American College of Cardiology

GIBBONS ET AL., MANAGEMENT OF PATIENTS WITH CHRONIC STABLE ANGINA UPDATE
http://www.acc.org/clinical/guidelines/stable/update_index.htm

ACC/AHA 2002 Guideline Update 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 to Update the 1999 Guidelines for the Management of Patients With Chronic Stable Angina)

This is a Guideline Update of the 1999 Chronic Stable Angina Guidelines. To highlight the changes, deleted text is indicated by strikeout, and revised text is presented in brown. A clean version of the document, with changes fully incorporated, is available for download and print.

IV. Treatment

A. Pharmacologic Therapy

Recommendations for Pharmacotherapy to Prevent MI and Death and to Reduce Symptoms

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) or without prior MI. (Level of Evidence: B)

3. Angiotensin converting enzyme inhibitor in all patients with CAD* who also have diabetes and/or LV systolic dysfunction. (Level of Evidence: A)

4. Low-density lipoprotein-lowering therapy in patients with documented or suspected CAD and LDL cholesterol greater than 130 mg per dl, with a target LDL of less than 100 mg per dl. (Level of Evidence: A)

5. Sublingual nitroglycerin or nitroglycerin spray for the immediate relief of angina. (Level of Evidence: B)

46. Calcium antagonists† or long-acting nitrates as initial therapy for reduction of symptoms when beta-blockers are contraindicated. (Level of Evidence: B)

57. Calcium antagonists† or long-acting nitrates in combination with beta-blockers when initial treatment with beta-blockers is not successful. (Level of Evidence: B)

68. Calcium antagonists† and long-acting nitrates as a substitute for beta-blockers if initial treatment with beta-blockers leads to unacceptable side effects. (Level of Evidence: C)

Class IIa

1. Clopidogrel when aspirin is absolutely contraindicated. (Level of Evidence: B)

2. Long-acting nondihydropyridine calcium antagonists† 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)

3. In patients with documented or suspected CAD and LDL cholesterol 100 to 129 mg per dl, several therapeutic options are available: (Level of Evidence: B)

a. Lifestyle and/or drug therapies to lower LDL to less than 100 mg per dl.

b. Weight reduction and increased physical activity in persons with the metabolic syndrome (see page 74).

c. Institution of treatment of other lipid or nonlipid risk factors; consider use of nicotinic acid or fibric acid for elevated triglycerides or low HDL cholesterol.

4. Angiotensin converting enzyme inhibitor in patients with CAD or other vascular disease. (Level of Evidence: B)

*Significant CAD by angiography or previous MI.

†Short-acting, dihydropyridine calcium antagonists should be avoided.

Class IIb

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)

1. Overview of Treatment

The treatment of stable angina has two major purposes. The first is to prevent MI and death and thereby increase the “quantity” of life. The second is to reduce symptoms of angina and occurrence of ischemia, which should improve the quality of life.

Therapy directed toward preventing death has the highest priority. When two different therapeutic strategies are equally effective in alleviating symptoms of angina, the therapy with a definite or very likely advantage in preventing death should be recommended. For example, coronary artery bypass surgery is the preferred therapy for patients with significant left main CAD because it prolongs life. However, in many patients with mild angina, one-vessel CAD, and normal LV function, medical therapy, coronary angioplasty, and coronary artery bypass surgery are all reasonable options. The choice of therapy often depends on the clinical response to initial medical therapy, although some patients may prefer coronary revascularization. Patient education, cost-effectiveness, and patient preference are important components in this decision-making process.

The section on pharmacologic therapy considers treatments to prevent MI and death first; antianginal and antiischemic therapy to alleviate symptoms, reduce ischemia, and improve quality of life are considered in a second section. Pharmacologic therapy directed toward prevention of MI and death has expanded greatly in recent years with the emergence of evidence that demonstrates the efficacy of lipid-lowering agents for this purpose. For that reason, the committee has chosen to discuss lipid-lowering drugs in two sections of these guidelines: briefly in the following section on pharmacological therapy and in more detail in the later section on risk factor reduction. The committee believes that the emergence of such medical therapy for prevention of MI and death represents a new treatment paradigm that should be recognized by all healthcare professionals involved in the care of patients with stable angina.

2. Measurement of Health Status and Quality of Life in Patients With Stable Angina

The traditional method to rate the severity of angina is the CCS classification (described earlier) or related schemas. These systems, however, are relatively general, may be insensitive to modest changes in symptoms or physicl function, and may not permit accurate comparisons among patients. For example, two patients who experience symptoms with “usual activity” may in fact maintain very different levels of usual activity. Moreover, the CCS classification is intended to be applied by physicians and may not accurately reflect patients’ own perceptions. For these reasons, questionnaires have been created to measure health status and physical function, both in general and specifically in relation to the symptoms and limitations associated with ischemic heart disease. Because both types of instruments are often used in clinical trials of new therapies such as revascularization and medications, practicing clinicians should possess a basic understanding of them to interpret the results.

Measures of health-related quality of life are often criticized as being overly subjective and unreliable in comparison with “hard” clinical end points such as death and MI. Such criticisms, however, overlook the fact that many of these measures have scales with internal consistencies (reflected by the Cronbach alpha statistic) that typically exceed 0.7 or 0.8 (908-912) and test-retest reliabilities that typically range from 0.7 to 0.9 or higher (910,913). This level of reliability approximates or exceeds that for total exercise time on treadmill testing (914) or interrater reliability of measurements of significant stenosis on coronary angiograms (915). Moreover, scores on health status questionnaires are predictive of future clinical events and utilization of health resources (916-919).

A thorough discussion of health-related quality of life is beyond the scope of these guidelines, and for more detail, the interested reader should consult general texts on this topic (920,921). A basic understanding includes knowledge of the attributes of a valid, reliable, and sensitive measure, as well as the differences between generic and condition-specific measures. A valid questionnaire is one that actually measures the characteristics of interest. By way of analogy, sphygmomanometry is valid because it produces measurements that are highly correlated with direct measurements of true intraarterial pressure. Unfortunately, when attempting to quantify subjective characteristics, such as the severity of pain or dyspnea, there is no gold or reference standard by which to prove validity. Thus, measures of health status must often be compared with other indirect measures. For example, questionnaires measuring physical function in patients with CAD have been validated against treadmill performance (909,922), and measures of anginal severity have been compared with use of antianginal medications or degree of improvement after revascularization (911,923,924). Additionally, questionnaires should be shown to be clinically responsive, i.e., capable of differentiating clinically important improvement or deterioration from random or nonspecific changes in condition.

Generic measures of health status are designed to measure the global health of an individual, including physical and mental function and symptoms. Of the dozens of generic health-related quality of life questionnaires, three reliable and valid ones have been used most commonly in patients with heart disease-the Medical Outcomes Study Short-Form 36 (SF-36) (925,926), the Sickness Impact Profile (927,928), and the Nottingham Health Survey (929). Because generic questionnaires are designed for use with a wide variety of persons, including those who are healthy and those with chronic illnesses, they are often long and may be insensitive to subtle but clinically important changes in the status of a specific condition such as angina. For this reason, several reliable and valid questionnaires have been developed specifically to evaluate patients with ischemic heart disease and are usually preferred to generic instruments (Table 24a). Testing to determine responsiveness to clinical change has been less uniform. At present, there is no general consensus that the performance of any one instrument is clearly superior, although the Seattle Angina Questionnaire is probably used most widely at the present time (930-934). On the basis of demonstration of reliability, validity, and responsiveness, the Seattle Angina Questionnaire was certified by the Medical Outcomes Trust, which has assumed its international distribution, and it has been translated into more than a dozen languages (935). The Seattle Angina Questionnaire has been or is currently being used in more than two dozen randomized trials of therapy and cohort studies of patients with ischemic heart disease and has been demonstrated to accurately predict mortality for a period of two years (936-948). Unfortunately, scores from one questionnaire cannot readily be compared with those from a different questionnaire. Furthermore, there is presently no conclusive evidence that use of either general or condition-specific health status measures in clinical practice improves outcomes.

3. Pharmacotherapy to Prevent MI and Death

Antiplatelet Agents

Aspirin exerts an antithrombotic effect by inhibiting cyclooxygenase and synthesis of platelet thromboxane A2. The use of aspirin in more than 3000 patients with stable angina was associated with a 33% (on average) reduction in the risk of adverse cardiovascular events (512,513). In patients with unstable angina, aspirin decreases the short and long-term risk of fatal and nonfatal MI (514,515). In the Physicians’ Health Study (516), aspirin (325 mg), given on alternate days to asymptomatic persons, was associated with a decreased incidence of MI. In the Swedish Angina Pectoris Aspirin Trial (517) in patients with stable angina, the addition of 75 mg of aspirin to sotalol resulted in a 34% reduction in primary outcome events of MI and sudden death and a 32% decrease in secondary vascular events.

Ticlopidine is a thienopyridine derivative that inhibits platelet aggregation induced by adenosine diphosphate and low concentrations of thrombin, collagen, thromboxane A2, and platelet activating factor (518,519). It also reduces blood viscosity because of a reduction in plasma fibrinogen and an increase in red cell deformability (520). Ticlopidine decreases platelet function in patients with stable angina but, unlike aspirin, has not been shown to decrease adverse cardiovascular events (521,522). It may, however, induce neutropenia and, albeit infrequently, thrombotic thrombocytopenic purpura (TTP).

Clopidogrel, also a thienopyridine derivative, is chemically related to ticlopidine but appears to possess a greater antithrombotic effect than ticlopidine (523). Clopidogrel prevents adenosine diphosphate-mediated activation of platelets by selectively and irreversibly inhibiting the binding of adenosine diphosphate to its platelet receptors and thereby affecting blocking adenosine diphosphate-dependent activation of the glycoprotein IIb/IIIa complex. In a randomized trial that compared clopidogrel with aspirin in patients with previous MI, stroke, or symptomatic peripheral vascular disease (i.e., at risk of ischemic events), clopidogrel appeared to be slightly more effective than aspirin in decreasing the combined risk of MI, vascular death, or ischemic stroke (524). However, no further studies have been performed to confirm the efficacy of clopidogrel in patients with stable angina.

Dipyridamole is a pyrimido-pyrimidine derivative that exerts vasodilatory effects on coronary resistance vessels and also has antithrombotic effects. Dipyridamole increases intracellular platelet cyclic adenosine monophosphate by inhibiting the enzyme phosphodiesterase, activating the enzyme adenylate cyclase, and inhibiting uptake of adenosine from vascular endothelium and erythrocytes (525). Increased plasma adenosine is associated with vasodilation. Because even the usual oral doses of dipyridamole can enhance exercise-induced myocardial ischemia in patients with stable angina (526), it should not be used as an antiplatelet agent.

Aspirin (75 to 325 mg daily) should be used routinely in all patients with acute and chronic ischemic heart disease with or without manifest symptoms in the absence of contraindications. A meta-analysis of 287 randomized trials showed that the reduction in vascular events was comparable for doses of 75 to 150 mg daily and 160 to 325 mg daily; however, daily doses of less than 75 mg had less benefit (949).

Antithrombotic Therapy

Disturbed fibrinolytic function, such as elevated tissue plasminogen activator antigen, high plasminogen activator inhibitor, and low tissue plasminogen activator antigen responses after exercise, has been found to be associated with an increased risk of subsequent cardiovascular deaths in patients with chronic stable angina (527), providing the rationale for long-term antithrombotic therapy. In small placebo-controlled studies among patients with chronic stable angina, daily subcutaneous administration of low-molecular-weight heparin decreased the fibrinogen level, which was associated with improved clinical class and exercise time to 1-mm ST depression and peak ST depression (528). However, the clinical experience of such therapy is extremely limited. The efficacy of newer antiplatelet and antithrombotic agents such as glycoprotein IIb/IIIa inhibitors and recombinant hirudin in the management of patients with chronic stable angina has not been established (529). Lowintensity oral anticoagulation with warfarin (international normalized ratio 1.47) has been shown to decrease the risk of ischemic events (coronary death and fatal and nonfatal MI) in a randomized trial of patients with risk factors for atherosclerosis but without symptoms of angina (530). This benefit was incremental to that provided by aspirin.

Lipid-Lowering Agents

Earlier lipid-lowering trials with the use of bile acid sequestrant (cholestyramine), fibric acid derivatives (gemfibrozil and clofibrate), or niacin reported reductions in total cholesterol of 6% to 15%. The pooled data from these studies also suggested that every 1% reduction in total cholesterol could reduce coronary events by 2% (531). Angiographic trials have addressed the effects of lipid-lowering therapy on anatomic changes of coronary atherosclerotic plaques. Active treatment was associated with less progression, more stabilization, and more regression of these plaque lesions and decreased incidence of clinical events. A meta-analysis (532) of 37 trials demonstrated that treatment-mediated reductions in cholesterol are significantly associated with the observed reductions in CHD mortality and total mortality rates.

