Stable or predictable angina on effort predominantly occurs in the setting of a fixed atherosclerotic stenosis of the coronary artery. Similar symptoms can also arise in other conditions, such as aortic stenosis and hypertrophic cardiomyopathy. Conversely, obstructive coronary heart disease can occur in the absence of typical angina of effort or, indeed, without any symptoms at all. This chapter discusses chronic stable angina in relation to obstructive coronary atheroma, although other forms of angina exist ( Table 8-1 ) and vasospasm associated with nonobstructive atheromatous plaques can occur.
| VASCULAR DISORDERS | CARDIAC DISORDERS |
|---|---|
| Variant angina | Hypertrophic cardiomyopathy |
| Atheroma-associated vasospasm | Aortic stenosis |
| Microvascular angina or syndrome X | Hypertensive heart disease and left ventricular hypertrophy |
| Mitral valve prolapse | |
| Severe pulmonary hypertension and right ventricular hypertrophy |
Epidemiology
Coronary atherosclerosis is associated with many risk factors, such as cigarette smoking, hyperlipidemia, family history, hypertension, and diabetes mellitus (see Chapter 24 , Chapter 25 , Chapter 26 , Chapter 27 , Chapter 28 , Chapter 29 ). The prevalence and extent of both coronary atheroma and angina pectoris increase with age and have a male preponderance. Distribution among ethnic groups is unequal, with higher rates in Indo-Asians and lower rates in East Asians and Afro-Caribbeans compared with whites.
The epidemiology of coronary heart disease (CHD) and angina pectoris is changing. In some regions of the world—such as North America, Western Europe, Japan, and Australia—the incidence, mortality rates, and in-hospital case fatalities are declining, although the overall prevalence of CHD is still rising, in keeping with an aging population. However, Eastern Europe in particular is experiencing escalating rates of CHD and associated mortality, with age-adjusted death rates also rising in many of the developing economies. The World Health Organization (WHO) estimates that the global number of deaths from CHD will have risen from approximately 7 million in 2002 to 11 million by 2020.
Natural History
Angina pectoris results in substantial morbidity. In two thirds of patients, angina limits the ability to work and to undertake recreational, sexual, and other daily activities. On average, a patient with angina pectoris will consult a primary health care professional two or three times each year. The complications of angina pectoris in part relate to the extent and severity of CHD and include myocardial infarction (MI), congestive heart failure, dysrhythmias, and sudden cardiac death. In general, patients with stable angina pectoris have a 2.5% to 5% risk of death or nonfatal MI each year. In middle-aged men, the annual event rate is 2.4% for a major CHD event, 0.6% for stroke, and 3.0% for death.
The likelihood of sustaining an acute MI increases with the severity and extent of atheromatous involvement of the coronary arteries ( Figure 8-1 ). In addition, left ventricular (LV) function and the frequency and severity of angina ( Figures 8-2 and 8-3 ), as well as demographics such as age and gender, all influence the risk of MI. There is a 10-fold range in risk of death, MI, or stroke according to baseline characteristics.
Assessment and Investigation
Clinical Assessment
In patients with chronic stable angina, episodes of angina are usually initiated at consistent levels of physical stress and promptly disappear with cessation of activity ( Box 8-1 ). Worsening angina provoked by progressively less exertion over a short period of time, often culminating in pain at rest, is indicative of an acute coronary syndrome (ACS; see Chapter 9 , Chapter 10 ).
Canadian Cardiovascular Society Functional Classification of Stable Angina Pectoris Class 1
Ordinary physical activity, such as walking and climbing stairs, does not cause angina. Angina comes with strenuous or rapid or prolonged exertion at work or during recreation.
Class 2
Slight limitation of ordinary activity occurs walking or climbing stairs rapidly, walking uphill, walking or stair climbing after meals, in cold, in wind, or when under emotional stress, or only during the few hours after awakening. Walking more than two blocks on level ground and climbing more than one flight of ordinary stairs at a normal pace and in normal conditions triggers angina.
Class 3
Marked limitation of ordinary physical activity occurs walking one to two blocks on level ground and climbing more than one flight of stairs under normal conditions.
Class 4
Patient is unable to carry on any physical activity without discomfort; anginal syndrome may be present at rest.
