Coronary heart disease (CHD), or atherosclerotic CAD, is the number one cause of death in the United States and worldwide. Every minute, an American dies of CHD. About 37% of people who experience an acute coronary event, either angina or myocardial infarction, will die of it in the same year. Death rates of CHD have declined every year since 1968, with about half of the decline from 1980 to 2000 due to treatments and half due to improved risk factors. CHD is still responsible for approximately one of five deaths and over 600,000 deaths per year in the United States. CHD afflicts nearly 16 million Americans and the prevalence rises steadily with age; thus, the aging of the US population promises to increase the overall burden of CHD.
Most patients with CHD have some identifiable risk factor. These include a positive family history (the younger the onset in a first-degree relative, the greater the risk), male sex, blood lipid abnormalities, diabetes mellitus, hypertension, physical inactivity, abdominal obesity, and cigarette smoking, psychosocial factors, consumption of too few fruits and vegetables, and too much alcohol. Many of these risk factors are modifiable. Smoking remains the number one preventable cause of death and illness in the United States. Although smoking rates have declined in the United States in recent decades, 18% of women and 21% of men still smoke. According to the World Health Organization, 1 year after quitting, the risk of CHD decreases by 50%. Various interventions have been shown to increase the likelihood of successful smoking cessation (see Chapter 1).
Hypercholesterolemia is an important modifiable risk factor for CHD. Risk increases progressively with higher levels of low-density lipoprotein (LDL) cholesterol and declines with higher levels of high-density lipoprotein (HDL) cholesterol. Composite risk scores, such as the Framingham score (see eTable 28–2) and the 10-year atherosclerotic cardiovascular disease risk calculator (http://my.americanheart.org/cvriskcalculator), provide estimates of the 10-year probability of development of CHD that can guide primary prevention strategies. The 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults suggests statin therapy in four populations: patients with (1) clinical atherosclerotic disease, (2) LDL cholesterol 190 mg/dL or higher, (3) diabetes who are aged 40–75 years, and (4) an estimated 10-year atherosclotic risk of 7.5% or more aged 40–75 years (Figure 10–4). Importantly, the updated guidelines do not recommend treating to a target LDL cholesterol, an approach that has never been shown to be effective in randomized trials. Patients in these categories should be treated with moderate or high intensity statin, with high intensity statin for the higher risk populations (Table 10–9). The ACC/AHA atherosclerotic cardiovascular disease risk estimator allows clinicians to determine the 10-year CHD risk to determine treatment decisions (http://tools.cardiosource.org/ASCVD-Risk-Estimator/). The predominant therapy recommended based on patient risk is either moderate- or high-intensity statin therapy.
Table 10–9.High-, moderate-, and low-intensity statin therapy (used in the RCTs reviewed by the expert panel).1,2 |Favorite Table|Download (.pdf) Table 10–9. High-, moderate-, and low-intensity statin therapy (used in the RCTs reviewed by the expert panel).1,2
|High-Intensity Statin Therapy ||Moderate-Intensity Statin Therapy ||Low-Intensity Statin Therapy |
|Daily dose lowers LDL-C on average by approximately ≥ 50% ||Daily dose lowers LDL-C on average by approximately 30% to < 50% ||Daily dose lowers LDL-C on average by < 30% |
Atorvastatin (403)–80 mg
Rosuvastatin 20 (40) mg
Atorvastatin 10 (20) mg
Rosuvastatin (5) 10 mg
Simvastatin 20–40 mg4
Pravastatin 40 (80) mg
Lovastatin 40 mg
Fluvastatin XL 80 mg
Fluvastatin 40 mg twice daily
Pitavastatin 2–4 mg
Simvastatin 10 mg
Pravastatin 10–20 mg
Lovastatin 20 mg
Fluvastatin 20–40 mg
Pitavastatin 1 mg
Major recommendation for statin therapy for ASCVD prevention. Adapted from Stone NJ et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Jun 24;129(25 Suppl 2):S1–45. [PMID: 24222016])
The metabolic syndrome is defined as a constellation of three or more of the following: abdominal obesity, triglycerides 150 mg/dL or higher, HDL cholesterol less than 40 mg/dL for men and less than 50 mg/dL for women, fasting glucose 110 mg/dL or higher, and hypertension. This syndrome is increasing in prevalence at an alarming rate. Related to the metabolic syndrome, the epidemic of obesity in the United States is likewise a major factor contributing to CHD risk. It is estimated that 155 million people (68%) in the United States age 20 years or older are overweight or obese in 2010, and nearly 35% are obese (body mass index 30 kg/m2 or more). ACC/AHA guidelines highlight that sustained weight loss of 3–5% is likely to reduce triglycerides, blood glucose, HbA1C, and development of diabetes, and greater amount of weight loss will also likely reduce BP. Increasing physical activity is an important goal to help combat obesity and its consequences. Although the AHA continues to promote a diet based largely on low saturated fat, more information is needed on the health consequences of all diets, especially given the lack of protection from a low-fat diet in the largest randomized study ever done, the Women's Health Initiative trial. Low carbohydrate diets, even when high in saturated fat, may improve the cholesterol profile in overweight men and are as effective at achieving weight loss. Fish, rich in omega-3 fatty acids, may help protect against vascular disease, and it is recommended that it be eaten three times a week by patients at risk. A Mediterranean diet supplemented with olive oil or mixed nuts has been shown to reduce the risk of cardiovascular events.
Markers of inflammation are strong risk factors for CAD. High-sensitivity CRP (hsCRP) is the best-characterized inflammatory marker, but others include interleukin-6, CD-40 ligand, myelopyroxidase, and placental growth factor. Although hsCRP levels greater than 10 mg/dL (greater than 100 mg/L) are often found in systemic inflammation, levels less than .1, .1–.3, and greater than .3 mg/dL, respectively, identify patients at low, intermediate, and high risk for future cardiovascular events. The prognostic value of CRP levels is independent and additive to lipid levels. Use of CRP may be helpful in determining which patients at intermediate risk according to risk scores are at high enough risk to warrant more intensive primary prevention, including use of statins. HsCRP 2 mg/L or more can identify older people without vascular disease and with normal cholesterol who benefit from statin therapy, specifically rosuvastatin. HsCRP levels are often elevated in patients who have other conditions associated with accelerated atherosclerosis, such as diabetes, the metabolic syndrome, and obesity. Even with these data, it is controversial when hsCRP should be measured to guide clinical decisions.
The pathophysiology of atherosclerosis is well characterized. Abnormal lipid metabolism or excessive intake of cholesterol and saturated fats—especially when superimposed on a genetic predisposition—is important in early stages of the atherosclerotic process (eFigure 10–45). The initial step is the "fatty streak," or subendothelial accumulation of lipids and lipid-laden monocytes (macrophages) (eFigure 10–46). LDLs, especially small dense LDLs, are the major atherogenic lipid. HDLs, in contrast, are protective by virtue of their role in reverse cholesterol transport, removing cholesterol from the vascular wall. The pathogenetic role of other lipids, including triglycerides, is less clear. LDLs undergo in situ oxidation, which makes them more difficult to mobilize as well as locally cytotoxic.
Lipid metabolism in relation to formation of atherosclerotic lesions. Fatty acids from dietary lipids are reesterified in intestinal cells and exported as protein-containing chylomicrons. Lipoprotein lipase from endothelial cells catalyzes the release of triglycerides from the chylomicrons, and the chylomicron remnants are taken up by the liver. In the liver, they take up cholesterol and are released into the bloodstream as very low-density lipoprotein (VLDL) particles. These engage in exchange reactions with intermediate density lipoproteins (IDL) and high-density lipoproteins (HDL). Low-density lipoprotein (LDL) particles are formed, and these constitute the major source of cholesterol for the tissues. Oxidized LDL enter the macrophages and smooth muscle cells, forming foam cells. In addition, HDL carry cholesterol from tissues to the liver for excretion in the bile, and LDL receptors in the liver (not shown) take up VLDL, IDL, and LDL, lowering circulating cholesterol. (Reproduced, with permission, from Hajjar DP, Nicholson AC. Atherosclerosis. Am Scientist. 1995;83:460.)
Formation of a fatty streak in an artery. Following vascular injury, monocytes bind to the endothelium, then cross it to the subendothelial space and become activated tissue microphages. The macrophages take up oxidized LDL, becoming foam cells. T cells release cytokines, which also activate macrophages. In addition, the cytokines cause smooth muscle cells to proliferate. Under the influence of growth factors, the smooth muscle cells then move to the subendothelial space, where they produce collagen and take up LDL, adding to the population of foam cells. (Reproduced, with permission, from Hajjar DP, Nicholson AC. Atherosclerosis. Am Scientist. 1995;83:460.)
Macrophages migrate into the subendothelial space and take up lipids, giving them the appearance of "foam" cells. As the plaque progresses, smooth muscle cells also migrate into the lesion (eFigure 10–47). At this stage, the lesion may be hemodynamically insignificant, but endothelial function is abnormal and its ability to limit the entry of lipoproteins into the vessel wall is impaired. If the plaque remains stable, a fibrous cap forms, the lesion becomes calcified, remodeling of the vessel wall occurs, and ultimately the vessel lumen may become narrowed, although extensive atherosclerosis may be present even before this occurs.
Mechanisms of production of atheroma. A: S tructure of normal muscular artery. The adventitia, or outermost layer of the artery, consists principally of recognizable fibroblasts intermixed with smooth muscle cells loosely arranged between bundles of collagen and surrounded by proteoglycans. It is usually separated from the media by a discontinuous sheet of elastic tissue, the external elastic lamina. B: Platelet aggregates, or microthrombi, which may form as a result of adherence of the platelets to the exposed subendothelial connective tissue. Platelets that adhere to the connective tissue release granules whose constituents may gain entry into the arterial wall. Platelet factors thus interact with plasma constituents in the artery wall and may stimulate events shown in the next illustration. C: S mooth muscle cells migrating from the media into the intima through fenestrae in the internal elastic lamina and actively multiplying within the intima. Endothelial cells regenerate in an attempt to recover the exposed intima, which thickens rapidly, owing to smooth muscle proliferation and formation of new connective tissue. (Reproduced, with permission, from Ross R, Glomset JA. The pathogenesis of atherosclerosis. [Part 1.] N Engl J Med. 1976;295:369.)
Atherosclerotic plaques may remain stable or progress only gradually, and these may result in chronic stable angina, when myocardial oxygen demand may be greater than the limited flow past stenotic coronary artery segments. It should be noted that severe stenosis (greater than 90%) is required to reduce myocardial oxygen supply at rest. Precipitants include exercise, eating, cold weather, and emotional stress. Some episodes of myocardial ischemia are symptomatic, causing angina pectoris; others are completely silent.
