Chronic stable angina treatment

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Cafer Zorkun, M.D., Ph.D. [2]

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Overview of the management of chronic stable angina

Identification and treatment of exacerbating conditions

While chronic stable angina may be due to underlying atherosclerosis, other factors may either precipitate or exacerbate angina. Identification and management of these conditions may reduce the frequency and intesity of anginal episodes. These conditions include anemia, uncontrolled hypertension, thyroid disorders (thyrotoxicosis), heart rhythm abnormalities (tachyarrhythmias), decompensated congestive heart failure and concomitant valvular heart disease.

Risk factor modification

Initiate risk factor modification, promote regular physical exercise (all patients should be encouraged to obtain 30 to 60 minutes/day of regular aerobic activity), low fat diet, and lifestyle modification.

Pharmacotherapy

First line therapy in the patient with chronic stable angina includes aspirin to minimize the risk of thrombosis superimposed on the chronic fixed obstruction and beta blockade to reduce heart rate and myocardial oxygen demands, as well as reduce the risk of fatal arrhythmias should plaque rupture occur. Strong consideration should be given to initiaion of ACE inhibition as potential disease modifying therapy.

Evaluate fasting lipid profile and initiate proper lipid lowering drug therapy when necessary. Ideally start with HMG-CoA reductase inhibitor to reduce LDL cholesterol level below 100 mg/dl (<70 mg/dl in high risk patients).

Use sublingual nitroglycerin for alleviation of symptoms.

If angina episodes occur >2-3 times in a week, consider adding a calcium channel antagonist drug or a long acting nitrate. Regardless of the frequency and severity of angina symptoms, adding a calcium antagonists and/or long lasting nitrates to the main treatment regimen may help to reduce blood pressure and therefore treat ventricular function abnormalities.

Consider adding a third agent if angina persists despite of two anti-anginal drugs.

Coronary angiography is indicated in patients with refractory symptoms or ischemia if administration of optimal medical therapy has failed to control the symptoms or ischemia. It should also be carried out in "high-risk" patients with non invasive test results, and in those with special occupations or sedentary life styles that require a more aggressive approach.

The treatment essentials

Alphabet of chronic stable angina management: elements listed below are the most important components of stable angina management.

• A=Aspirin use
• A=Anti anginal therapy
• B=Beta blocker use
• B=Blood pressure control
• C=Cholesterol lowering therapy
• C=Cigarette smoking cessation
• D=Diabetes Mellitus control
• D=Diet
• E=Exercise
• E=Education

Lifestyle modifications

Initiation of intensive modification is urgent and an essential part of the main therapy.

Smoking cessation

The 1989 Surgeon General’s report concluded, on the basis of case-control and cohort studies, that smoking increased cardiovascular disease mortality by 50%. Hence, this is an important component of lifestyle modification. Smoking cessation and avoidance of exposure to environmental tobacco smoke at work and home is recommended. Goal is to achieve complete smoking cessation. Follow-up, referral to special programs, and/or pharmacotherapy (including nicotine replacement) is recommended, as is a stepwise strategy for smoking cessation (Ask, Advise, Assess, Assist, Arrange). (Class I recommendation, Evidence Level B)

The cardiovascular effects of nicotine, such as increases in heart rate with small rises in blood pressure, have provoked some concerns about the use of Nicotine Replacement Therapy(NRT) in patients with coronary artery disease. However, nicotine patches have been used successfully in heart disease patients without any adverse effects. Similarly, it is suggested that nicotine replacement therapy may be initiated as early as 2–3 days after acute myocardial infarction and that it may be used in all patients with stable angina pectoris and cardiac arrhythmias.

Weight Management

BMI (Body Mass Index) and waist circumference should be assessed regularly. On each patient visit, it is useful to consistently encourage weight maintenance/reduction through an appropriate balance of physical activity, caloric intake, and formal behavioral programs when indicated to achieve and maintain a BMI between 18.5 and 24.9 kg/m2. (Class I recommendation, Evidence Level B)

If waist circumference is greater than or equal to 35 inches (89 cm) in women or greater than or equal to 40 inches (102 cm) in men, it is beneficial to initiate lifestyle changes and consider treatment strategies for metabolic syndrome as indicated. Some male patients can develop multiple metabolic risk factors when the waist circumference is only marginally increased (e.g., 37 to 40 inches [94 to 102 cm]). Such persons may have a strong genetic contribution to insulin resistance. They should benefit from changes in life habits, similarly to men with categorical increases in waist circumference. (Class I recommendation, Evidence Level B)

The initial goal of weight loss therapy should be to gradually reduce body weight by approximately 10% from baseline. With success, further weight loss can be attempted if indicated through further assessment. (Class I recommendation, Evidence Level B)

Physical Activity

Physical activity of 30 to 60 minutes, 7 days per week (minimum 5 days per week) is recommended. All patients should be encouraged to obtain 30 to 60 minutes of moderate-intensity aerobic activity, such as brisk walking, on most, preferably all, days of the week, supplemented by an increase in daily activities(such as walking breaks at work, gardening, or household work). (Class I recommendation, Evidence Level B)

The patient’s risk should be assessed with a physical activity history. Where appropriate, an exercise test is useful to guide the exercise prescription (see Exercise Testing Guideline). Medically supervised programs (cardiac rehabilitation) are recommended for at-risk patients (e.g., recent acute coronary syndrome or revascularization, heart failure). (Class I recommendation, Evidence Level B)

Expanding physical activity to include resistance training on 2 days per week may be reasonable. (Class IIb recommendation, Evidence Level C)

Lipid Management

Recommended lipid management includes assessment of a fasting lipid profile. Primary goal of lipid management is to achieve a LDL-C level of less than 100 mg/dL. If baseline LDL-C is greater than or equal to 100 mg per dL, LDL lowering drug therapy should be initiated in addition to therapeutic lifestyle changes. When LDL-lowering medications are used in high-risk or moderately high-risk persons, it is recommended that intensity of therapy be sufficient to achieve a 30% to 40% reduction in LDL-C levels. If on-treatment LDL-C is greater than or equal to 100 mg per dL, LDL-lowering drug therapy should be intensified. (Class I recommendation, Evidence Level A)

If baseline LDL-C is 70 to 100 mg per dL, it is reasonable to treat LDL-C to less than 70 mg per dL. (Class IIa recommendation, Evidence Level B)

Secondary goal of lipid management is to achieve non–HDL-C‡ of less than 130 mg per dL if TG are 200 to 499 mg per dL. (Class I recommendation, Evidence Level B) Further reduction of non–HDL-C‡ to less than 100 mg per dL is reasonable, if TG are greater than or equal to 200 to 499 mg per dL. (Class IIa recommendation, Evidence Level B)

Therapeutic options to reduce non–HDL-C are:

• Niacin can be useful as a therapeutic option to reduce non–HDLC (after LDL-C–lowering therapy) or
• Fibrate therapy as a therapeutic option can be useful to reduce non–HDL-C‡ (after LDL-C–lowering therapy). (Class IIa recommendation, Evidence Level B)

If TG are greater than or equal to 500 mg per dL, therapeutic options to lower the TG to reduce the risk of pancreatitis are fibrate or niacin; these should be initiated before LDL-C lowering therapy. The goal is to achieve non–HDL-C‡ less than 130 mg per dL if possible. (Class I recommendation, Evidence Level C)

Other recommended strategies for lipid lowering and diet management are:

• Reduced intake of saturated fats (to less than 7% of total calories), trans-fatty acids, and cholesterol (to less than 200mg per day). (Class I recommendation, Evidence Level B)
• Adding plant stanol/sterols (2g per day) and/or viscous fiber (greater than 10 g per day) is reasonable to further lower LDL-C. (Class IIa Evidence Level A recommendation)
• Encouraging consumption of omega-3 fatty acids in the form of fish or in capsule form (1g per day) for risk reduction. (Class IIb recommendation, Evidence Level B)
• Daily physical activity and weight management are recommended for all patients. (Class I recommendation, Evidence Level B)
• Moderation of alcohol consumption. (Class I recommendation, Evidence Level B)
• Limited sodium intake. (Class I recommendation, Evidence Level B)

