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.

Medical therapy

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.

Revascularization

Revascularization is used only for select patients specially those who have uncontrolled symptoms with optimal medical therapy. This can be achieved with either percutaneous coronary intervention(PCI) with stent placement or coronary artery bypass surgery. In general, PCI 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 being performed for many lesions including more complex ones.

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 of risk factors is urgent and an essential part of the main therapy in chronic stable angina.

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)

The results of the Heart Outcomes Prevention Evaluation(HOPE) trial confirmed that use of the ACE inhibitor reduced cardiovascular death, MI, and stroke in patients who were at high risk for, or had, vascular disease in the absence of heart failure.

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 recommendation, Evidence Level A)

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 recommendation, Evidence Level B )

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 recommendation, Evidence Level B)

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 recommendation, Evidence Level A)

Angiotensin receptor blockers may be considered in combination with ACE inhibitors for heart failure due to left ventricular systolic dysfunction.(Class IIb recommendation, Evidence Level 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 recommendation, Evidence Level A)

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.

Alternative therapies for refractory angina

Transmyocardial Revascularization (TMR)

Transmyocardial Revascularization is an alternative procedure for patients with severe [coronary artery disease] who are not a candidate for revascularization via PCI or CABG. This technique is either performed in the operating room (using a carbon dioxide or holmium:YAG laser)known as Laser TMR or by a percutaneous approach with a specialized(holmium:YAG laser) catheter referred as Percutaneous TMR. However, only Laser TMR is currently FDA approved. Another way to perform TMR is through epicardial surgical approach. This can be done alone or in combination with CABG. The goal in both approaches is to create a series of transmural endomyocardial channels through the heart muscle to improve myocardial revascularization. The outside of the heart muscle seals up immediately. In time, as these channels heal, they stimulate the creation of new small vessels or capillaries(angiogenesis). Other mechanism of benefit in TMR is thought to be sympathetic denervation.

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

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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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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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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