treatment chronic myiocard ischemic

A. GENERAL APPROACH

Because myocardial ischemia is produced by an imbalance between myocardial oxygen supply and demand, in general, treatment consists of increasing supply or reducing demand—or both. Heart rate is a major determinant of myocardial oxygen demand, and attention to its control is imperative. Any treatment that accelerates heart rate is generally not going to be efficacious in preventing myocardial ischemia. Therefore, care must be taken with potent vasodilator drugs, which may lower blood pressure and induce reflex tachycardia. Furthermore, because most coronary blood flow occurs during diastole, the longer the diastole, the greater the coronary blood flow; and the faster the heart rate, the shorter the diastole.
Blood pressure is another important factor: Increases in blood pressure raise myocardial oxygen demand by elevating left ventricular wall tension, and blood pressure is the driving pressure for coronary perfusion. A critical blood pressure is required that does not excessively increase demand, yet keeps coronary perfusion pressure across stenotic lesions optimal. Unfortunately, it is difficult to tell in any given patient what this level of blood pressure should be, and a trial-and-error approach is often needed to achieve the right balance. Consequently, it is prudent to reduce blood pressure when it is very high, and it may be important to allow it to increase when it is very low. It is not uncommon to encounter patients whose myocardial ischemia has been so vigorously treated with a combination of pharmacologic agents that their blood pressure is too low to be compatible with adequate coronary perfusion. In such patients, withholding some of their medications may actually improve their symptoms. Although myocardial contractility and left ventricular volume also contribute to myocardial oxygen demand, they are less important than heart rate and blood pressure. Myocardial contractility usually parallels heart rate. Attention should be paid to reducing left ventricular volume in anyone with a dilated heart, but not at the expense of excessive hypotension or tachycardia because these factors are more important than volume for determining myocardial oxygen demand.
It is important to eliminate any aggravating factors that could increase myocardial oxygen demand or reduce coronary artery flow (Table 3–3). Hypertension and tachyarrhythmias are obvious factors that need to be controlled. Thyrotoxicosis leads to tachycardia and increases in myocardial oxygen demand. Anemia is a common problem that increases myocardial oxygen demand because of reflex tachycardia; it reduces oxygen supply by decreasing the oxygen-carrying capacity of the blood. Similarly, hypoxia from pulmonary disease reduces oxygen delivery to the heart. Heart failure increases angina because it often results in left ventricular dilatation, which increases wall stress, and in excess catecholamine tone, which increases contractility and produces tachycardia.

Table 3–3. Factors that can aggravate myocardial ischemia.

The long-term outlook for patients with coronary atherosclerosis must be addressed by reducing their risk factors for the disease. Once a patient is known to have atherosclerosis, risk-factor reduction should be fairly vigorous: If diet has not reduced serum cholesterol, strong consideration should be given to pharmacologic therapy because it has been shown to reduce cardiac events. Patients should be encouraged to exercise, lose weight, quit smoking, and try to reduce stress levels. Daily low-dose aspirin is important for preventing coronary thrombosis. The use of megadoses of vitamin E, b-carotene, and vitamin C should be discouraged in the patient with known coronary atherosclerosis because clinical trials have not demonstrated efficacy.
B. PHARMACOLOGIC THERAPY

1. Nitrates—Nitrates, which work on both sides of the supply-and-demand equation, are the oldest drugs used to treat angina pectoris (Table 3–4). These agents are now available in several formulations to fit the patient’s lifestyle and disease characteristics. Almost all patients with known coronary atherosclerosis should carry sublingual nitroglycerin to abort acute attacks of angina pectoris. Nitrates work principally by providing more nitrous oxide to the vascular endothelium and the arterial smooth muscle, resulting in vasodilation. This tends to ameliorate any increased coronary vasomotor tone and dilate coronary obstructions. As long as blood pressure does not fall excessively, nitrates increase coronary blood flow. Nitrates also cause venodilation, reducing preload and decreasing left ventricular end-diastolic volume. The reduced left ventricular volume decreases wall tension and myocardial oxygen demand.