The likelihood of CHD being the cause is increased by the presence of established risk factors. Beyond stigmata of hyperlipidemia (rare) or signs of peripheral atheromatous vascular disease, no physical signs of angina are usually present. However, patients should be examined for signs of other possible causes of anginal chest pain, such as aortic stenosis and hypertrophic obstructive cardiomyopathy.
Risk Stratification
Clinical Indicators
A number of clinical indicators identify patients at relatively high risk for clinical events ( Box 8-2 and Figure 8-4 ). The threshold for the consideration of invasive coronary angiography should be lower in high-risk patients than in those being considered purely on the basis of their symptoms. The list of high-risk indicators in Box 8-2 is not comprehensive but incorporates the principal factors that determine risk.
Clinical Indicators of Adverse Prognosis in Patients with Chronic Stable Angina - ▪
Previous myocardial infarction
- ▪
Recent episode of unstable angina or new-onset stable angina
- ▪
Coexisting heart failure or evidence of left ventricular dysfunction
- ▪
Coexisting risk factors for coronary artery disease, such as hypertension and diabetes mellitus
- ▪
Age (the likelihood of death or nonfatal ischemic event increases with age)
- ▪
Family history, an independent predictor of death
- ▪
Pattern of anginal symptoms (quiescent angina is associated with a reduced risk of death and cardiac ischemic events)
Noninvasive Evaluation
Electrocardiogram
A resting electrocardiogram (ECG) should always be recorded as part of the diagnostic evaluation of patients with chronic stable angina. The resting ECG may also be useful for adjusting medical therapy, such as for titration of β-blocker therapy. Although the sensitivity of the ECG is low for the diagnosis of CHD—in fact, it appears normal in almost one half of patients who come to medical attention with the disease —it does provide prognostic information. Resting ST-segment depression predicts an increased likelihood of subsequent MI and death. Patients with evidence of previous MI or ST-T–wave abnormalities without transmural Q-wave MI have a reduced survival rate.
Exercise ECG testing is usually performed for two principal reasons: the diagnosis of angina as a result of CHD and as an assessment of prognosis. However, exercise ECG is an inappropriate screening test for CHD when used in isolation. In a population with a low prevalence of CHD, the false-positive rate is high, particularly in the absence of symptoms ( Figure 8-5 ). The false-positive rate is also higher in younger individuals and in women. Conversely, the negative predictive value for CHD is poor, and the exercise ECG is therefore an inappropriate test to exclude its presence.
The clinical context, associated symptoms, and overall cardiovascular (CV) response to exercise can be as important as the ECG response to exercise ( Box 8-3 ). Exercise testing is easily performed and, when used appropriately, is a method of risk stratification in patients with stable angina. It is a particularly useful method of identifying individuals at highest risk and those who would benefit from further and potentially more invasive investigation and intervention.
Features on Exercise Electrocardiogram Associated with a Poor Prognosis and Indicative of Severe Disease - ▪
Poor maximal exercise capacity (less than stage 3 on the Bruce protocol)
- ▪
≥1 mm ST-segment depression during stage 2 or less (Bruce protocol)
- ▪
≥2 mm ST-segment depression at any time
- ▪
Limited blood pressure response (fall or no rise from baseline)
Echocardiography
Echocardiography is used to assess cardiac function at rest and during pharmacologic or physical stress. LV dysfunction at rest or with exercise identifies patients with a poor prognosis.
As with myocardial scintigraphy, stress echocardiography can be used to identify patients with CHD and those with LV dysfunction and hibernating myocardium who would potentially benefit from coronary revascularization. Stress echocardiography has some advantages and disadvantages over standard approaches to stress testing. Because of the problems associated with movement, pharmacologic stress echocardiography is sometimes the preferred approach; positive inotropes and chronotropes, such as dobutamine and arbutamine, are given as a continuous intravenous infusion, sometimes augmented by atropine to increase the heart rate further. The contractile performance of the heart is then assessed in multiple views, incorporating the 16 segments of the heart, both at rest and during graded stress. Stress echocardiography is therefore a demanding technique that requires a rigorous and skilled approach by highly trained operators.