Other plaques may rupture, often related to the inflammatory process and metalloproteinase activity. The rupture (often at the shoulder of the plaque) causes turbulent flow, extrusion of lipids and fatty gruel, and exposure of tissue factor that result in a cascade of events culminating in intravascular thrombosis. This may be accompanied by coronary vasospasm. The outcome of these events is determined in large part by whether the vessel becomes occluded, which depends on the lesion anatomy as well as the balance of prothrombotic and antithrombotic and profibrinolytic and antifibrinolytic forces. The result may be partial or complete vessel occlusion causing acute coronary syndrome in the form of unstable angina (accelerating or new symptoms of myocardial ischemia at rest or minimal activity) or myocardial infarction, or the plaque may become restabilized, often with more severe stenosis. There is a predilection for these episodes to occur in the early morning or shortly after arising. Transient occlusion and/or embolization of platelet and thrombin debris, which may result in elevation in serum troponin, predispose to clinical events and portend a worse prognosis. If the vessel becomes completely occluded during one of these events, then acute myocardial necrosis ensues.
Several features are associated with enhanced plaque vulnerability, including a higher lipid content, a higher concentration of macrophages, especially in the plaque shoulder, and a very thin fibrous cap. Lesions with these characteristics are often relatively early lesions that can be responsible for acute myocardial infarction or sudden death as the first manifestation of coronary disease. This abrupt progression explains why most infarctions do not occur at the site of preexisting critical stenosis. Conversely, the relatively greater reduction in clinical events than in lesion severity in statin treatment trials is probably explained by the stabilization of these early nonfibrotic lesions.
Myocardial Hibernation & Stunning
Areas of myocardium that are persistently underperfused but still viable may develop sustained contractile dysfunction. This phenomenon, which is termed myocardial hibernation, appears to represent an adaptive response that may be associated with depressed LV function. It is important to recognize this phenomenon, since this form of dysfunction is reversible following coronary revascularization. Hibernating myocardium can be identified by radionuclide testing, positron emission tomography (PET), contrast-enhanced MRI, or its retained response to inotropic stimulation with dobutamine. A related phenomenon, termed myocardial stunning, is the occurrence of persistent contractile dysfunction following prolonged or repetitive episodes of myocardial ischemia. Clinically, myocardial stunning is often seen after reperfusion of acute myocardial infarction and is defined with improvement following revascularization.
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Primary & Secondary Prevention of CHD
Although many risk factors for CHD are not modifiable, it is now clear that interventions, such as smoking cessation, treatment of dyslipidemia, and lowering of BP can both prevent coronary disease and delay its progression and complications after it is manifest.
Lowering LDL levels delays the progression of atherosclerosis and in some cases may produce regression. Even in the absence of regression, fewer new lesions develop, endothelial function may be restored, and coronary event rates are markedly reduced in patients with clinical evidence of vascular disease.
A series of clinical trials has demonstrated the efficacy of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) in preventing death, coronary events, and strokes. Beneficial results have been found in patients who have already experienced coronary events (secondary prevention), in those at particularly high risk for events (patients with diabetes and patients with peripheral artery disease), and those with elevated cholesterol without multiple risk factors, and those without vascular disease or diabetes with elevated hsCRP with normal LDL levels. The benefits of statin therapy at moderate and high doses (Table 10–9) are recommended by the cholesterol treatment guidelines. The IMPROVE-IT study showed that ezetimibe, 10 mg daily, combined with simvastatin was superior to simvastatin alone in reducing LDL cholesterol and in reducing the risk of myocardial infarction and ischemic stroke, but not mortality, in stabilized patients following an acute coronary syndrome. This was associated with a reduction of LDL to 53.7 mg/dL compared to 69.7 mg/dL.
Benefits occurred regardless of age, race, or the presence of hypertension. It is clear that for patients with vascular disease, statins provide benefit for those with normal cholesterol levels, and that more aggressive statin use is associated with greater benefits. The Heart Protection Study demonstrated that simvastatin 40 mg/day reduces vascular events by more than 20% in patients with prior myocardial infarction, stroke, peripheral vascular disease, or diabetes with total cholesterol levels as low as 135 mg/dL. The treatment benefit in this trial, and in an overview of major placebo-controlled randomized trials, was similar regardless of baseline LDL cholesterol, with equal benefit above or below 100 mg/dL. This result suggests that all patients at significant risk for vascular events should receive a statin regardless of their cholesterol levels. The PROVE-IT trial showed that vascular events were reduced with more aggressive lipid lowering (atorvastatin 80 mg/day compared to pravastatin 40 mg/day following an acute coronary syndrome), providing more evidence of "lower is better" for patients with vascular disease. The TNT (Treating to New Targets) trial likewise found greater benefit with more aggressive LDL lowering (atorvastatin 80 mg versus 10 mg) in a population of patients with CHD and LDL cholesterol less than 130 mg/dL. The IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trial provided only modest support for very aggressive lipid lowering, showing a nonstatistically significant reduction in major coronary events with 80 mg/day of atorvastatin compared with 20 mg/day of simvastatin in patients with prior myocardial infarction. Although true regression of plaque is uncommon even with intensive lipid therapy (as in the REVERSAL and ASTEROID trials), progression can be prevented at least in the short run in many patients. The failure of ezetimide and simvastatin versus simvastatin alone to reduce the progression of carotid intimal medial thickening in the ENHANCE trial has raised questions about whether the method of lowering LDL cholesterol may be important, and whether the LDL lowering of ezetimide leads to reduction in vascular events awaits the results of clinical outcome trials. The JUPITER trial showed that for men age 50 years or older and women age 60 years or older, with LDL less than 130 mg/dL and without cardiovascular disease or diabetes, and with hsCRP 2 mg/L or higher, rosuvastatin 20 mg/day reduced cardiovascular events by 44%.
Statins have not been shown to provide clinical benefit in patients who have heart failure with reduced LVEF or with end-stage renal disease, based on large randomized clinical trials. Patients with chronic heart failure may derive little benefit since they frequently die of progression of heart failure.
Novel monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) have been developed and have shown to reduce LDL cholesterol levels significantly beyond levels associated with traditional statin therapy. These therapies have been studied in initial randomized trials of patients with maximally tolerated statin therapy (and for patients with statin intolerance) and have lowered LDL with signals of improved cardiovascular outcomes, but with ongoing trials to test whether clinical outcomes are actually improved. Two such medications—alirocumab and evolocumab—have been approved by the FDA for patients on maximally tolerated statin therapy with familial hypercholesterolemia and atherosclerotic vascular disease, or both, and who require additional lowering of LDL. These medications cost approximately $14,000 per year in the United States.
Treatment to raise HDL levels has failed to show benefit. The AIM High trial found no benefit from the addition of niacin in patients with vascular disease and a serum LDL near 70 mg/dL who were receiving statin therapy. The HPS2-THRIVE trial found no benefit but rather substantial harm of extended-release niacin (2 g) plus laropiprant (an antiflushing agent) for preventing vascular events in a population of over 25,000 patients with vascular disease who were taking simvastatin. There was significant toxicity from niacin with increased diabetes, infection, gastrointestinal and musculoskeletal symptoms, and bleeding. A trial in postinfarction patients has demonstrated that gemfibrozil (600 mg twice daily), which increases HDL, in patients with relatively low LDL levels prolongs reinfarction-free survival, although the larger FIELD trial failed to show prevention of nonfatal myocardial infarction or CHD death with fenofibrate for patients with type 2 diabetes mellitus. The ACCORD trial likewise showed no benefit of statin with fenofibrate versus statin alone in a population of patients with type II diabetes at high risk for cardiovascular events. Three trials of cholesteryl ester transfer protein (CETP) inhibitors, which raise HDL levels with variable amounts of reduction in LDL levels, were stopped because of no benefit or harm. These trials emphasize that an impact on surrogate outcomes, like lipid levels, may not translate into benefits on clinical outcomes.
The value of medications that reduce elevated triglyceride levels is less clear, unless triglycerides are elevated to greater than 500 mg/dL despite diet intervention.
While antioxidant therapy has theoretical appeal, many large, well-controlled studies have failed to demonstrate a benefit with vitamin E therapy. In fact, the Heart Protection Study and the Heart Outcomes Prevention Evaluation (HOPE) trial found that vitamin E may even be harmful by increasing the likelihood of heart failure and other trials have suggested that vitamin E may hinder the effectiveness of statin therapy. The Physician's Health Study showed no benefit of a multivitamin in preventing cardiovascular disease in men averaging 64 years of age over 11 years of follow-up.
Elevated plasma homocysteine levels are associated with an increased risk of vascular events. Although homocysteine levels can be reduced with dietary supplements of folic acid (1 mg/day) in combination with vitamin B6 and vitamin B12, two randomized clinical trials have shown that they are of little or no value in preventing vascular events.
Antiplatelet therapy is another very effective preventive measure. Aspirin (325 mg every other day) in men over the age of 50 years reduces the incidence of myocardial infarction. A similar approach (100 mg every other day), however, did not prevent myocardial infarction in women age 45 years or older, although stroke did appear to be reduced. Thus, the role of aspirin in primary prevention, including the dose, remains controversial. A prudent approach would be to administer 81–325 mg daily to men with multiple coronary risk factors or concomitant diabetes starting at age 45–50 years if no contraindication is present. While clopidogrel was found to be effective at preventing vascular events for 9–12 months after acute coronary syndromes, it was not found to be effective at preventing vascular events with longer-term treatment in the CHARISMA trial. This trial included patients with clinically evident stable atherothrombosis or with multiple risk factors; all were treated with aspirin and observed for a median of 28 months. The previously mentioned GISSI Prevention Trial found a significant but modest reduction in mortality with administration of omega-3 fatty acid (850 mg daily) in postinfarction patients.
The effect of hormone replacement therapy in postmenopausal women has been clarified, and it is clear that neither combined estrogen–progesterone nor estrogen alone therapy is protective. In fact, both cause harm, although hormone replacement therapy for short-term managementof menopausal symptoms appears to be relatively safe. Transdermal estrogen may have lower risk of thromboembolic disease than oral hormone replacement therapy. Control of BP has been shown to prevent infarctions. Individuals who exercise for at least 30 minutes a week are at lower risk for subsequent coronary events, and 30 minutes of exercise five times a week reduces the risk of developing diabetes in half among people at risk.