Table 3–4. Common oral antianginal drugs.

Sublingual nitroglycerin takes 30–60 s to dissolve completely and begin to produce beneficial effects, which can last up to 30 min. Although most commonly used to abort acute attacks of angina, the drug can be used prophylactically if the patient can anticipate its need 30 min prior to a precipitating event. Prophylactic therapy is best accomplished, however, with longer acting nitrate preparations. Isosorbide dinitrate and mononitrate are available in oral formulations; each produces beneficial effects for several hours. Large doses of these agents must be taken orally to overcome nitrate reductases in the liver. Liver metabolism of the nitrates can also be avoided with cutaneous application. Nitroglycerin is available as a topical ointment that can be applied as a dressing; it is also available as a ready-made, self-adhesive patch that delivers accurate continuous dosing of the drug through a membrane. Although the paste and the patches produce similar effects, the patches are more convenient for patients to use.
Sublingual nitroglycerin tablets are extremely small and difficult for patients with arthritis to manipulate. A buccal preparation of nitroglycerin is available, which comes in a larger, more easily manipulable tablet that can be chewed and allowed to dissolve in the mouth, rather than being swallowed. This achieves nitrate effectiveness within 2–5 min and lasts about 30 min, as do the sublingual tablets. An oral nitroglycerin spray, which may be easier to manipulate and more convenient for some patients, is also available.
The major difficulty with all long-acting nitroglycerin preparations is the development of tolerance to their effects. The exact reason for tolerance development is not clearly understood, but it may involve liver enzyme induction or a lack of arterial responsiveness because of local adaptive factors. Regardless of the mechanism, however, round-the-clock nitrate administration will lead to progressively increasing tolerance to the drug after 24–48 h. Because of this, nitroglycerin is usually taken over the 16-h period each day that corresponds to the time period during which most of the ischemic episodes would be expected to occur. For most patients, this means not taking nitrate preparations before bed and allowing the ensuing 8 h for the effects to wear off and responsiveness to the drug to be regained. This timing would have to be adjusted for patients with nocturnal angina. The difficulty with the 8-h overnight hiatus in therapy, however, is that the patient has little protection during the critical early morning wakening period—when ischemic events are more likely to occur. Patients should therefore take the nitrate preparation as soon as they arise in the morning. For this reason, the nitroglycerin patches have a small amount of paste on the outside of the membrane that delivers a bolus of drug through the skin, which quickly elevates the patient’s blood level of the drug. It is important that the patient be careful not to wipe this paste off the patch before applying it.
Nitrates, which are effective in preventing the development of angina as well as aborting acute attacks, are helpful in both patients with fixed coronary artery occlusions and those with vasospastic angina. Their potency, compared with other agents, is limited, however, and patients with severe angina often must turn to other agents. In such patients, nitrates can be excellent adjunctive therapy.
2. Beta-blockers—Beta-adrenergic blocking agents are highly effective in the prophylactic therapy of angina pectoris. They have been shown to reduce or eliminate angina attacks and prolong exercise endurance time in double-blind, placebo-controlled studies. They can be used around the clock because no tachyphylaxis to their effects has been found. Beta-blockers mainly work by lowering myocardial oxygen demand through decreasing heart rate, blood pressure, and myocardial contractility. As mentioned earlier, however, they also increase myocardial oxygen supply by increasing the duration of diastole through heart rate reduction. Currently, several b-blocker preparations are available, with one or more features that may make them more—or less—attractive for a particular patient.
Among these features is the agent’s pharmacologic half-life, which ranges from 4 to 18 h. Various delivery systems have been developed to slow down the delivery of short-acting agents and prolong the duration of drug activity through sustained release or long-acting formulations. Note that the pharmacodynamic half-life of b-adrenergic blockers is often longer than their pharmacologic half-life, and drug effects can be detected for days after discontinuation of chronic b-blocker therapy.