Recent clinical trials have documented that LDL-lowering agents can decrease the risk of adverse ischemic events in patients with established CAD. In the Scandinavian Simvastatin Survival Study (4S) (533), treatment with a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor in patients with documented CAD (including stable angina) with a baseline total cholesterol between 212 and 308 mg per dl was associated with 30% to 35% reductions in both mortality rate and major coronary events. In the Cholesterol And Recurrent Events (CARE) study (534), in both men and women with previous MI and total plasma cholesterol levels less than 240 mg per dl (mean 209) and LDL cholesterol levels of 115 to 174 mg per dl (mean 139), treatment with an HMG-CoA reductase inhibitor (statin) was associated with a 24% reduction in risk for fatal or nonfatal MI. These clinical trials indicate that in patients with established CAD, including chronic stable angina, lipid-lowering therapy should be recommended even in the presence of mild to moderate elevations of LDL cholesterol.

Angiotensin Converting Enzyme Inhibitors

The potential cardiovascular protective effects of ACE inhibitors have been suspected for some time. As early as 1990, results from the Survival And Ventricular Enlargement (SAVE) and Studies Of Left Ventricular Dysfunction (SOLVD) trials showed that ACE inhibitors reduced the incidence of recurrent MI and that this effect could not be attributed to the effect on blood pressure alone (950). At the same time, Alderman demonstrated that a high plasma renin was associated with a significantly higher incidence of death from MI in patients with moderate hypertension and that this effect was independent of blood pressure level (951).

The results of the Heart Outcomes Prevention Evaluation (HOPE) trial now confirm that use of the ACE inhibitor ramipril (10 mg per day) reduced cardiovascular death, MI, and stroke in patients who were at high risk for, or had, vascular disease in the absence of heart failure (952). The primary outcome in HOPE was a composite of cardiovascular death, MI, and stroke. However, the results of HOPE were so definitive that each of the components of the primary outcome by itself also showed statistical significance. Furthermore, only a small part of the benefit could be attributed to a reduction in blood pressure (-2 to -3 mm Hg). These vasculoprotective effects of the ACE inhibitor ramipril should not be surprising when one considers the location and function of ACE within the vasculature.

Greater than 90% of ACE is tissue bound, whereas only 10% of ACE is present in soluble form in the plasma. In nonatherosclerotic arteries, the majority of tissue ACE is bound to the cell membranes of endothelial cells on the luminal surface of the vessel walls, and there is a large concentration of ACE within the adventitial vasa vasorum endothelium (953). It is now well appreciated that atherosclerosis represents different stages of a process that is in large part mediated by the endothelial cell. Thus, in the early stage, ACE, with its predominant location for the endothelial cells, would be an important mediator of local angiotensin II and bradykinin levels that could have an important impact on endothelial function. Indeed, treatment with the ACE inhibitor quinapril (40 mg per day) resulted in amelioration of endothelial dysfunction of coronary arteries in patients who did not have severe hyperlipidemia or evidence of heart failure (954). In more advanced lesions, ACE was also localized to the endothelium of the microvasculature throughout the plaque in association with increased angiotensin II.

Angiotensin converting enzyme generates angiotensin II from angiotensin I and catalyzes the degradation of bradykinin to inactive metabolites (955). Thus, ACE provides an important physiologic function in the balance between angiotensin II and bradykinin within the plasma, but more importantly in the vessel wall (956). Indeed, Vaughn and coworkers have shown that ramipril treatment resulted in a 44% reduction in plasma plasminogen activator inhibitor-1 antigen levels (p = 0.004) and a 22% reduction in plasminogen activator inhibitor-1 activity (p = 0.02) in post-MI patients compared with placebo (957) . Thus, ramipril shifted the fibrinolytic balance toward lysis after a MI, a biochemical action that may account for the reduced risk of MI in clinical trials (950,952). Taken together, ACE inhibition shifts the balance of ongoing vascular mechanisms in favor of those promoting vasodilatory, antiaggregatory, antiproliferative, and antithrombotic effects.

The results of HOPE were extremely impressive when one considers the magnitude of the difference between ramipril and placebo in the primary outcomes of cardiovascular death, MI, and stroke. The HOPE study was unique in that of the 9541 patients in this study, 3577 (37.5%) had diabetes. There was a very significant reduction in diabetic complications, a composite for the development of diabetic nephropathy, need for renal dialysis, and laser therapy for diabetic retinopathy, in those patients receiving ramipril. Even more fascinating was the finding that among the patients who were not designated as diabetic at the beginning of the trial, fewer were diagnosed with diabetes during the four-year observation period if they were treated with ramipril. Prior to the HOPE trial, numerous clinical trials suggested that ACE inhibitor treatment may delay or prevent cardiovascular outcomes in patients with diabetes after an MI, in the presence of hypertension, and in the presence of a low ejection fraction or heart failure (Table 24b). Furthermore, ACE inhibitors may also prevent overt nephropathy and other microvascular outcomes in patients with type 1 or type 2 diabetes (Table 24b).

The Microalbuminuria, Cardiovascular, and Renal Outcomes (MICRO)-HOPE (957a), a substudy of the HOPE study, has provided new clinical data on the cardiorenal therapeutic benefits of ACE inhibitor intervention in a broad range of middle-aged patients with diabetes mellitus who are at high risk for cardiovascular events. The risk of MI was reduced by 22% (p = 0.01), stroke by 33% (p = 0.0074), cardiovascular death by 37% (p = 0.0001), and the combined primary outcome of these events by 25% (p = 0.0004). Ramipril also lowered the risk of overt nephropathy by 24% (p = 0.027).

Angiotensin converting enzyme inhibitors should be used as routine secondary prevention for patients with known CAD, particularly in diabetics without severe renal disease. There are two ongoing clinical trials evaluating the effect of two different ACE inhibitors (trandolapril and perindopril) in patient populations that are similar but in many respects distinctly different from the HOPE patient population. The Prevention of Events with Angiotensin-Converting Enzyme inhibition (PEACE) study is randomizing patients who have had a percutaneous transluminal angioplasty or CABG, an MI, or angiographic evidence of single-vessel disease to trandolapril or placebo. The European trial on reduction of cardiac events with perindopril in stable CAD (EUROPA) will enroll a similar group of patients and will also include those with positive stress tests. Both studies will exclude patients with heart failure. Furthermore, these studies do not include patients with diabetes mellitus. Accordingly, these studies should answer the question whether a vasculoprotective effect can be accomplished in a lower-risk group of patients than those enrolled in the HOPE study.

Another important question is whether the vasculoprotective effect would be obtained with any one of the many ACE inhibitors available to the clinician. This is the subject of continuing controversy. Quantitative differences do exist among the ACE inhibitors, and optimal doses for therapeutic benefit must be established in large-scale clinical trials such as those outlined above. It is of interest that the HOPE, PEACE, and EUROPA trials use “tissue ACE inhibitors” that have high lipophilicity and enzyme-binding capabilities. It has been postulated but not proved that ACE inhibitors with these properties provide greater penetrance into the atherosclerotic plaque and more effective inhibition of tissue ACE inhibitors. Others believe that this is a “class effect,” because enalapril improved outcomes in CONSENSUS II (Cooperative North Scandinavian Enalapril Survival Study) (959) and SOLVD (960), and captopril improved five-year survival in the SAVE trial (961). Regardless of the outcome of these studies, there appears to be a particular mandate for the use of ACE inhibitors in secondary prevention in patients with diabetes and CAD. In the ongoing Bypass and COURAGE trials, ACE inhibitors are prescribed for all diabetics with documented ischemic heart disease unless contraindicated. The ACE inhibitor used in the BARI-2-D trial is quinapril (an agent with high lipophilicity and enzyme-binding capabilities-a tissue ACE).

Antianginal and Anti-ischemic Therapy

Antianginal and anti-ischemic drug therapy consists of betaadrenoreceptor blocking agentsare administered in conjunction with pharmacotherapy to prevent MI and death, although some interventions, such as beta-blockers and CABG in certain high-risk groups, simultaneously improve angina and ischemia while preventing MI and sudden cardiac death. The main goal of antianginal therapy, however, is to reduce symptoms of cardiac ischemia and thus improve physical function and quality of life. The most effective agents for relieving ischemia and angina are beta-blockers, calcium antagonists, and nitrates. Other classes of drugs, such as ACE inhibitors, amiodarone, “metabolic agents,” and nonconventional therapy, also have been used in certain subsets of patients with stable angina, but their clinical effectiveness has not been confirmed.

BETA-BLOCKERS. Mechanism of action. Activation of betareceptors is associated with an increase in heart rate, acceleration of conduction through the AV node, and increased contractility. Inhibition of beta-receptors is associated with a reduction in inotropic state and sinus rate and slowing of AV conduction. Some beta-blockers have partial agonist activity, also called intrinsic sympathomimetic activity, and may not decrease heart rate and blood pressure at rest.

The decrease in heart rate, contractility, and arterial pressure with beta-blockers is associated with decreased myocardial oxygen demand. A reduction in heart rate also increases diastolic perfusion time, which may enhance LV perfusion. Although beta-blockers have the potential to increase coronary vascular resistance by the formation of cyclic adenosine monophosphate, the clinical relevance of this pharmacodynamic effect remains uncertain. A marked slowing of heart rate may increase LV diastolic wall tension, which may increase myocardial oxygen demand; the concomitant use of nitrates can offset these potentially deleterious effects of beta-blockers.

Clinical effectiveness. Various types of beta-blockers are available for treatment of hypertension and angina. The pharmacokinetic and pharmacodynamic effects of these agents are summarized in Table 25. All beta-blockers appear to be equally effective in angina pectoris. In patients with chronic stable exertional angina, these agents decrease the heart rate-blood pressure product during exercise, and the onset of angina or the ischemic threshold during exercise is delayed or avoided (535,536). In the treatment of stable angina, it is conventional to adjust the dose of beta-blockers to reduce heart rate at rest to 55 to 60 beats per min. In patients with more severe angina, heart rate can be reduced to less than 50 beats per min provided that there are no symptoms associated with bradycardia and heart block does not develop. In patients with stable exertional angina, beta-blockers limit the increase in heart rate during exercise, which ideally should not exceed 75% of the heart rate response associated with onset of ischemia. Beta-blockers with additional vasodilating properties have also been found to be effective in stable angina (537-539). Agents with combined alpha- and beta-adrenergic antagonist properties have also proved effective in the management of chronic stable angina (540,541). Beta-blockers are clearly effective in controlling exercise-induced angina (542,543). Controlled studies comparing beta-blockers with calcium antagonists have reported equal efficacy in controlling stable angina (544-547). In patients with postinfarction stable angina and those who require antianginal therapy after revascularization, treatment with beta-blockers appears to be effective in controlling symptomatic and asymptomatic ischemic episodes (548). In elderly patients with hypertension without manifest CAD, beta-blockers as first-line therapy were reported to be ineffective in preventing cardiovascular mortality and all-cause mortality compared with diuretics. However, beta-blockers are still the anti-ischemic drug of choice in elderly patients with stable angina (549).

Beta-blockers are frequently combined with nitrates for treatment of chronic stable angina. Nitrates tend to increase sympathetic tone and may cause reflex tachycardia, which is attenuated with the concomitant use of beta-blockers. The potential increase in LV volume and end-diastolic pressure and wall tension associated with decreased heart rate with beta-blockers is counteracted by the concomitant use of nitroglycerin. Thus, combination therapy with nitrates and beta-blockers appears to be more effective than nitrates or beta-blockers alone (550,551). Beta-blockers may also be combined with calcium antagonists. For combination therapy, slow-release dihydropyridines or new-generation, longacting dihydropyridines are the calcium antagonists of choice (552-556). The tendency to develop tachycardia with these calcium antagonists is counteracted by the concomitant use of beta-blockers. Beta-blockers should be combined with verapamil and diltiazem with caution, because extreme bradycardia or AV block may occur. When beta-blockers are added to high-dose diltiazem or verapamil, marked fatigue may also result.

In patients with pure vasospastic angina (Prinzmetal angina) without fixed obstructive lesions, beta-blockers are ineffective and may increase the tendency to induce coronary vasospasm from unopposed alpha-receptor activity (557); therefore, they should not be used.

Patient outcomes. Beta-blockers have been shown in many randomized trials to improve the survival rate of patients with recent MI. These agents have also been shown in several large randomized trials to improve the survival rate and prevent stroke and CHF in patients with hypertension (558).