Stress echocardiography is directed mainly at assessing the development of, or improvement in, myocardial wall motion abnormalities during stress. Deteriorating regional wall motion during increasing stress suggests the development of myocardial ischemia and underlying coronary artery disease (CAD). Alternatively, previously akinetic or hypokinetic areas of myocardium can improve during dobutamine stress and may indicate the presence of “stunned” myocardium, in which a recent period of profound ischemia has led to a temporary reduction in contractile function. A combination of features may also exist, where the contractile function initially improves with low-dose dobutamine infusion, only to deteriorate at higher doses. This suggests the presence of “hibernating” myocardium, in which a critical coronary artery stenosis causes contractile dysfunction at rest, but the myocardium retains the ability to develop short-lived improvement in contractile function with inotropic stimulation before subsequent ischemic deterioration occurs at higher workloads. A completely unresponsive akinetic segment indicates an area of infarcted myocardium.
Cardiac Magnetic Resonance Imaging
Magnetic resonance coronary angiography has been reported but does require long acquisition times, cooperative subjects, and high field-strength scanners. Because of this, it is not sufficiently robust for routine clinical use. In contrast, magnetic resonance (MR) first-pass myocardial perfusion imaging is an established noninvasive method to detect myocardial perfusion defects and to quantify infarct size without the need for ionizing radiation. MR imaging has excellent spatial and temporal resolution, and with the small addition of further imaging sequences, it can also provide quantification of myocardial fibrosis and infarct volumes. Several studies have demonstrated that perfusion cardiac magnetic resonance imaging (MRI) has high sensitivity (89%), specificity (81%), and accuracy (86%) for detection of CHD. Cardiac MRI perfusion also has prognostic value in the assessment of patients with CAD and is now a well-established noninvasive standard for assessment of CHD.
Myocardial Perfusion Scintigraphy
Stress myocardial perfusion imaging or scintigraphy has greater accuracy for diagnosing CHD than does exercise testing, with a sensitivity of 80% versus 68% and a specificity of 92% versus 84%, respectively. However, stress myocardial scintigraphy adds little additional information for patients already identified as high risk through the use of conventional exercise testing. It is particularly helpful in individuals who have equivocal exercise ECG changes, an abnormal resting ECG, suspected false-positive or false-negative exercise ECG results, or submaximal exercise tolerance. It may also prove useful in identifying the territory of ischemia in patients with multivessel disease, in whom selective revascularization strategies, such as culprit lesion angioplasty, are being considered. The identification of hibernating myocardium may be of particular benefit in patients with LV dysfunction who have the most to gain from coronary revascularization.
Normal stress myocardial scintigraphy is associated with an excellent prognosis of less than 1% annual risk of a major adverse cardiac event, even in patients with CHD. However, severe and extensive perfusion defects identify patients at high risk for future cardiac events and point to a poor prognosis ( Box 8-4 ).
Features on Stress Myocardial Perfusion Scintigraphy Associated with a Poor Prognosis and Indicative of Severe Disease - ▪
Reversible radionuclide perfusion defect in more than one territory
- ▪
Reduced radionuclide ejection fraction with exercise
- ▪
Increased lung uptake of radionuclide
The use of scintigraphy is likely to decline further with the greater availability, and similar or superior performance, of other techniques such as cardiac MR, echocardiography, and computed tomography (CT).
Computed Tomography
All of the noninvasive techniques above use surrogate measures—such as ST-segment shift, myocardial contraction, and tissue perfusion—to diagnose CHD. However, these techniques identify the functional significance, rather than the presence, of CAD, which underlies the relative lack of specificity and sensitivity in diagnosing the presence of epicardial CAD. In contrast, CT coronary angiography can directly identify the presence of CAD and also provides information regarding the extent of atherosclerotic plaque burden that even invasive coronary angiography cannot. The potential weakness of CT coronary angiography lies in its inability to determine whether a lesion limits flow.
Coronary Calcium Score
Coronary artery calcification is an independent risk factor for CHD, with even low coronary calcium scores doubling the risk of coronary events. The relative risk associated with coronary calcification is similar to that associated with established factors such as smoking, hypertension, and diabetes mellitus. Progression of coronary artery calcification is associated with a higher incidence of coronary events even in those people who are asymptomatic at the time of initial scanning. Thus, the presence of coronary artery calcification is indicative of not only atheromatous plaque disease, but also its progression may correspond with CV event rates.
