, but reflex tachycardia and coronary steal phenomenon are potential explanations.

c.Side effects. The most common side effects are hypotension, flushing, dizziness, and headache. Because a negative inotropic effect can precipitate heart failure, the use of calcium channel blockers to treat patients with impaired LV function is relatively contraindicated. Conduction disturbances and symptomatic bradycardia occur with the use of compounds that have a marked inhibitory effect on the sinoatrial and atrioventricular nodes. Bepridil is known to prolong QTc, and QT monitoring is necessary when this medication is used. Lower extremity edema is often seen with the use of dihydropyridine calcium channel blockers, which may necessitate lowering the dose or discontinuing the medication. The non–dihydropyridine calcium channel blockers are known to cause constipation.

d.Drug interactions. Digitalis levels are increased by the non–dihydropyridine calcium channel blockers verapamil and diltiazem. The use of these drugs is contraindicated in the presence of digitalis toxicity.

e.Selection of preparations. Calcium channel blockers have a variable negative inotropic effect.

(1)Amlodipine is most likely to be tolerated by patients with compensated heart failure. In decompensated heart failure, all calcium channel blockers should be avoided.

(2)Amlodipine, diltiazem, nifedipine, and verapamil are the only calcium channel blockers approved for angina by the US Food and Drug Administration.

(3)Patients with conduction disturbances should take agents with minimal effects on the conduction system. Longer acting preparations minimize the risk for precipitation of angina caused by reflex tachycardia.

7.ACE inhibitors. The rationale for using ACE inhibitors to manage chronic stable angina comes from post-MI and heart failure trials that demonstrated a significant reduction in ischemic events with the use of ACE inhibitors.

a.It is possible that ACE inhibitors, by decreasing mainly the preload and, to some extent, afterload, decrease myocardial oxygen demand and help in the management of chronic stable angina. The Heart Outcomes Prevention Evaluation trial in high-risk patients with CAD, stroke, diabetes, and peripheral vascular disease showed that ramipril was associated with a significant reduction in death, MI, and stroke in this population. A recent meta-analysis found that ACE inhibitors reduce the risk of these outcomes even in patients with atherosclerosis who do not have evidence of systolic dysfunction. It is notable that the randomized Prevention of Events with Angiotensin-Converting Enzyme Inhibition study evaluating the use of trandolapril in patients with preserved LV function did not find a benefit with respect to death, MI, angina, revascularization, or stroke. Numerous hypotheses to explain these divergent results, including dose effects, difference in medication effects, and the risk level of enrolled patients, have been postulated. Nevertheless, the use of ACE inhibitors is recommended (class I) for patients with hypertension, diabetes, chronic kidney disease, or an LV ejection fraction of less than 40% and is considered reasonable (class IIa, LOE B) for patients without class I indications but who have both stable angina and other vascular disease.

b.Serious side effects of ACE inhibitors include cough, hyperkalemia, and decreased glomerular filtration rate. They are contraindicated in the care of patients with hereditary angioedema or bilateral renal artery stenosis. Angiotensin receptor blockers may be substituted in this population.

8.Hormone replacement therapy (HRT). The lipid profiles of women change unfavorably after menopause. LDL, total cholesterol, and triglyceride levels increase and HDL level decreases. All these changes have an adverse effect on cardiovascular morbidity and mortality. Several large case-controlled and prospective cohort studies suggested that the postmenopausal use of estrogen alone or in combination with medroxyprogesterone acetate has a favorable effect on lipid profile and cardiovascular events. However, both the Women’s Health Initiative study on primary prevention and the Heart and Estrogen/progestin Replacement Study on secondary prevention showed an increased risk of cardiovascular and cerebrovascular events in postmenopausal women receiving HRT. Another randomized trial quantifying coronary atherosclerosis angiographically showed negative results with respect to estrogen use. As a result, it has been postulated that the previously shown benefits might have been caused by the “healthy user” effect, and the use of HRT for primary prophylaxis against cardiovascular events is not recommended, as the most recent ACC/AHA guidelines assign HRT a class III, LOE A, recommendation.

a.Benefits of use. Although the use of estrogen has shown an increase in cardiovascular events, it is associated with some specific favorable findings. The positive effects of estrogen use include maintenance of normal endothelial function, reduction in levels of oxidized LDL, alteration in vascular tone, maintenance of normal hemostatic profile, a favorable effect on plasma glucose levels, reduction of osteoporotic fractures, and a reduction in menopausal symptoms.

b.Side effects include bleeding, nausea, and water retention. Because doses of estrogen are small, these side effects are uncommon. For patients with an intact uterus, routine gynecologic examination is mandatory for cancer surveillance. The risk of breast cancer is also increased with the use of HRT, and routine screening is beneficial.