The effects of beta-blockers in patients with stable angina without prior MI or hypertension have been investigated in a few small randomized, controlled trials (Table 26). In the Total Ischemic Burden European Trial (TIBET) (559), the combination of atenolol and nifedipine produced a nonsignificant trend toward a lower rate of cardiac death, nonfatal MI, and unstable angina. There was no difference between atenolol and nifedipine. The Angina Prognosis Study in Stockholm (APSIS) (560) reported no difference between metoprolol and verapamil treatment in patients with chronic stable angina in relation to mortality, cardiovascular end points, and measures of quality of life. In the Atenolol Silent Ischemia Trial (ASIST) (413), patients with documented CAD and mild angina (CCS class I or II) were treated with 100 mg of atenolol daily; the number and mean duration of ischemic episodes detected by 48 h of ambulatory ECG monitoring were decreased after four weeks of therapy compared with placebo. After one year, fewer patients in the atenolol group experienced the combined end point of death, ventricular tachycardia and fibrillation, MI, hospitalization, aggravation of angina, or revascularization (413). The atenolol-treated patients had a longer time until their first adverse event.

In patients with stable angina, the effects of bisoprolol (a vasodilator beta-blocker) and nifedipine on transient myocardial ischemia were studied in a prospective randomized, controlled trial, Total Ischemic Burden Bisoprolol Study (TIBBS) (561). In this study, 330 patients with stable angina pectoris and a positive exercise test with ST-segment depression and at least two episodes of transient myocardial ischemia during 48 h of ambulatory ECG monitoring were randomized to either 10 mg of bisoprolol once daily or 20 mg of slow-release nifedipine twice daily for four weeks. The doses were then doubled for an additional four weeks. Both bisoprolol and nifedipine reduced the number and duration of ischemic episodes in patients with stable angina. However, bisoprolol was more effective than nifedipine. In the International Multicenter Angina Exercise Study (IMAGE) (562), the efficacy of metoprolol alone, nifedipine alone, and the combination of metoprolol and nifedipine was assessed in patients with stable angina pectoris. In this study, 280 patients less than or equal to 75 years old with stable angina for at least six months and a positive exercise test were randomized to receive 200 mg of metoprolol daily or 20 mg of nifedipine twice daily for six weeks after a two-week placebo period. The patients were then randomized to the addition of the second drug or placebo for four more weeks. Both metoprolol and nifedipine were effective as monotherapy in increasing exercise time, although metoprolol was more effective than nifedipine (562). The combination therapy also increased the exercise time compared with either drug alone.

Contraindications. The absolute cardiac contraindications for the use of beta-blockers are severe bradycardia, pre-existing high degree of AV block, sick sinus syndrome, and severe, unstable LV failure (mild CHF may actually be an indication for beta-blockers (563). Asthma and bronchospastic disease, severe depression, and peripheral vascular disease are relative contraindications. Most diabetic patients will tolerate beta-blockers, although these drugs should be used cautiously in patients who require insulin.

Side effects. Fatigue, inability to perform exercise, lethargy, insomnia, nightmares, worsening claudication, and impotence are frequently experienced the most common side effects. The mechanism of fatigue is not clear. During exercise, the total maximal work achievable is reduced by approximately 15% with long-term therapy, and the sense of fatigue may be increased (564). The average incidence of impotence is about 1%; however, lack of or inadequate erection has been observed in less than or equal to 26% of patients (565). Changes in quality of life have not been systematically studied in patients with chronic stable angina treated with beta-blockers.

CALCIUM ANTAGONISTS. Mechanisms of action. These agents reduce the transmembrane flux of calcium via the calcium channels. There are three types of voltage-dependent calcium channels: L type, T type, and N type. They are categorized according to whether they are characteristically large in conductance, transient in duration of opening, or neuronal in distribution (566). The pharmacodynamics of calcium antagonists are summarized in Table 27.

All calcium antagonists exert a variable negative inotropic effect. In smooth muscle, calcium ions also regulate the contractile mechanism, and calcium antagonists reduce smooth muscle tension in the peripheral vascular bed, which is associated with vasodilation.

Calcium antagonists, including the newer, second-generation vasoselective dihydropyridine agents and nondihydropyridine drugs such as verapamil and diltiazem, decrease coronary vascular resistance and increase coronary blood flow. All of these agents cause dilation of the epicardial conduit vessels and the arteriolar resistance vessels. Dilation of the epicardial coronary arteries is the principal mechanism of the beneficial effect of calcium antagonists for relieving vasospastic angina. Calcium antagonists also decrease myocardial oxygen demand primarily by reduction of systemic vascular resistance and arterial pressure. The negative inotropic effect of calcium antagonists also decreases the myocardial oxygen requirement. However, the negative inotropic effect varies considerably with different types of calcium antagonist. Among dihydropyridines, nifedipine probably exerts the most pronounced negative inotropic effect, and newer-generation, relatively vasoselective dihydropyridines such as amlodipine and felodipine exert much less of a negative inotropic effect. The new T-channel blocker mibefradil also appears to exert a less negative inotropic effect (567,568). However, mibefradil has been withdrawn from clinical use because of adverse drug interactions and is not discussed further in this document. Diltiazem and verapamil can reduce heart rate by slowing the sinus node or decreasing ventricular response in patients with atrial flutter and fibrillation due to reduction in AV conduction. Calcium antagonists are therefore useful for treatment of both demand and supply ischemia (569-575).

Calcium antagonists in chronic stable angina. Randomized clinical trials comparing calcium antagonists and beta-blockers have demonstrated that calcium antagonists are generally as effective as beta-blockers in relieving angina (Fig. 9) and improving exercise time to onset of angina or ischemia (Fig. 10). The clinical effectiveness of calcium antagonists was evident with both dihydropyridine and nondihydropyridine agents and various dosing regimens.

Calcium antagonists in vasospastic angina. In patients with vasospastic (Prinzmetal) angina, calcium antagonists have been shown to be effective in reducing the incidence of angina. Short-acting nifedipine, diltiazem, and verapamil all appeared to completely abolish the recurrence of angina in approximately 70% of patients; in another 20% of patients, the frequency of angina was reduced substantially (576-579). A randomized placebo-controlled trial has also been performed with the use of newer, vasoselective, long-acting dihydropyridine amlodipine in the management of patients with vasospastic angina (580). In this study, 52 patients with well-documented vasospastic angina were randomized to receive either amlodipine or placebo. The rate of anginal episodes decreased significantly with amlodipine treatment compared with placebo, and the intake of nitroglycerin tablets showed a substantial reduction.

Patient outcomes. Retrospective case-control studies report that in patients with hypertension, treatment with immediate-acting nifedipine, diltiazem, and verapamil was associated with increased risk of MI by 31%, 63%, and 61%, respectively (581). A meta-analysis of 16 trials that used immediate-release and short-acting nifedipine in patients with MI and unstable angina reported a dose-related influence on excess mortality (582). However, further analysis of the published reports has failed to confirm an increased risk of adverse cardiac events with calcium antagonists (583,584). Furthermore, slow-release or long-acting vasoselective calcium antagonists have been reported to be effective in improving symptoms and decreasing the risk of adverse cardiac events (585). However, in the Appropriate Blood pressure Control in Diabetes (ABCD) study (586), the use of nisoldipine, a relatively short-acting dihydropyridine calcium antagonist, was associated with a higher incidence of fatal and nonfatal MI compared with enalapril, an ACE inhibitor. In an earlier trial of patients with stable angina, nisoldipine was not effective in relieving angina compared with placebo. Furthermore, larger doses tended to increase the incidence of adverse events (587). These data indicate that relatively short-acting dihydropyridine calcium antagonists have the potential to enhance the risk of adverse cardiac events and should be avoided. In contrast, long-acting calcium antagonists, including slow-release and long-acting dihydropyridines and nondihydropyridines, are effective in relieving symptoms in patients with chronic stable angina. They should be used in combination with beta-blockers when initial treatment with beta-blockers is not successful or as a substitute for beta-blockers when initial treatment leads to unacceptable side effects. However, their use is not without potential hazard, as demonstrated by the Fosinopril versus Amlodipine Cardiovascular Events randomized Trial (FACET) (588), in which amlodipine was associated with a higher incidence of cardiovascular events than fosinopril, an ACE inhibitor.

Contraindications. In general, overt decompensated heart failure is athe major contraindication for the use of calcium antagonists, although new-generation vasoselective dihydropyridines (i.e., amlodipine, felodipine) are tolerated by patients with reduced LV ejection fraction. Bradycardia, sinus node dysfunction, and AV nodal block are contraindications for the use of heart rate-modulating calcium antagonists. A long QT interval is a contraindication for the use of mibefradil andbepridil.

Side effects. Hypotension, depression of cardiac function, and worsening heart failure may occur during long-term treatment with any calcium antagonist (589-591) (Table 27). Peripheral edema and constipation are recognized side effects of all calcium antagonists. Headache, flushing, dizziness, and nonspecific central nervous system symptoms may also occur. Bradycardia, AV dissociation, AV block, and sinus node dysfunction may occur with heart rate-modulating calcium antagonists. Bepridil can induce polymorphic ventricular tachycardia associated with an increased QT interval (592).

Combination therapy with calcium antagonists. In general, in combination with beta-blockers, calcium antagonists produce greater antianginal efficacy in patients with stable angina (552-556). In the IMAGE trial (562), the combination of metoprolol and nifedipine was effective in reducing the incidence of ischemia and improving exercise tolerance compared with either drug alone. In the TIBBS trial (561), the combination of bisoprolol and nifedipine was effective in reducing the number and duration of ischemic episodes in patients with stable angina. In the Circadian Anti-ischemic Program in Europe (CAPE) trial (593), the effect of one daily dose of amlodipine on the circadian pattern of myocardial ischemia in patients with stable angina pectoris was assessed. In this randomized, double-blind, placebo-controlled, multicenter trial, 315 men, aged 35 to 80 years, with stable angina, at least three attacks of angina per week, and at least four ischemic episodes during 48 h of ambulatory ECG monitoring were randomized to receive either 5 or 10 mg of amlodipine per day or placebo for 8 weeks. Amlodipine was used in addition to regular antianginal therapy. There was a substantial reduction in the frequency of both symptomatic and asymptomatic ischemic episodes with the use of amlodipine. The long-acting, relatively vasoselective dihydropyridine calcium antagonists enhance antianginal efficacy in patients with stable angina when combined with beta-blockers (594-596). Maximal exercise time and work time to angina onset are increased, and subjective indexes, including anginal frequency and nitroglycerin tablet consumption, decrease.

NITROGLYCERIN AND NITRATES. Mechanisms of action. Nitrates are endothelium-independent vasodilators that produce beneficial effects by both reducing the myocardial oxygen requirement and improving myocardial perfusion (597,598). The reduction in myocardial oxygen demand and consumption results from the reduction of LV volume and arterial pressure primarily due to reduced preload. A reduction in central aortic pressure can also result from improved nitroglycerin-induced central arterial compliance. Nitroglycerin also exerts antithrombotic and antiplatelet effects in patients with stable angina (599). A reflex increase in sympathetic activity, which may increase heart rate and contractile state, occurs in some patients. In general, however, the net effect of nitroglycerin and nitrates is a reduction in myocardial oxygen demand.

Nitrates dilate large epicardial coronary arteries and collateral vessels. The vasodilating effect on epicardial coronary arteries with or without atherosclerotic CAD is beneficial in relieving coronary vasospasm in patients with vasospastic angina. Because nitroglycerin decreases myocardial oxygen requirements and improves myocardial perfusion, these agents are effective in relieving both demand and supply ischemia.

Clinical effectiveness. In patients with exertional stable angina, nitrates improve exercise tolerance, time to onset of angina, and ST-segment depression during the treadmill exercise test. In combination with beta-blockers or calcium antagonists, nitrates produce greater antianginal and antiischemic effects in patients with stable angina (564,566,600-605).

The properties of commonly used preparations available for clinical use are summarized in Table 28. Sublingual nitroglycerin tablets or nitroglycerin sprays are suitable for immediate relief of effort or rest angina and can also be used for prophylaxis to avoid ischemic episodes when used several minutes before planned exercise. As treatment to prevent the recurrence of angina, long-acting nitrate preparations such as isosorbide dinitrate, mononitrates, transdermal nitroglycerin patches, and nitroglycerin ointment are used. All long-acting nitrates, including isosorbide dinitrates and mononitrates, appear to be equally effective when a sufficient nitrate-free interval is provided (606,607).

Contraindications. Nitroglycerin and 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. In patients with severe aortic valve stenosis, nitroglycerin should be avoided because of the risk of inducing syncope. However, nitroglycerin can be used for relief of angina.

The interaction between nitrates and sildenafil is discussed in detail elsewhere (608). The coadministration of nitrates and sildenafil significantly increases the risk of potentially life-threatening hypotension. Patients who take nitrates should be warned of the potentially serious consequences of taking sildenafil within the 24-h interval after taking a nitrate preparation, including sublingual nitroglycerin.