The HOPE and the EUROPA trials demonstrated that ACE inhibitors (ramipril 10 mg/day and perindopril 8 mg/day, respectively) reduced fatal and nonfatal vascular events (cardiovascular deaths, nonfatal myocardial infarctions, and nonfatal strokes) by 20–25% in patients at high risk, including patients with diabetes with additional risk factors or patients with clinical coronary, cerebral, or peripheral arterial atherosclerotic disease. The PEACE trial did not show benefit of the ACE inhibitor trandolapril in a lower-risk population of patients with CHD, most of whom had been treated aggressively with medical and revascularization therapies. An overview of these trials has demonstrated that while low-risk patients may not derive substantial benefits from ACE inhibitors, most patients with vascular disease, even in the absence of heart failure or LV dysfunction, should be treated with an ACE inhibitor.
ARBs may have similar effects as ACE inhibitors in preventing vascular events, as shown in the 25,620 patient ONTARGET trial that randomized patients to ramipril, telmisartan, or both. Outcomes were similar with ramipril and telmisartan, and there was no added benefit (and increased risk of kidney dysfunction and hypotension) with using both. However, the use of telmisartan in patients intolerant to ACE inhibitors did not show a significant benefit in reducing cardiovascular death, myocardial infarction, stroke, or heart failure hospitalization in the TRANSCEND trial.
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CHRONIC STABLE ANGINA PECTORIS
ESSENTIALS OF DIAGNOSIS
Precordial chest pain, usually precipitated by stress or exertion, relieved rapidly by rest or nitrates.
ECG or scintigraphic evidence of ischemia during pain or stress testing.
Angiographic demonstration of significant obstruction of major coronary vessels.
Angina pectoris is usually due to atherosclerotic heart disease. Coronary vasospasm may occur at the site of a lesion or, less frequently, in apparently normal vessels. Other unusual causes of coronary artery obstruction, such as congenital anomalies, emboli, arteritis, or dissection may cause ischemia or infarction. Angina may also occur in the absence of coronary artery obstruction as a result of severe myocardial hypertrophy, severe aortic stenosis or regurgitation, or in response to increased metabolic demands, as in hyperthyroidism, marked anemia, or paroxysmal tachycardias with rapid ventricular rates. Rarely, angina occurs with angiographically normal coronary arteries and without other identifiable causes. This presentation has been labeled syndrome X and is most likely due to inadequate flow reserve in the resistance vessels (microvasculature). Syndrome X remains difficult to diagnose. Although treatment is often not very successful in relieving symptoms, the prognosis of syndrome X is good.
The diagnosis of angina pectoris depends principally upon the history, which should specifically include the following information: circumstances that precipitate and relieve angina, characteristics of the discomfort, location and radiation, duration of attacks, and effect of nitroglycerin.
1. Circumstances that precipitate and relieve angina
Angina occurs most commonly during activity and is relieved by resting. Patients may prefer to remain upright rather than lie down, as increased preload in recumbency increases myocardial work. The amount of activity required to produce angina may be relatively consistent under comparable physical and emotional circumstances or may vary from day to day. The threshold for angina is usually lower after meals, during excitement, or on exposure to cold. It is often lower in the morning or after strong emotion; the latter can provoke attacks in the absence of exertion. In addition, discomfort may occur during sexual activity, at rest, or at night as a result of coronary spasm.
2. Characteristics of the discomfort
Patients often do not refer to angina as “pain” but as a sensation of tightness, squeezing, burning, pressing, choking, aching, bursting, “gas,” indigestion, or an ill-characterized discomfort. It is often characterized by clenching a fist over the mid chest. The distress of angina is rarely sharply localized and is not spasmodic.
3. Location and radiation
The distribution of the distress may vary widely in different patients but is usually the same for each patient unless unstable angina or myocardial infarction supervenes. In most cases, the discomfort is felt behind or slightly to the left of the mid sternum. When it begins farther to the left or, uncommonly, on the right, it characteristically moves centrally substernally. Although angina may radiate to any dermatome from C8 to T4, it radiates most often to the left shoulder and upper arm, frequently moving down the inner volar aspect of the arm to the elbow, forearm, wrist, or fourth and fifth fingers. It may also radiate to the right shoulder or arm, the lower jaw, the neck, or even the back.
Angina is generally of short duration and subsides completely without residual discomfort. If the attack is precipitated by exertion and the patient promptly stops to rest, it usually lasts under 3 minutes. Attacks following a heavy meal or brought on by anger often last 15–20 minutes. Attacks lasting more than 30 minutes are unusual and suggest the development of an acute coronary syndrome with unstable angina, myocardial infarction, or an alternative diagnosis.
5. Effect of nitroglycerin
The diagnosis of angina pectoris is supported if sublingual nitroglycerin promptly and invariably shortens an attack and if prophylactic nitrates permit greater exertion or prevent angina entirely.
Examination during angina frequently reveals a significant elevation in systolic and diastolic BP, although hypotension may also occur, and may reflect more severe ischemia or inferior ischemia (especially with bradycardia) due to a Bezold-Jarisch reflex. Occasionally, a gallop rhythm and an apical systolic murmur due to transient mitral regurgitation from papillary muscle dysfunction are present during pain only. Supraventricular or ventricular arrhythmias may be present, either as the precipitating factor or as a result of ischemia (see eFigure 10–3 and eFigure 10–4).
It is important to detect signs of diseases that may contribute to or accompany atherosclerotic heart disease, eg, diabetes mellitus (retinopathy or neuropathy), xanthelasma tendinous xanthomas, (eFigure 10–48), hypertension, thyrotoxicosis, myxedema, or peripheral artery disease. Aortic stenosis or regurgitation, hypertrophic cardiomyopathy, and mitral valve prolapse should be sought, since they may produce angina or other forms of chest pain (see AUDIO 10-18 and AUDIO 10-20) (AUDIO 10-21) (see AUDIO 10-8).
Tendinous (Achilles) xanthomas. (Used, with permission, from M Siperstein.)
Hypertrophic cardiomyopathy (HCM). A mid-systolic rough 3/6 murmur and S2 is heard with the patient supine. This murmur is louder when the patient stands, performs a Valsalva maneuver, or inhales amyl nitrite. (Reproduced, with permission, from T. Anthony Don Michael, MD. Mastering Auscultation [CD-ROM], 2000.)
Hypertrophic obstructive cardiomyopathy (HOCM).
Other than standard laboratory tests to evaluate for acute coronary syndrome (troponin and CK-MB), factors contributing to ischemia (such as anemia), and to screen for risk factors that may increase the probability of true CHD (such as hyperlipidemia and diabetes mellitus), blood tests are not helpful to diagnose chronic angina.
The resting ECG is often normal in patients with angina. In the remainder, abnormalities include old myocardial infarction, nonspecific ST–T changes, and changes of LVH (see eFigures 10–13, 10–14) (eFigure 10–49). During anginal episodes, as well as during asymptomatic ischemia, the characteristic ECG change is horizontal or downsloping ST-segment depression that reverses after the ischemia disappears (see eFigure 10–12). T wave flattening or inversion may also occur. Less frequently, transient ST-segment elevation is observed; this finding suggests severe (transmural) ischemia from coronary occlusion, and it can occur with coronary spasm (eFigure 10–50).
First-degree atrioventricular (AV) block. The PR interval is prolonged to 0.28 s. The laddergram beneath the ECG illustrates the three levels of AV conduction: the atrium, the AV node, and the ventricles, with the delay in AV conduction represented as occurring in the AV node. (Reproduced, with permission, from Goldschlager N, Goldman MJ. Principles of Clinical Electrocardiography, 13th ed. Originally published by Appleton & Lange. Copyright © 1989 by The McGraw-Hill Companies, Inc.)
Spontaneous angina with ST elevation, indicating transmural myocardial ischemia. A: Tracing taken during an episode of anginal pain that occurred while the patient was at bed rest in the hospital. There is marked ST elevation in leads V2-5 with ST depression in aVF. B: Tracing taken 30 minutes after A when the patient was pain-free and asymptomatic. The ST segments are isoelectric, and the ECG is normal. Subsequent evaluation, including serial ECG sand enzyme determinations, revealed no evidence of acute myocardial infarction. Although tracing A is quite typical of early infarction, the rapid disappearance of the ST elevation and the absence of clinical and ECG evidence of infarction on subsequent examinations indicate that tracing A represents severe acute but reversible ischemia. (Reproduced, with permission, from Goldschlager N, Goldman MJ. Principles of Clinical Electrocardiography, 13th ed. Originally published by Appleton & Lange. Copyright © 1989 by The McGraw-Hill Companies, Inc.)
The history as detailed above, the physical examination findings, and laboratory and ECG findings are used to develop a pretest probability of CAD as the cause of the clinical symptoms. Other important factors to include in calculating the pretest probability of CAD are patient age, sex, and clinical symptoms. Patients with low to intermediate pretest probability for CAD should undergo noninvasive stress testing whereas patients with high pretest probability are generally referred for cardiac catheterization. Of note, a 2010 large review of diagnostic cardiac catheterization findings in patients without known CAD undergoing invasive angiography, found that 38% had significant obstruction in one or more coronary arteries. These findings have highlighted the importance of careful pretest probability assessment. Novel imaging strategies such as coronary CT angiography with and without hemodynamic assessment of coronary lesions is being studied in the PROMISE randomized trial evaluating patients with chest pain.
Exercise ECG testing is the most commonly used noninvasive procedure for evaluating for inducible ischemia in the patient with angina. Exercise ECG testing is often combined with imaging studies (nuclear or echocardiography), but in low-risk patients without baseline ST segment abnormalities or in whom anatomic localization is not necessary, the exercise ECG remains the recommended initial procedure because of considerations of cost, convenience, and longstanding prognostic data.
Exercise testing can be done on a motorized treadmill or with a bicycle ergometer. A variety of exercise protocols are utilized, the most common being the Bruce protocol, which increases the treadmill speed and elevation every 3 minutes until limited by symptoms. At least two ECG leads should be monitored continuously.
The risk of exercise testing is about one infarction or death per 1000 tests, but individuals who have pain at rest or minimal activity are at higher risk and should not be tested. Many of the traditional exclusions, such as recent myocardial infarction or heart failure, are no longer used if the patient is stable and ambulatory, but symptomatic aortic stenosis remains a relative contraindication.
Exercise testing is used (1) to confirm the diagnosis of angina; (2) to determine the severity of limitation of activity due to angina; (3) to assess prognosis in patients with known coronary disease, including those recovering from myocardial infarction, by detecting groups at high or low risk; and (4) to evaluate responses to therapy. Because false-positive tests often exceed true positives, leading to much patient anxiety and self-imposed or mandated disability, exercise testing of asymptomatic individuals should be done only for those whose occupations place them or others at special risk (eg, airline pilots) and older individuals commencing strenuous activity.