Blood Pressure Control

• Patients should initiate and/or maintain lifestyle modifications—weight control; increased physical activity; moderation of alcohol consumption; limited sodium intake; and maintenance of a diet high in fresh fruits, vegetables, and low-fat dairy products. (Class I recommendation, Evidence Level B)

• Blood pressure control according to Joint National Conference VII guidelines is recommended (i.e., blood pressure less than 140/90 mm Hg or less than 130/80 mm Hg for patients with diabetes or chronic kidney disease). (Class I recommendation, Evidence Level A)

• For hypertensive patients with well established coronary artery disease, it is useful to add blood pressure medication as tolerated, treating initially with beta blockers and/or ACE inhibitors, with addition of other drugs as needed to achieve target blood pressure. (Class I recommendation, Evidence Level C)

Diabetes Management

• Diabetes management should include lifestyle and pharmacotherapy measures to achieve a near-normal HbA1c. (Class I recommendation, Evidence Level B)

• Vigorous modification of other risk factors (e.g., physical activity, weight management, blood pressure control, and cholesterol management) as recommended should be initiated and maintained. (Class I recommendation, Evidence Level B)

ACC / AHA Guidelines- Recommendations for cardiovascular risk factor reduction (DO NOT EDIT)

“

Class I 1. Treatment of Hypertension accoring to Joint National Conference VII guidelines(i.e., blood pressure less than 140/90 mm Hg or less than 130/80 mm Hg for patients with diabetes or chronic kidney disease). (Level of Evidence: A) 2. Smoking cessation therapy. (Level of Evidence: B) 3. Management of diabetes. (Level of Evidence: C) 4. Comprehensive cardiac rehabilitation program(including exercise). (Level of Evidence: B) 5. Low-density lipoprotein-lowering therapy in patients with documented or suspected CAD and LDL cholesterol greater than or equal to 100 mg per dl. (Level of Evidence: A) 6. If TG are 200 to 499 mg per dL, non–HDL-C‡ should be less than 130 mg per dL. (Level of Evidence: B) 7. If TG are greater than or equal to 500 mg per dL, therapeutic options to lower the TG to reduce the risk of pancreatitis are fibrate or niacin; these should be initiated before LDL-C lowering therapy. The goal is to achieve non–HDL-C‡ less than 130 mg per dL if possible. (Level of Evidence: C) 8. Weight reduction to achieve and maintain a BMI of 18.5-24.9 kg/m2. (Level of Evidence: B) 9. Dietary therapy for all patients should include reduced intake of saturated fats (to less than 7% of total calories), trans-fatty acids, and cholesterol (to less than 200 mg per day). (Level of Evidence: B) 10. An annual influenza vaccination is recommended for patients with cardiovascular disease. (Level of Evidence: B) Class IIa 1. Reduction of LDL-C to less than 70 mg per dL or high-dose statin therapy is reasonable. (Level of Evidence: A) 2. If baseline LDL-C is 70 to 100 mg per dL, it is reasonable to treat LDL-C to less than 70 mg per dL. (Level of Evidence: B) 3. If TG are 200 to 499 mg per dL, Niacin and Fibrate therpay can be used to reduce the non-HDL-C. (Level of Evidence: B) 4. Weight reduction in obese patients in the absence of hypertension, hyperlipidemia, or diabetes mellitus. (Level of Evidence: C) Class IIb 1. Expanding physical activity to include resistance training on 2 days per week may be reasonable. (Level of Evidence: C) 2. For all patients, encouraging consumption of omega-3 fatty acids in the form of fish* or in capsule form (1 g per day) for risk reduction may be reasonable. For treatment of elevated TG, higher doses are usually necessary for risk reduction. (Level of Evidence: B) Class III 1. Initiation of hormone replacement therapy in postmenopausal women for the purpose of reducing cardiovascular risk. (Level of Evidence: A) 2. Vitamin C and E supplementation. (Level of Evidence: A) 3. Chelation therapy (intravenous infusions of ethylenediamine tetraacetic acid or EDTA) is not recommended for the treatment of chronic angina or arteriosclerotic cardiovascular disease and may be harmful because of its potential to cause hypocalcemia.. (Level of Evidence: C) 4. Garlic. (Level of Evidence: C) 5. Acupuncture. (Level of Evidence: C) 6. Coenzyme Q. (Level of Evidence: C)

”

Pharmacotherapy

Antiplatelet Agents

Aspirin inhibits cyclo oxygenase and the subsequent suppression of thromboxane A2, the key moderator of irreversible platelet aggregation. Aspirin is a potent anti platelet agent and has been shown to improve survival and to prevent infarction in patients with unstable angina or after myocardial infarction. A 75-mg dose has been shown to be effective and causes less gastrointestinal bleeding than the commonly prescribed 325 mg dose.

Meta-analysis of 140,000 patients from the Antiplatelet Trialists’ Collaboration showed that aspirin (75-325 mg/day) reduced the rate of subsequent myocardial infarction, stroke, and death in patients with history of angina pectoris, myocardial infarction, CABG, and stroke. In the Swedish Angina Pectoris Aspirin Trial (SAPAT), aspirin (75 mg/day) in conjunction with the beta blocker sotalol conferred an additional 34% reduction in acute myocardial infarction and sudden death among men and women with chronic stable angina. Aspirin also improves endothelial function and, when used in high dose (300 mg/day), has been shown to reduce circulating levels of C-reactive protein. Therefore, it should be started at 75 to 162 mg/day and continued indefinitely in all patients with chronic stable angina pectoris, unless contraindicated (Class I recommendation, Evidence Level A). This dosing range appears to have comparable efficacy for secondary prevention compared to dosing at 160-325 mg/day and also reduces bleeding risk.

If aspirin use is contraindicated, clopidogrel is advisable. Clopidogrel is a thienopyridine derivative which prevents adenosine diphosphate–mediated activation of platelets by selectively and irreversibly inhibiting the binding of adenosine diphosphate to its platelet receptors and thereby blocking adenosine diphosphate–dependent activation of the glycoprotein IIb/IIIa complex. Ticlopidine, another thienopyridine derivative, decreases platelet function in patients with stable angina but, unlike aspirin, has not been shown to decrease adverse cardiovascular events.

Dipyridamole is a pyrimido-pyrimidine derivative that exerts vasodilatory effects on coronary resistance vessels and also has antithrombotic effects. However, even the usual oral doses of dipyridamole can enhance exercise-induced myocardial ischemia in patients with stable angina, and therefore, it should not be used as an antiplatelet agent.

Use of warfarin in conjunction with aspirin and/or clopidogrel is associated with an increased risk of bleeding and should be monitored closely. (Class I recommendation, Evidence Level B)

In the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, randomized comparison between clopidogrel and aspirin showed that clopidogrel resulted in 8.7% relative risk reduction of vascular death, ischemic stroke, or myocardial infarction among patients with established atherosclerotic vascular disease. In the latest Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial, dual anti platelet therapy with clopidogrel + aspirin was not significantly more effective compared to aspirin alone in reducing the rate of myocardial infarction, stroke, or cardiovascular death in patients with established vascular disease or at high risk for developing vascular disease.

Antianginal agents

Nitroglycerin and Long Acting Nitrates

Nitroglycerin and other nitrates are endothelium independent vasodilators that produce their beneficial effects both by decreasing myocardial oxygen requirements and by improving myocardial perfusion.

It has been postulated that nitrates, after entering the vessel wall, are converted to nitric oxide (NO), which stimulates guanylate cyclase to produce cyclic guanosine mono phosphate (cGMP), the substance that is responsible for vasodilation.

Nitrates dilate large coronary arteries and collateral vessels, relieve coronary vasospasm, and decrease the degree of coronary artery stenosis produced by an eccentric atherosclerotic plaque. Nitrates, therefore, have the potential to improve myocardial perfusion by coronary vasodilatation, by decreasing the degree of epicardial coronary artery stenosis, and by increasing collateral blood flow to the ischemic myocardium. Nitrates also decrease myocardial oxygen requirements by decreasing intra cardiac volumes consequent to reduced venous return resulting from peripheral venous dilatation and by reducing arterial pressure. These beneficial effects may be offset partly by a reflex increase in heart rate, which can be prevented by simultaneous beta adrenergic blockade.

Nitrates are effective for the management of various clinical subsets of stable angina pectoris. In patients with exertional angina, nitrates improve exercise tolerance, the time to the onset of angina, and ST segment depression during the treadmill exercise test.