Side effects. The major problem with long-term use ofnitroglycerin and long-acting nitrates is development of nitrate tolerance (609). Tolerance develops not only to antianginal and hemodynamic effects but also to platelet antiaggregatory effects (610). The mechanism for development of nitrate tolerance remains unclear. The decreased availability of sulfhydryl (SH) radicals, activation of the renin-angiotensin-aldosterone system, an increase in intravascular volume due to an altered transvascular Starling gradient, and generation of free radicals with enhanced degradation of nitric oxide have been proposed. The concurrent administration of an SH donor such as SH-containing ACE inhibitors, acetyl or methyl cysteine (611), and diuretics has been suggested to reduce the development of nitrate tolerance. Concomitant administration of hydralazine has also been reported to reduce nitrate tolerance. However, for practical purposes, less frequent administration of nitroglycerin with an adequate nitrate-free interval (8 to 12 h) appears to be the most effective method of preventing nitrate tolerance (553). The most common side effect during nitrate therapy is headache. Sometimes the headaches abate during long-term nitrate therapy even when antianginal efficacy is maintained. Patients may develop hypotension and presyncope or syncope (554,555). Rarely, sublingual nitroglycerin administration can produce bradycardia and hypotension, probably due to activation of the Bezold-Jarisch reflex.

OTHER ANTIANGINAL AGENTS AND THERAPIES. Molsidomine, a sydnonimine that has pharmacologic properties similar to those of nitrates, has been shown to be beneficial in the management of symptomatic patients with chronic stable angina (612). Nicorandil, a potassium channel activator, also has pharmacologic properties similar to those of nitrates and may be effective in treatment of stable angina (613-615). Metabolic agents such as trimetazidine, ranolazine, and Lcarnitine have been observed to produce antianginal effects in some patients (616-619). Bradycardic agents such as alindine and zatebradin have been used for treatment of stable angina (620,621), but their efficacy has not been well documented (622,623). Angiotensin converting enzyme inhibitors have been investigated for treatment of stable angina, but their efficacy has not been established (624,625). A reduction of exercise-induced myocardial ischemia has been reported with the addition of an ACE inhibitor in patients with stable angina with optimal beta-blockade and normal LV function (962). The serotonin antagonist ketanserin appears not to be an effective antianginal agent (626). Labetalol, a beta- and alpha-adrenoceptor blocking agent, has been shown to produce beneficial antianginal effects (620,627). Nonselective phosphodiesterase inhibitors such as theophylline and trapidil have been reported to produce beneficial antianginal effects (621,628). Fantofarone, a calcium antagonist, exerts an inhibitory effect on the sinus node and decreases heart rate. Like other calcium antagonists, it is a potent peripheral and coronary vasodilator. In controlled studies, its beneficial antianginal effects in patients with chronic stable angina have been observed (629). Further studies, however, will be required to determine the efficacy of these newer antianginal drugs.

Controversies exist regarding antianginal efficacy of the sex hormones. Both an increase in the treadmill exercise time to myocardial ischemia and lack of such benefit has been observed with 17-beta-estradiol in postmenopausal women with stable angina (963,964). In a randomized, double-blind, placebo-controlled study that included a relatively small number of men with chronic stable angina, low-dose transdermal testosterone therapy has been reported to improve angina threshold (965). Further studies, however, will be required to determine the efficacy of these newer antianginal drugs.

Chelation therapy and acupuncture have not been found to be effective to relieve symptoms and are not recommended for treatment of chronic stable angina. The use of antibiotics to treat CAD is not recommended. Although several small observational studies have suggested benefit from enhanced external counterpulsation (639,631), the available evidence does not support a recommendation for its use. The standard use of antibiotics is also not recommended.

4. Choice of Pharmacologic Therapy in Chronic Stable Angina

The primary consideration in the choice of pharmacologic agents for treatment of angina should be to improve prognosis. Aspirin and lipid-lowering therapy have been shown to reduce the risk of death and nonfatal MI in both primary and secondary prevention trials. These data strongly suggest that cardiac events will also be reduced among patients with chronic stable angina, an expectation corroborated by direct evidence in small, randomized trials with aspirin.

Beta-blockers also reduce cardiac events when used as secondary prevention in postinfarction patients and reduce mortality and morbidity among patients with hypertension. On the basis of their potentially beneficial effects on morbidity and mortality, beta-blockers should be strongly considered as initial therapy for chronic stable angina. They appear to be underused (632). Diabetes mellitus is not a contraindication to their use. Nitrates have not been shown to reduce mortality with acute MI or in patients with CAD. Immediate-release or short-acting dihydropyridine calcium antagonists have been reported to increase adverse cardiac events. However, long-acting or slow-release dihydropyridines, or nondihydropyridines, have the potential to relieve symptoms in patients with chronic stable angina without enhancing the risk of adverse cardiac events. No conclusive evidence exists to indicate that either long-acting nitrates or calcium antagonists are superior for long-term treatment for symptomatic relief of angina. The committee believes that long-acting calcium antagonists are often preferable to long-acting nitrates for maintenance therapy because of their sustained 24-h effects. However, the patient’s and treating physician’s preferences should always be considered.

Special Clinical Situations

Newer-generation, vasoselective, long-acting dihydropyridine calcium antagonists such as amlodipine or felodipine can be used in patients with depressed LV systolic function. In patients who have sinus node dysfunction, rest bradycardia, or AV block, beta-blockers or heart rate-modulating calcium antagonists should be avoided. In patients with insulindependent diabetes, beta-blockers should be used with caution because they can mask hypoglycemic symptoms. In patients with mild peripheral vascular disease, there is no contraindication for use of beta-blockers or calcium antagonists. However, in patients with severe peripheral vascular disease with ischemic symptoms at rest, it is desirable to avoid beta-blockers, and calcium antagonists are preferred. In patients with hypertrophic obstructive cardiomyopathy, the use of nitrates and dihydropyridine calcium antagonists should be avoided. In these patients, beta-blockers or heart rate-modulating calcium antagonists may be useful. In patients with severe aortic stenosis, all vasodilators, including nitrates, should be used cautiously because of the risk of inducing hypotension and syncope. Associated conditions that influence the choice of therapy are summarized in Table 29.

Patients with angina may have other cardiac conditions, e.g., CHF, that will require other special treatment, such as diuretics and ACE inhibitors. These issues are covered in other ACC/AHA guidelines.

B. Definition of Successful Treatment and Initiation of Treatment

1. Successful Treatment

Definition of Successful Treatment of Chronic Stable Angina

The treatment of chronic stable angina has two complementary objectives: to reduce the risk of mortality and morbid events and to reduce symptoms. From the patient’s perspective, it is often the latter that is of greater concern. The cardinal symptom of stable CAD is anginal chest pain or equivalent symptoms, such as exertional dyspnea. Often the patient suffers not only from the discomfort of the symptom itself but also from accompanying limitations on activities and the associated anxiety that the symptoms may produce. Uncertainty about prognosis may be an additional source of anxiety. For some patients, the predominant symptoms may be palpitations or syncope that is caused by arrhythmias or fatigue, edema, or orthopnea caused by heart failure.

Because of the variation in symptom complexes among patients and patients’ unique perceptions, expectations, and preferences, it is impossible to create a definition of treatment success that is universally accepted. For example, given an otherwise healthy, active patient, the treatment goal may be complete elimination of chest pain and a return to vigorous physical activity. Conversely, an elderly patient with more severe angina and several coexisting medical problems may be satisfied with a reduction in symptoms that enables performance of only limited activities of daily living.

The committee agreed that for most patients, the goal of treatment should be complete, or nearly complete, elimination of anginal chest pain and return to normal activities and a functional capacity of CCS class I angina. This goal should be accomplished with minimal side effects of therapy. This definition of successful therapy must be modified in light of the clinical characteristics and preferences of each patient.

2. Initial Treatment

The initial treatment of the patient should include all the elements in the following mnemonic:

A = Aspirin and Antianginal therapy

B = Beta-blocker and Blood pressure

C = Cigarette smoking and Cholesterol

D = Diet and Diabetes

E = Education and Exercise

In constructing a flow diagram to reflect the treatment process, the committee thought that it was clinically helpful to divide the entire treatment process into two parts: 1) antianginal treatment and 2) education and risk factor modification. The assignment of each treatment element to one of these two subdivisions is self-evident, with the possible exception of aspirin. Given the fact that aspirin clearly reduces the risk of subsequent heart attack and death but has no known benefit in preventing angina, the committee thought that it was best assigned to the education and risk factor component, as reflected in the flow diagram.

All patients with angina should receive a prescription for sublingual nitroglycerin and education about its proper use. It is particularly important for patients to recognize that this is a short-acting drug with no known long-term consequences so that they will not be reluctant to use it.

If the patient’s history has a prominent feature of rest and nocturnal angina suggesting vasospasm, initiation of therapy with long-acting nitrates or calcium antagonists is appropriate.

As mentioned previously, medications or conditions that are known to provoke or exacerbate angina must be recognized and treated appropriately. On occasion, angina may resolve with appropriate treatment of these conditions. If so, no further antianginal therapy is required. Usually, anginal symptoms improve but are not relieved by the treatment of such conditions, and further therapy should then be initiated.

The committee favored the use of a beta-blocker as initial therapy in the absence of contraindications. The evidence for this approach is strongest in the presence of prior MI, for which this class of drugs has been shown to reduce mortality. Because these drugs have also been shown to reduce mortality in the treatment of isolated hypertension, the committee favored their use as initial therapy even in the absence of prior MI.

If serious contraindications with beta-blockers exist, unacceptable side effects occur with their use, or angina persists despite their use, calcium antagonists should then be administered. If serious contraindications to calcium antagonists exist, unacceptable side effects occur with their use, or angina persists despite their use, long-acting nitrate therapy should then be prescribed.

At any point, on the basis of coronary anatomy, severity of anginal symptoms, and patient preferences, it is reasonable to consider evaluation for coronary revascularization. As discussed in the revascularization section, certain categories of patients, a minority of the total group, have a demonstrated survival advantage with revascularization. However, for most patients, for whom no demonstrated survival advantage is associated with revascularization, medical therapy should be attempted before angioplasty or surgery is considered. The extent of the effort that should be undertaken with medical therapy obviously depends on the individual patient. In general, the committee thought that low-risk patients should be treated with at least two, and preferably all three, available classes of drugs before medical therapy is considered a failure.

3. Asymptomatic Patients

Recommendations for Pharmacotherapy to Prevent MI and Death in Asymptomatic Patients

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 per dl, with a target LDL of less than 100 mg per dl. (Level of Evidence: A)

4. ACE inhibitor in patients with CAD who also have diabetes and/or 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 of 100 to 129 mg per dl, with a target LDL of 100 mg per dl. (Level of Evidence: C)

4. Angiotensin converting enzyme inhibitor in all patients with diabetes who do not have contraindications due to severe renal disease. (Level of Evidence: B)

Even in asymptomatic patients, aspirin and beta-blockers are recommended in patients with prior MI. The data in support of these recommendations are detailed in the ACC/AHA Guideline for the Management of Patients With Acute Myocardial Infarction: 1999 Update (892).

In the absence of prior MI, patients with documented CAD on the basis of noninvasive testing or coronary angiography probably also benefit from aspirin, although the data on this specific subset of patients are limited.

Several studies have investigated the potential role of beta-blockers in patients with asymptomatic ischemia demonstrated on exercise testing and/or ambulatory monitoring (966-968). The data generally demonstrate a benefit from beta-blocker therapy, but not all trials have been positive (966-969).

Lipid-lowering therapy in asymptomatic patients with documented CAD was demonstrated to decrease the rate of adverse ischemic events in the 4S trial (533), as well as in the CARE study (534) and the Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) trial (970), as previously mentioned.

C. Education of Patients With Chronic Stable Angina

Because the presentation of ischemic heart disease is often dramatic and because of impressive recent technological advances, healthcare providers tend to focus on diagnostic and therapeutic interventions, often overlooking critically important aspects of high-quality care. Chief among these neglected areas is the education of patients. In the 1995 National Ambulatory Medical Care Survey (666), counseling about physical activity and diet occurred during only 19% and 23%, respectively, of general medical visits. This shortcoming was observed across specialties, including cardiology, internal medicine, and family practice.

Effective education is critical to enlisting patients’ full and meaningful participation in therapeutic and preventive efforts and in allaying their natural concerns and anxieties. This in turn is likely to lead to a patient who not only is better informed and more satisfied with his or her care but who is also able to achieve a better quality of life and improved survival (667-669).

A particularly important facet of education is helping patients to understand their medication regimens. That many patients with cardiac disease fail to properly use prescribed medications is well documented (971). Moreover, poor adherence with cardiac medications is associated with increased mortality, increased morbidity, and excess hospitalization (972-975). Problems with medication adherence are related to the number of medications prescribed and the complexity and expense of the regimen. Improving patients’ adherence to medications require a multifaceted approach that can involve nurses, pharmacists, health educators, educational materials, and automated systems, as well as physicians (976).