9.Antioxidants. The role of vitamins A, C, and E is unclear in patients with CAD. All carry a class III recommendation from the ACC/AHA (LOE A). The initial observational studies on the role of daily vitamin E supplementation in reducing the risk of cardiovascular events among patients with proven atherosclerotic heart disease appeared promising. However, when vitamin E was tested in a randomized fashion, no benefit in its use was proved. There are also data suggesting that vitamin E may attenuate the effect of statins. Data are lacking about vitamins A and C. Most of the available information suggests no benefit in taking supranormal doses of these vitamins. Vitamin A does not prevent LDL oxidation, even though it binds to LDL molecules. Because it is water soluble, vitamin C does not bind to the LDL molecule. These two vitamins are not recommended for the prevention of progression of atherosclerosis.

10.Ranolazine

a.Mechanism. Ranolazine has been shown to work by inhibiting the late sodium channel in myocytes, which can otherwise remain open in pathologic states such as ischemia and heart failure. By reducing the late sodium entry into myocytes, ranolazine causes reduced sodium-dependent calcium entry into the cytosol. This downstream reduction in intracellular calcium levels is thought to reduce diastolic stiffness, thereby improving diastolic blood flow and reducing ischemia and angina. Earlier studies had suggested that effects of ranolazine were primarily through its impact on fatty acid metabolism; however, the weight of evidence now suggests that late sodium channel inhibition is its primary mechanism.

b.Efficacy. Numerous randomized studies of ranolazine, with or without background antianginal therapy, have shown a benefit in patients with stable angina with respect to frequency of anginal attacks, exercise duration, time to ST-segment depression on treadmill testing, and use of sublingual nitroglycerin. The most recent ACC/AHA guidelines suggest that ranolazine can be used either in combination with β-blockers when symptoms are uncontrolled (class IIa, LOE B) or in place of β-blockers if the patient does not tolerate β-blockers or if β-blockers are ineffective (class IIa, LOE B).

c.Side effects. Dizziness, headache, and GI intolerance are the most common side effects noted. Prolongation of the QT interval has been reported, especially in patients with hepatic or liver dysfunction because of decreased metabolism. Prolonged QT interval at baseline or during treatment follow-up is a contraindication to its use.

d.Drug interactions. Inhibitors of CYP3A4, such as azole antifungals, non–dihydropyridine calcium channel blockers, macrolide antibiotics, protease inhibitors, and grapefruit juice, should not be used concomitantly because of inhibition of ranolazine metabolism.

11.Growth factors. Therapy with direct infusion of vascular endothelial growth factor and basic fibroblast growth factor proteins has been shown to increase collateral blood flow in animal models. Thus far, no clinical benefit has been shown for these agents in several trials.

C.Enhanced external counterpulsation (EECP) has become a treatment option for patients with stable angina.

1.EECP involves the intermittent compression of the lower extremities in an effort to increase diastolic pressure and augment coronary blood flow. Three sets of balloons are wrapped around the lower legs, lower thighs, and upper thighs, with precise cuff inflation and deflation gated with the ECG. The lower cuffs are inflated at the start of diastole, as represented by the beginning of the T-wave, and simultaneous deflation of all three chambers is triggered just before systole at the onset of the P-wave.

2.In patients with refractory angina, clinical trials have demonstrated improvements in exercise tolerance, reduction in anginal symptoms, decreased use of nitroglycerin, and improvements in objective measures of ischemia as measured by thallium scintigraphy. These benefits are maintained at 2 years of follow-up. EECP carries a class IIb, LOE B, recommendation at present.

D.Coronary sinus obstruction. Coronary sinus occluder devices obstruct coronary sinus flow, increasing coronary sinus pressure. This theoretically increases perfusion of ischemic areas by decreasing the myocardial pressure gradient. Small, non-blinded trials have demonstrated some benefit in patients with Canadian Cardiovascular Society class III or IV angina on maximal medical therapies. Larger trials are underway to confirm this observation. At present, these devices are not being clinically used in the United States.