The usual ECG criterion for a positive test is 1 mm (0.1 mV) horizontal or downsloping ST-segment depression (beyond baseline) measured 80 msec after the J point (eFigure 10–51). By this criterion, 60–80% of patients with anatomically significant coronary disease will have a positive test, but 10–30% of those without significant disease will also be positive. False positives are uncommon when a 2-mm depression is present. Additional information is inferred from the time of onset and duration of the ECG changes, their magnitude and configuration, BP and heart rate changes, the duration of exercise, and the presence of associated symptoms. In general, patients exhibiting more severe ST-segment depression (more than 2 mm) at low workloads (less than 6 minutes on the Bruce protocol) or heart rates (less than 70% of age-predicted maximum)—especially when the duration of exercise and rise in BP are limited or when hypotension occurs during the test—have more severe disease and a poorer prognosis. Depending on symptom status, age, and other factors, such patients should be referred for coronary arteriography and possible revascularization. On the other hand, less impressive positive tests in asymptomatic patients are often “false positives.” Therefore, exercise testing results that do not conform to the clinical suspicion should be confirmed by stress imaging.
Abnormal exercise ECG in a patient with severe three-vessel coronary artery disease and chest pain. The resting ECG shows horizontal ST depression in leads II, aVF, and V3, and downsloping ST depression in lead V1. After exercise, downsloping ST depression is present in leads II, aVF, and V2-5. The additional 1 or more mm of J point depression as well as the changes in ST-segment configuration constitute an ischemic response, despite the baseline ECG abnormalities. (Reproduced, with permission, from Goldschlager N, Goldman MJ. Principles of Clinical Electrocardiography, 13th ed. Originally published by Appleton & Lange. Copyright © 1989 by The McGraw-Hill Companies, Inc.)
G. Myocardial Stress Imaging
Myocardial stress imaging (scintigraphy, echocardiography, or MRI) is indicated (1) when the resting ECG makes an exercise ECG difficult to interpret (eg, left bundle branch block, baseline ST–T changes, low voltage); (2) for confirmation of the results of the exercise ECG when they are contrary to the clinical impression (eg, a positive test in an asymptomatic patient); (3) to localize the region of ischemia; (4) to distinguish ischemic from infarcted myocardium; (5) to assess the completeness of revascularization following bypass surgery or coronary angioplasty; or (6) as a prognostic indicator in patients with known coronary disease. Published criteria summarize these indications for stress testing.
1. Myocardial perfusion scintigraphy
This test, also known as radionuclide imaging, provides images in which radionuclide uptake is proportionate to blood flow at the time of injection. Isotopes that are used in addition to thallium-201 are technetium-99m sestamibi, and tetrafosmin. If the radiotracer is injected during exercise or dipyridamoleor adenosine-induced coronary vasodilation, scintigraphic defects indicate a zone of hypoperfusion that may represent either ischemia or scar. If the myocardium is viable, as relative blood flow equalizes over time or during a scintigram performed under resting conditions, these defects tend to "fill in" or reverse, indicating reversible ischemia (eFigure 10–52) (eFigure 10–53). Defects observed when the radiotracer is injected at rest or still present 3–4 hours after an injection during exercise or pharmacologic vasodilation (intravenous adenosine or dipyridamole) usually indicate myocardial infarction (old or recent) but may be present with severe ischemia.
Reversible inferior and lateral defects. A 64-year-old man with exertional chest pain. The angiogram showed 80% stenosis of the left circumflex coronary artery. Short (A) and vertical long (B) axis images show reversible inferior and lateral defects. (Used, with permission, from R Caretta, F Weiland, and M Ortiz.)
Pre- and postoperative thallium-201 stress scintigrams and ECGs obtained before and after placement of right coronary (RCA) and left anterior descending (LAD) grafts for treatment of angina pectoris. The preoperative study revealed an inferior wall perfusion abnormality (arrows). Perfusion is normal in the postoperative stress scintigram, and the patient was symptom-free. (ANT, anterior; LAO, left anterior oblique; LLAT, left lateral.) (Reproduced, with permission, from Greenberg BH et al. Thallium-201 myocardial perfusion scintigraphy to evaluate patients after coronary bypass surgery. Am J Cardiol. 1978;42:167.)
Stress imaging is positive in about 75–90% of patients with anatomically significant coronary disease and in 20–30% of those without it. Occasionally, other conditions, including infiltrative diseases (sarcoidosis, amyloidosis), left bundle branch block, and dilated cardiomyopathy, may produce resting or persistent perfusion defects. False-positive radionuclide tests may occur as a result of diaphragmatic attenuation or, in women, attenuation through breast tissue. Tomographic imaging (single-photon emission computed tomography, SPECT) can reduce the severity of artifacts. Gated imaging allows for analysis of ventricular size, EF, and regional wall motion (eFigure 10–54) (eFigure 10–55).
Diastolic (D) and systolic (S) frames from an equilibrium multiple-gated blood pool scintigram in the right anterior oblique (RAO) and left anterior oblique (LAO) positions. The upper images were obtained on the second day after the patient suffered a myocardial infarction. Left ventricular function was better on this occasion than in the study illustrated below, obtained 3 weeks later when left ventricular failure had developed. (Reproduced, with permission, from Botvinick EH, Shames DM. Nuclear Cardiology: Clinical Applications. Williams & Wilkins, 1979.)
Ischemic cardiomyopathy. Abnormal left ventricular function following coronary artery bypass surgery. A: The patient is a 68-year-old man with a prior myocardial infarction and recent coronary artery bypass surgery. Left anterior oblique view shows marked hypokinesis in the apex and septum. The left ventricle is dilated. The last frame is "noisy" because of occasional extrasystoles during acquisition. B: The summary report confirms the poor wall motion in the apex and septum. Global left ventricular ejection fraction was 27%. In patients with prior coronary artery bypass surgery, abnormalities in the septum ("paradoxical septal motion") are common and do not by themselves reliably reflect prior septal infarction. Note that there is compensation in the motion of the lateral wall with a regional ejection fraction of 60%. (Reproduced, with permission, from Baum S et al. Atlas of Nuclear Medicine Imaging, 2nd ed. Originally published by Appleton & Lange. Copyright © 1993 by The McGraw-Hill Companies, Inc.)
2. Radionuclide angiography
This procedure, also known as Multi-Gated Acquisition Scan, or MUGA scan, uses radionuclide tracers to image the LV and measures its EF and wall motion. In coronary disease, resting abnormalities usually represent infarction, and those that occur only with exercise usually indicate stress-induced ischemia. Exercise radionuclide angiography has approximately the same sensitivity as myocardial perfusion scintigraphy, but it is less specific in older individuals and those with other forms of heart disease. In addition, because of the precision around LVEF, the test is also used for monitoring patients exposed to cardiotoxic therapies (such as chemotherapeutic agents).
3. Stress echocardiography
Echocardiograms performed during supine exercise or immediately following upright exercise may demonstrate exercise-induced segmental wall motion abnormalities as an indicator of ischemia. In experienced laboratories, the test accuracy is comparable to that obtained with scintigraphy—though a higher proportion of tests is technically inadequate. While exercise is the preferred stress because of other information derived, pharmacologic stress with high-dose dobutamine (20–40 mcg/kg/min) can be used as an alternative to exercise (see VIDEO 10-4).
1. Positron emission tomography
PET scanning uses positron-emitting agents to demonstrate either perfusion or metabolism of myocardium. PET and SPECT scanning can accurately distinguish transiently dysfunctional (“stunned”) myocardium from scar tissue. The SPECT camera can provide acceptable images without the more expensive PET technology.
CT scanning can image the heart and, with contrast medium and multislice technology, the coronary arteries. Coronary artery images can be obtained by 64- and higher-slice CT technology, and, if the images are normal, this technology has high sensitivity for excluding significant CAD. Multislice CT angiography may be useful in evaluating patients with low likelihood of significant CAD to rule out disease. With similar radiation exposure as radionuclide SPECT imaging, CT angiography may also be useful for evaluating chest pain and suspected acute coronary syndrome. In the large randomized comparative effectiveness PROMISE trial, patients with stable chest pain undergoing anatomic imaging with CT angiography had similar outcomes to patients undergoing functional testing (stress ECG, stress radionuclide, or stress echocardiography). CT angiography with noninvasive functional assessment of coronary stenosis (fractional flow reserve), termed “CT-FFR,” has also been evaluated in patients with low-intermediate likelihood of CAD. CT-FFR has been shown to reduce the number of patients without coronary disease requiring invasive angiography.
Electron beam CT (EBCT) can quantify coronary artery calcification, which is highly correlated with atheromatous plaque and has high sensitivity, but low specificity, for obstructive coronary disease. Thus, although this test can stratify patients into lower and higher risk groups, the appropriate management of individual patients with asymptomatic coronary artery calcification—beyond aggressive risk factor modification—is unclear. This test has not traditionally been used in symptomatic patients. According to the American Heart Association, persons who are at low risk (less than 10% 10-year risk) or at high risk (greater than 20% 10-year risk) for obstructive coronary disease do not benefit from coronary calcium assessment (class III, level of evidence: B) (see Table 28–1 and eTable 28–2). However, in clinically selected, intermediate-risk patients, it may be reasonable to determine the atherosclerosis burden using EBCT in order to refine clinical risk prediction and to select patients for more aggressive target values for lipid-lowering therapies (class IIb, level of evidence: B).
Cardiac MRI using gadolinium provides high-resolution images of the heart and great vessels without radiation exposure or use of iodinated contrast media. Gadolinium has been associated with a rare but fatal complication in patients with severe kidney disease, called necrotizing systemic fibrosis. Cardiac MRI provides excellent assessment of pericardial disease, neoplastic disease of the heart, myocardial thickness, chamber size, and many congenital heart defects. It is an excellent noninvasive test for nonemergently evaluating dissection of the aorta. Rapid acquisition sequences are a useful alternative when the echocardiogram is suboptimal. Gadolinium can demonstrate perfusion using dobutamine or adenosine to produce pharmacologic stress. Advances have been made in imaging the proximal coronary arteries, but this application remains investigational. Perhaps the most clinically used indication of cardiac MRI is for identification of myocardial fibrosis, either from myocardial infarction or infiltration. This allows high resolution imaging of myocardial viability.
I. Ambulatory ECG Monitoring
Ambulatory ECG recorders can monitor for ischemic ST-segment depression (eFigure 10–56) but this modality is rarely used for ischemia detection. In patients with CAD, these episodes usually signify ischemia, even when asymptomatic (“silent”). In many patients, silent episodes are more frequent than symptomatic ones. In most cases, they occur in patients with other evidence of ischemia, so the role of ambulatory monitoring is limited. Twenty-four to forty-eight hour ambulatory ECG monitoring is often used for arrhythmia detection.
Holter monitor ECG of a 65-year-old man showing marked ST depression of myocardial ischemia when the patient carried out his ordinary work routine as a salesperson. There were no symptoms during the time of the ischemic changes on the ECGs, but angina pectoris of effort occurred at other times. (Used, with permission, from W Atchley.)