Patient education should be viewed as a continuous process that ought to be part of every patient encounter. It is a process that must be individualized so that information is presented at appropriate times and in a manner that is readily understandable. It is frequently advisable to address patients’ overriding concerns initially, for example, their short-term prognosis. In directly addressing worrisome issues, it is possible to put patients more at ease and make them more receptive to addressing other issues, such as modification of risk factors. This is true even when the short-term prognosis cannot be fully addressed until additional testing has been conducted. It is also essential to recognize that adequate education is likely to lead to better adherence to medication regimens and programs for risk factor reduction. Even brief suggestions from a physician about exercise or smoking cessation can have a meaningful effect (670,671). Moreover, an informed patient will be better able to understand treatment decisions and express preferences that are an important component of the decision-making process (672).

1. Principles of Patient Education

A thorough discussion of the philosophies of and approaches to patient education is beyond the scope of this section. There are several useful reviews on this topic, including several that focus on ischemic heart disease (673-675). It has been demonstrated that well-designed educational programs can improve patients’ knowledge, and in some instances, they have been shown to improve outcomes (676). These approaches form the basis for commonly used educational programs, such as those conducted before CABG (677) and after MI (678,679). A variety of principles should be followed to help ensure that educational efforts are successful.

1. Assess the patient’s baseline understanding. This serves not only to help establish a starting point for education but also to engage the patient. Healthcare providers are often surprised at the idiosyncratic notions that patients have about their own medical conditions and therapeutic approaches (680,681).

2. Elicit the patient’s desire for information. Adults prefer to set their own agendas, and they learn better when they can control the flow of information.

3. Use epidemiologic and clinical evidence. As clinical decision making becomes increasingly based on scientific evidence, it is reasonable to share that evidence with patients. Epidemiologic data can assist in formulating an approach to patient education. In many patients, for example, smoking reduction/cessation is likely to confer a greater reduction in risk than treatment of modestly elevated lipid levels; thus, smoking should be addressed first. Scientific evidence can help persuade patients about the effectiveness of various interventions.

4. Use ancillary personnel and professional patient educators when appropriate. One reason that physicians often fail to perform adequate patient education is that the time available for a patient encounter is constrained, and education must be performed along with a long list of other tasks. Reimbursement for educational activities is poor. Furthermore, physicians are not trained to be effective health educators, and many feel uncomfortable in this role. Fortunately, in many settings, trained health educators, such as those specializing in diabetes or cardiac disease, are available. Personnel from related disciplines such as physical therapy, nutrition, pharmacology, and so forth also have much to offer patients with ischemic heart disease (682).

5. Use professionally prepared resources when available. A vast array of informational materials and classes are available to assist with patient education. These materials include books, pamphlets, and other printed materials; audiotapes and videotapes; computer software; and most recently, sites on the World Wide Web. The latter source is convenient for medical personnel and patients with access to personal computers. The AHA, for example, maintains a Web site (http://www.americanheart.org) that presents detailed and practical dietary recommendations, information about physical activity, and a thorough discussion of heart attacks and cardiopulmonary resuscitation (CPR). There also are links to other Web sites, such as the National Cholesterol Education Program. For patients who do not have access to a computer, work stations can be set up in the clinic or physician’s office, relevant pages can be printed, or patients can be referred to hospital or public libraries.

6. Develop a plan with the patient. It is necessary to convey a great deal of information to patients about their condition. It is advisable to hold discussions over time, taking into consideration many factors, which include the patient’s level of sophistication and prior educational attainment, language barriers, relevant clinical factors, and social support. For example, it might be counterproductive to attempt to coax a patient into simultaneously changing several behaviors, such as smoking, diet, exercise, and taking (and purchasing) multiple new medications. Achieving optimal adherence often requires problem solving with the patient. To improve compliance with medications, the healthcare provider may need to spend time understanding the patient’s schedule and suggesting strategies such as placing pill containers by the toothbrush or purchasing a watch with multiple alarms to serve as reminders.

7. Involve family members in educational efforts. It is advisable and often necessary to include family members in educational efforts. Many topics such as dietary changes require the involvement of the person who actually prepares the meals. Efforts to encourage smoking cessation or weight loss or increase physical activity may be enhanced by enlisting the support of family members who can reinforce messages and may themselves benefit from participation.

8. Remind, repeat, and reinforce. Almost all learning deteriorates without reinforcement. At regular intervals, the patients’ understanding should be reassessed, and key information should be repeated as warranted. Patients should be congratulated for progress even when their ultimate goals are not fully achieved. Even though the patient who has reduced his or her use of cigarettes from two packs to one pack per day has not quit smoking, that 50% reduction in exposure is important and may simply represent a milestone on the path to complete cessation.

2. Information for Patients

There is a great deal of information that patients with ischemic heart disease want to and should learn. This information falls into the categories listed in the following section.

General Aspects of Ischemic Heart Disease

PATHOLOGY AND PATHOPHYSIOLOGY. Patients vary in the level of detail they want to know about ischemic heart disease. Because therapy for angina is closely tied to the underlying pathophysiology, an understanding of these derangements and the effects of medications or interventions often helps patients to comply with therapy. Patients are often interested in learning about their own coronary anatomy and its relationship to cardiac events (683).

RISK FACTORS. It is useful to review the important known risk factors.

Complications. Some patients may want to know about the potential complications of ischemic heart disease, such as unstable angina, MI, heart failure, arrhythmia, and sudden cardiac death.

Patient-Specific Information

PROGNOSIS. Most patients are keenly interested in understanding their own risk of complications, especially in the short term. To the extent possible, it is useful to provide numerical estimates for risk of infarction or death due to cardiovascular events, because many patients assume that their short-term prognosis is worse than it actually is.

TREATMENT. Patients should be informed about their medications, including mechanisms of action, method of administration, and potentially adverse effects. It is helpful to be as specific as possible and to tie this information in with discussions of pathophysiology. For example, it can be explained that aspirin reduces platelet aggregation and prevents clot formation or that beta-blockers reduce myocardial oxygen demand. Patients should be carefully instructed about how and when to take their medications. For example, they should be told exactly when (i.e., immediately when pain begins or before stressful activity) and how often (i.e., three times spaced five minutes apart if pain persists) to take sublingual nitrates and to sit down before taking the medication. Complete explanations of other tests and interventions should also be provided.

PHYSICAL ACTIVITY. The healthcare provider should have an explicit discussion with all patients about any limitations on physical activity. For most patients, this will consist of reassurance about their ability to continue normal activities, including sexual relations (684). Patients in special circumstances, for example, those who engage in extremely strenuous activity or have a high-risk occupation, may require special counseling. As mentioned previously, men with impotence who are considering the use of sildenafil should be warned of the potentially serious consequences of using both sildenafil and nitrates within 24 hours of one another (608).

RISK FACTOR REDUCTION. It is essential that individual risk factors be reviewed with every patient. To engage patients in an effective program of behavioral change that will lessen the probability of subsequent cardiovascular events, a clear understanding of their relevant risk factors is required. The greatest emphasis should be placed on modifiable factors, beginning with those that have the greatest potential for reducing risk or are most likely to be favorably influenced. For example, for an obese smoker, a greater initial reduction in risk would likely be realized through attention to smoking cessation than by pursuit of significant weight reduction.

CONTACTING THE MEDICAL SYSTEM. It is critically important that all patients and their families be clearly instructed about how and when to seek medical attention. In many communities, a major obstacle to effective therapy for acute coronary events is the failure of patients to promptly activate the emergency medical system (685,686). Patients should be given an action plan that covers 1) prompt use of aspirin and nitroglycerin if available, 2) how to access emergency medical services, and 3) location of the nearest hospital that offers 24-h emergency cardiovascular care. Reviewing the description of possible symptoms of myocardial infarction and the action plan in simple, understandable terms at each visit is extremely important. Discussions with patients and family members should emphasize the importance of acting promptly.

Other Information. In individual circumstances, special counseling is warranted. One quarter million people with ischemic heart disease die suddenly each year (687). For this reason, in many patients, CPR training for family members is advisable. Although some may find this anxiety-provoking, others appreciate having the potential to intervene constructively and not feel helpless if cardiac arrest occurs (688).

Patients and their families should also be counseled when a potentially heritable condition such as familial hypercholesterolemia is responsible for premature coronary disease. In summary, patient education requires a substantial investment in time by primary-care providers and specialists using an organized and thoughtful approach. The potential rewards for patients are also substantial in terms of improved quality of life, satisfaction, and adherence to medical therapy. As a result, many should also have improved physical function and survival.

D. Coronary Disease Risk Factors and Evidence That Treatment Can Reduce the Risk for Coronary Disease Events Recommendations for Treatment of Risk Factors

Class I

1. Treatment of hypertension according to Joint National Conference VI guidelines. (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).Exercise training program. (Level of Evidence: B)

5. LipidLow-density lipoprotein-lowering therapy in patients with documented or suspected CAD and LDL cholesterol greater than or equal to 130 mg per dl, with a target LDL of less than 100 mg/dl. (Level of Evidence: A)

6. Weight reduction in obese patients in the presence of hypertension, hyperlipidemia, or diabetes mellitus. (Level of Evidence: C)

Class IIa

1. Lipid-lowering therapyIn patients with documented or suspected CAD and LDL cholesterol 100 to 129 mg/dl, several therapeutic options are available: with a target LDL <100 mg/dl. (Level of Evidence: B)

a. Lifestyle and/or drug therapies to lower LDL to less than 100 mg per dl. (Level of Evidence: B)

b. Weight reduction and increased physical activity in persons with the metabolic syndrome. (Level of Evidence: B)

c. Institution of treatment of other lipid or nonlipid risk factors; consider use of nicotinic acid or fibric acid for elevated triglycerides or low HDL cholesterol. (Level of Evidence: B)

2. Therapy to lower non-HDL cholesterol in patients with documented or suspected CAD and triglycerides of greater than 200 mg per dl, with a target non-HDL cholesterol of less than 130 mg per dl. (Level of Evidence: B)

3. Weight reduction in obese patients in the absence of hypertension, hyperlipidemia, or diabetes mellitus. (Level of Evidence: C)

Class IIa
1. Hormone replacement therapy in postmenopausal women in the absence of contraindications. (Level of Evidence: B)

2. Weight reduction in obese patients in the absence of hypertension, hyperlipidemia or diabetes mellitus. (Level of Evidence: C)

31.Folate therapy in patients with elevated homocysteine levels. (Level of Evidence: C)

4. Vitamin C and E supplementation. (Level of Evidence: B)

52. Identification and appropriate treatment of clinical depression to improve CAD outcomes. (Level of Evidence: C)

63. Intervention directed at psychosocial stress reduction. (Level of Evidence: C)

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)

13. Chelation therapy. (Level of Evidence: C)

24.Garlic. (Level of Evidence: C)

35.Acupuncture. (Level of Evidence: C)

46.Coenzyme Q. (Level of Evidence: C)

1. Categorization of Coronary Disease Risk Factors

The 27th Bethesda Conference proposed the following categorization of CAD risk factors based both on the strength of evidence for causation and the evidence that risk factor modification can reduce risk for clinical CAD events (688). The benefit of this system is that it allows for changes in the categorization as new evidence becomes available. Of note, evidence of benefit from treating these risk factors comes from observational studies and clinical trials. Secondary prevention trials providing evidence of benefit from risk factor modification are identified, but rarely have such trials been limited to patients with chronic stable angina. Consequently, recommendations about risk factor treatment in patients with chronic stable angina are based largely on inference from primary and secondary intervention studies.

Category

I. Risk factors clearly associated with an increase in coronary disease risk for which interventions have been shown to reduce the incidence of coronary disease events.

II. Risk factors clearly associated with an increase in coronary disease risk for which interventions are likely to reduce the incidence of coronary disease events.

III. Risk factors clearly associated with an increase in coronary disease risk for which interventions might reduce the incidence of coronary disease events.

IV. Risk factors associated with an increase in coronary disease risk but that cannot be modified or the modification of which would be unlikely to change the incidence of coronary disease events.

2. Risk Factors for Which Interventions Have Been Shown to Reduce the Incidence of Coronary Disease Events

Category I risk factors must be identified and, when present, treated as part of an optimal secondary prevention strategy in patients with chronic stable angina (see Fig. 11). They are common in this patient population and readily amenable to modification, and their treatment can have a favorable effect on clinical outcome. For these reasons, they are discussed in greater detail than other risk factors.

Cigarette Smoking

The evidence that cigarette smoking increases the risk for cardiovascular disease events is based primarily on observational studies, which have provided overwhelming support for such an association (690). The 1989 Surgeon General’s report concluded, on the basis of case-control and cohort studies, that smoking increased cardiovascular disease mortality by 50% (691). A dose-response relationship has been reported between cigarettes smoked and cardiovascular disease risk in men (692) and women (693), with relative risks approaching 5.5 for fatal cardiovascular disease events among heavy smokers compared with nonsmokers (693). Smoking also amplifies the effect of other risk factors, thereby promoting acute cardiovascular events (694). Events related to thrombus formation, plaque instability, and arrhythmias are all influenced by cigarette smoking. A smoking history should be obtained in all patients with coronary disease as part of a stepwise strategy aimed at smoking cessation (Table 30).