E.Percutaneous coronary intervention. The effectiveness of PCI to control symptoms in chronic stable angina and to prevent death or MI has been compared with medical management and CABG.

1.Compared with medical treatment

a.The Angioplasty Compared with Medicine trial compared PCI with medical therapy in approximately 200 patients with single-vessel and multivessel CAD. Patients with single-vessel CAD showed better symptomatic relief at 6 months with PCI but no difference in mortality or MI. Patients with multivessel CAD had no significant differences in symptoms, mortality, or MI.

b.The Medicine, Angioplasty, or Surgery Study randomized approximately 200 patients with proximal left anterior descending (LAD) artery disease to medical therapy, PCI, or CABG. This study demonstrated no difference in the primary end point (i.e., death, MI, or refractory angina necessitating revascularization). Patients randomized to CABG had a lower incidence of events compared with the other two groups, driven by a decrease in repeat revascularization procedures.

c.The Randomized Intervention Treatment of Angina-2 trial randomized more than 1,000 patients with stable angina to medical therapy or PCI. After 2.7 years of follow-up, the primary end point (i.e., death or MI) was lower in the medically treated group. There was also a higher incidence of revascularization in the medically treated group. There was an improvement in angina, exercise capacity, and perceived quality of life in patients who underwent PCI.

d.The study on Optimal Medical Therapy (OMT) with or without PCI for Stable Coronary Disease (by the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation [COURAGE] Trial Research group) evaluated patients with severe angiographic disease of one or more vessels, and either classic symptoms or documented ischemia on provocative testing. Compared with aggressive medical therapy, an initial strategy of PCI with BMS did not reduce the primary end point of death or major adverse cardiovascular events including symptom relief. Notable limitations to the interpretation of this study include the fact that the OMT group had stringent follow-up to achieve the high rates of medical adherence, one-third of patients in the medical therapy group crossed over to PCI (but were included in the OMT group as intention-to-treat analysis), and almost 80% of patients had no or minimal angina. Furthermore, it should be stressed that all patients were enrolled after angiography had been performed.

e.In a substudy of patients enrolled in COURAGE on the basis of positive stress imaging, investigators found that PCI in addition to OMT was superior in reducing ischemia than OMT alone. Furthermore, the degree of residual ischemia was related to future risk of death or MI. The adequately powered International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial has been funded by the National Heart, Lung, and Blood Institute to address this issue.

f.The Occluded Artery Trial tested the hypothesis that routine PCI of totally occluded arteries 3 to 28 days after MI in high risk but asymptomatic patients would improve outcomes. In the 2,166 patients studied, there was no statistically significant difference in long-term cardiac events between the PCI and the medical therapy groups, although the PCI group had more rapid relief of angina.

g.The use of fourth-generation DES in comparison with BMS has significantly decreased the risk of in-stent restenosis and the need for target vessel revascularization, thereby improving quality of life, providing freedom from angina, and reducing the risk of repeat procedures. The FAME-2 trial randomized 888 patients with functionally significant stenosis, defined by a fractional flow reserve of less than 0.8, to either stenting with a DES or OMT. At 12 months, stented patients had a lower need for future urgent revascularization but no difference in all-cause mortality or MI.

2.Compared with CABG

a.The Emory Angioplasty versus Surgery Trial randomized approximately 400 patients with multivessel disease to PCI or CABG. After 8 years of follow-up, there was no difference in the combined end point of mortality, Q-wave MI, and large thallium perfusion defect. In patients with proximal LAD artery disease or diabetes, there was a nonsignificant trend toward improved survival with CABG.

b.The Bypass Angioplasty Revascularization Investigators (BARI) compared PCI with CABG in the management of multivessel disease. In this trial, there was no difference in survival between patients randomized to PCI or CABG at 7 years of follow-up, although the subgroup of patients with diabetes had a better survival rate with CABG than with PCI (76.4% vs. 55.7%).

c.The Arterial Revascularization Therapies Study (ARTS) randomized 1,200 patients with multivessel disease to CABG or BMS placement. After 1 and 5 years of follow-up, there was no difference in mortality, MI, or stroke. Outcomes were similar for patients with stable and unstable angina. Among diabetic patients, however, mortality was greater for those who received PCI. There was a greater incidence of repeat revascularization in the PCI group, although the use of DES in ARTS 2 (compared with the historic CABG group from ARTS 1) shows a similar 1-year rate of revascularization between PCI and CABG groups.