In patients with vasospastic angina, nitrates relax the smooth muscles of the epicardial coronary arteries and thereby relieve coronary artery spasm. In patients with mixed angina and postprandial angina, nitrates reduce myocardial oxygen demand and promote coronary vasodilation.

A variety of nitrate preparations are currently available. The onset of action of sublingual nitroglycerin tablets or nitroglycerin spray is within 1 to 3 minutes, making these the preferred agents for the acute relief of effort or rest angina.

The patient should be instructed that active nitroglycerin will cause some tingling under the tongue, and that if this does not occur, the efficacy of their nitroglycerine tablets may be expired. Nitroglycerin is also very useful for prophylaxis when used several minutes before planned exertion. However, its short duration of action (20 to 30 min) makes it less practical for long-term prevention of ischemia in patients with stable angina.

For angina prophylaxis, long acting nitrate preparations such as isosorbide dinitrate, mono nitrates, transdermal nitroglycerin patches, and nitroglycerin paste are preferable. However, the major clinical problem for long term nitrate therapy is nitrate tolerance. ”’The most reliable method for the prevention of nitrate tolerance is to ensure a nitrate free period of approximately 10 hours, usually including sleeping hours, in patients with effort angina’”. Isosorbide dinitrate should not be used more frequently than three times a day, or a transdermal patch more often than every 12 hours.

The most common side effect of nitrate therapy is a throbbing headache, which tends to decrease with continued use. Although postural dizziness and weakness occur in some patients, frank syncope due to hypotension is relatively uncommon. Nitrates do not worsen glaucoma, once thought to be a contraindication to their use, and they can be used safely in the presence of increased intraocular pressure. Nitrates are relatively contraindicated in hypertrophic obstructive cardiomyopathy, because in these patients, nitrates can increase LV outflow tract obstruction and severity of mitral regurgitation and can precipitate presyncope or syncope. For the same reason, nitrates should be avoided in patients with aortic valve stenosis.

Beta Blockers

It is beneficial to start and continue beta blocker drug therapy indefinitely in all patients who have had myocardial infarction, acute coronary syndrome (ACS) or left ventricular dysfunction with or without heart failure symptoms, unless contraindicated (Class I recommendation, Evidence Level A).

In general, beta blocking drugs decrease heart rate, blood pressure, and contractility and, as a result, reduce myocardial oxygen consumption.

A slowing of heart rate is associated with an increased left ventricular perfusion time. Exercise induced increases in heart rate and blood pressure are also blunted. In patients with stable angina, beta adrenergic blocking agents increase exercise duration and the time to the onset of angina and of ST segment depression, although the double product threshold (heart rate multiplied by blood pressure) at which ischemia occurs remains unchanged.

Beta blocking agents with beta selectivity (such as metoprolol and atenolol) are preferable in patients with mild asthma, chronic obstructive pulmonary disease (COPD), insulin dependent diabetes mellitus (IDDM) or intermittent claudication. However, with increased doses of beta blockers, selectivity is lost and both types of beta receptors are blocked.

The major side effects of beta blocker therapy include fatigue, impaired exercise tolerance, depression, insomnia, nightmares, and worsening claudication and bronchospasm. Severe bradycardia, episodes of second or third degree atrioventricular (AV) blocks, poorly controlled left ventricular failure, severe depression of left ventricular function, and severe peripheral vascular disease are contraindications to the use of beta blockers. Beta blockers may increase the blood sugar level and impair insulin sensitivity, particularly when used concurrently with diuretics. They may decrease the reaction to hypoglycemia in patients with insulin dependent diabetes mellitus (IDDM) and may exert unfavorable effects on the blood lipid profile with an increase in triglycerides and reduction in high density lipoprotein (HDL-C). However, the clinical significance of these adverse changes in the lipid profile with beta blockers has not yet been defined.

The effective dose of any beta blocker drug varies considerably from patient to patient. For an effective treatment; resting heart rate should be reduced to between 45 and 60 bpm (beats per minute) and heart rate should be below 90 beats per minute during moderate exercise, such as climbing two stairs at a normal pace.

If administration of beta blockers induces symptomatic heart failure, they should be discontinued or the dose reduced. For maintenance therapy of stable angina, beta blocking drugs with a relatively long half-life are preferable. The sudden withdrawal of beta blocker therapy may result in worsening of angina (rebound effect) and precipitation of acute ischemic episodes; it is preferable to taper these medications gradually over 2 to 3 weeks.

Calcium Channel Blockers

Calcium antagonists consist of three subclasses as dihydropyridines (e.g., nifedipine), phenylalkylamines (e.g., verapamil), and the modified benzothiazepines (e.g., diltiazem). These agents are used as second line therapy when beta blockers are genuinely contraindicated. Several trials have shown that verapamil is as effective as beta-blockers in the control of angina, but this agent does not prolong life. Verapamil is a more effective anti anginal agent than diltiazem or dihydropyridines (DHPs) and is considered a first choice, but the drug must be used with caution and must not be combined with a beta blocker.

Calcium Channel Blockers reduce the transmembrane flux of calcium via slow calcium channels. The dihydropyridines, for example, nifedipine, exert a greater inhibitory effect on vascular smooth muscle than on the myocardium. Thus, the major therapeutic effect can be expected to be peripheral or coronary vasodilation. These agents, however, also exert a negative inotropic effect and therefore can produce myocardial depression, which is less pronounced with amlodipine and nisoldipine. The peripheral vasodilation caused by the dihydropyridines also can cause reflex adrenergic activation, tachycardia, and stimulation of the rennin-angiotensin system. These agents increase coronary blood flow owing to vasodilation of both conductance and resistance coronary vessels. Intermittent adrenergic activation with short-acting dihydropyridines has been implicated as the mechanism for the potentially adverse cardiovascular effects.

The non-dihydropyridine calcium channel blockers such as verapamil and diltiazem cause slowing of the sinus node and hence may potentiate the bradycardia of beta blockers. However, they are less potent peripheral vasodilators than the dihydropyridines and less likely to cause hypotension, flushing, and dizziness.

Epicardial coronary artery spasm is effectively relieved and prevented by calcium channel blockers, so that these are the agents of choice (along with nitrates) for the treatment of vasospastic angina. Some patients with coronary spasm may require a combination of two calcium channel blockers to achieve efficacy. With some calcium channel blockers, such as verapamil and diltiazem, heart rate may also decrease, associated with a reduced myocardial oxygen requirement. In patients with mixed, walk through, postprandial, and late nocturnal angina, in which increased coronary vascular tone appears to contribute to the pathogenesis of the ischemia, the use of calcium channel blockers may be of benefit, particularly when nitrate therapy alone is inadequate.

In patients with stable exertional angina, calcium channel blockers improve exercise tolerance (longer time to the onset of angina and to ST segment depression) during treadmill exercise tests. The mechanism of these beneficial effects is primarily decreased myocardial oxygen consumption. Calcium channel blockers and beta-adrenergic blocking drugs in combination can produce synergistic beneficial effects in patients with stable angina pectoris.

Controversy exists for the use of calcium channel blockers for the long term treatment of stable exertional angina, since the short acting, immediate release dihydropyridines, such as nifedipine, may increase the risk of myocardial infarction and mortality.

Worsening congestive heart failure and increased mortality has also been observed with diltiazem in postinfarction patients with depressed left ventricular ejection fraction.

However, second generation vasoselective dihydropyridine derivative calcium channel blockers, such as amlodipine and felodipine, are well tolerated by patients with left ventricular dysfunction and even overt clinical heart failure, and no increase in the risk of mortality has been described. Furthermore, vasoselective long acting dihydropyridines (such as amlodipine) and extended release (nifedipine) and slow release (verapamil and diltiazem) have all been shown to reduce frequency and symptoms of angina.

Thus, if necessary, these agents can be used for treatment of stable exertional angina. The new T channel types of calcium blockers are also effective in controlling hypertension and angina. They appear to possess little negative inotropic effect and produce little or no edema or constipation. The general side effects of calcium channel blockers are constipation, peripheral edema, dizziness, flushing and occasionally, headache. With dihydropyridines, a reflex tachycardia may produce palpitation. With diltiazem and verapamil, sinus bradycardia and different grades of atrioventricular blocks may occur. Verapamil may cause constipation. In choosing a particular calcium channel blocker in a given patient, the hemodynamic profile should be considered. Dihydropyridines are preferable in the presence of sinus bradycardia, sinus node dysfunction, or atrioventricular block, particularly when the blood pressure is not adequately controlled. Diltiazem or verapamil is preferable in patients with relative tachycardia.