The 1990 Surgeon General’s report (695) summarized clinical data that strongly suggested that smoking cessation reduces the risk of cardiovascular events. Prospective cohort studies show that the risk of MI declines rapidly in the first several months after smoking cessation. Patients who continue to smoke after acute MI have an increase in the risk of reinfarction and death; the increase in risk of death has ranged from 22% to 47%. Smoking also has been implicated in coronary bypass graft atherosclerosis and thrombosis. Continued smoking after bypass grafting is associated with a two-fold increase in the relative risk of death and an increase in nonfatal MI and angina.

Randomized clinical trials of smoking cessation have not been performed in patients with chronic stable angina. Three randomized smoking cessation trials have been performed in a primary prevention setting (696-698). Smoking cessation was associated with a reduction of 7% to 47% in cardiac event rates in these trials. The rapidity of risk reduction after smoking cessation is consistent with the known adverse effects of smoking on fibrinogen levels (699) and platelet adhesion (700). Other rapidly reversible effects of smoking include increased blood carboxyhemoglobin levels, reduced HDL cholesterol (701), and coronary artery vasoconstriction (702).

Patients with symptomatic coronary disease form the group most receptive to treatment directed to smoking cessation. Taylor and coworkers (703) have shown that no more than 32% of patients will stop smoking at the time of a cardiac event and that this rate can be significantly enhanced to 61% by a nurse-managed smoking cessation program. New behavioral and pharmacological approaches (including nicotine replacement therapy and buproprion) to smoking cessation are available for use by trained healthcare professionals (703). Few physicians are adequately trained in smokingcessation techniques. Identification of experienced allied healthcare professionals who can implement smoking cessation programs for patients with coronary disease is a priority. The importance of a structured approach cannot be overemphasized. The rapidity and magnitude of risk reduction, as well as the other health-enhancing benefits of smoking cessation, argue for the incorporation of smoking cessation in all programs of secondary prevention of coronary disease.

LDL Cholesterol

Total cholesterol level has been linked to the development of CAD events with a continuous and graded relation, beginning at levels of less than 180 mg per dl (719,720). Most of this risk is due to LDL cholesterol. Evidence linking LDL cholesterol and CAD is derived from extensive epidemiologic, laboratory, and clinical trial data. Epidemiologic studies indicate a 2% to 3% increase in risk for coronary events per 1% increase in LDL cholesterol level (721). Measurement of LDL cholesterol is warranted in all patients with coronary disease.

Evidence that LDL cholesterol plays a causal role in the pathogenesis of atherosclerotic coronary disease comes from randomized, controlled clinical trials of lipid-lowering therapy. Several primary and secondary prevention trials have shown that LDL cholesterol lowering is associated with a reduced risk of coronary disease events. Earlier lipid-lowering trials used bile-acid sequestrants (cholestyramine), fibric acid derivatives (gemfibrozil and clofibrate), or niacin in addition to diet. The reduction in total cholesterol in these early trials was 6% to 15% and was accompanied by a consistent trend toward a reduction in fatal and nonfatal coronary events. In seven of the early trials, the reduction in coronary events was statistically significant. Although the pooled data from these studies suggested that every 1% reduction in total cholesterol could reduce coronary events by 2%, the reduction in clinical events was 3% for every 1% reduction in total cholesterol in studies lasting at least five years.

Angiographic trials, for which a much smaller number of participants are required, provide firm evidence linking cholesterol reduction to favorable trends in coronary anatomy. In virtually all studies, the active treatment groups experienced less progression, more stabilization of lesions, and more regression than the control groups. More importantly, these trends toward more favorable coronary anatomy were linked to reductions in clinical events. A meta-analysis (707) of more than 2000 participants in 14 trials suggests that both LDL and HDL were important contributors to the beneficial effects.

The most recent studies of lipid-lowering therapy involve the HMG-CoA reductase inhibitors (statins). A reduction in clinical events has been demonstrated in both primary and secondary prevention settings. Among the most conclusive secondary prevention trials to evaluate the effects of cholesterol lowering on clinical events were 4S (533), CARE (534), and LIPID (970). In the 4S trial, mean changes with simvastatin in total cholesterol (-25%), LDL cholesterol (-35%), and HDL cholesterol (+8%) were statistically significant. These changes in blood lipids were associated with reductions of 30% to 35% in both mortality rate and major coronary events. Reductions in clinical events were noted in patients with LDL cholesterol levels in the lower quartiles at baseline, women, and patients greater than 60 years old. The study also demonstrated that long-term (five-year) administration of an HMG-CoA reductase-inhibiting drug statin was safe, and there was no increase in non-CHD death. In the CARE study, 4159 patients (3583 men and 576 women) with prior MI who had plasma total cholesterol levels less than 240 mg per dl (mean 209) and LDL cholesterol levels of 115 to 174 mg per dl (mean 139) were randomized to receive pravastatin or placebo. Active treatment was associated with a 24% reduction in risk (95% confidence interval, 9% to 36%; p = 0.003) for nonfatal MI or a fatal coronary event.

LIPID was similar to CARE, although with a larger sample size (9014 patients); the 24% reduction in death from CHD (8.3% in the placebo group, 6.4% in the treatment group) was highly significant (p less than 0.001).

The results of the largest cholesterol-lowering trial yet performed, the Heart Protection Study (HPS), were published as this update was in the final stages of preparation (958). This trial included more than 20 000 men and women aged 40 to 80 years with coronary disease, other vascular disease, diabetes, and/or hypertension. Patients were randomized to simvastatin 40 mg or matching placebo and were followed up for a mean of five years. The primary end point, total mortality, was reduced by statin treatment by approximately 25% overall and similarly in all important prespecified subgroups, including women, patients more than 75 years old, diabetics, and individuals with baseline LDL cholesterol of less than 100 mg per dl. Analysis of these data by all appropriate authorities, including the National Cholesterol Education Project, will be necessary to clarify their implications for these guidelines.

Thus, the clinical trial data indicate that in patients with established coronary disease, including chronic stable angina pectoris, dietary intervention and treatment with lipid-lowering medications should not be limited to those with extreme values. The benefits of lipid-lowering therapy were evident in patients in the lowest baseline quartile of LDL cholesterol (modest elevations) in 4S and in those with minimal elevation of LDL cholesterol level in the CARE study. These trials establish the benefits of aggressive lipid-lowering treatment for the most coronary disease patients, even when LDL cholesterol is within a range considered acceptable for patients in a primary prevention setting. For patients with established coronary disease, nonpharmaceutical treatment should be initiated when LDL cholesterol is >100 mg/dL, and drug treatment are warranted when LDL cholesterol is >130 mg/dL in the vast majority of patients. The goal of treatment is an LDL cholesterol level less than 100 mg per dl. When LDL cholesterol is 101 to 129 mg per dl, either at baseline or with LDL-lowering therapy, several therapeutic options are available:

•Initiate or intensify lifestyle and/or drug therapies specifically to lower LDL.

•Emphasize weight reduction and increased physical activity in persons with the metabolic syndrome (see page 74).

•Delay use or intensification of LDL-lowering therapies and institute treatment of other lipid or nonlipid risk factors; consider use of other lipid-modifying drugs (eg, nicotinic acid or fibric acid) if the patient has elevated triglyceride or low HDL cholesterol levels.

Finally, despite LDL cholesterol reduction, arteriographic progression continues in many patients with coronary disease. Arteriographic trials demonstrate continued coronary lesion progression in 25% to 60% of subjects even with the most aggressive LDL cholesterol lowering treatments.

Maximum benefit may require management of other lipid abnormalities (elevated triglycerides, low HDL cholesterol) and treatment of other atherogenic risk factors.

Hypertension

Data from numerous observational studies indicate a continuous and graded relation between blood pressure and cardiovascular disease risk (708,709). A meta-analysis by MacMahon and colleagues (710) of nine prospective, observational studies involving more than 400 000 subjects showed a strongly positive relationship between both systolic and diastolic blood pressure and CHD; the relationship was linear, without a threshold effect, and showed a relative risk that approached 3.0 at the highest pressures.

Hypertension probably predisposes patients to coronary events both as a result of the direct vascular injury caused by increases in blood pressure and because of its effects on the myocardium, including increased wall stress and myocardial oxygen demand.

The first and second Veterans Affairs Cooperative studies (711,712) were the first to definitively demonstrate the benefits of hypertension treatment. A meta-analysis of 17 randomized trials of therapy in more than 47 000 patients confirmed the beneficial effects of hypertension treatment on cardiovascular disease risk (713). More recent trials in older patients with systolic hypertension have underscored the benefits to be derived from lowering blood pressure in the elderly. A recent meta-analysis found that the absolute reduction of coronary events in older subjects (2.7 per 1000 person-years) was more than twice as great as that in younger subjects (1.0 per 1000 person-years) (714). This finding contrasts with clinical practice, in which hypertension often is less aggressively treated in older persons.

Clinical trial data on the effects of lowering blood pressure in hypertensive patients with established coronary disease are lacking. Nevertheless, blood pressure should be measured in all patients with coronary disease.

Hypertension Treatment

The National High Blood Pressure Education Program Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (21) recently recommended a system for categorizing levels of blood pressure and risk classes. Hypertension is present when the average blood pressure is greater than or equal to 140 mm Hg systolic or greater than or equal to 90 mm Hg diastolic. High normal blood pressure is present when the systolic blood pressure is 130 to 139 mm Hg or diastolic pressure is 85 to 89 mm Hg. The level of blood pressure and the concomitant presence of risk factors, coexisting cardiovascular disease, or evidence of target-organ damage are used in the classification of blood pressure severity and to guide treatment. Coronary disease, diabetes, LVH, heart failure, retinopathy, and nephropathy are indicators of increased cardiovascular disease risk. The target of therapy is a reduction in blood pressure to less than 130 mm Hg systolic and less than 85 mm Hg diastolic in patients with coronary disease and coexisting diabetes, heart failure, or renal failure and less than 140 per 90 mm Hg in the absence of these coexisting conditions.

Hypertensive patients with chronic stable angina are at high risk for cardiovascular disease morbidity and mortality. The benefits and safety of hypertension treatment in such patients have been established (715,716). Treatment begins with nonpharmacologic means. When lifestyle modifications and dietary alterations adequately reduce blood pressure, pharmacologic intervention may be unnecessary. The modest benefit of antihypertensive therapy for coronary event reduction in clinical trials may underestimate the efficacy of this therapy in hypertensive patients with established coronary disease, because in general, the higher the absolute risk of the population, the greater the magnitude of response to therapy.

Lowering the blood pressure too rapidly, especially when it precipitates reflex tachycardia and sympathetic activation, should be avoided. Blood pressure should be lowered to less than 140 over 90 mm Hg, and even lower blood pressure is desirable if angina persists. When pharmacologic treatment is necessary, beta-blockers or calcium channel antagonists may be especially useful in patients with hypertension and angina pectoris; however, short-acting calcium antagonists should not be used (581,582,717). In patients with chronic stable angina who have had a prior MI, beta-blockers without intrinsic sympathomimetic activity should be used, because they reduce the risk for subsequent MI or sudden cardiac death. Use of ACE inhibitors is also recommended in hypertensive patients with angina in whom LV systolic dysfunction is present, to prevent subsequent heart failure and mortality (715). If beta-blockers are contraindicated (e.g., because of the presence of asthma) or ineffective in controlling blood pressure or angina symptoms, verapamil or diltiazem should be considered, because they have been shown to modestly reduce cardiac events and mortality after non-Qwave MI and after MI with preserved LV function (1,718,719,892).

Finally, the risk of hypertension cannot be taken in isolation. This risk is unevenly distributed and closely related to the magnitude and number of coexisting risk factors, including hyperlipidemia, diabetes, and smoking (720).

Left Ventricular Hypertrophy

Left ventricular hypertrophy is the response of the heart to chronic pressure or volume overload. Its prevalence and incidence are higher with increasing levels of blood pressure (721). Epidemiologic studies have implicated LVH as a risk factor for development of MI, CHF, and sudden death (722,723). Its association with increased risk has been described in hospital and clinic-based studies (373,724,725) and population studies (371,372,726). Left ventricular hypertrophy has also been shown to predict outcome in patients with established CAD (727).

There is a growing body of evidence in hypertensive patients that LVH regression can occur in response to pharmacologic and nonpharmacologic (728,729) antihypertensive treatment. Recent data suggest that regression of LVH can reduce the cardiovascular disease burden associated with this condition. A report from the Framingham Heart Study found that subjects who demonstrated ECG evidence of LVH regression were at a substantially reduced risk for a cardiovascular event (50) compared with subjects who did not. Studies are needed to definitively establish the direct benefits of LVH regression. There are no clinical trials of LVH regression in patients with chronic stable angina.