Ideally, b-blockers should be titrated against the heart rate response to exercise because blunting of the exercise heart rate response is the hallmark of their efficacy. Adverse effects of b-blockers include such expected pharmacologic effects as excessive bradycardia, heart block, hypotension, and—in susceptible individuals—bronchospasm. This is less commonly found in the b1-selective agents. Blocking b2-peripheral vasodilatory actions may aggravate claudication in patients with severe peripheral vascular disease. Beta-adrenergic stimulation is also important for the gluconeogenic response to hyperglycemia in severely insulin-dependent diabetics. Although b-blockers may impair this response, the major problem with their use in insulin-dependent diabetics is that they block the warning signals of hypoglycemia (sweating, tachycardia, piloerection) to the patient. Because of their negative inotropic properties, b-blockers may also precipitate heart failure in patients with markedly reduced left ventricular performance.
Other side effects of b-blockers are less predictably related to their anti-b-adrenergic effects. Adverse central nervous system effects are especially troublesome and include fatigue, mental slowness, and impotence. These side effects are somewhat less common with agents that are less lipophilic, such as atenolol and nadolol. Unfortunately, it is these side effects that make many patients unable to tolerate b-blockers.
3. Calcium channel antagonists—Calcium channel antagonists theoretically work on both sides of the supply-and-demand equation. By blocking calcium access to smooth muscle cells, they produce peripheral vasodilatation and are effective antihypertensive agents. In the myocardium, they block sinus node and atrioventricular node function and reduce the inotropic state. They dilate the coronary arteries and increase myocardial blood flow. The calcium blockers available today produce a variable spectrum of these basic pharmacologic effects. The biggest group is the dihydroperidine calcium blockers, which are potent arterial dilators and thereby cause reflex sympathetic activation, which overshadows their negative chronotropic and inotropic effects.
A second major group of calcium blockers are the heart rate-lowering calcium blockers. Because these drugs have less peripheral vasodilatory action in individuals with normal blood pressure, they produce little reflex tachycardia. The average daily heart rate is usually reduced with these agents because their inherent negative chronotropic effects are not suppressed; negative inotropic effects are also more common with these agents. Hypertensive and normotensive individuals seem to have a different vascular responsiveness to calcium blockers; interestingly, in hypertensive individuals, they lower the blood pressure as well as do the dihydroperidine agents. The two most commonly used drugs in this class are diltiazem and verapamil. Diltiazem is more widely used because of its low side effect profile. Verapamil, which is an excellent treatment for patients with supraventricular arrhythmias, has potent effects on the arteriovenous (AV) node; this can cause excessive bradycardia and heart block in patients with angina pectoris. Verapamil is also more likely than diltiazem to precipitate heart failure, and it often produces troublesome constipation, especially in elderly individuals. All the calcium blockers can produce peripheral edema. This is due not to their negative inotropic effects but rather to an imbalance between the efferent and afferent peripheral arteriolar tone, which increases capillary hydrostatic pressure. Other adverse effects of these drugs are idiosyncratic and include gastrointestinal and dermatologic effects.
Calcium blockers are titrated to the patient’s symptomatology because no physiologic marker of their effect corresponds well to the heart rate response to exercise with b-blockers. This makes choosing the appropriate dosage difficult, and many physicians increase the dose until some side effect occurs, and then they reduce it. The most common side effects are related to the pharmacologic effects of the drugs. With the dihydroperidines, vasodilatory side effects such as orthostatic hypotension, flushing, and headache, occur. Hypotension is less common with the heart rate-lowering calcium blockers, and their side effects are more related to cardiac effects such as excessive bradycardia. These drugs are very useful because they are excellent for preventing angina pectoris, lowering high blood pressure, and, in the case of the heart rate-lowering agents, controlling supraventricular arrhythmias.