d.The Surgery or Stenting study compared almost 1,000 patients with multivessel disease in the setting of ACS or non-ACS presentation. There was increased mortality and need for repeat revascularization in the PCI group, which could not be attributed to a diabetic population.

e.In the BARI 2 Diabetes (BARI 2D) trial, investigators compared prompt revascularization (PCI or CABG as deemed appropriate) and OMT in a group of patients with type 2 diabetes mellitus and CAD. The primary outcome of death was not significantly different in the two groups, nor was the rate of major cardiovascular events (the major secondary end point including death, MI, and stroke). When stratified by revascularization strategy, patients in the CABG group had greater freedom from major cardiovascular events (77.6% vs. 69.5%, p = 0.01); this finding was not significant in patients undergoing PCI. Notably, however, this trial was not designed to compare CABG and PCI as revascularization strategies.

f.The SYNergy between PCI with TAXus and cardiac surgery (SYNTAX) was a pivotal trial randomizing patients with three-vessel disease or left main trunk (LMT) stenosis to multivessel PCI versus CABG. The primary end point of death, stroke, MI, and repeat revascularization favored CABG (12.3% vs. 17.6%, p = 0.002). The secondary end point which included death, stroke, and MI was not different between the two groups (7.7% vs. 7.6%, p = 0.98). The primary end point favoring CABG was therefore driven primarily by increased rates of repeat revascularization in the PCI group (13.5% vs. 5.9%, p < 0.001), although, notably, the rate of stroke was also significantly lower in the PCI group (2.2% vs. 0.6%, p = 0.003).

g.The other major take-home point of the SYNTAX trial was the formulation of the SYNTAX score, which received a class I indication for evaluation of LMT or multivessel disease in the ACC/AHA PCI guidelines. The SYNTAX score grades coronary anatomy on the basis of lesion location, complexity, and functional impact and is a helpful tool for assessing patients at the individual level when discussing CABG versus PCI. In the trial, outcomes were assessed by SYNTAX score tertile: Patients with a low (0 to 22) or intermediate (23 to 32) score had no difference between the two modes of revascularization for the primary outcome. In patients with a score >32, however, CABG was favored for the primary outcome (10.9% vs. 23.4%, p < 0.001).

h.The Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease trial enrolled 1,900 patients with stenoses of greater than 70% in two or more epicardial vessels, randomizing them to DES placement or CABG. At 1 year, the risk of MI (5.8% vs. 3.4%, p = 0.02) and the combined outcome of death, MI, or stroke (16.8% vs. 11.8%, p = 0.004) were significantly higher for patients in the PCI arm of the trial. The risk of stroke was higher with CABG than with PCI (1.9% vs. 0.9%, p = 0.06), and there was no difference in death (4.2% vs. 3.4%, p = 0.35) between the two groups. The benefit of CABG over PCI was maintained for patients of all SYNTAX scores.

i.In patients with LMT stenosis, guidelines had long recommended CABG as the treatment of choice. However, in the modern era of stent placement, PCI of “unprotected” LMT stenosis has gained favor. The most recent ACC/AHA guidelines assign a class IIa, LOE B, recommendation to left main stenting in patients with a low SYNTAX score and a high operative risk. In patients who are good candidates for surgery, CABG carries a class I, LOE B, recommendation in patients with LMT stenosis.

(1)In the prespecified subgroup of patients undergoing unprotected LMT PCI versus CABG in the SYNTAX trial, the primary outcome was similar between the two groups. As in the main study population, stroke was higher in the CABG group (2.7% vs. 0.3%, p = 0.009) and repeat revascularization was higher in the PCI group (11.8% vs. 6.5%, p = 0.02).

(2)The Evaluation of Xience Prime versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization trial randomized 1,905 patients with LMT stenosis and a SYNTAX score <32. At 3 years, PCI was noninferior to CABG for the primary composite end point of death, stroke, or MI (15.4% vs. 14.7%).