Thrombogenic Factors

Coronary artery thrombosis is a trigger of acute MI. Aspirin has been documented to reduce risk for CHD events in both primary and secondary prevention settings (730). A number of prothrombotic factors have been identified and can be quantified (731). In the Physicians’ Health Study, men in the top quartile of C-reactive protein values had three times the risk of MI and two times the risk of ischemic stroke compared with men with the lowest quartile values (732). The reduction in risk of MI associated with the use of aspirin was directly related to the level of C-reactive protein.

Elevated plasma fibrinogen levels predict CAD risk in prospective observational studies (733). The increase in risk related to fibrinogen is continuous and graded (734). In the presence of hypercholesterolemia, a high fibrinogen level increases CHD risk more than six times (735), whereas a low fibrinogen level is associated with reduced risk, even in the presence of high total cholesterol levels (736). Elevated triglycerides, smoking, and physical inactivity are all associated with increased fibrinogen levels. Exercise and smoking cessation appear to favorably alter fibrinogen levels, as do fibric acid-derivative drugs. Reducing fibrinogen levels could lower coronary disease risk by improving plasma viscosity and myocardial oxygen delivery and diminishing the risk of thrombosis (731). Anticoagulant or antiplatelet therapy may reduce the hazards associated with an elevated fibrinogen level even though these agents do not lower the fibrinogen level itself.

Several studies support an association between platelet function and vascular disease, a finding consistent with the known role of platelets in thrombosis, which is a precipitant of acute CAD events (731). Measures of platelet hyperaggregability, including the presence of spontaneous platelet aggregation (737) and increased platelet aggregability induced by conventional stimuli (738), provide evidence of an association between platelet aggregability and an increased risk for CAD events in both cohort and cross-sectional studies. This may explain the proved benefits of aspirin therapy in both primary and secondary prevention settings.

Other potential thrombogenic/hemostatic risk factors include factor VII, plasminogen activator inhibitor-1, tissue plasminogen activator, von Willebrand factor, protein C, and antithrombin III (731,739). It is probable that anticoagulants can affect several of these factors, partially explaining their influence on decreasing CAD risk in certain secondary

prevention settings.

3. Risk Factors for Which Interventions Are Likely to Reduce the Incidence of Coronary Disease Events

Diabetes Mellitus

Diabetes, which is defined as a fasting blood sugar greater than 126 mg per dl (740), is present in a significant minority of adult Americans. Data supporting an important role of diabetes mellitus as a risk factor for cardiovascular disease come from a number of observational settings. This is true for both type I, insulin-dependent diabetes mellitus, and type II, non-insulin-dependent diabetes mellitus. Atherosclerosis accounts for 80% of all diabetic mortality (741-743), with coronary disease alone responsible for 75% of total atherosclerotic deaths. In persons with type I diabetes, coronary mortality is increased three- to ten-fold; in patients with type II diabetes, risk for coronary mortality is two-fold greater in men and four-fold greater in women. The National Cholesterol Education Program estimates that 25% of all heart attacks in the United States occur in patients with diabetes (744,745). Diabetes is associated with a poor outcome in patients with established coronary disease, even after angiographic and other clinical characteristics are considered. For example, diabetic persons in the CASS registry experienced a 57% increase in the hazard of death after controlling for other known risk factors (746).

Although better metabolic control in persons with type I diabetes has been shown to lower the risk for microvascular complications (741,747-749), there is a paucity of data on the benefits of tighter metabolic control in type I or type II diabetes with regard to reducing risk for coronary disease in either primary or secondary prevention settings. At present, it is worthwhile to pursue strict glycemic control in diabetic persons with chronic stable angina with the belief that this will provide benefits with regard to microvascular complications and also may reduce risk for other cardiovascular disease complications. However, convincing data from clinical trials are lacking. The long-standing controversy regarding the potentially adverse effects of oral hypoglycemic agents persists (750).

The common coexistence of other modifiable factors in the diabetic patient contributes to increased coronary disease risk, and they must be managed aggressively (751,752). These risk factors include hypertension, obesity, and increased LDL cholesterol levels. In addition, elevated triglyceride levels and low HDL cholesterol levels are common in persons with diabetes.

NON-HDL CHOLESTEROL. The finding that elevated triglycerides are an independent CHD risk factor suggests that some triglyceride-rich lipoproteins are atherogenic. The latter are partially degraded very low density lipoproteins (VLDL), commonly called “remnant lipoproteins.” In clinical practice, non-HDL cholesterol is the most readily available measure of atherogenic remnant lipoproteins. Thus, non-HDL cholesterol can be a target of cholesterol-lowering therapy. Moreover, non-HDL cholesterol is highly correlated with total apolipoprotein B (apoB) (977,978); apoB is the major apolipoprotein of all atherogenic lipoproteins. Serum total apoB also has been shown to have a strong predictive power for severity of coronary atherosclerosis and CHD events (979-986). Because of the high correlation between non-HDL cholesterol and apoB levels (977,978), non-HDL cholesterol represents an acceptable surrogate marker for total apoB; the latter is not widely available for routine measurement in clinical practice. Therefore, the National Cholesterol Education Program Adult Treatment Panel III (ATP III) (987) identifies the sum of LDL and VLDL cholesterol (termed “non-HDL cholesterol” [total cholesterol - HDL cholesterol]) as a secondary target of therapy in persons with high triglycerides (greater than 200 mg per dl). The goal for non-HDL cholesterol (for persons with serum triglycerides greater than or equal to 200 mg per dl) is 130 mg per dl; this is 30 mg per dl higher than the goal for LDL cholesterol, because the normal VLDL cholesterol level is 30 mg per dl.

HDL CHOLESTEROL. Observational studies and clinical trials have documented a strong inverse association between HDL cholesterol and CAD risk. It has been estimated that a 1-mg per dl decline in HDL cholesterol is associated with a 2% to 3% increase in risk for coronary disease events (753). This inverse relation is observed in men and women and among asymptomatic persons as well as patients with established coronary disease.

Low levels of HDL cholesterol are often observed in persons with adverse risk profiles (obesity, metabolic syndrome [see page 74], impaired glucose tolerance, diabetes, smoking, high levels of LDL cholesterol and triglycerides, and physical inactivity). Although low levels of HDL are clearly associated with increased risk for CHD and there is good reason to conclude that such a relation is causal (e.g., biological plausibility), it has been difficult to demonstrate that raising HDL lowers CHD risk. No completed trial has been able to address the efficacy of raising HDL cholesterol alone;Analysis is complicated because completed trials have used drugs that raise HDL and also lower LDL cholesterol or triglyceride levels. The recent Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) trial (988), however, revealed that modification of other lipid risk factors can reduce risk for CHD when LDL cholesterol is in the range of 100 to 129 mg per dl. In this trial, patients with low LDL (mean 112 mg per dl) were treated with gemfibrozil for five years. Gemfibrozil therapy, which raised HDL and lowered triglyceride, reduced the primary end point of fatal and nonfatal MI by 22% without significantly lowering LDL cholesterol levels. There was no suggestion of an increased risk of non-CHD mortality. As mentioned previously, when LDL cholesterol is 101 to 129 mg per dl, the use of other lipid-modifying drugs (e.g., nicotinic acid or fibric acid) should be considered if the patient has a low HDL cholesterol.

The National Cholesterol Education Program ATP IIIII has defined a low HDL cholesterol level as less than 35 40 mg per dl (754,987). Patients with established coronary disease and low HDL cholesterol are at high risk for recurrent events and should be targeted for aggressive nonpharmacologic treatment (dietary modification, weight loss, and/or physical exercise) and, when appropriate, drug treatment directed at the entire lipid profile. ATP III does not specify a goal for HDL raising. Although clinical trial results suggest that raising HDL will reduce risk, the evidence is insufficient to specify a goal of therapy. Furthermore, currently available drugs do not robustly raise HDL cholesterol. A low HDL level should receive clinical attention and management according to the following sequence. In all persons with low HDL cholesterol, the primary target of therapy is LDL cholesterol; ATP III guidelines for diet, exercise, and drug therapy should be followed to achieve the LDL cholesterol goal. Second, after the LDL goal has been reached, emphasis shifts to other issues. When a low HDL cholesterol level is associated with high triglycerides (200 to 499 mg per dl), secondary priority goes to achieving the non-HDL cholesterol goal, as outlined earlier. Also, if triglycerides are less than 200 mg per dl (isolated low HDL cholesterol), drugs to raise HDL (fibrates or nicotinic acid) can be considered. Nicotinic acid and fibrates usually raise HDL levels appreciably, as do HMG-CoA reductase inhibitors. and estrogen replacement therapy to a lesser degree. The benefits of lowering LDL levels in coronary disease patients who have low HDL cholesterol and LDL levels <130 mg/dL have not been established, nor have the benefits of raising HDL levels in such persons.

Triglycerides

Triglyceride levels are predictive of CHD risk in a variety of observational studies and clinical settings (817). Much of the association of triglycerides with CHD risk is related to other factors, including diabetes, obesity, hypertension, high LDL cholesterol, and low HDL cholesterol (818). In addition, hypertriglyceridemia is often found in association with abnormalities in hemostatic factors (819). Recently, however, a borderline (150 to 199 mg per dl) or high triglyceride level (greater than 200 mg per dl) has been established by meta-analyses of prospective studies as an independent risk factor for CHD (987,989,990).

Nonpharmacologic management of high triglycerides consists of weight loss, reduction in alcohol consumption for those in whom this mechanism may be causal, smoking cessation, and increased physical activity. Drugs that can lower triglycerides include nicotinic acid, fibrate derivatives, and, to a lesser degree, statins. It is not clear whether treatment directed at high triglyceride levels will reduce risk for initial or recurrent CHD events. Also, triglyceride measurements vary considerable for individual patients. Accordingly, the ATP III (987) provides guidance for the management of elevated triglyceride levels by focusing on a combination of therapeutic lifestyle changes and by a secondary lipid target for non-HDL cholesterol.

Obesity

Obesity is a common condition associated with increased risk for coronary disease and mortality (755,756). Obesity is defined as a body mass index (weight in kilograms divided by the square of height in meters) of 30 kg per m2, and overweight begins at 25 kg per m2 (991). Obesity is associated with and contributes to other coronary disease risk factors, including high blood pressure, glucose intolerance, low HDL cholesterol, and elevated triglyceride levels. Hence, much of the increased CAD risk associated with obesity is mediated by these risk factors. Risk is particularly raised in the presence of abdominal obesity, which can be identified by a waist circumference greater than 102 cm (40 inches) in men or 88 cm (35 inches) in women (991). Because weight reduction in overweight and obese people is a method to reduce multiple other risk factors, it is an important component of secondary prevention of CHD. It is likely that for obese patients with coronary disease, weight reduction can reduce risk for future coronary events because weight reduction will bring about improvements in these other modifiable risk factors. Because of the increased myocardial oxygen demand imposed by obesity and the demonstrated effects of weight loss on other coronary disease risk factors, weight reduction is indicated in all obese patients with chronic stable angina. Referral to a dietitian is often necessary to maximize the likelihood of success of a dietary weight loss program. No clinical trials have specifically examined the effect of weight loss on risk for coronary disease events.

Physical Inactivity

The evidence and recommendations presented here are based heavily on previously published documents, particularly the 27th Bethesda Conference on risk factor management (23), the Agency for Health Care Policy and Research (AHCPR)/NHLBI clinical practice guideline on cardiac rehabilitation (24), and the AHA scientific statement on exercise (757). Interested readers are referred to those documents for more detailed discussions of the evidence and organizational issues regarding performance of exercise training. Although this section focuses on the effects of exercise training, it is important to recognize that such training is usually incorporated into a multifactorial risk factor reduction effort, which includes smoking cessation, lipid management, and hypertension treatment, all of which have been covered in previous sections. Many of the studies performed in the literature have tested multifactorial intervention rather than exercise training alone. The evidence presented here therefore assumes that exercise training is incorporated into such a multifactorial program whenever possible.

A large portion of the published evidence regarding exercise training focuses on post-MI or post-coronary revascularization patients. Although it is attractive to apply this evidence to patients with stable angina, such an extrapolation is not appropriate, because most patients with stable angina have not had an MI or undergone coronary revascularization, and patients with MI are more likely to have three-vessel or left main coronary artery disease and a more adverse shortterm prognosis. This section therefore focuses on published data from patients with stable angina and, for the most part, will exclude data derived from patients with previous MI or coronary revascularization. The single exception is the sub-section on safety issues, because the committee thought that the risk of exercise training in patients with stable angina should be no greater than that in patients with recent MI, who have been studied extensively.