4. Combination therapy—Although monotherapy is desirable for patient convenience and cost considerations, many patients, especially those with severe inoperable coronary artery disease, require more than one antianginal agent to control their symptoms. Because all antianginal agents have a synergistic effect in preventing angina, the initial choices should be for agents with complementary pharmacologic effects. For example, nitrates can be added to b-blocker therapy: Nitrates have an effect on dilating coronary arteries and increasing coronary blood flow, and their peripheral effects may increase reflex sympathetic tone and counteract some of the negative inotropic and chronotropic effects of the b-blockers. This has proved to be a highly effective combination. Similarly, combining a b-blocker with dihydroperidine drugs, when the b-blockers suppress the reflex tachycardia produced by the dihydroperidine, has also proved to be highly effective. Combinations of the heart rate-lowering calcium blockers and nitrates have also proved efficacious. Extremely refractory patients may respond to the combination of a dihydroperidine calcium blocker and a heart rate-lowering calcium blocker.
Combining a dihydroperidine calcium blocker and nitrates makes little sense, however, because of the high likelihood of producing potent vasodilatory side effects. This combination may excessively lower blood pressure to the point that coronary perfusion pressure is compromised and the patient’s angina actually worsens. In fact, in as many as 10% of patients with moderately severe angina, both the nitrates and the dihydroperidine calcium blockers alone have been reported to aggravate angina. Although few corroborative data exist, this percentage is certainly higher with the combination of the two agents.
The most difficult cases often involve triple therapy, with a calcium blocker, a b-blocker, and a nitrate. Although there are few objective data on the benefits of this approach, it has proven efficacious in selected patients. The major problem with triple therapy is that side effects, such as hypotension, are increased, which often limits therapy.
Gibbons RJ, Chaterjee K, Daley J et al: ACC/AHA/ACP-ASIM Guidelines for the management of patients with chronic stable angina: A report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee on Management of Patients with Chronic Stable Angina). J Am Coll Cardiol 1999;3:2092.
Opie LH: Calcium channel antagonists in the treatment of coronary artery disease: fundamental pharmacological properties relevant to clinical use. Prog Cordiovasc Dis 1996;38:273.
Pitt B, Waters D, Brown WV et al. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. N Engl J Med 1999;341:70–76.
Thadani U: Management of stable angina pectoris. Prog Cardiovasc Dis1999;14:349–358.
C. REVASCULARIZATION

1. Catheter-based methods—The standard percutaneous coronary intervention (PCI) is balloon dilatation with placement of a metal stent. Such treatment is limited to the larger epicardial arteries and can be complicated by various types of acute vessel injury, which can result in myocardial infarction unless surgical revascularization is immediately employed. Smaller arteries may be amenable to plain old balloon angioplasty (POBA), and large arteries with complicated lesions may be candidates for other forms of PCI. PCI requires intense antiplatelet therapy usually with aspirin and clopidogrel for a month to prevent stent thrombosis. After the stent has been covered with endothelium this risk is much less.
In the absence of acute complications, initial success rates for significantly dilating the coronary artery are > 85%, and the technique can be of tremendous benefit to patients—without their undergoing the risk of cardiac surgery. The principal disadvantage to PCI is restenosis, which occurs in about one-fourth of patients during the first 6 months. Repeat PCI can be as effective as initial PCI, but, again, the restenosis rate remains around one fourth; however, a second PCI can result in a long-term success. Although many agents are under intense investigation, there is currently no pharmacologic approach to preventing restenosis.
PCI is ideal for symptomatic patients with one or two discrete lesions in one or two arteries. In patients with more complex lesions or those with three or more vessels involved bypass surgery is preferable for several reasons. First, the restenosis risk is the same for each lesion treated by PCI, so that if enough vessels are worked on the risk of restenosis in one of them will approach 100%. Second, the ability to completely revascularize patients with multivessel disease is less with PCI compared with bypass surgery. Finally, clinical trials have shown that diabetics have better outcomes after bypass surgery relative to PCI.
2. Coronary artery bypass graft surgery—Controlled clinical trials have shown that coronary artery bypass graft (CABG) surgery can successfully alleviate angina symptoms in up to 80% of patients. These results compare very favorably with pharmacologic therapy and catheter-based techniques and can be accomplished in selected patients with less than 2% operative mortality rates. Although the initial cost of surgery is high, studies have shown it can be competitive with repeated angioplasty and lifelong pharmacologic therapy in selected patients.