Amlodipine has minimal negative inotropic effects and can be combined with a beta blocker in patients with EF> 35%. Although beta-blockers may be used in patients with EF <30%, the combination of a beta-blocker with diltiazem or dihydropyridine should be avoided in patients with EF <40%. Verapamil and, to a lesser extent, diltiazem, when added to a beta-blocker, may cause conduction disturbances or HF, and the verapamil combination is considered unsafe.

Calcium antagonists have also been postulated to have anti atherosclerotic properties. The Prospective Randomized Evaluation of the Vascular Effect of Norvasc Trial (PREVENT) did demonstrate slowing of atherosclerotic progression in carotid but not in the coronary vasculatures.

Given to patients prior to undergoing PTCA, amlodipine was shown to reduce major cardiovascular end points (death, MI, CABG, repeat PCI) in the Coronary Angioplasty Amlodipine Restenosis Study (CAPARES).

Angiotensin Converting Enzyme Inhibitors (ACEI) and Renin Angiotensin Aldosterone System Blockers (RAAS Blockers)

ACE inhibitors should be started and continued indefinitely in all patients with left ventricular ejection fraction less than or equal to 40% and in those with hypertension, diabetes, or chronic kidney disease unless contraindicated. (Class I Evidence Level A recommendation)

ACE inhibitors should be started and continued indefinitely in patients who are not lower risk (lower risk defined as those with normal left ventricular ejection fraction in whom cardiovascular risk factors are well controlled and revascularization has been performed), unless contraindicated. (Class I Evidence Level B recommendation)

It is reasonable to use ACE inhibitors among lower-risk patients with mildly reduced or normal left ventricular ejection fraction in whom cardiovascular risk factors are well controlled and revascularization has been performed. (Class IIa Evidence Level B recommendation)

Angiotensin receptor blockers are recommended for patients who have hypertension, have indications for but are intolerant of ACE inhibitors, have heart failure, or have had a myocardial infarction with left ventricular ejection fraction less than or equal to 40%. (Class I Evidence Level A recommendation)

Angiotensin receptor blockers may be considered in combination with ACE inhibitors for heart failure due to left ventricular systolic dysfunction. IIb (B)

Aldosterone blockade is recommended for use in post myocardial infarction patients without significant kidney dysfunction or hyperkalemia who are already receiving therapeutic doses of an ACE inhibitor and a beta blocker, have a LV EF ≤40% and have either diabetes mellitus or heart failure (Class I Evidence Level A recommendation)

Anti-lipid agents

If baseline LDL-Cholesterol is ≥100 mg/dL, LDL lowering drug therapy should be initiated in addition to therapeutic lifestyle changes. When LDL lowering medications are used in high risk or moderately high risk persons, it is recommended that intensity of therapy be sufficient to achieve a 30% to 40% reduction in LDL-Cholesterol levels.

If baseline LDL-C is 70 to 100 mg/dL, it is reasonable to treat LDL-C to <70 mg/dL. If on-treatment LDL-C is ≥100 mg/dL, LDL lowering drug therapy should be intensified.

If Triglycerides are 200-499 mg/dL, the sum of non–HDL-Cholesterol levels should be <130 mg/dL. Moreover this, further reduction of non–HDL Cholesterol to <100 mg/dL is reasonable, if Triglycerides are ≥200 to 499 mg/dL.

Therapeutic options to reduce non–HDL-C are: ’’’Niacin”’ can be useful as a therapeutic option to reduce non–HDL-C (after LDL-C lowering therapy) or ’’’Fibrate”’ therapy as a therapeutic option can be useful to reduce non–HDL-C (after starting to LDL-C–lowering therapy).

If Triglycerides are ≥500 mg/dL, therapeutic options to lower the Triglycerides to reduce the risk of pancreatitis are fibrate or niacin; these should be initiated before LDL-Choesterol lowering therapy. The goal is to achieve non–HDL-C <130 mg/dL if possible.

If LDL-Cholesterol <70 mg/dL is the chosen target, consider drug titration to achieve this level to minimize side effects and cost of therapy. When LDL-Cholesterol level of <70 mg/dL is not achievable because of high baseline LDL-Cholesterol levels, it is generally possible to achieve reductions of >50% in LDL-Cholesterol levels by either statins or any other LDL-Cholesterol –lowering drug combinations. Treatment with anti lipid drug combinations is beneficial for patients on lipid lowering therapy who are unable to achieve LDL-Cholesterol <100 mg/dL.

Choices among Pharmacologic Agents for Angina

In patients with stable exertional angina, beta blocker therapy is the preferred as an initial treatment. These agents reduce or prevent ischemia with a single daily dose and their known long term prognostic benefit may also be generalized to other patients with ischemic heart disease. All patients should also be given nitroglycerin and instructions about its therapeutic and prophylactic use.

Calcium channel blockers are not preferred initial therapy for the management of patients with stable exertional angina. In patients with special circumstances or concomitant diseases, specific medications, or combinations of medications are preferable. For most patients, however, the initial therapy should consist of use of beta-adrenergic blocking agents, and nitrates should be added if the response to beta blocker therapy is inadequate. Calcium channel blockers should be considered in patients who cannot tolerate beta blockers or nitrates or who respond inadequately to these drugs. Extended release nifedipine, second generation vasoselective calcium channel blockers, and extended-release verapamil or diltiazem are the calcium blockers of choice.

Revascularization

Introduction

The goals of treatment of stable angina are to reduce symptoms, delay the progression of atherosclerosis, and prevent cardiovascular events. This is usually established with medical therapy with revascularization used only in selected patients. The main indications for revascularization therapy (PCI or CABG) in stable angina are:

• Patients with symptoms uncontrolled with optimal medical therapy (see above).

The definition of an inadequate response to medical therapy is fairly wide and depends on the patient’s lifestyle, occupation, and expectations. At one extreme are patients who are limited by angina pectoris despite optimal drug treatment and lifestyle modifications, including achievement of optimal weight and cessation of smoking (see above). At the other end of the range are patients who consider medical therapy to have failed if control of angina pectoris requires higher doses of anti-anginal medications that cause side effects.

• Patients who would have a survival benefit from revascularization (PCI or CABG).

This depends on the location, severity, and number of lesions; the presence or absence of left ventricular dysfunction is an important factor as well.

There is evidence and/or general agreement that coronary angiography should be performed to risk stratify patients with chronic stable angina in the following settings:

• Disabling anginal symptoms (Canadian Cardiovascular Society [CCS] classes III and IV) despite medical therapy.
• High-risk criteria on noninvasive testing independent of the severity of angina (The amount and distribution of viable but jeopardized left ventricular myocardium and the percentage of irreversibly scarred myocardium).
• Survivors of sudden cardiac death or serious ventricular arrhythmia.
• Symptoms and signs of heart failure.
• Clinical features that suggest that the patient has a high likelihood of severe coronary artery disease.

On the other hand, angiography is not recommended for patients with CCS class I or II angina that responds to medical therapy and, on noninvasive testing, shows no evidence of ischemia.

There are currently two well-established revascularization approaches to treatment of chronic stable angina caused by coronary atherosclerosis. Since the introduction of bypass surgery in 1967 and percutaneous transluminal coronary angioplasty [PTCA] in 1977, it has become clear that both strategies can contribute to the effective treatment of patients with chronic stable angina and both have weaknesses. The choice between PCI and CABG is based upon anatomy and other factors such as left ventricular function and the presence or absence of diabetes. In general, PTCA is reserved for single or some cases of two vessel disease, while CABG is reserved for patients with two or three vessel disease or left main disease. With the availability of drug-eluting stents, PCI is increasingly performed for many lesions including more complex ones.