The degree of calcification correlates with atherosclerotic burden, but it does not identify soft plaque and may not predict the response to medical interventions. The presence of coronary artery calcification does not in itself predict the presence of obstructive atheroma. Calcification can therefore be used as a surrogate marker of the extent of coronary atherosclerotic disease rather than as a measure of luminal stenosis.
Computed Tomography Coronary Angiography
Major advances in scanning technology have now led to the establishment of noninvasive coronary angiography by multidetector CT ( Figure 8-6 ). Indeed, coronary angiography performed by modern multidetector CT scanners has a very good agreement with invasive coronary angiography and intravascular ultrasound. The temporal and spatial resolution of modern scanners allows quantification of luminal stenoses and identification of uncalcified, “soft” atherosclerotic plaque.
Pooled analysis of more than 800 patients indicates a sensitivity of 89% (95% confidence interval [CI], 87% to 90%) and specificity of 96% (95% CI, 96% to 97%) for 64-row multidetector CT in comparison with invasive coronary angiography. The major strength is in the negative predictive value of 98% (95% CI, 98% to 99%). The major limitations have been the poor image quality in those with arrhythmia or fast heart rates and the high radiation dose of the examination (approximately 20 mSv). Pulsed sequences, dual-source systems, and dynamic volume scanners with greater detector numbers are now overcoming these limitations. Thus, the current evolution of scanning technology has led to greater spatial and temporal resolution with lower radiation doses (2 to 4 mSv). This translates into a highly effective and safe imaging strategy. The most promising application is in the evaluation of stable patients with possible CHD and the exclusion of coronary atherosclerosis. However, despite the high sensitivity, the specificity for the identification of obstructive CAD is low because of “blooming” artifacts from coronary calcification. This is particularly an issue in populations with a high prevalence of coronary calcification, such as those with stable angina and CHD.
With the advent of large (256 to 320) rows of detectors, dynamic volume CT scanning is now possible. Here, the entire heart is encompassed within the field of view, and extra images can be obtained during the transit of contrast through the myocardium (see Figure 8-6 ). This enables stress CT perfusion to be performed that has very high spatial resolution, which is superior to radionuclide techniques and, to a certain degree, MR techniques.
Selection and Frequency of Noninvasive Stress Testing
There are advantages and disadvantages with each of the four main noninvasive modalities of stress testing ( Table 8-2 ). Exercise ECG testing is easily performed, has been extensively validated, and remains the noninvasive test of choice for many patients. However, the sensitivity and specificity of exercise ECG are suboptimal and can lead to significant misclassification. This also applies to the other noninvasive forms of stress testing. For the diagnosis of CHD, CT coronary angiography is increasingly likely to play a major role.
| STRESS ELECTROCARDIOGRAPHY | MYOCARDIAL PERFUSION SCINTIGRAPHY | STRESS ECHOCARDIOGRAPHY | CARDIAC MAGNETIC RESONANCE PERFUSION | |
|---|---|---|---|---|
| Technical difficulty | + | ++ | +++ | +++ |
| Ease of interpretation | +++ | ++ | +++ | ++ |
| Diagnostic sensitivity (%) | 50-80 | 65-90 | 65-90 | 70-90 |
| Diagnostic specificity (%) | 80-95 | 90-95 | 90-95 | 90-95 |
| Risk stratification | ++ | ++ | ++ | + |
| Identification of hibernating myocardium | − | ++ | +++ | +++ |
| Identification of ischemic territory | + | ++ | ++ | +++ |
| Limitations | Conduction or repolarization anomalies | Radiation exposure | Diagnostic images not possible in all patients | Claustrophobia and incompatibility with devices |
| Cost | + | +++ | ++ | +++ |
No clear guidelines exist as to how frequently noninvasive testing should be undertaken in patients with chronic stable angina. After the initial prognostic assessment, recurrent testing is unlikely to be helpful unless new symptoms arise or other symptoms change, vocational requirements change, or the patient has undergone, or is being considered for, an intervention such as coronary revascularization or major noncardiac surgery.