The standard surgical approach is to use the saphenous veins, which are sewn to the ascending aorta and then, distal to the obstruction, in the coronary artery, effectively bypassing the obstruction with blood from the aorta. Although single end-to-side saphenous-vein-to-coronary-artery grafts are preferred, occasionally surgeons will do side-to-side anastomoses in one coronary artery (or more) and then terminate the graft in an end-to-side anastomosis in the final coronary artery. There is some evidence that although these skip grafts are easier and quicker to place than multiple single saphenous grafts, they may not last as long. The major problem with saphenous vein grafts is recurrent atherosclerosis in the grafts, which is often quite bulky and friable, and ostial stenosis, probably from cicatrization at the anastomotic sites. Although these problems can be approached with PCI and other interventional devices, the success rate of catheter-delivered devices to open obstructed saphenous vein grafts is not as high as that seen with native coronary artery obstructions, and many patients require repeat saphenous vein grafting after an average of about 8 years. It is believed that meticulous attention to a low-fat diet, cessation of smoking, and the ingestion of one aspirin a day (80–325 mg) will retard the development of saphenous vein atherosclerosis; some patients do well for 20 years or more after CABG.
There is now considerable evidence that arterial conduits make better bypass graft materials. The difficulty is finding large enough arteries that are not essential to other parts of the body. The most popular arteries used today are the internal thoracic arteries. Their attachment to the subclavian artery is left intact, and the distal end is used as an end-to-side anastomosis into a single coronary artery. If a patient requires more than two grafts, some surgeons, rather than using a saphenous vein, have employed the radial artery or abdominal vessels, such as the gastroepiploic. There are less data on these alternative conduits, but theoretically they would have the same advantages as the internal thoracic arteries in terms of graft longevity. Efforts at preventing bypass graft failure are worthwhile because the risk of repeat surgery is usually higher than that of the initial surgery. There are several reasons for this, including the fact that the patient is older, the scar tissue from the first operation makes the second one more difficult, and finally, any progression of atherosclerosis in the coronary arteries makes finding good-quality insertion sites for the graft more difficult.
D. SELECTION OF THERAPY

Pharmacologic therapy is indicated when other conditions may be aggravating angina pectoris and can be successfully treated. For example, in the patient with coexistent hypertension and angina, it is often prudent to treat the hypertension and lower blood pressure to acceptable levels before pursuing revascularization for angina, because lowering the blood pressure will often eliminate the angina. For this purpose, it is wise to use antihypertensive medications that are also antianginal (eg, b-blockers, calcium channel blockers) rather than other agents with no antianginal effects (eg, angiotensin-converting enzyme (ACE) inhibitors, centrally acting agents). The presence of heart failure can also produce or aggravate angina, and this should be treated. Care must be taken in choosing antianginal drugs that they do not aggravate heart failure. For this reason, nitrates are frequently used in heart failure and angina because these drugs may actually benefit both conditions. Calcium channel blockers should be avoided if the left ventricular ejection fraction is below 35%, unless it is clear that the heart failure is episodic and is being produced by ischemia. In this situation, however, revascularization may be a more effective strategy. Beta-blockers can be effective, but they must be started at low doses and uptitrated carefully. Although beta blockers are now part of standard therapy for heart failure, there is little data on their use in patients with angina and reduced left ventricular performance. Finally, the presence of ventricular or supraventricular tachyarrhythmias may aggravate angina. Rhythm disorders also afford an opportunity for using dual-purpose drugs. The heart rate-lowering calcium blockers may effectively control supraventricular arrhythmias and also benefit angina. Beta-blockers can often be effective treatment for ventricular arrhythmias in patients with coronary artery disease and should be tried before other, more potent antiarrhythmics or devices are contemplated. Keep in mind that digoxin blood levels may be increased by concomitant treatment with calcium blockers. In addition, the combination of digoxin and either heart rate-lowering calcium blockers or b-blockers may cause synergistic effects on the AV node and lead to excessive bradycardia or heart block.