Complications of percutaneous coronary intervention

Ideal candidates for PTCA/PCI are under 75 years of age, with single-vessel, single-lesion CAD, without a history of diabetes. Lesions that are best for these procedures are short (<10 mm), concentric, discrete, and readily accessible. The risk of morbidity and mortality from the procedure is increased, particularly in patients with long (>20 mm), tortuous, irregular, angulated, calcified, severely stenotic (>90% stenosis) lesions and when more than one such lesion is present in an artery. Other important factors include operator volume and the presence or absence of on site cardiovascular surgeon. The 2005 ACC/AHA/SCAI guidelines for percutaneous coronary intervention made recommendations about hospital and operator volume and the importance of onsite cardiac surgery for both elective and primary PCI. The improvements in devices, the use of stents, and aggressive antiplatelet therapy have significantly reduced the incidence of major procedural complications of PCI over the past 2 decades despite the increasing complexity of cases.

Primary success of coronary interventions is generally defined as an absolute increase of 20 percentage points in luminal diameter and a final diameter obstruction less than 30%. Such angiographic success can be anticipated in more than 90% of properly selected patients.

The major complications of PTCA/PCI include coronary artery dissection and acute closure, intramural hematoma, coronary artery perforation, and occlusion of branch vessels: Dissections are found in up to 50 percent of patients immediately after PTCA. Intimal tears or dissections following PTCA have been arbitrarily divided into types A to F. • Type A — Luminal haziness • Type B — Linear dissection • Type C — Extraluminal contrast staining • Type D — Spiral dissection • Type E — Dissection with reduced flow • Type F — Dissection with total occlusion These problems are now much less frequent since stent placement is performed in most percutaneous coronary procedures. Abrupt closure is most often due to arterial dissection and is manifested as acute ischemic chest pain and ECG changes. The incidence of abrupt closure with conventional balloon angioplasty (PTCA) is approximately 5% and is associated with a 10-fold increase in mortality to about 1 percent and nonfatal MI. The frequency of this complication, however, has now been greatly reduced by pretreatment with the platelet glycoprotein IIb/IIIa receptor blockers and by the insertion of an intracoronary stent. If stenting does not restore adequate flow, emergency CABG can be performed.

Coronary artery intramural hematoma is defined as an accumulation of blood within the medial space displacing the internal elastic membrane inward and the external elastic membrane outward, with or without identifiable entry and exit points. It is identified in 6.7 percent of procedures by intravascular ultrasound (IVUS).

Coronary artery perforation in the stent era is a rare but potentially disastrous complication.

Downstream embolization of thrombus or plaque contents with microvascular obstruction is common after PCI and occlusion of side branches has been reported in up to 19 percent of cases in which a stent was placed across a major side branch.

Stent thrombosis is catastrophic complication that usually leads to death or ST segment elevation MI. It is therefore a medical emergency. Stent thrombosis can occur acutely (during or soon after the PCI), subacutely (within 30 days after stent placement), or as a complication. Late stent thrombosis is associated with the cessation of aspirin or clopidogrel therapy. On the other hand, very late stent thrombosis, occurring after one year, is associated with drug-eluting stents.

Restenosis is the result of arterial damage with subsequent neointimal tissue proliferation. It is usually defined as a greater than 50% diameter stenosis. The incidence of angiographic restenosis is approximately 30% to 40% after PTCA. Intracoronary stents reduce the rate of angiographic and clinical restenosis and post-procedural myocardial infarction compared to percutaneous transluminal coronary angioplasty (PTCA) alone. Trials have demonstrated that the sirolimus and paclitaxel drug-eluting stents markedly reduced the incidence of in-stent restenosis and the rate of target lesion revascularization compared to bare metal stents. As a result, stents are currently utilized in nearly all percutaneous coronary interventions. However, the benefits of drug-eluting stents on restenosis must be weighed against rates of stent thrombosis, which often leads to death or MI, if dual antiplatelet therapy is prematurely discontinued. Restenosis occurs more frequently in diabetics, smaller arteries, among total occlusions, and in left anterior descending arteries, particularly proximal lesions. Since not all angiographic restenosis results in recurrent symptoms, the rates of clinical restenosis are lower than these angiographic estimates. Recurrent sever angina occurs in approximately half of the patients who develop angiographic restenosis and usually responds to stenting. In symptomatic patients with BMS restenosis, a repeat stenting using a DES is usually recommended. In symptomatic patients with intracoronary DES restenosis, there are insufficient data to suggest any specific treatment.

Clinical trials: PTCA/PCI versus medical treatment in the management of stable angina pectoris:

There are important limitations concerning the applicability of the results of older trials and even newer trials to the current clinical practice.

In early trials of percutaneous intervention versus medical therapy, the majority of patients underwent coronary angioplasty alone without stenting. For example, the benefits of PTCA have been compared to medical therapy in single vessel disease in the randomized Veterans Affairs Angioplasty Compared to Medicine (ACME) trial. PTCA resulted in a reduction in anginal symptoms compared to medical therapy (50% angina free versus 24% at one month), however, while the benefit of PTCA was still significant at 6 months, the magnitude of this benefit was reduced (64% angina free versus 45%). Patients treated with PTCA also had an improvement of 2.1  3.1 minutes in exercise duration which was significantly greater than the 0.5  2.2 minutes experienced in the medical therapy group.

Other older trials compared PTCA to both limited (AVERT trial) and optimal medical interventions (RITA-2 and MASS II). The findings of these trials were that patients undergoing PTCA had similar rates of death and myocardial infarction as those on medical therapy and were less likely to have angina during the first few years.

More recent literature provides comparison between the use of stents and medical management, however, there is few data examining the extensive use of drug eluting stents and current extensive antithrombotic regimens (clopidogrel and GP IIb/IIIa inhibitors). In the most recent trial, COURAGE, drug-eluting stents were used in only 15 percent of patients. However, the COURAGE trial has the data most applicable to current practice. In this study 2287 patients were randomized to either aggressive medical therapy alone or aggressive medical therapy plus PCI with bare metal stenting. Patients were required to have both objective evidence of ischemia and significant CHD in a least one vessel; 87 percent were symptomatic and 58 percent had Canadian Cardiovascular Society [CCS] class II or III angina. Patients were excluded if they had CCS class IV angina, ≥50 percent left main disease, a markedly positive treadmill test (significant ST segment depressions and/or a hypotensive response during stage I of the Bruce protocol), an LVEF less than 30 percent, or coronary lesions deemed unsuitable for PCI. All patients received optimal medical therapy with beta blockers, calcium channel blockers, nitrates, antiplatelet therapy (either aspirin or clopidogrel), and aggressive lipid-lowering therapy with statin (attained median LDL-cholesterol was 72 mg/dL at five years). Exercise was recommended to achieve further improvements in the lipid profile when necessary. The results were published at a median follow-up of 4.6 years. There was no significant difference between the two treatment strategies for the primary end point of death from any cause and non-fatal MI. There was no significant difference in the rates of hospitalization for ACS. Patients in the PCI group underwent significantly fewer subsequent revascularization procedures (21 versus 33 percent, HR 0.60, 95% CI 0.51-71).

The issue of whether patients who receive PCI plus optimal medical therapy have a better quality of life and less angina than those who receive optimal medical therapy was addressed in COURAGE as well:

At baseline, 22 percent of patients were free of angina. At three months, significantly more patients who received PCI were angina free (53 versus 42 percent), but at 36 months there was no significant difference (59 versus 56 percent). Patients in both groups showed significant improvements from baseline values in various measures of quality of life. The percent of patients with clinically significant improvement in parameters such as physical limitation, angina stability, angina frequency, and overall quality of life was significantly higher in the PCI group by the sixth months. However, there was no significant difference in these rates at 36 months.

The results of COURAGE demonstrate that PCI with bare metal stents plus optimal medical therapy and initial, optimal medical therapy with revascularization as necessary are comparable strategies.