Invasive Evaluation
Invasive coronary angiography is used to aid the diagnosis and management of known or suspected CHD and is considered when either medical therapy has failed to provide effective symptomatic control or clinical and noninvasive tests suggest that the patient may be at high risk or may otherwise benefit from intervention. This can be further complemented by the functional assessment of coronary stenoses using the pressure-wire assessment of fractional flow reserve. This can guide the appropriate management and revascularization of patients with CHD ( Box 8-5 ).
Indications for Coronary Angiography Severe or Disabling Angina
The severity of symptoms indicating the need for coronary angiography will vary depending on the patient’s, and the physician’s, perception of the illness. However, most experts agree that despite optimal medical therapy, patients with symptoms in Canadian Cardiovascular Society class 3 or 4 may benefit symptomatically from coronary artery bypass graft surgery or percutaneous coronary intervention.
Clinical Indicators and Noninvasive Testing Suggestive of Adverse Prognosis
Continuing Chest Pain with Inconclusive or Negative Noninvasive Tests
In this context, a normal coronary angiogram can be very helpful in excluding obstructive coronary artery disease, removing uncertainty about the diagnosis, reassuring the patient, and thereby reducing their use of health care resources. This will be of particular concern when the symptoms limit the lifestyle of the patient, or when a diagnosis of coronary artery disease will have occupational ramifications.
Overall Assessment of Risk
A number of scoring systems have been developed that incorporate both clinical characteristics and noninvasive investigations in the determination of risk. These models provide a more comprehensive assessment of risk and prognosis in patients with stable angina. Coronary angiography is appropriate in patients whose clinical characteristics or noninvasive investigations suggest they have an adverse prognosis and may therefore benefit prognostically from coronary artery bypass graft surgery (CABG; Figure 8-7 ).
The hazards of any intervention are more likely to outweigh the potential symptomatic and prognostic benefits in patients at low risk. In contrast, patients at high risk have the most to gain from interventions such as revascularization. Risk stratification is therefore an essential part of the initial assessment of a patient with stable angina. The main determinants of risk are patient characteristics such as age; diabetes mellitus; hypertension; and the results of clinical investigations, such as exercise or other forms of stress testing, the extent of coronary disease (the number and type of vessels affected), and LV function (see Figures 8-1 to 8-3 ).
Therapeutic Interventions
The treatment of patients with chronic stable angina pectoris should be directed toward both the alleviation of symptoms and an improvement in prognosis. This involves several approaches that include lifestyle modification, management of risk factors, pharmacologic therapy, and coronary revascularization. All forms of intervention present certain hazards and should be instituted only if the perceived benefits, in terms of improved symptoms and prognosis, are likely to outweigh the associated risks. Such judgments are best made in the context of an overall treatment strategy that seeks to minimize the impact of the disease throughout the remainder of the patient’s life. Figure 8-4 and Figures 8-7 through 8-10 provide a general guide to the initial investigation and management of patients with chronic stable angina.
Lifestyle and Risk Factor Modifications
Lifestyle and risk factor modifications are integral parts of, and complementary to, the treatment of patients with chronic stable angina because they may provide both symptomatic and prognostic benefits. The benefits of exercise and exercise programs and the management of hyperlipidemia are discussed later in this chapter. The treatment and management of hypertension are discussed in Chapter 28 , Chapter 29 , Chapter 30 , Chapter 31 , Chapter 32 , Chapter 33 , Chapter 34 .
Smoking
Cigarette smoking is a major risk factor for the development of fatal and nonfatal MI. Cessation of smoking is associated with major benefits, and repeated brief and supportive advice should be given to all patients. Short-term nicotine replacement therapy should be offered to individuals who are heavy consumers of tobacco (>10 cigarettes per day) because it is associated with up to a ninefold increased likelihood of success. The antidepressants bupropion and nortriptyline also aid long-term smoking cessation, but selective serotonin reuptake inhibitors, such as fluoxetine, do not. This suggests that these agents produce their beneficial effects independent of an antidepressant effect. The partial nicotine receptor agonist, varenicline, increases the likelihood of smoking cessation twofold to threefold and appears to be more effective than bupropion. Although no previous specific treatment strategy has been able to prevent relapses, varenicline does appear to sustain smoking cessation and prevent subsequent relapses. Some reports have linked varenicline with serious adverse events that include a depressed mood, agitation, and suicidal thoughts, but these are so far unsubstantiated.