Selective coronary arteriography is the definitive diagnostic procedure for CAD. It can be performed with low mortality (about 0.1%) and morbidity (1–5%), but due to the invasive nature and cost, it is recommended only in patients with a high pretest probability of CAD.
Coronary arteriography should be performed in the following circumstances if percutaneous transluminal coronary angioplasty or bypass surgery is a consideration:
Life-limiting stable angina despite an adequate medical regimen.
Clinical presentation (unstable angina, postinfarction angina, etc) or noninvasive testing suggests high-risk disease (see Indications for Revascularization).
Concomitant aortic valve disease and angina pectoris, to determine whether the angina is due to accompanying coronary disease.
Asymptomatic older patients undergoing valve surgery so that concomitant bypass may be done if the anatomy is propitious.
Recurrence of symptoms after coronary revascularization to determine whether bypass grafts or native vessels are occluded.
Cardiac failure where a surgically correctable lesion, such as LV aneurysm, mitral regurgitation, or reversible ischemic dysfunction, is suspected.
Survivors of sudden death, symptomatic, or life-threatening arrhythmias when CAD may be a correctable cause.
Chest pain of uncertain cause or cardiomyopathy of unknown cause.
Emergently performed cardiac catheterization with intention to perform primary PCI in patients with suspected acute myocardial infarction.
Appropriate use criteria for the use of diagnostic heart catheterization and coronary angiography were developed by the ACC/AHA in 2012.
A narrowing of more than 50% of the luminal diameter is considered hemodynamically (and clinically) significant, although most lesions producing ischemia are associated with narrowing in excess of 70% (VIDEO 10-12) (VIDEO 10-13). In those with strongly positive exercise ECGs or scintigraphic studies, three-vessel or left main disease may be present in 75–95% depending on the criteria used. Intravascular ultrasound (IVUS) is useful when the angiogram is equivocal as well as for assessing the results of angioplasty or stenting. In addition, IVUS is the invasive diagnostic method of choice for ostial left main lesions and coronary dissections. In fractional flow reserve (FFR), a pressure wire is used to measure the relative change in pressure across a coronary lesion after adenosine-induced hyperemia. Revascularization based on abnormal FFR improves clinical outcomes compared to revascularization of all angiographically stenotic lesions. FFR is an important invasive tool to aid with ischemia-driven revascularization and has become the standard tool to evaluate borderline lesions in cases in which the clinical team is evaluating the clinical and hemodynamic significance of a coronary stenosis.
VIDEO 10-12: Coronary angiography revealing highgrade stenosis in the proximal left anterior descending coronary artery.
(Used, with permission, from T Amidon and T Chou.)
VIDEO 10-13: Coronary angiography revealing highgrade stenosis in the proximal right coronary artery.
(Used, with permission, from T Amidon and T Chou.)
LV angiography is usually performed at the same time as coronary arteriography. Global and regional LV function are visualized, as well as mitral regurgitation if present. LV function is a major determinant of prognosis in CHD.
When atypical features are present—such as prolonged duration (hours or days) or darting, or knifelike pains at the apex or over the precordium—ischemia is less likely.
Anterior chest wall syndrome is characterized by a sharply localized tenderness of the intercostal muscles. Inflammation of the chondrocostal junctions may result in diffuse chest pain that is also reproduced by local pressure (Tietze syndrome). Intercostal neuritis (due to herpes zoster or diabetes mellitus, for example) also mimics angina.
Cervical or thoracic spine disease involving the dorsal roots produces sudden sharp, severe chest pain suggesting angina in location and “radiation” but related to specific movements of the neck or spine, recumbency, and straining or lifting. Pain due to cervical or thoracic disk disease involves the outer or dorsal aspect of the arm and the thumb and index fingers rather than the ring and little fingers.
Reflux esophagitis, peptic ulcer, chronic cholecystitis, esophageal spasm, and functional gastrointestinal disease may produce pain suggestive of angina pectoris. The picture may be especially confusing because ischemic pain may also be associated with upper gastrointestinal symptoms, and esophageal motility disorders may be improved by nitrates and calcium channel blockers. Assessment of esophageal motility may be helpful.
Degenerative and inflammatory lesions of the left shoulder and thoracic outlet syndromes may cause chest pain due to nerve irritation or muscular compression; the symptoms are usually precipitated by movement of the arm and shoulder and are associated with paresthesias.
Pneumonia, pulmonary embolism, and spontaneous pneumothorax may cause chest pain as well as dyspnea. Dissection of the thoracic aorta can cause severe chest pain that is commonly felt in the back; it is sudden in onset, reaches maximum intensity immediately, and may be associated with changes in pulses. Other cardiac disorders, such as mitral valve prolapse, hypertrophic cardiomyopathy, myocarditis, pericarditis, aortic valve disease, or RVH may cause atypical chest pain or even myocardial ischemia.
Sublingual nitroglycerin is the drug of choice for acute management; it acts in about 1–2 minutes. Nitrates decrease arteriolar and venous tone, reduce preload and afterload, and lower the oxygen demand of the heart. As soon as the attack begins, one fresh tablet is placed under the tongue. This may be repeated at 3- to 5-minute intervals, but if pain is not relieved or improving after 5 minutes, the patient should call 9-1-1; pain not responding to three tablets or lasting more than 20 minutes may represent evolving infarction. The dosage (0.3, 0.4, or 0.6 mg) and the number of tablets to be used before seeking further medical attention must be individualized. Nitroglycerin buccal spray is also available as a metered (0.4 mg) delivery system. It has the advantage of being more convenient for patients who have difficulty handling the pills and of being more stable.
Prevention of Further Attacks
Angina may be aggravated by hypertension, LV failure, arrhythmia (usually tachycardias), strenuous activity, cold temperatures, and emotional states. These factors should be identified and treated when possible.
Nitroglycerin, 0.3–0.6 mg sublingually or 0.4–0.8 mg translingually by spray, should be taken 5 minutes before any activity likely to precipitate angina. Sublingual isosorbide dinitrate (2.5–5 mg) is only slightly longer-acting than sublingual nitroglycerin.
Longer-acting nitrate preparations include isosorbide dinitrate, 10–40 mg orally three times daily; isosorbide mononitrate, 10–40 mg orally twice daily or 60–120 mg once daily in a sustained-release preparation; oral sustained-release nitroglycerin preparations, 6.25–12.5 mg two to four times daily; nitroglycerin ointment, ointment 2%, 0.5 to 2 inches (7.5 to 30 mg in the morning and six hours later); and transdermal nitroglycerin patches that deliver nitroglycerin at rates of 0.2, 0.4, and 0.6 mg/h rate (0.1–0.8 mg/h), and should be taken off after 12–14 hours of use for a 10–12 hour patch-free interval daily. The main limitation to long-term nitrate therapy is tolerance, which can be limited by using a regimen that includes a minimum 8- to 10-hour period per day without nitrates. Isosorbide dinitrate can be given three times daily, with the last dose after dinner, or longer-acting isosorbide mononitrate once daily. Transdermal nitrate preparations should be removed overnight in most patients.
Nitrate therapy is often limited by headache. Other side effects include nausea, light-headedness, and hypotension.
Beta-blockers are the only antianginal agents that have been demonstrated to prolong life in patients with coronary disease (post-myocardial infarction). They are at least as effective at relieving angina as alternative agents in studies employing exercise testing, ambulatory monitoring, and symptom assessment. Beta-blockers should be considered for first-line therapy in most patients with chronic angina and are recommened as such by the Stable Ischemic Heart disease guidelines (Figure 10–5).
Algorithm for guideline-directed medical therapy for patients with stable ischemic heart disease. The use of bile acid sequestrant is relatively contraindicated when triglycerides are 200 mg/dL or higher and contraindicated when triglycerides are 500 mg/dL or higher. Dietary supplement niacin must not be used as a substitute for prescription niacin. (Reproduced, with permission, from Fihn SD et al; American College of Cardiology Foundation/American Heart Association Task Force. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease. Circulation. 2012 Dec 18;126(25):e354-471.) © 2012 American Heart Association, Inc.
Beta-blockers with intrinsic sympathomimetic activity, such as pindolol, are less desirable because they may exacerbate angina in some individuals and have not been effective in secondary prevention trials. The pharmacology and side effects of the beta-blockers are discussed in Chapter 11 (see Table 11–6). The dosages of all these medications when given for angina are similar. The major contraindications are severe bronchospastic disease, bradyarrhythmias, and decompensated heart failure.
Ranolazine is indicated as first-line use for chronic angina. It decreases the late sodium current and thereby decreases intracellular calcium overload. Ranolazine has no effect on heart rate and BP, and it has been shown in clinical trials to prolong exercise duration and time to angina, both as monotherapy and when administered with conventional antianginal therapy. It is safe to use with erectile dysfunction drugs. The usual dose is 500 mg orally twice a day. Because it can cause QT prolongation, it is contraindicated in patients with existing QT prolongation; in patients taking QT prolonging medications, such as class I or III antiarrhythmics (eg, quinidine, dofetilide, sotalol); and in those taking potent and moderate CYP450 3A inhibitors (eg, clarithromycin and rifampin). Of interest, in spite of the QT prolongation, there is a significantly lower rate of ventricular arrhythmias with its use following acute coronary syndromes, as shown in the MERLIN trial. It also decreases occurrence of atrial fibrillation and results in a small decrease in HbA1c. It is contraindicated in patients with significant liver and kidney disease. Ranolazine is not to be used for treatment of acute anginal episodes. Ranolazine does not improve outcomes of patients who do not get complete coronary revascularization.
F. Calcium Channel Blocking Agents
Unlike the beta-blockers, calcium channel blockers have not been shown to reduce mortality postinfarction and in some cases have increased ischemia and mortality rates. This appears to be the case with some dihydropyridines (eg, nifedipine) and with diltiazem and verapamil in patients with clinical heart failure or moderate to severe LV dysfunction. Meta-analyses have suggested that short-acting nifedipine in moderate to high doses causes an increase in mortality. It is uncertain whether these findings are relevant to longer-acting dihydropyridines. Nevertheless, considering the uncertainties and the lack of demonstrated favorable effect on outcomes, calcium channel blockers should be considered third-line anti-ischemic drugs in the postinfarction patient. Similarly, these agents, with the exception of amlodipine (which proved safe in patients with heart failure in the PRAISE-2 trial), should be avoided in patients with heart failure or low EFs.
The pharmacologic effects and side effects of the calcium channel blockers are discussed in Chapter 11 and summarized in Table 11–8. Diltiazem, amlodipine, and verapamil are preferable because they produce less reflex tachycardia and because the former, at least, may cause fewer side effects. Nifedipine, nicardipine, and amlodipine are also approved agents for angina. Isradipine, felodipine, and nisoldipine are not approved for angina but probably are as effective as the other dihydropyridines.