Indications for CABG

CABG is carried out to prolong life or improve its quality (see above). Prolongation of life has been shown in patients with more than 50% luminal diameter stenosis of the left main coronary artery and in those with impaired left ventricular function (left ventricular ejection fraction <40%) and critical, >70% stenosis in all three major coronary arteries or in two arteries, one of which is the proximal left anterior descending artery. The presence of a high-risk result on a noninvasive test also increases the benefit of surgery. Patients with severe left ventricular dysfunction obtain a survival benefit from CABG if the myocardium with impaired contractile function is viable (hibernating myocardium) rather than necrotic. The stenotic arteries are bypassed with an internal mammary (arterial) or saphenous vein graft. Arterial grafts have excellent long-term patency rates (90% at 10 years), whereas saphenous vein grafts show accelerated atherosclerosis with approximately 50% patency at 10 years. The use of internal mammary artery grafts is associated with a 27% reduction in 15-year mortality compared with saphenous vein grafts. The left internal mammary artery is most favorable to a graft to the left anterior descending coronary artery and the right internal mammary artery is most applicable to graft to the right coronary artery. Patients who require more than two grafts generally receive a combination of arterial and venous grafts. Minimally invasive CABG via a smaller thoractomy incision or a thorascopic approach reduces the morbidity and hospital length-of-stay. The operative mortality of CABG is about 2%. The steady improvements in perioperative care have been offset by the progressively sicker patients who are referred for this procedure. Angina pectoris is relieved in more than 90% of patients who undergo CABG. The recurrence of angina is due to graft stenosis or progression of disease in nongrafted vessels.

Clinical trials: coronary artery bypass surgery versus medical treatment in the management of stable angina pectoris:

It is well established that CABG provides more symptoms relief and survival benefits in some patients with chronic stable angina. However, the long term benefit of CABG is limited by the progression of atherosclerosis in other unbypassed vessels and stenosis of the graft itself. The CASS Trial (Coronary Artery Surgery Study) showed that more patients remained symptom-free after CABG compared to medical therapy at one year (66 versus 30 percent) and five years (63 versus 38 percent). However, by 10 years, this difference had disappeared (47 versus 42 percent). Trials from the 1970's showed that CABG offered no significant overall mortality benefits compared to medical therapy. However, several trials established the survival benefits in selected patients:

• Left main coronary artery stenosis or left main equivalent disease (defined as severe (≥70 percent) proximal left anterior descending and proximal left circumflex disease):

The Veterans Administration Cooperative Study compared a strategy of initial CABG versus deferred CABG: there was a substantial survival advantage patients assigned to initial CABG at two years (93 versus 71 percent) and at 11 years, but not at 18 years. The benefit was greatest in high-risk patients with >75 percent left main stenosis and/or left ventricular dysfunction. The CASS registry demonstrated similar results. Yusuf S et al published an overview of 10-year results from randomized trials by the Coronary Artery Bypass Graft Surgery Trialists Collaboration. They found that the relative risk reduction for death provided by CABG over medical therapy alone was greater at five years for left main disease than for three vessel or one or two vessel disease (odds ratio 0.32 versus 0.58 and 0.77); the absolute survival benefit from CABG among those with left main disease was 19.3 months.

PCI for left main coronary artery stenosis: PCI has been performed in patients with angina and left main disease who are considered inoperable, at high risk for CABG, or with prior CABG and one patent graft to either the left anterior descending or circumflex artery ("protected" left main).

• Multivessel coronary disease and left ventricular dysfunction:

Reduced left ventricular function is an important determinant of prognosis in patients with stable angina and is an indication for revascularization. CABG may improve survival in patients with left ventricular dysfunction and hibernating myocardium; therefore, myocardial viability should be assessed prior to recommending CABG in patients with multivessel coronary disease and left ventricular dysfunction. CASS registry showed that survival at seven years was improved with CABG compared to medical treatment (88 versus 65 percent) in patients with an LVEF between 35 and 49 percent and had three vessel disease. No benefit from CABG could be identified in patients with one or two vessel disease.

Clinical trials: Bypass surgery versus percutaneous intervention in the management of stable angina pectoris:

Limitations of the clinical trials

Multiple trials have compared the strategy of initial PTCA with initial CABG for treatment of CAD. These large randomized trials were published in the mid-1990s. The findings from these studies constitute the primary source of data upon which clinical decision making has been made.

1. The patients entered into these trials are poorly reflective of the general population (numerous patients were excluded and most included patients had preserved left ventricular function and focal atherosclerotic coronary disease).
2. The initial trials are probably not relevant to current practice because of the lack of use of stents (especially drug eluting stents or DES) during PCI or of internal mammary artery rather than saphenous vein grafts during CABG. In addition, current antithrombotic regimens (eg, clopidogrel and glycoprotein IIb/IIIa inhibitors) were not employed during PCI.

Percutaneous intervention versus CABG for isolated LAD disease

There is great evidence that CABG of the LAD using an arterial conduit is associated with improved survival compared to medical therapy, especially if the LAD lesion is severe or associated with multi-vessel disease and/or left ventricular dysfunction. The internal mammary artery grafts are preferred because of the increases in long-term patency and survival compared to venous grafts. On the other hand, medical therapy can be considered for patients with isolated LAD disease with minimal evidence of ischemia on stress testing. In regards to percutaneous interventions on the LAD (usually PTCA with stent), this can be performed with a great success and low risk of complications in proximal LAD disease. However, surgical revascularization should be considered in more complex lesions such as ostial location, particularly with involvement of the distal left main, adjacent circumflex ostial disease, or complex bifurcation lesions involving a dominant first diagonal branch. Despite this low incidence of major complications with stenting of the proximal lesion, the need for revascularization is still lower with CABG than with stenting. This was illustrated in the SIMA trial (Stent versus Internal Mammary Artery grafting):

• SIMA trial: The SIMA trial involved 123 patients with a proximal, isolated LAD stenosis, and compared stenting using bare-metal stent (BMS) to CABG using an internal mammary artery. At 10 years, the incidence of death and myocardial infarction was identical; only the need for additional revascularization was significantly higher in the stent group. It is remarkable that no patients randomized to CABG required a second revascularization of the LAD.

The restenosis rate after PCI is likely to decrease with the increased use of drug-eluting stents(DES). In fact, clinical trials of sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES) have demonstrated a marked reduction in the incidence of restenosis in trials evaluating patients with both single and multivessel coronary disease:

• The RAVEL trial (A Randomized Comparison of a Sirolimus-Eluting Stent With a Standard Stent for Coronary Revascularization) is the first controlled trial of a coronary drug-eluting stent. The The 5-year rate of target lesion revascularization (TLR) associated with SES was significantly lower than that with BMS.

• The role of drug-eluting stents in patients with LAD disease was evaluated in a post hoc analysis of data from the SIRIUS trial. Of 1101 patients enrolled in the original study, 459 had an LAD stenosis. All patients were randomly assigned to either a sirolimus-eluting stent or a bare metal stent. At eight months, the incidence of angiographic LAD restenosis was significantly lower among patients treated with a sirolimus-eluting stent (2 versus 42 percent). At one year, the incidence of major adverse events (death, MI, or target lesion revascularization) was also significantly reduced (10 versus 25 percent).

• Paclitaxel stent (PES): In 536 randomized patients with an LAD lesion in the TAXUS IV trial, at one year, the Paclitaxel stent was associated with significant reductions in target vessel revascularization (7.9 versus 18.6 percent) and the need for CABG (2.6 versus 6.3 percent).

• TAXi trial compared both types of drug-eluting stents: These stents were associated with very low rates of target lesion revascularization (1 and 3 percent at seven months). The three-year follow-up study, the TAXi-LATE trial, showed no difference in mortality of all causes in the PES and the SES groups (3% vs. 7%, P=0.98) or in major adverse cardiac event free survival (89% vs. 83%, P=0.28). Four stent thromboses were observed, two in the PES group (205 and 788 days) and two in the SES group (210 and 772 days).

Drug-eluting stents also appear to improve outcomes in patients with lesions at the origins of the LAD. This was illustrated in a study comparing sirolimus stents in 68 consecutive patients with such lesions to 77 patients treated with bare metal stents during the preceding two years. Positioning of the sirolimus stent into the distal left main trunk was required in one-third of patients for complete lesion coverage. The sirolimus stent was associated with significant reductions in angiographic restenosis at six months (5 versus 32 percent with bare metal stents) and target vessel revascularization at one year (0 versus 17 percent).

Percutaneous intervention (PTCA/PCI) versus CABG for multivessel disease

The two U.S. trials of PTCA versus CABG are the multicenter Bypass Angioplasty Revascularization Investigation (BARI) trial and the single-center Emory Angioplasty Surgery Trial (EAST).