Dietary Intervention
Dietary intervention clearly complements the use of lipid-lowering therapy. Although a low-fat diet reduces serum cholesterol concentrations by an average of only 5% even in motivated individuals, dietary modification may provide additional preventive benefits, such as those obtained from a Mediterranean-type diet or those high in polyunsaturated (n-3) fatty acids of fish oils. Observational studies and randomized trials have suggested that the consumption of fruits and vegetables containing high levels of antioxidant vitamins or supplementation with vitamin E is protective against the development of coronary events. However, three large-scale (6000 to 30,000) multicenter, randomized, controlled trials (RCTs) demonstrated that low- or high-dose vitamin E supplementation has no effect on CV outcomes. Modest alcohol consumption is associated with a reduced risk of CHD and should be limited to 21 to 28 U/week (1 U = 8 g of absolute alcohol) for men and 14 to 21 U/week for women.
Obesity
A significant and independent association has been found between body mass index (BMI) and the risk of CV events. Despite the high prevalence of obesity, no interventional trials have been done to show that weight reduction in obese patients with chronic stable angina or CHD improves symptoms or outcome. However, it is reasonable to assume that weight reduction would reduce the frequency of anginal episodes and potentially improve prognosis.
Currently escalating levels of obesity, particularly in Western societies, are associated with the development of metabolic syndrome, which is characterized by obesity, insulin resistance, hypertension, hyperuricemia, and dyslipidemia. This has raised concerns about the incidence and prevalence of CV disease in the future. Novel therapeutic strategies, such as the endocannabinoid receptor antagonis rimonabant, may be able to reduce obesity and the associated metabolic abnormalities. However, in an RCT of nearly 20,000 at-risk subjects, rimonabant had no effect on adverse CV outcomes but was associated with increased general and serious neuropsychiatric problems, including suicide.
Diabetes Mellitus
Good glycemic control is essential in all patients with diabetes mellitus because of the reduced risk of long-term complications, including CHD. Although no specific trials of diabetic control in patients with chronic stable angina have been done, primary prevention trials and secondary prevention trials in patients after MI indicate that CV morbidity and mortality rates are reduced with intensive hypoglycemic therapy regimens. Moreover, poor glycemic control at the time of presentation with MI is a poor prognostic sign. Although previous studies had suggested that sulfonylureas, tolbutamide in particular, are associated with an increased risk of CV death, this was not confirmed in the U.K. Prospective Diabetes Study (UKPDS) trial. That trial did, however, suggest that metformin should be the first-line agent of choice in overweight patients with diabetes mellitus because it is associated with a decreased risk of diabetes-related endpoints, less weight gain, and fewer hypoglycemic episodes.
The control of hyperglycemia is important, but overly strict glycemic control can be harmful. The application of intensive blood glucose control in patients with type 2 diabetes mellitus is associated with an increase in adverse CV outcomes. This is likely to arise from the harmful effects of hypoglycemia, especially in those with concurrent CHD; therefore a balance must be struck between avoidance of prolonged hyperglycemia and invocation of adverse hypoglycemic episodes.
Symptomatic Therapy
Cardiac Rehabilitation
Cardiac rehabilitation involves a multidisciplinary approach that addresses needs related to medical and psychosocial care that include exercise, education, secondary prevention, and vocational advice. Although predominantly applied to the immediate post-MI or postoperative period (after CABG), it is equally applicable to patients with chronic stable angina. The rehabilitation process encompasses the following three main components: 1) explanation and understanding; 2) specific intervention, such as secondary prevention, exercise training, and psychological support; and 3) long-term adaptation and education.
Patients with stable angina who attend a regular exercise and rehabilitation program have less angina and may have fewer recurrent MIs, and they have better cardiorespiratory fitness and vocational status. Exercise programs improve patient confidence and functional capacity, and although such programs are labor intensive, they are an efficacious and potentially cost-effective approach to the treatment of patients with stable angina (see Chapter 49). Indeed, an RCT suggested that an exercise program produced a better improvement in exercise capacity, was associated with fewer adverse cardiac events, and was more cost-effective than percutaneous coronary intervention (PCI).