The major indication for revascularization of chronic ischemic heart disease is the failure of medications to control the patient’s symptoms. Drug-refractory angina pectoris is the major indication for revascularization. Note that myocardial ischemia should be established as the source of the patient’s symptoms before embarking on revascularization, lest one find out after revascularization that the symptoms were actually due to gastroesophageal reflux. Consequently, some form of stress testing that verifies the relationship between demonstrable ischemia and symptoms is advisable before performing any revascularization procedure.
In some other instances—patient preference, for example—revascularization therapy might be considered before even trying pharmacologic therapy. Some patients do not like the prospect of lifelong drug therapy and would rather have open arteries. Although this is a valid reason to perform revascularization, the physician must be careful that his or her own enthusiasm for revascularization as treatment does not pressure the patient into such a decision. Other candidates for direct revascularization are patients with high-risk occupations who cannot return to these occupations unless they are completely revascularized (eg, airline pilots).
Revascularization is preferred to medical therapy in managing certain types of coronary anatomy that are known (through clinical trials) to have a longer survival if treated with CABG rather than medically. Such lesions include left main obstructions of more than 50%, three-vessel disease, and two-vessel disease in which one of the vessels is the left anterior descending artery. Currently, left main stenoses are not effectively treated with catheter-based techniques, but two- and three-vessel coronary disease could potentially be treated by PCI. Clinical trials have shown equivalent long-term outcomes between PCI and CABG in patients with multivessel disease.
CABG is also recommended for patients with two- or three-vessel coronary artery disease and resultant heart failure from reduced left ventricular performance, especially if viable myocardium can be demonstrated. Because the tests for viable myocardium are not perfect, however, many physicians believe that all these patients should be revascularized in the hope that some myocardial function will return. This seems a prudent approach, given that donor hearts for cardiac transplantation are difficult to obtain—and many patients with heart failure and coronary artery disease improve following bypass surgery.
Surgery is also recommended when the patient has a concomitant disease that requires surgical therapy, such as significant valvular heart disease, heart failure in the presence of a large left ventricular aneurysm, or mechanical complications of myocardial infarction, such as a ventricular septal defect. In the presence of hemodynamic indications for repairing these problems, any significant coronary artery disease that is found should be corrected with bypass surgery at the same time.
The risk of bypass surgery in a given individual must also be considered because several factors can increase the risk significantly and might make catheter-based techniques or medical therapy more desirable. Age is always a risk factor for any major surgery, and CABG is no exception. Also, female gender tends to increase the risk of CABG, possibly because women are, on the average, smaller and have smaller arteries than men. Some data indicate that if size is the only factor considered, gender disappears as a risk predictor with CABG. Other medical conditions that may complicate the perioperative period (eg, obesity, lung disease, diabetes) also raise the risks of surgery. Another factor (discussed earlier) is whether this is a repeat bypass operation. The technical difficulties are especially troublesome when a prior internal thoracic artery graft has been placed because this artery lies right behind the sternum and can be easily compromised when opening the chest.
The choice between catheter-based techniques and CABG surgery is based on several considerations: Is it technically feasible to perform either technique with a good anticipated result? What does the patient wish to do? The patient may have a strong preference for one technique over the other. Again, the physician must be careful not to unduly influence the patient in this regard, lest it give the appearance of a conflict of interest. Consideration must also be given to factors that increase the risk of surgery. The most difficult decision involves the patient who is suitable for either surgery or a catheter-based technique. The few controlled, randomized clinical trials that have been done on such patients have shown equivalent clinical results with PCI and surgery in terms of mortality and symptom relief. Note that this is accomplished by PCI at the cost of repeated procedures in many patients. Despite the necessity for these repeated procedures, the overall cost of bypass surgery is higher over the short term. Unfortunately, the trials do not leave us with clear guidelines for choosing PCI or CABG in the patient who is a good candidate for either treatment; this continues to be a decision to be made by the physician and the patient on a case-by-case basis.