In both trials, a majority of patients had two- rather than three-vessel disease and normal LV function. In the BARI trial, 37% of patients had a proximal LAD lesion. In the EAST trial, more than 70% of patients had proximal LAD lesions. The results of both these trials at an approximately seven to eight-year follow-up interval have shown that early and late survival rates have been equivalent for the PTCA and CABG groups. In the BARI trial, the subgroup of patients with treated diabetes had a significantly better survival rate with CABG. That survival advantage for CABG was focused in the group of diabetic patients with multiple severe lesions. In the EAST trial, persons with diabetes had an equivalent survival rate with CABG or PTCA at five years, after which the curves began to diverge but failed to reach a statistically significant difference at eight years (surgical survival 75.5%, PTCA 60.1%; p = 0.23). In both trials, the biggest differences in late outcomes were the need for repeat revascularization procedures and symptom status. In both BARI and EAST, 54% of PTCA patients underwent subsequent revascularization procedures during the five-year follow-up versus 8% of the BARI CABG group and 13% of the EAST CABG group. In addition, the rate of freedom from angina was better in the CABG group in both EAST and BARI, and fewer patients in the CABG groups needed to take anti-anginal medications.

Non U.S. trials:

• RITA trial: The Randomized Intervention Treatment of Angina (RITA) trial was the first of the large scale trials to be published, involving 1011 patients from the United Kingdom. The long-term outcome of patients in the RITA trial (median follow up of 6.5 years) showed that the rates of death or nonfatal infarction for PTCA or CABG were the same (17 versus 16 percent). Angina was consistently higher in the PTCA group, 26 percent of whom required CABG, and 19 percent of whom required another PTCA. Repeat revascularization was usually performed within the first year, while the reintervention rate was 4 percent per year after the first three years.
• GABI trial: The German Angioplasty Bypass Surgery Investigation showed that both bypass surgery and angioplasty were equally effective in relieving angina at one year. This was associated with an increased rate of periprocedural morbidity with bypass surgery but more reinterventions with angioplasty.
• CABRI trial: The Europe-based multicenter Coronary Angioplasty versus Bypass Revascularization Investigation (CABRI) compared CABG to PTCA in 1054 patients. There was a similar mortality rate in the two groups at one year. However, patients assigned to PTCA required more repeat procedures and had a higher incidence of clinically significant angina. Restenosis after PTCA only partially accounted for this difference; of greater importance was the higher likelihood of residual disease after PTCA compared with CABG.

Stenting versus CABG for multivessel disease:

The introduction of stents has resulted in a significant reduction of restenosis and of target vessel revascularization. 2 trials address this question: The ARTS and the SoS. However, these 2 trials did use bare metal stents and not the drug-eluting stents that further reduce the risk of restenosis. In addition, only few patients were treated with GP IIb/IIa inhibitors.

Bare metal stents

1205 patients were included in the ARTS 1 trial and were randomized to undergo bare metal stent implantation or bypass surgery. There was no difference in mortality (2.5 versus 2.8 percent at one year, 3.7 versus 4.6 percent at three years, 8.0 versus 7.6 percent at five years) or the rate of the combined end point of death, MI, or stroke for stented patients compared to those undergoing CABG. There was, however, a significant increase in the need for repeat revascularization with stenting (21 versus 4 percent at one year, 27 versus 7 percent at three years, and 30 versus 9 percent at five years). Diabetics and those with incomplete revascularization had the worse outcomes.

The Medicine, Angioplasty, or Surgery Study for Multivessel Coronary Artery Disease (MASS II), the Argentine Randomized Study of Coronary Angioplasty with Stenting versus Coronary Bypass Surgery in Patients with Multiple Vessel Disease (ERACI-II) and the Angina with Extremely Serious Operative Mortality Evaluation (AWESOME) showed similar survival rates but higher revascularization rates among patients with bare-metal stents at 5 years. Others (the Stent or Surgery trial; SoS) have shown a significant long-term survival advantage with surgery.

SoS trial: This trial included 988 patients between 1996 and 1999. At a median follow-up of two years, PCI was associated with a significantly higher rate of repeat revascularization (21 versus 6 percent) with CABG. At six years, mortality was significantly higher in the PCI group (10.9 versus 6.8; hazard ratio 1.66, 95% CI 1.08 to 2.55. Of note, there was a large number of death related to cancer in the stenting group.

Meta-analyses: Three meta-analyses published in 1995, 2007, and 2008 showed no significant difference between the PCI and CABG in all-cause mortality or cardiac death at one to five years, although angioplasty for multivessel disease was associated with a significant increase in mortality compared to CABG at five and eight years in a subgroup analysis.

Drug eluting stents:

Data from randomized, controlled trials of drug-eluting stents as compared with bare-metal stents have shown significant reductions in the rate of repeat intervention, with similar rates of death and myocardial infarction. Studies comparing PCI involving drug-eluting stents with CABG have generally been smaller and nonrandomized.

Sirolimus-eluting stents (SES):

In ARTS II study, the CABG-control group was a historical group from the ARTS I trial. As a result, conclusions should be made with caution. This trial demonstrated lower rates of revascularization and major adverse cardiac and cerebrovascular events (MACCE) with SES compared with BMS, as well as a higher rate of revascularization with equivalent MACCE to CABG at one year.

Paclitaxel-eluting stents (PES):

The Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX): The SYNTAX trial is a prospective, clinical trial conducted in 85 sites that randomly assigned 1800 patients with three-vessel or left main coronary artery disease to undergo CABG or PCI (in a 1:1 ratio). A noninferiority comparison of the two groups was performed for the primary end point — a major adverse cardiac or cerebrovascular event (i.e., death from any cause, stroke, myocardial infarction, or repeat revascularization) during the 12-month period after randomization. The trial showed that the rates of major adverse cardiac or cerebrovascular events at 12 months were significantly higher in the PCI group (17.8%, vs. 12.4% for CABG; P=0.002), in large part because of an increased rate of repeat revascularization (13.5% vs. 5.9%, P<0.001); as a result, the criterion for noninferiority was not met. The study concluded that CABG remains the standard of care for patients with three-vessel or left main coronary artery disease.

A randomized trial is under way — the Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) study — that specifically compares drug-eluting stents with bypass surgery in patients with diabetes who have multivessel disease.

Non-pharmacological anti anginal applications

Transmyocardial Revascularization (TMR)

Transmyocardial Revascularization is an alternative, and invasive therapy for refractory angina. It effects;

Spinal Cord Stimulation(SCS)

SCS uses an implanted device with an electrode tip that extends into the dorsal epidural space, usually at the C7-T1 level. In patients with refractory angina not amenable to coronary revascularization, spinal cord stimulation using specific electrodes inserted into the epidural space uses neuromodulation to reduce painful stimulus.

Several observational studies have reported success rates of up to 80% in decreasing anginal frequency and severity. This method is proposed for patients with chronic stable angina refractory to medical, catheter intervention, and surgical therapy (more data are still needed and therefore, spinal cord stimulation should be only considered when other treatment options have failed).

• Decreases neurotransmission of painful stimuli
• Increases release of endogenous opiates
• Redistributes myocardial blood flow to ischemic areas

Enhanced External Counter Pulsation (EECP)

Enhanced external counter pulsation (EECP) is another alternative therapy for refractory angina. Most data are from observational studies, which have reported improvement in exercise tolerance and reduction in anginal frequency as well as nitroglycerin use among patients treated with EECP.

EECP has been postulated to decrease myocardial oxygen demand, enhance myocardial collateral flow via increased transmyocardial pressure, and improve endothelial function. The therapy is usually administered over 7 weeks consisting of 35 one hour treatments. Possible placebo effect associated with EECP has not been addressed in many studies, which have not included sham controls.

EECP uses three paired pneumatic cuffs that are applied to the lower extremities. The cuffs are sequentially inflated then deflated.

• Increases endothelial function
• Promotes coronary collateral formation
• Decreases peripheral vascular resistance
• Increases ventricular function
• Placebo effect

Therapies no longer recommended in the treatment of chronic stable angina pectoris

Estrogen Replacement Therapy (ERT)

Randomized, controlled secondary prevention trials like the Heart and Estrogen / Progestin Replacement Study (HERS), HERS-II and the Women’s Health Initiative (WHI) have suggested that hormone replacement therapy does not reduce cardiovascular events or mortality in patients with stable angina pectoris. Therefore current recommendations and practice guidelines do not support the use of hormone replacement therapy to reduce the risk of heart disease.