Pharmacologic Therapy
No single class of drug has been shown to be superior to another in the reduction of anginal episodes. However, because of the inferred secondary preventive benefits, β-blockers should be the first-line agents of choice (see Figure 8-9 ). Moreover, a meta-analysis suggests that β-blockers are better tolerated and may be more efficacious than CCBs in the treatment of chronic stable angina.
If monotherapy does not control anginal symptoms, the introduction of a second antianginal agent provides significant but modest additional benefits (see Figure 8-9 ). The combination of β-blockade and rate-limiting calcium channel blockade may cause excessive bradycardia or heart block. However, this interaction is uncommon, and if there is concern, a long-acting dihydropyridine-type CCB should also be prescribed. No definitive evidence is available to suggest that triple or quadruple antianginal therapy produces further benefit beyond dual therapy. Two large-scale RCTs (n = 5126 and n = 7665) of the addition of nicorandil or nifedipine to one or more antianginal medications, predominantly β-blocker therapies, demonstrated no major change in anginal symptoms, although nifedipine use was associated with a modest reduction in the need for coronary angiography (absolute reduction of 1.23% per year) and coronary artery bypass surgery (absolute reduction of 0.44% per year). Once-daily and sustained-release preparations should be used whenever possible to aid compliance.
β-Blockers
β-Blockers inhibit the β-adrenergic receptors of the myocardium to produce negative chronotropism and negative inotropism of the heart. The attenuation of the heart rate response to exercise and stress reduces the myocardial oxygen demand and severity of ischemia. It also prolongs diastole, a major determinant of myocardial perfusion time. RCTs have demonstrated that β-blocker therapy is efficacious in reducing symptoms of angina and episodes of ischemia and in improving exercise capacity.
No evidence supports the suggestion that one type of β-blocker is superior to another. The highly selective β-blockers, such as celiprolol or bisoprolol—or those with combined vasodilation and antioxidant properties, such as carvedilol—have no proven benefits above conventional β-blockers such as atenolol or metoprolol. However, the secondary preventive benefits of β-blockers may be lost when agents have intrinsic sympathomimetic action, and the use of such agents should be avoided.
True side effects from β-blocker therapy are uncommon and occur in less than 10% of patients but include symptoms such as fatigue and lethargy, commonly reported on routine inquiry. A causative association should be established before permanent discontinuation of β-blocker therapy. Because of β-adrenergic receptor upregulation in the presence of β-blockade, patients should not be rapidly withdrawn from therapy, as this can cause an acute withdrawal syndrome; also, it has been suggested that this may even precipitate acute MI.
Calcium Channel Blockers
Patients who are intolerant of a β-blocker should be considered for a rate-limiting calcium channel blocker (CCB) such as diltiazem or verapamil. In the second Danish Verapamil Infarction Trial (DAVIT II), a post hoc analysis suggested that verapamil may be beneficial after MI in the absence of heart failure. However, other CCBs and classes of antianginal agents are equally effective in relieving symptoms. The addition of nifedipine to other antianginal therapies does appear to reduce the need for further invasive investigation and revascularization.
Controversy exists as to whether CCBs can be used safely in patients with heart failure. Amlodipine has been shown to have a neutral effect on mortality rates in patients with heart failure and is an appropriate choice in patients with angina and significant LV dysfunction.
Nitrates
Nitrates were the first form of antianginal drug therapy to be discovered and used. Their mechanism of action is exerted through the release of nitric oxide (NO) either indirectly—as with glyceryl trinitrate (GTN) and reactions with sulfhydryl groups, such as methionine or cysteine—or directly (sodium nitroprusside), by interaction with plasma or cell membranes. The liberated NO causes endothelium-independent relaxation of vascular smooth muscle by increasing intracellular cyclic guanidine monophosphate (cGMP; see Chapter 7 ).
RCTs have demonstrated that nitrates are effective in reducing the frequency of anginal symptoms and in improving exercise capacity. However, as with CCBs, their use in severe aortic stenosis and hypertrophic obstructive cardiomyopathy should be avoided because of the potential to compromise coronary perfusion through peripheral vasodilation and systemic arterial hypotension.
Acute Relief of Angina
Sublingual or buccal nitrates produce rapid and effective relief of acute anginal episodes. All patients should be provided with a sublingual nitrate preparation. Buccal preparations provide a more protracted release of nitrate, which is appropriate for prolonged activities that may provoke episodes of angina.