(3)In the Nordic-Baltic-British left main revascularization study trial, 1,201 patients were randomized to left main intervention with PCI (biolimus stent) versus CABG. In this study, PCI did not meet the set boundaries of noninferiority compared with CABG. The event rate for the composite of death, MI, repeat revascularization, and stroke with PCI was 28% compared with 18% for CABG making the latter the superior strategy (p = 0.004).

j.At present, strong consideration is given to CABG in the group of patients with multivessel disease and diabetes, LV dysfunction, or LMT disease who are able to undergo open heart surgery. In the general population with multivessel or LMT disease, however, there is a paucity of evidence showing a survival advantage to CABG over PCI, and recent trials with modern treatment practices (including DES implantation, aggressive antiplatelet therapy, off-pump coronary artery bypass procedures, and use of arterial grafts) have shown favorable comparisons between the two treatment strategies. The ACC/AHA guidelines indicate that in patients with three-vessel CAD or with severe stenosis of the proximal LAD and another vessel, CABG should be pursued (class I, LOE B). For patients who are able to undergo either of the treatments, an educated decision should be made by the patient, the cardiologist, and a cardiac surgeon using a heart team approach.

3.Revascularization methods. For details of PCI strategy and equipment, please see Chapter 63.

F.Coronary artery bypass grafting

1.Compared with medical treatment. Compared with medical treatment, CABG improves the survival rate among patients with high-risk stable angina. The benefit is most profound in patients with three-vessel CAD, impaired LV function, or substantial LMCA stenosis.

a.This information is derived from the Coronary Artery Surgery Study, European Coronary Surgery Study, and Veterans Administration Cooperative Study. These trials were completed before generalized awareness grew regarding the benefits of medical management with β-blockers, ACE inhibitors, antiplatelet agents, or lipid-lowering medications.

b.Surgical techniques have also changed significantly, with greater use of arterial conduits including internal mammary artery (IMA) grafts, minimally invasive surgery, and improved techniques of cardiac tissue preservation and anesthesia.

2.Venous or arterial grafts. There are different techniques of CABG. The use of minimally invasive bypass surgery involving the left internal mammary artery (LIMA) in patients with isolated LAD artery stenosis has not shown any difference in the rate of mortality, MI, or stroke in comparison to PCI but has shown a decrease in the need for repeat revascularization. With open sternotomy, in which the use of LIMA is well studied, mammary arterial grafting has better long-term outcome compared with vein graft conduits. Given the success of the (LIMA) graft, other arterial conduits have been used, such as the right internal mammary artery (RIMA), the radial artery, and the right gastroepiploic artery.

a.Twenty percent of venous grafts are nonfunctional at 5 years and only 60% to 70% are functional after 10 years. In contrast, >90% of LIMA to LAD artery grafts are patent 20 years after the operation.

b.IMA grafts have a better patency rate at 10 years when used for LAD lesions (95%) than for circumflex (88%) or right coronary artery (76%) lesions. The patency rates are higher for LIMA compared with RIMA and for in situ grafts compared with free grafts.

c.Patient survival is better with an IMA graft than when only saphenous venous grafts are used. This survival benefit persists for up to 20 years.

d.The radial artery graft was introduced into clinical practice around the year 1970 and initially had mixed results. However, at approximately 1 year, 92% of the grafts are patent, and at 5 years, 80% to 85% of grafts are open. The 5-year angiographic patency rates of 92% have been reported for right gastroepiploic arterial grafts.

3.Previous CABG. Little information is available on the treatment of patients who have already undergone bypass surgery and have stable angina. Although another bypass operation may be offered to these patients, direct comparison with medical treatment in this patient population has not been made. The use of multiple arterial grafts at the time of first CABG reduces the need for reoperation. The most recent ACC/AHA guidelines recommend PCI in patients with prior CABG who have one or more significant (greater than 70%) stenoses who have angina despite OMT.

4.Compared with PCI. This is discussed in Section IV.C.E.2.

G.Hybrid coronary revascularization: In some patients, in whom the aorta is calcified or who possess poor targets for full surgical revascularization, hybrid revascularization is an option. In this procedure, a combination of bypasses (almost always including the LIMA anastomosed to the LAD) and PCI (to lesions unable to be bypassed) is performed. The procedure may be performed simultaneously, in a hybrid operating room, or sequentially, with PCI occurring hours to days after CABG. Although no published randomized trials have assessed the efficacy and outcomes of this in comparison to traditional PCI or CABG, this procedure carries a class IIa, LOE B, recommendation in the most recent ACC/AHA guidelines.