Antioxidants

The Heart Protection Study Collaborative Group enrolled more than 20,000 patients with established atherosclerotic vascular disease or diabetes mellitus and conclusively demonstrated no reduction in all cause mortality, MI, or other vascular events with the regimen of vitamin C, vitamin E, and beta carotene.

Chelation therapy

Intravenous infusion of ethylene diamine tetra acetic acid (EDTA) is not recommended for the treatment of chronic angina or arteriosclerotic cardiovascular disease and may be harmful because of its potential to cause hypocalcaemia.

ACC / AHA Guidelines- Pharmacotherapy to Prevent MI and Death and Reduce Symptoms (DO NOT EDIT)

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Class I 1. Aspirin in the absence of contraindications. (Level of Evidence: A) 2. Beta-blockers as initial therapy in the absence of contraindications in patients with prior MI. (Level of Evidence: A) 3. Beta-blockers as initial therapy in the absence of contraindications in patients without prior MI. (Level of Evidence: B) 4. Calcium antagonists (short-acting dihydropyridine calcium antagonists should be avoided) and/or long-acting nitrates as initial therapy when beta-blockers are contraindicated. (Level of Evidence: B) 5. Calcium antagonists (short-acting dihydropyridine calcium antagonists should be avoided) and/or long-acting nitrates in combination with beta-blockers when initial treatment with beta-blockers is not successful. (Level of Evidence: B) 6. Calcium antagonists (short-acting dihydropyridine calcium antagonists should be avoided) and/or long-acting nitrates as a substitute for beta-blockers if initial treatment with beta-blockers leads to unacceptable side effects. (Level of Evidence: C) 7. Sublingual nitroglycerin or nitroglycerin spray for the immediate relief of angina. (Level of Evidence: C) 8. Lipid-lowering therapy in patients with documented or suspected CAD and LDL cholesterol >130 mg/dL with a target LDL of <100 mg/dL. (Level of Evidence: A) Class IIa 1. Clopidogrel when aspirin is absolutely contraindicated. (Level of Evidence: B) 2. Long-acting nondihydropyridine calcium antagonists (short-acting dihydropyridine calcium antagonists should be avoided) instead of beta-blockers as initial therapy. (Level of Evidence: B) 3. Lipid-lowering therapy in patients with documented or suspected CAD and LDL cholesterol 100 to 129 mg/dL, with a target LDL of 100 mg/dL. (Level of Evidence: B) Class IIb 1. Low-intensity anticoagulation with warfarin in addition to aspirin. (Level of Evidence: B) Class III 1. Dipyridamole. (Level of Evidence: B) 2. Chelation therapy. (Level of Evidence: B)

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ACC / AHA Guidelines- Pharmacotherapy to Prevent MI and Death in Asymptomatic Patients (DO NOT EDIT)

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Class I 1. Aspirin in the absence of contraindication in patients with prior MI. (Level of Evidence: A) 2. Beta-blockers as initial therapy in the absence of contraindications in patients with prior MI. (Level of Evidence: B) 3. Lipid-lowering therapy in patients with documented CAD and LDL cholesterol greater than 130 mg/dL, with a target LDL of less than 100 mg/dL. (Level of Evidence: A) 4. ACE inhibitor in patients with CAD who also have diabetes and/or left ventricular systolic dysfunction. (Level of Evidence: A) Class IIa 1. Aspirin in the absence of contraindications in patients without prior MI. (Level of Evidence: B) 2. Beta-blockers as initial therapy in the absence of contraindications in patients without prior MI. (Level of Evidence: C) 3. Lipid-lowering therapy in patients with documented CAD and LDL cholesterol 100 to 129 mg/dL, with a target LDL of 100 mg/dL. (Level of Evidence: C) 4. ACE inhibitor in all patients with CAD or other vascular disease. (Level of Evidence: B)

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ACC / AHA Guidelines- Revascularization for Chronic Stable Angina (DO NOT EDIT)

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Class I 1. CABG for patients with significant left main coronary disease. (Level of Evidence: A) 2. CABG for patients with 3-vessel disease. The survival benefit is greater in patients with abnormal LV function (ejection fraction <50%). (Level of Evidence: A) 3. CABG for patients with 2-vessel disease with significant proximal left anterior descending CAD and either abnormal LV function (ejection fraction <50%) or demonstrable ischemia on noninvasive testing. (Level of Evidence: A) 4. PTCA for patients with 2- or 3-vessel disease with significant proximal left anterior descending CAD, who have anatomy suitable for catheter-based therapy, normal LV function, and who do not have treated diabetes. (Level of Evidence: B) 5. PTCA or CABG for patients with 1- or 2-vessel CAD without significant proximal left anterior descending CAD but with a large area of viable myocardium and high-risk criteria on noninvasive testing. (Level of Evidence: B) 6. CABG for patients with 1- or 2-vessel CAD without significant proximal left anterior descending CAD who have survived sudden cardiac death or sustained ventricular tachycardia. (Level of Evidence: C) 7. In patients with prior PTCA, CABG or PTCA for recurrent stenosis associated with a large area of viable myocardium and/or high-risk criteria on noninvasive testing. (Level of Evidence: C) 8. PTCA or CABG for patients who have not been successfully treated by medical therapy and can undergo revascularization with acceptable risk. (Level of Evidence: B) Class IIa 1. Repeat CABG for patients with multiple saphenous vein graft stenoses, especially when there is significant stenosis of a graft supplying the left anterior descending coronary artery. PTCA may be appropriate for focal saphenous vein graft lesions or multiple stenoses in poor candidates for reoperative surgery. (Level of Evidence: C) 2. PTCA or CABG for patients with 1- or 2-vessel CAD without significant proximal left anterior descending CAD but with a moderate area of viable myocardium and demonstrable ischemia on noninvasive testing. (Level of Evidence: B) 3. PTCA or CABG for patients with 1-vessel disease with significant proximal left anterior descending CAD. (Level of Evidence: B) Class IIb 1. Compared with CABG, PTCA for patients with 3- or 2-vessel disease with significant proximal left anterior descending CAD who have anatomy suitable for catheter-based therapy and who have treated diabetes or abnormal LV function. (Level of Evidence: B) 2. PTCA for patients with significant left main coronary disease who are not candidates for CABG. (Level of Evidence: C) 3. PTCA for patients with 1- or 2-vessel CAD without significant proximal left anterior descending CAD who have survived sudden cardiac death or sustained ventricular tachycardia. (Level of Evidence: C) Class III 1. PTCA or CABG for patients with 1- or 2-vessel CAD without significant left anterior descending CAD who a. Have mild symptoms that are unlikely due to myocardial ischemia or have not received an adequate trial of medical therapy and 1) Have only a small area of viable myocardium or 2) Have no demonstrable ischemia on noninvasive testing. (Level of Evidence: C) 2. PTCA or CABG for patients with borderline coronary stenoses (50% to 60% diameter in locations other than the left main) and no demonstrable ischemia on noninvasive testing. (Level of Evidence: C) 3. PTCA or CABG for patients with insignificant coronary stenosis (<50% diameter). (Level of Evidence: C) 4. PTCA in patients with significant left main CAD who are candidates for CABG. (Level of Evidence: B)

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ACC / AHA Guidelines- Alternative Therapies for Chronic Stable Angina in Patients Refractory to Medical Therapy Who Are Not Candidates for Percutaneous Intervention or Revascularization (DO NOT EDIT)

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Class IIa 1. Surgical laser transmyocardial revascularization (TMR). (Level of Evidence: A) Class IIb 1. Enhanced external counterpulsation (EECP). (Level of Evidence: B) 2. Spinal cord stimulation (SCS). (Level of Evidence: B)

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See Also

• The Chronic Stable Angina Living Guidelines: Vote on current recommendations and suggest revisions to the guidelines

Sources

• The ACC/AHA/ACP–ASIM Guidelines for the Management of Patients With Chronic Stable Angina

• The ACC/AHA 2002 Guideline Update for the Management of Patients With Chronic Stable Angina

• The 2007 Chronic Angina Focused Update of the ACC/AHA 2002 Guidelines for the Management of Patients With Chronic Stable Angina

References

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