Prevention of Anginal Episodes
Long-acting nitrates, either oral or transdermal, provide effective relief of angina. Nitrates undergo extensive first-pass metabolism through hepatic glutathione reductases; however, topical and transdermal nitrate preparations are able to bypass such metabolism, and consequently, the overall dosage can be reduced. Alternatively, some nitrate preparations, such as isosorbide mononitrate, undergo less extensive hepatic metabolism and have better bioavailability and more prolonged action.
One of the main limitations of prophylactic nitrate use is the development of tolerance (see Chapter 7 ). This phenomenon requires a daily nitrate-free period, usually nocturnal, to prevent the loss of efficacy—a problem with all of the established nitrate preparations. The mechanism of nitrate tolerance appears, at least in part, to be due to the depletion of sulfhydryl groups. The development of S-nitrosothiols potentially heralds a novel class of nitrates that may be devoid of nitrate tolerance and may have additional antiplatelet actions.
Potassium Channel Agonists
This class of antianginal agents has vasodilatory and potential cardioprotective actions. Potassium channel openers act on the ion channels of the vascular smooth muscle cell and cardiac myocyte. Consequently, they may have a role in enhancing ischemic preconditioning and improving the myocardial response to an ischemic insult.
Nicorandil is the only preparation of this class in clinical use. It is effective in the treatment of angina and has both nitrate and potassium channel–opening properties. However, no evidence suggests that potassium channel openers are superior to other classes of antianginal agents, and their addition to preexisting antianginal therapy does not appear to improve symptoms. The Impact of Nicorandil in Angina (IONA) trial in 5126 patients with stable angina did demonstrate that nicorandil 20 mg twice daily was associated with a modest 17% relative risk reduction in its primary endpoint of CHD death, nonfatal MI, or unplanned hospitalization. However, the trial failed to demonstrate a difference in the secondary endpoint of CHD death and MI.
Miscellaneous Medical Therapies
Ivabradine is an inhibitor of I f , the so-called funny ion channel found in the sinoatrial (SA) node, and it reduces heart rate in patients who are in sinus rhythm. This heart rate–lowering effect is associated with antianginal effects that are comparable and additive to other antianginal therapies. Ivabradine is particularly useful in those patients who are intolerant of β-blockers and who also have a high resting heart rate.
Ranolazine is a novel antianginal therapy that does not have a clearly understood mechanism of action, but it appears to modulate the metabolism of ischemic myocardial cells and improve the efficiency of oxygen use. It also appears to provide additional antianginal benefits when added to other therapies. Ranolazine has also been shown to safely reduce ischemia in patients following ACS.
Coronary Revascularization
Both CABG and PCI carry measurable early morbidity and mortality risks. As indicated, all interventions should be instituted only if the perceived benefits, in terms of improved symptoms and prognosis, are likely to outweigh the associated risks. This is particularly important when the therapy is targeted at symptomatic, rather than prognostic, benefits such as with PCI or CABG for single-vessel disease.
Selection of the appropriateness and type of revascularization procedure will be heavily influenced by technical aspects of the coronary anatomy and by factors such as comorbidity and patient preference. What is considered to be an acceptable level of symptoms, optimal medical therapy, and tolerable drug side effects may vary greatly from patient to patient. Thus the need for and type of coronary revascularization should take into account both objective clinical criteria and the patient’s symptoms (see Chapter 11 ).
Several factors must be considered when evaluating the applicability and evidence of the clinical usefulness of coronary revascularization strategies. First, the major randomized trials are based on highly selected patient groups and may not reflect the broad mix of patients who present to the clinic. For example, the Angioplasty Compared with Medicine (ACME) trial recruited only 212 patients of the nearly 5000 who were screened. Second, most trials have not exclusively selected patients with chronic stable angina pectoris. Third, many datasets reported in the literature are outdated. Medical therapy has improved and has become more effective; similarly, the surgical results do not take into account the improvements in techniques and the increasing use of arterial conduits ( Figure 8-11 ). Indeed, the initial failure and restenosis rate in PCI has been reduced by the introduction of coronary artery stent deployment ( Figure 8-12 ), drug-eluting stents, and adjuvant therapy with antiplatelet agents.