Ivabradine selectively blocks the If current and specifically lowers heart rate. It has been shown to reduce angina in patients with chronic stable angina and is approved in Europe. However, the SIGNIFY trial found that there may have been harm for patients with significant angina with regard to outcomes of cardiovascular death and myocardial infarction, thus raising concerns regarding its use for this indication.
H. Alternative and Combination Therapies
Patients who do not respond to one class of antianginal medication often respond to another. It may, therefore, be worthwhile to use an alternative agent before progressing to combinations. The stable ischemic heart disease guidelines recommend starting with a beta-blocker as initial therapy, followed by calcium channel blockers, long-acting nitrates, or ranolazine. A few patients will have further response to a regimen including all four agents.
I. Platelet-Inhibiting Agents
Several studies have demonstrated the benefit of antiplatelet drugs for patients with stable and unstable vascular disease. Therefore, unless contraindicated, aspirin (81–325 mg orally daily) should be prescribed for all patients with angina. Clopidogrel, 75 mg orally daily, reduces vascular events in patients with stable vascular disease (as an alternative to aspirin) and in patients with acute coronary syndromes (in addition to aspirin). Thus, it is also a good alternative in aspirin-intolerant patients. Clopidogrel in addition to aspirin did not reduce myocardial infarction, stroke, or cardiovascular death in the CHARISMA trial of patients with cardiovascular disease or multiple risk factors, with about a 50% increase in bleeding. However, it might be reasonable to use combination clopidogrel and aspirin for certain high-risk patients with established coronary disease. Specifically, prolonged used of dual antiplatelet therapy with aspirin and clopidogrel may be beneficial in patients post-percutaneous stenting with drug-eluting stents.
Ticagrelor, a P2Y12 inhibitor, has been shown to reduce cardiovascular events in patients with acute coronary syndromes. Additionally, in patients with prior myocardial infarction, long-term treatment with ticagrelor plus aspirin reduced cardiovascular events compared to aspirin alone.
The latest antiplatelet agent to be approved by the FDA, vorapaxar, is an inhibitor of the protease-activated receptor-1. It was shown to reduce cardiovascular events for patients with stable atherosclerosis with a history of myocardial infarction or peripheral artery disease in the TRA 2P trial. It is contraindicated for patients with a history of stroke or transient ischemic attack due to increased risk of intracranial hemorrhage.
Patients with coronary disease should undergo aggressive risk factor modification. This approach, with a particular focus on statin treatment, treating hypertension, stopping smoking, and exercise and weight control (especially for patients with metabolic syndrome or at risk for diabetes), may markedly improve outcomes. For patients with diabetes and cardiovascular disease, there is uncertainty about the optimal target blood sugar control. The ADVANCE trial suggested some benefit for tight blood sugar control with target HbA1C of 6.5% or less but the ACCORD trial found that routine aggressive targeting for blood sugar control to HbA1C to less than 6.0% in patients with diabetes and coronary disease was associated with increased mortality. Therefore, tight blood sugar control should be avoided particularly in patients with a history of severe hypoglycemia, long-standing diabetes, and advanced vascular disease. Aggressive BP control (target systolic BP less than 120 mm Hg) in the ACCORD trial was not associated with reduction in CHD events, although stroke was reduced.
There is general agreement that otherwise healthy patients in the following groups should undergo revascularization: (1) Patients with unacceptable symptoms despite medical therapy to its tolerable limits. (2) Patients with left main coronary artery stenosis greater than 50% with or without symptoms. (3) Patients with three-vessel disease with LV dysfunction (EF less than 50% or previous transmural infarction). (4) Patients with unstable angina who after symptom control by medical therapy continue to exhibit ischemia on exercise testing or monitoring. (5) Post-myocardial infarction patients with continuing angina or severe ischemia on noninvasive testing. The use of revascularization for patients with acute coronary syndromes and acute ST elevation myocardial infarction is discussed below.
Data from the COURAGE trial have shown that for patients with chronic angina and disease suitable for PCI, PCI in addition to stringent guideline-directed medical therapy aimed at both risk reduction and anti-anginal care offers no mortality benefit beyond excellent medical therapy alone, and relatively moderate long-term symptomatic improvement. Therefore, for patients with mild to moderate CAD and limited symptoms, revascularization may not provide significant functional status quality-of-life benefit. For patients with moderate to significant coronary stenosis, such as those who have two-vessel disease associated with underlying LV dysfunction, anatomically critical lesions (greater than 90% proximal stenoses, especially of the proximal left anterior descending artery), or physiologic evidence of severe ischemia (early positive exercise tests, large exercise-induced thallium scintigraphic defects, or frequent episodes of ischemia on ambulatory monitoring), a Heart Team consisting of revascularization physicians (interventional cardiologists and surgeons) may be required to review and provide patients with the best revascularization options.
a. Percutaneous coronary intervention including stenting
PCI, including balloon angioplasty and coronary stenting, can effectively open stenotic coronary arteries (VIDEO 10-14) (VIDEO 10-15) (VIDEO 10-16). Coronary stenting, with either bare metal stents or drug-eluting stents, has substantially reduced restenosis. Stenting can also be used selectively for left main coronary stenosis, particularly when CABG is contraindicated or deemed high risk.
VIDEO 10-14: Coronary angiography revealing highgrade stenosis in the proximal right coronary artery.
(Used, with permission, from T Amidon and T Chou.)
VIDEO 10-15: Percutaneous transluminal coronary angioplasty (PTCA) of the high-grade stenosis in the proximal right coronary artery.
(Used, with permission, from T Amidon and T Chou.)
VIDEO 10-16: Coronary angiography of right coronary artery after PTCA.
(Used, with permission, from T Amidon and T Chou.)
PCI is possible but often less successful in bypass graft stenoses. Experienced operators are able to successfully dilate more than 90% of lesions attempted. The major early complication is intimal dissection with vessel occlusion, although this is rare with coronary stenting. The use of intravenous platelet glycoprotein IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban) substantially reduces the rate of periprocedural myocardial infarction, and placement of intracoronary stents markedly improves initial and long-term angiographic results, especially with complex and long lesions. After percutaneous coronary intervention, all patients should have CK-MB and troponin measured. The definition of a periprocedural infarction has been debated, with many experts advocating for a clinical definition that incorporates different enzyme cutpoints, angiographic findings, and electrocardiographic evidence. Acute thrombosis after stent placement can largely be prevented by aggressive antithrombotic therapy (long-term aspirin, 81–325 mg, plus clopidogrel, 300–600 mg loading dose followed by 75 mg daily, for between 30 days and 1 year, and with acute use of platelet glycoprotein IIb/IIIa inhibitors).
A major limitation with PCI has been restenosis, which occurs in the first 6 months in less than 10% of vessels treated with drug-eluting stents, 15–30% of vessels treated with bare metal stents, and 30–40% of vessels without stenting. Factors associated with higher restenosis rates include diabetes, small luminal diameter, longer and more complex lesions, and lesions at coronary ostia or in the left anterior descending coronary artery. Drug-eluting stents that elute antiproliferative agents, such as sirolimus, everolimus, zotarolimus, or paclitaxel, have substantially reduced restenosis (VIDEO 10-17) (VIDEO 10-18) (VIDEO 10-19). In-stent restenosis is often treated with restenting with drug-eluting stents, and rarely with brachytherapy. The nearly 2 million PCIs performed worldwide per year far exceed the number of CABG operations, but the rationale for many of the procedures performed in patients with stable angina should be for angina symptom reduction. The COURAGE trial has confirmed earlier studies in showing that even for patients with moderate anginal symptoms and positive stress tests PCI provides no benefit over medical therapy with respect to death or myocardial infarction. PCI was more effective at relieving angina, although most patients in the medical group had improvement in symptoms. Thus, in patients with mild or moderate stable symptoms, aggressive lipid-lowering and antianginal therapy may be a preferable initial strategy, reserving PCI for patients with significant and refractory symptoms or for those who are unable to take the prescribed medicines.
VIDEO 10-17: Coronary angiography reveals serial high-grade stenoses in the left circumflex coronary artery.
(Used, with permission, from T Amidon and T Chou.)
VIDEO 10-18: Deployment of coronary stents to stenoses in left main and left circumflex coronary arteries.
(Used, with permission, from T Amidon and T Chou.)
VIDEO 10-19: Coronary angiography after coronary stenting.
(Used, with permission, from T Amidon and T Chou.)
Several studies of PCI, including those with drug-eluting stents, versus CABG in patients with multivessel disease have been reported. The SYNTAX trial as well as previously performed trials with drug-eluting stent use in PCI patients show comparable mortality and infarction rates over follow-up periods of 1–3 years but a high rate (approximately 40%) of repeat procedures following PCI. Stroke rates are higher with CABG. As a result, the choice of revascularization procedure may depend on details of coronary anatomy and is often a matter of patient preference. However, it should be noted that less than 20% of patients with multivessel disease meet the entry criteria for the clinical trials, so these results cannot be generalized to all multivessel disease patients. Outcomes with percutaneous revascularization in patients with diabetes have generally been inferior to those with CABG. The FREEDOM trial demonstrated that CABG surgery was superior to PCI with regards to death, myocardial infarction, and stroke for patients with diabetes and multivessel coronary disease at 5 years across all subgroups of SYNTAX score anatomy.
b. Coronary artery bypass grafting
CABG can be accomplished with a very low mortality rate (1–3%) in otherwise healthy patients with preserved cardiac function. However, the mortality rate of this procedure rises to 4–8% in older individuals and in patients who have had a prior CABG.
Grafts using one or both internal mammary arteries (usually to the left anterior descending artery or its branches) provide the best long-term results in terms of patency and flow. Segments of the saphenous vein (or, less optimally, other veins) or the radial artery interposed between the aorta and the coronary arteries distal to the obstructions are also used. One to five distal anastomoses are commonly performed.
Minimally invasive surgical techniques may involve a limited sternotomy, lateral thoracotomy (MIDCAB), or thoracoscopy (port-access). They are more technically demanding, usually not suitable for more than two grafts, and do not have established durability. Bypass surgery can be performed both on circulatory support (on-pump) and without direct circulatory support (off-pump). Randomized trial data have not shown a benefit with off-pump bypass surgery but minimally invasive surgical techniques allow earlier postoperative mobilization and discharge.