H.Lifestyle modification

1.Exercise

a.Rationale. Exercise conditions the skeletal muscles, which decreases total body oxygen consumption for the same amount of workload. Exercise training also lowers heart rate for any level of exertion, which decreases the oxygen demand on the myocardium for any workload. Some evidence shows that higher physical activity and exercise can decrease cardiovascular morbidity and mortality.

b.Recommendation. For secondary prevention, aerobic and isotonic exercises with a goal of achieving a sustained heart rate of approximately 70% to 85% of the maximum predicted heart rate for at least 30 to 60 minutes at least 5 times per week has been shown to improve survival and carries a class I, LOE B, recommendation. For beginners, a supervised exercise or rehabilitative program, in which 50% to 70% of maximal predicted heart rate is achieved, is also helpful. Isometric exercises are not recommended because they increase myocardial oxygen demand substantially.

2.Diet. A low-fat diet that includes cereals and grains, skimmed dairy products, fruits and vegetables, fish, and lean meats should be recommended and this is effective in providing cardiovascular risk reduction in patients with CAD. These are integral components of the “Mediterranean Diet,” which has been shown to reduce cardiovascular risk. Consumption of one (for nonpregnant women) or one to two (for men) standard alcoholic beverages per day is reasonable if not contraindicated (i.e., because of liver disease or alcoholism). This is a class IIb, LOE C, recommendation. A multidisciplinary approach to the care of patients with CAD that includes a nutritionist/dietician can be quite helpful in personalizing patients’ eating habits.

3.Smoking cessation. Cigarette smoking is associated with progression of atherosclerosis, increased myocardial demand because of an α-adrenergic increase in coronary tone, and adverse effects on hemostatic values, all of which can lead to worsening of stable angina. Smoking cessation decreases cardiovascular risk among patients with established CAD, including patients who have undergone CABG. Physician counseling is the best approach to achieve this goal and adjunctive therapies include nicotine replacement patches, gum, or sprays, or medications such as bupropion and varenicline.

4.Psychological factors. Anger, hostility, depression, and stress are shown to adversely affect CAD. Results of small, nonrandomized trials show that biofeedback and various relaxation techniques can help modify these factors.

V.RECOMMENDED APPROACH TO STABLE ANGINA

A.The following approach is suggested for the treatment of patients with stable angina.

1.It is reasonable to risk-stratify patients with stable angina using stress testing with imaging, such as nuclear isotope imaging or echocardiography.

a.LV systolic function should be assessed with echocardiography to guide therapy and to identify patients with LV systolic dysfunction.

b.Patients with small perfusion defects or small wall motion abnormalities, high threshold for ischemia, normal LV systolic function, and clear symptoms should be treated with medication.

2.If symptoms continue after medical therapy is maximized, angiography should be planned. Coronary angiography should also be performed for patients with evidence of impaired perfusion involving multiple territories, a low threshold for ischemia, and LV systolic dysfunction.

3.Single-vessel disease. If a patient has single-vessel CAD that does not involve the LMT or supply a large myocardial territory, medical management with risk factor modification is the appropriate first step.

a.If patients cannot tolerate medical treatment or have symptoms despite maximum medical therapy, revascularization should be offered.

4.Among patients with multivessel CAD, medical treatment remains an alternative for patients who have normal LV systolic function, mild symptoms, and relatively smaller areas of myocardium at risk.

a.The decision for multivessel PCI versus CABG in this group of patients should be made on an individual basis, taking into consideration the angiographic anatomy, LV function, patient comorbidities (especially diabetes), surgical risk, and patient preference.

b.Any doubt regarding viability of the myocardium at risk should be addressed with appropriate diagnostic studies before revascularization.

5.In patients with “unprotected” LMT stenosis, the previous recommendations of CABG in all patients who are able to undergo surgery have been revised. PCI for severe LMT disease may be appropriate in select patients.

6.Regardless of treatment strategy, aggressive risk factor modification, including use of lipid-lowering agents, lifestyle modification, and aspirin therapy, is an essential component of management.

ACKNOWLEDGMENT: The author thanks Drs. Keith Ellis, Amar Krishnaswamy, and Samir Kapadia for their contributions to earlier editions of this chapter.