The operative mortality rate is increased in patients with poor LV function (LVEF less than 35%) or those requiring additional procedures (valve replacement or ventricular aneurysmectomy). Patients over 70 years of age, patients undergoing repeat procedures, or those with important noncardiac disease (especially chronic kidney disease and diabetes) or poor general health also have higher operative mortality and morbidity rates, and full recovery is slow. Thus, CABG should be reserved for more severely symptomatic patients in this group. Early (1–6 months) graft patency rates average 85–90% (higher for internal mammary grafts), and subsequent graft closure rates are about 4% annually. Early graft failure is common in vessels with poor distal flow, while late closure is more frequent in patients who continue smoking and those with untreated hyperlipidemia. Antiplatelet therapy with aspirin improves graft patency rates. Smoking cessation and vigorous treatment of blood lipid abnormalities (particularly with statins) are necessary. Repeat revascularization may be necessitated because of recurrent symptoms due to progressive native vessel disease and graft occlusions. Reoperation is technically demanding and less often fully successful than the initial operation. In addition, in patients with ischemic mitral regurgitation, mitral repair at the time of a CABG does not offer any clinical benefit.
L. Mechanical Extracorporeal Counterpulsation
Extracorporeal counterpulsation entails repetitive inflation of a high-pressure chamber surrounding the lower half of the body during the diastolic phase of the cardiac cycle for daily 1-hour sessions over a period of 7 weeks. Randomized trials have shown that extracorporeal counterpulsation reduces angina thus it may be considered for relief of refractory angina in patients with stable coronary disease.
Spinal cord stimulation can be used to relieve chronic refractory angina. Spinal cord stimulators are subcutaneously implantable via a minimally invasive procedure under local anesthesia.
The prognosis of angina pectoris has improved with development of therapies aimed at secondary prevention. Mortality rates vary depending on the number of vessels diseased, the severity of obstruction, the status of LV function, and the presence of complex arrhythmias. Mortality rates are progressively higher in patients with one-, two-, and three-vessel disease and those with left main coronary artery obstruction (ranging from 1% per year to 25% per year). The outlook in individual patients is unpredictable, and nearly half of the deaths are sudden. Therefore, risk stratification is attempted. Patients with accelerating symptoms have a poorer outlook. Among stable patients, those whose exercise tolerance is severely limited by ischemia (less than 6 minutes on the Bruce treadmill protocol) and those with extensive ischemia by exercise ECG or scintigraphy have more severe anatomic disease and a poorer prognosis. The Duke Treadmill Score, based on a standard Bruce protocol exercise treadmill test, provides an estimate of risk of death at 1 year. The score uses time on the treadmill, amount of ST-segment depression, and presence of angina (Table 10–10).
Table 10–10.Duke treadmill score: Calculation and interpretation. |Favorite Table|Download (.pdf) Table 10–10. Duke treadmill score: Calculation and interpretation.
|Time in minutes on Bruce protocol ||= _________________ |
|–5 × amount of depression (in mm) ||= _________________ |
–4 × angina index
0 = no angina on test
1 = angina, not limiting
2 = limiting angina
|= _________________ |
|Total Summed Score ||Risk Group ||Annual Mortality |
|≥ 5 ||Low ||0.25% |
|–10 to 4 ||Intermediate ||1.25% |
|≤–11 ||High ||5.25% |
Several randomized trials have shown that over follow-up periods of several years, the mortality and infarction rates with percutaneous revascularization and CABG are generally comparable. Exceptions are patients with left main or three-vessel disease with reduced ventricular function, and perhaps diabetic patients, who have had better outcomes with CABG. The increasing popularity of PCI and stenting primarily reflects the lower cost and shorter hospitalization, the perception that CABG is best done only once and can be reserved for later, and the preference of patients for less invasive treatment. These arguments make PCI the procedure of choice for revascularization of symptomatic single-vessel and some two-vessel disease. The situation is less clear with multivessel disease. It should also be noted that the excellent outcome of patients treated medically has made it difficult to show an advantage with either revascularization approach except in patients who remain symptom limited or have left main lesions or three-vessel disease and LV dysfunction. The issue of late stent thrombosis shifts the balance toward bare metal stents, especially for patients who cannot tolerate or take long-term clopidogrel, although newer generation drug-eluting stents appear to have lower rates of stent thrombosis.
All patients with new or worsening symptoms believed to represent progressive angina or a positive stress test for myocardial ischemia with continued angina despite medical therapy (or both) should be referred to a cardiologist.
Patients with elevated cardiac biomarkers, ischemic ECG findings, or hemodynamic instability.
Patients with new or worsened symptoms, possibly thought to be ischemic, but who lack high-risk features can be observed with serial ECGs and biomarkers, and discharged if stress testing shows low-risk findings.
ACCORD Study Group; Cushman
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CORONARY VASOSPASM & ANGINA WITH NORMAL CORONARY ARTERIOGRAMS
ESSENTIALS OF DIAGNOSIS
Precordial chest pain, often occurring at rest during stress or without known precipitant, relieved rapidly by nitrates.
ECG evidence of ischemia during pain, sometimes with ST-segment elevation.
Angiographic demonstration of:
Although most symptoms of myocardial ischemia result from fixed stenosis of the coronary arteries, intraplaque hemorrhage, or thrombosis at the site of lesions, some ischemic events may be precipitated or exacerbated by coronary vasoconstriction.
Spasm of the large coronary arteries with resulting decreased coronary blood flow may occur spontaneously or may be induced by exposure to cold, emotional stress, or vasoconstricting medications, such as ergot-derivative medications. Spasm may occur both in normal and in stenosed coronary arteries. Even myocardial infarction may occur as a result of spasm in the absence of visible obstructive CHD, although most instances of such coronary spasm occur in the presence of coronary stenosis.
Cocaine can induce myocardial ischemia and infarction by causing coronary artery vasoconstriction or by increasing myocardial energy requirements. It also may contribute to accelerated atherosclerosis and thrombosis. The ischemia in Prinzmetal (variant) angina usually results from coronary vasoconstriction. It tends to involve the right coronary artery and there may be no fixed stenoses. Myocardial ischemia may also occur in patients with normal coronary arteries as a result of disease of the coronary microcirculation or abnormal vascular reactivity. This has been termed “syndrome X.”
Ischemia may be silent or result in angina pectoris.
Prinzmetal (variant) angina is a clinical syndrome in which chest pain occurs without the usual precipitating factors and is associated with ST-segment elevation rather than depression. It often affects women under 50 years of age. It characteristically occurs in the early morning, awakening patients from sleep, and is apt to be associated with arrhythmias or conduction defects. It may be diagnosed by challenge with ergonovine (a vasoconstrictor), although the results of such provocation are not specific and it entails risk.
Patients with chest pain associated with ST-segment elevation should undergo coronary arteriography to determine whether fixed stenotic lesions are present. If they are, aggressive medical therapy or revascularization is indicated, since this may represent an unstable phase of the disease. If significant lesions are not seen and spasm is suspected, avoidance of precipitants, such as cigarette smoking and cocaine, is the top priority. Episodes of coronary spasm generally respond well to nitrates, and both nitrates and calcium channel blockers (including long-acting nifedipine, diltiazem, or amlopidine [see Table 11–8]) are effective prophylactically. By allowing unopposed alpha-1-mediated vasoconstriction, beta-blockers have exacerbated coronary vasospasm, but they may have a role in management of patients in whom spasm is associated with fixed stenoses.
All patients with persistent symptoms of chest pain that may represent spasm should be referred to a cardiologist.
et al. Nonacute coronary syndrome anginal chest pain. Med Clin North Am. 2010 Mar;94(2):201–16.
et al. Pathophysiology, diagnosis, and current management strategies for chest pain in patients with normal findings on angiography. Mayo Clin Proc. 2001 Aug;76(8):813–22.
ACUTE CORONARY SYNDROMES WITHOUT ST-SEGMENT ELEVATION
ESSENTIALS OF DIAGNOSIS
Distinction in acute coronary syndrome between patients with and without ST-segment elevation at presentation is essential to determine need for reperfusion therapy.
Fibrinolytic therapy is harmful in acute coronary syndrome without ST-segment elevation, unlike with ST-segment elevation, where acute reperfusion saves lives.
Antiplatelet and anticoagulation therapies and coronary intervention are mainstays of treatment.
Acute coronary syndromes comprise the spectrum of unstable cardiac ischemia from unstable angina to acute myocardial infarction. Acute coronary syndromes are classified based on the presenting ECG as either “ST-segment elevation” (STEMI) or “non–ST-segment elevation” (NSTEMI). This allows for immediate classification and guides determination of whether patients should be considered for acute reperfusion therapy. The evolution of cardiac biomarkers then allows determination of whether myocardial infarction has occurred.
Acute coronary syndromes represent a dynamic state in which patients frequently shift from one category to another, as new ST elevation can develop after presentation and cardiac biomarkers can become abnormal with recurrent ischemic episodes.
Chest pain is one of the most frequent reasons for emergency department visits. Algorithms have been developed to aid in determining the likelihood that a patient has an acute coronary syndrome, and for those patients who do have an acute coronary syndrome, the risk of ischemic events and death.
Patients with acute coronary syndromes generally have symptoms and signs of myocardial ischemia either at rest or with minimal exertion. These symptoms and signs are similar to the chronic angina symptoms described above, consisting of substernal chest pain or discomfort that may radiate to the jaw, left shoulder or arm. Dyspnea, nausea, diaphoresis, or syncope may either accompany the chest discomfort or may be the only symptom of acute coronary syndrome. About one-third of patients with myocardial infarction have no chest pain per se—these patients tend to be older, female, have diabetes, and be at higher risk for subsequent mortality. Patients with acute coronary syndromes have signs of heart failure in about 10% of cases, and this is also associated with higher risk of death.
Many hospitals have developed chest pain observation units to provide a systematic approach toward serial risk stratification to improve the triage process. In many cases, those who have not experienced new chest pain and have insignificant ECG changes and no cardiac biomarker elevation undergo treadmill exercise tests or imaging procedures to exclude ischemia at the end of an 8- to 24-hour period and are discharged directly from the emergency department if these tests are negative.
Depending on the time from symptom onset to presentation, initial laboratory findings may be normal. The markers of cardiac myocyte necrosis, myoglobin, CK-MB, and troponin I and T may all be used to identify acute myocardial infarction. These markers have a well-described pattern of release over time in patients with myocardial infarction (see Laboratory Findings, Acute Myocardial Infarction with ST-Segment Elevation, below). In patients with STEMI, these initial markers are often within normal limits as the patient is being rushed to immediate reperfusion. In patients without ST-segment elevation, it is the presence of abnormal CK-MB or troponin values that are associated with myocyte necrosis and the diagnosis of myocardial infarction. The universal definition of myocardial infarction is a rise of cardiac biomarkers with at least one value above the 99th percentile of the upper reference limit together with evidence of myocardial ischemia with at least one of the following: symptoms of ischemia, ECG changes of new ischemia, new Q waves, or imaging evidence of new loss of viable myocardium or new wall motion abnormality.
Serum creatinine is an important determinant of risk, and estimated creatinine clearance is important to guide dosing of certain antithrombotics, including eptifibatide and enoxaparin.
Many patients with acute coronary syndromes will exhibit ECG changes during pain—either ST-segment elevation, ST-segment depression, or T wave flattening or inversion. Dynamic ST segment shift is the most specific for acute coronary syndrome. ST-segment elevation in lead AVR suggests left main or three vessel disease.
Treatment of acute coronary syndromes without ST elevation should be multifaceted. Patients who are at medium or high risk should be hospitalized, maintained at bed rest or at very limited activity for the first 24 hours, monitored, and given supplemental oxygen. Sedation with a benzodiazepine agent may help if anxiety is present.
Figure 10–6 provides an algorithm for initial management of non–ST-segment myocardial infarction.
Flowchart for class 1 and class IIa recommendations for initial management of unstable angina/non–ST-segment elevation myocardial infarction (UA/NS TEMI). ASA, aspirin; CABG, coronary artery bypass grafting; GP IIb/IIIa, glycoprotein IIb/IIIa; LOE, level of evidence; UFH, unfractionated heparin. (Reproduced, with permission, from Wright RS et al. 2011 ACCF/AHA Focused Update of the Guidelines for the Management of Patients With Unstable Angina/ Non-ST-Elevation Myocardial Infarction (Updating the 2007 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011 May 10;123(18):2022–60. Erratum in: Circulation. 2011 Sep 20;124(12):e337–40; Circulation. 2011 Jun 7;123(22):e625–6. © 2011 American Heart Association, Inc. [PMID: 21444889])
C. Antiplatelet and Anticoagulation Therapy
Patients should receive a combination of antiplatelet and anticoagulant agents on presentation. Fibrinolytic therapy should be avoided in patients without ST-segment elevation since they generally do not have an acute coronary occlusion, and the risk of such therapy appears to outweigh the benefit.
Aspirin, 162–325 mg loading dose, then 81–325 mg daily, should be commenced immediately and continued for the first month. The large CURRENT trial comparing 81 mg versus 325 mg of aspirin (in addition to clopidogrel) for the first month following diagnosis of acute coronary syndrome found little difference in thrombotic events or in major bleeding. Thus, either dose is reasonable, at least for the first month. The longer-term optimal aspirin dose may be 75–162 mg/day (versus 325 mg/day) based on similar thrombotic event rates and lower rates of bleeding. The 2012 ACC/AHA guidelines for longer-term aspirin treatment recommend aspirin 75–162 mg/day as preferable to higher doses with or without coronary stenting.
ACC/AHA guidelines call for either a P2Y12 inhibitor (clopidogrel, prasugrel [at the time of PCI], or ticagrelor) as a class I recommendation. The ESC guidelines provide a stronger recommendation for a P2Y12 inhibitor up-front, as a class IA recommendation for all patients. Both sets of guidelines recommend postponing elective CABG surgery for at least 5 days after the last dose of clopidogrel or ticagrelor and at least 7 days after the last dose of prasugrel, due to risk of bleeding.
The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial demonstrated a 20% reduction in the composite end point of cardiovascular death, myocardial infarction, and stroke with the addition of clopidogrel (300 mg loading dose, 75 mg/day for 9–12 months) to aspirin in patients with non–ST-segment elevation acute coronary syndromes. The large CURRENT trial showed that “double-dose” clopidogrel (600 mg initial oral loading dose, followed by 150 mg orally daily) for 7 days reduced stent thrombosis with a modest increase in major (but not fatal) bleeding and, therefore, it is an option for patients with acute coronary syndrome undergoing PCI.
The ESC guidelines recommend ticagrelor for all patients at moderate to high risk for acute coronary syndrome (class 1 recommendation). Prasugrel is recommended for patients who have not yet received another P2Y12 inhibitor, for whom a PCI is planned, and who are not at high risk for life-threatening bleeding. Clopidogrel is reserved for patients who cannot receive either ticagrelor or prasugrel. Some studies have shown an association between assays of residual platelet function and thrombotic risk during P2Y12 inhibitor therapy, and both the European and the US guidelines do not recommend routine platelet function testing to guide therapy (class IIb recommendation).
Prasugrel is both more potent and has a faster onset of action than clopidogrel. The TRITON trial compared prasugrel with clopidogrel in patients with STEMI or NSTEMI in whom PCI was planned; prasugrel resulted in a 19% relative reduction in death from cardiovascular causes, myocardial infarction, or stroke, at the expense of an increase in serious bleeding (including fatal bleeding). Stent thrombosis was reduced by half. Because patients with prior stroke or transient ischemic attack had higher risk of intracranial hemorrhage, prasugrel is contraindicated in such patients. Bleeding was also higher in patients with low body weight (less than 60 kg) and age 75 years or older, and caution should be used in these populations. For patients with STEMI treated with PCI, prasugrel appears to be especially effective without a substantial increase in bleeding. For patients who will not receive revascularization, prasugrel, when compared to clopidogrel, had no overall benefit in the TRILOGY trial (the dose of prasugrel was lowered for the elderly).
Ticagrelor has a faster onset of action than clopidogrel and a more consistent and potent effect. The PLATO trial showed that when ticagrelor was started at the time of presentation in acute coronary syndrome patients (UA/NSTEMI and STEMI), it reduced cardiovascular death, myocardial infarction, and stroke by 16% when compared with clopidogrel. In addition, there was a 22% relative risk reduction in mortality with ticagrelor. The overall rates of bleeding were similar between ticagrelor and clopidogrel, although non-CABG related bleeding was modestly higher. The finding of a lesser treatment effect in the United States may have been related to use of higher-dose aspirin, and thus when using ticagrelor, low-dose aspirin (81 mg/day) is recommended.
c. Glycoprotein IIb/IIIa inhibitors
Small-molecule inhibitors of the platelet glycoprotein IIb/IIIa receptor are useful adjuncts in high-risk patients (usually defined by fluctuating ST-segment depression or positive biomarkers) with acute coronary syndromes, particularly when they are undergoing PCI. Tirofiban, 25 mcg/kg over 3 minutes, followed by 0.15 mcg/kg/min, and eptifibatide, 180 mcg/kg bolus followed by a continuous infusion of 2 mcg/kg/min, have both been shown to be effective. Downward dose adjustments of the infusions are required in patients with reduced kidney function. The bolus or loading dose remains unadjusted. For example, if the estimated creatinine clearance is below 50 mL/min, the eptifibatide infusion should be cut in half to 1 mcg/kg/min. The ISAR-REACT 2 trial showed that for patients undergoing PCI with high-risk acute coronary syndrome, especially with elevated troponin, intravenous abciximab (added to a 600-mg loading dose of clopidogrel) reduces ischemic events by about 25%. The EARLY-ACS trial in over 10,000 patients with high-risk acute coronary syndrome found no benefit from eptifibatide started at the time of admission and higher rates of bleeding compared with eptifibatide treatment started at the time of invasive coronary angiography.
Several trials have shown that LMWH (enoxaparin 1 mg/kg subcutaneously every 12 hours) is somewhat more effective than unfractionated heparin in preventing recurrent ischemic events in the setting of acute coronary syndromes. However, the SYNERGY trial showed that unfractionated heparin and enoxaparin had similar rates of death or (re)infarction in the setting of frequent early coronary intervention.
Fondaparinux, a specific factor Xa inhibitor given in a dose of 2.5 mg subcutaneously once a day, was found in the OASIS-5 trial to be equally effective as enoxaparin among 20,000 patients at preventing early death, myocardial infarction, and refractory ischemia, and resulted in a 50% reduction in major bleeding. This reduction in major bleeding translated into a significant reduction in mortality (and in death or myocardial infarction) at 30 days. While catheter-related thrombosis was more common during coronary intervention procedures with fondaparinux, the FUTURA trial found that it can be controlled by adding unfractionated heparin (in a dose of 85 units/kg without glycoprotein IIb/IIIa inhibitors, and 60 units/kg with glycoprotein IIb/IIIa inhibitors) during the procedure. Guidelines recommend fondaparinux, describing it as especially favorable for patients who are initially treated medically and who are at high risk for bleeding, such as the elderly.
c. Direct thrombin inhibitors
The ACUITY trial showed that bivalirudin appears to be a reasonable alternative to heparin (unfractionated heparin or enoxaparin) plus a glycoprotein IIb/IIIa antagonist for many patients with acute coronary syndromes who are undergoing early coronary intervention. Bivalirudin (without routine glycoprotein IIb/IIIa inhibitor) is associated with substantially less bleeding than heparin plus glycoprotein IIb/IIIa inhibitor. The ISAR REACT-4 trial showed that bivalirudin has similar efficacy compared to abciximab but better bleeding outcomes in NSTEMI patients. Bivalrudin does not currently have an FDA-approved indication for NSTEMI care.
D. Temporary Discontinuation of Antiplatelet Therapy for Procedures
Patients who have had recent coronary stents are at risk for thrombotic events, including stent thrombosis, if P2Y12 inhibitors are discontinued for procedures (eg, dental procedures or colonoscopy). If possible, these procedures should be delayed until the end of the necessary treatment period with P2Y12 inhibitors, which generally is at least 1 month with bare metal stents and 3–6 months with drug-eluting stents. Before that time, if a procedure is necessary, risk and benefit of continuing the antiplatelet therapy through the time of the procedure should be assessed. Aspirin should generally be continued throughout the period of the procedure. A cardiologist should be consulted before temporary discontinuation of these agents.
Nitrates are first-line therapy for patients with acute coronary syndromes presenting with chest pain. Nonparenteral therapy with sublingual or oral agents or nitroglycerin ointment is usually sufficient. If pain persists or recurs, intravenous nitroglycerin should be started. The usual initial dosage is 10 mcg/min. The dosage should be titrated upward by 10–20 mcg/min (to a maximum of 200 mcg/min) until angina disappears or mean arterial pressure drops by 10%. Careful—usually continuous—BP monitoring is required when intravenous nitroglycerin is used. Avoid hypotension (systolic BP less than 100 mm Hg). Tolerance to continuous nitrate infusion is common.
Beta-blockers are an important part of the initial treatment of unstable angina unless otherwise contraindicated. The pharmacology of these agents is discussed in Chapter 11 and summarized in Table 11–6. Use of agents with intrinsic sympathomimetic activity should be avoided in this setting. Oral medication is adequate in most patients, but intravenous treatment with metoprolol, given as three 5-mg doses 5 minutes apart as tolerated and in the absence of heart failure, achieves a more rapid effect. Oral therapy should be titrated upward as BP permits.
G. Calcium Channel Blockers