Any discussion of exercise training must acknowledge that it not only will usually be incorporated into a multifactorial intervention program but will have multiple effects. It is biologically difficult to separate the effects of exercise training from the multiple secondary effects that it may have on confounding variables. For example, exercise training may lead to changes in patient weight, patient’s sense of well-being, and antianginal medication. These effects will be clear confounders in interpreting the impact of exercise training on exercise tolerance, patient symptoms, and subsequent cardiac events. This presentation will assume that the primary and secondary effects of exercise training are closely intertwined and will make no effort to distinguish them.

4. Effects of Exercise Training on Exercise Tolerance, Symptoms, and Psychological Well-Being

Multiple randomized, controlled trials comparing exercise training with a no-exercise control group have demonstrated a statistically significant improvement in exercise tolerance for the exercise group versus the control group. These data, which are summarized in Table 31, are remarkable for several features. First, they are remarkably consistent (eight of nine studies with positive results; the single exception studied disabled patients) despite small sample sizes, multiple different outcome variables, and variable length of follow-up (24 days to 4 years). Four of the nine studies incorporated exercise training into a multifactorial intervention; five tested exercise training alone. A variety of different settings were used, including outpatient rehabilitation centers, home rehabilitation monitoring, and a residential unit. The major limitation of the published evidence is that it is based almost exclusively on male patients. Six of the nine studies (705,758-762) enrolled male patients exclusively. Two studies did not provide data about the gender of the patients enrolled (763,764). The largest study of 300 patients (765) enrolled only 41 women. Thus, there is relatively little evidence from randomized trials to confirm the efficacy of exercise training in female patients. Observational studies (766-768) have suggested that women benefit at least as much as men.

Given the consistently positive effect of exercise training on exercise capacity, it is not surprising that it also results in an improvement in symptomatology. However, the number of randomized trials demonstrating this point in patients with stable CHD is far fewer. As shown in Table 32, the three published randomized trials (758,769,770) have enrolled fewer than 250 patients. Two of the three studies (758,770) demonstrated a statistically significant decrease in patient symptoms, but one did not (769). The overall magnitude of these effects was modest.

Four randomized trials have examined the potential benefit of exercise training on objective measures of ischemia (Table 32). One study used ST-segment depression on ambulatory monitoring, and three used exercise myocardial perfusion imaging with 201T1. Three of the four studies (759,763,770) demonstrated a reduction in objective measures of ischemia in those patients randomized to the exercise group compared with the control group. The last study (705) reported a significant decrease in ST depression during exercise but not in the exercise thallium defect or thallium redistribution. Although it is not specifically demonstrated in these studies, the threshold for ischemia is likely to increase with exercise training, because training reduces the heart rate-blood product at a given submaximal exercise workload. There is a widespread belief among cardiac rehabilitation professionals that exercise training improves patients’ sense of well-being. Although multiple randomized trials have used a variety of instruments to measure significant differences in various psychological outcomes between the exercise group and the control group, these trials have been conducted in post-MI patients. Given the underlying biological differences outlined above and the well-documented effects of MI on patients’ sense of well-being, these results are not easily extrapolated to patients with stable angina. A single nonrandomized trial compared multifactorial intervention (including exercise and psychological intervention) in 60 treated patients with 60 control patients (771). Follow-up was performed three months later. There was a significant reduction in disability scores, an improvement in well-being scores, and an improvement in positive affect scores in the intervention group. Thus, the evidence supporting an improvement in psychological parameters with exercise training in patients with stable angina is very limited.

Lipid Management and Disease Progression

Multiple randomized trials have examined the potential benefit of exercise training in the management of lipids (Table 33). Some of these trials have examined exercise training alone; others have studied exercise training as part of a multifactorial intervention. Again, the majority of subjects studied have been male. Of the 1827 patients studied, only 52 were women. Most studies had a follow-up of one year. One study used a 24-day follow-up. Two other studies used much longer follow-ups of 39 months and four years, respectively.

Most studies have found a statistically significant reduction in total cholesterol and LDL cholesterol (where reported) favoring the intervention group, but this finding has not been totally uniform. One larger, older study (772) did not show a significant reduction in cholesterol in the treatment group, along with one more recent small study (773). Five of the seven studies that reported the results of intervention on triglycerides found a significant reduction favoring the treatment group; two studies of 88 and 48 patients, respectively, did not (761,762). The results of intervention on HDL cholesterol have been far less impressive. Only one study (765) reported a statistically significant increase in HDL cholesterol favoring the treatment group. Four others (705,761, 762,774) have not found any difference between the control and treatment groups. One study found a decrease in HDL cholesterol in the treatment group. The preponderance of evidence clearly suggests that exercise training is beneficial and associated with a reduction in total cholesterol, LDL cholesterol, and triglycerides compared with controlled therapy but that it has little effect on HDL cholesterol. However, it must be recognized that exercise training alone is unlikely to be sufficient in patients with a true lipid disorder.

Not surprisingly, this reduction in lipids has been associated with less disease progression according to angiographic follow-up. Four of the randomized trials of lipid management, all involving multifactorial intervention, performed follow-up angiography to assess disease progression. Three of the studies performed follow-up angiography at one year; the remaining study performed angiographic follow-up at four years. All the studies demonstrated significantly less disease progression and more disease regression in the intervention group.

Although exercise training has a beneficial effect on disease progression, it has not been associated with any consistent changes in cardiac hemodynamic measurements (775-777), LV systolic function (778-780), or coronary collateral circulation (763). In patients with heart failure and decreased LV function, exercise training does produce favorable changes in the skeletal musculature (781), but there has not been a consistent effect on LV dysfunction (782,783).

Safety and Mortality

Physicians and patients are sometimes concerned about the safety of exercise training in patients with underlying coronary disease. Two major surveys of rehabilitation programs have been conducted to determine the rates of cardiovascular events based on questionnaire responses. One study of 30 programs in North America covering the period of 1960 to 1977 (780) found a nonfatal cardiac arrest rate of 1 per 32593 patient-hours of exercise and a nonfatal MI rate of 1 per 34600 patient-hours of exercise. A more recent study of 142 U.S. cardiac programs from 1980 to 1984 (784) reported an even lower nonfatal MI rate of 1 per 294 000 patient-hours. Thus, there is clearly a very low rate of serious cardiac events during cardiac rehabilitation.

These survey data are supported by the results of randomized trials after MI. As indicated earlier, the committee believes that these data can be appropriately extrapolated to patients with stable angina, because it is unlikely that patients with stable angina are at greater risk than those who have experienced an MI. Fifteen randomized control trials, 10 of which involved exercise as the major intervention and five of which used exercise as part of a multifactorial intervention, reported no statistically significant differences in the rates of reinfarction comparing patients in the intervention group with those in the control group (24). These randomized data clearly support the safety of exercise training. It is important to recognize that recent clinical practice, including acute reperfusion therapy for MI, the use of beta-blockers and ACE inhibitors after MI, and the aggressive use of revascularization, has probably further reduced the risk of exercise training compared with the previously reported literature.

Given its effects on lipid management and disease progression, it is attractive to hypothesize that exercise training will reduce the subsequent risk of cardiac events. However, only one clinical trial has examined the influence of exercise training on subsequent cardiac events in patients with stable angina. Haskell et al. (765) enrolled 300 patients with stable angina, including some who were postrevascularization, in a four-year follow-up study comparing multifactorial intervention with usual care. The cardiac event rate in the study was low. There were three cardiac deaths in the usual-care group and two in the intervention group, as well as ten nonfatal MIs in the usual-care group and four in the intervention group. When cardiac events initiating hospitalization, including death, MI, PCI, and CABG, were tabulated, there were a total of 25 events in the intervention group and 44 in the usual-care group (risk ratio 0.61; p = 0.05). However, the cardiac event rate was not a primary a priori end point of the study. Although these data suggest a favorable effect of exercise training on patient outcome, they are clearly not definitive. In contrast, several meta-analyses of randomized trials in patients with previous MI have shown a 20% to 30% reduction in cardiac deaths with exercise training (678,785) but no reduction in nonfatal MI.

THE METABOLIC SYNDROME. Evidence is accumulating that risk for future CHD events can be reduced beyond LDL-lowering therapy by modification of a specific secondary target of therapy-the metabolic syndrome-represented by a constellation of lipid and nonlipid risk factors of metabolic origin. This syndrome is closely linked to a generalized metabolic disorder called insulin resistance, in which the normal actions of insulin are impaired. Excess body fat (particularly abdominal obesity) and physical inactivity promote the development of insulin resistance, but some individuals also are genetically predisposed to insulin resistance. In a field that has been confused by nomenclature, ATP III has introduced a standard definition for the diagnosis of the metabolic syndrome, as shown in Table 33a. The metabolic syndrome is considered to be present when three or more of the characteristics are present.

Management of the metabolic syndrome has a two-fold objective: (1) to reduce underlying causes (i.e., obesity and physical inactivity) and (2) to treat associated nonlipid and lipid risk factors. First-line therapies for all lipid and nonlipid risk factors associated with the metabolic syndrome are weight reduction and increased physical activity, after appropriate control of LDL cholesterol. In patients with triglycerides greater than 200 mg per dl, a non-HDL cholesterol goal of less than 130 mg per dl is a secondary target (see Table 33a).

5. Risk Factors for Which Interventions Might Reduce the Incidence of Coronary Disease Events

Psychosocial Factors

The evidence and recommendations presented here are based heavily on previously published documents, including the 27th Bethesda Conference on Risk Factor Management (23) and the AHCPR/NHLBI clinical practice guideline on cardiac rehabilitation (24). More detailed discussions of the complex issues involved are available in those documents.

Education, counseling, and behavioral interventions are important elements of a multifactorial risk factor reduction effort directed at smoking cessation, lipid management, and hypertension treatment, as previously mentioned. The evidence presented here therefore assumes that appropriate multifactorial intervention has been initiated in those areas and considers the specific application of similar broad-based efforts to reduce stress and address other psychological problems.

Most of the published evidence on stress management focuses on patients who are post-MI or postrevascularization. The extrapolation of the findings from such patient populations to patients with stable angina is questionable. Patients with MI are further along in the natural history of CAD, and the occurrence of MI may have itself altered their psyche, creating psychological problems or a difference in their overall response to general life stresses. Unfortunately, the published data regarding stress management in patients with stable angina are quite limited.

EVIDENCE LINKING STRESS AND PSYCHOLOGICAL FACTORS TO CAD. A variety of psychological factors, particularly type A personality, have been associated with the development of clinically apparent CAD (800,801). Epidemiologic evidence linking such psychological factors to CAD has not always been consistent (802-805). Psychological stress, depression, anger, and hostility (806,807) may be even more closely associated with coronary risk. More recently, studies have focused more specifically on measures of hostility, which appears to have a more powerful influence on coronary disease outcome than other psychosocial factors (808,809).

TREATMENT DIRECTED AT STRESS REDUCTION AND PSYCHOLOGICAL WELL-BEING. A number of randomized trials involving post-MI patients have shown that interventions designed to reduce stress can reduce recurrent cardiac events by 35% to 75% (810-812). The trials were generally small and used a wide variety of different approaches, including relaxation training, behavior modification, and psychosocial support. Other psychological outcomes were also improved by intervention (24). However, for the reasons indicated above, it is not evident whether such results apply to patients with stable angina.

Two studies on stress management are potentially applicable to patients with stable angina. One was a small, nonrandomized trial of three weeks of relaxation training in association with a cardiac exercise program (813). Anxiety, somatization, and depression scores were all lower in the treatment than the control group. More recently, Blumenthal et al. (814) examined the effects of a four-month program of exercise or stress management training in 107 patients with CAD and documented ischemia. Forty patients were assigned to a nonrandom, usual-care comparison group. The remaining patients were randomized to either exercise or stress management. The stress-management program included patient education, instruction in specific skills to reduce the components of stress, and biofeedback training. During follow-up of 38 plus or minus 17 months, there was a significant reduction in overall cardiac events in the stress-management group compared with the nonrandom usual-care group. However, virtually all the events consisted of CABG or angioplasty. The exercise group had an event rate that was not statistically significantly different from either of the other groups. The predominance of revascularization events could potentially reflect a change in patient preference for revascularization as a result of education.

DEPRESSION AND ANXIETY. Many patients with CAD have depression or anxiety related to their disease that may be severe enough to benefit from short-term psychological treatment (815,816). Identification and treatment of depression should therefore be incorporated into the clinical management of patients with stable angina, but there is no evidence that it will reduce cardiac events. The safety of pharmacologic therapy for depression in patients with ischemic heart disease is under investigation.

Triglycerides

Triglyceride levels are predictive of CHD risk in a variety of observational studies and clinical settings (817). Much of the association of triglycerides with CHD risk is related to other factors, including diabetes, obesity, hypertension, high LDL cholesterol and low HDL cholesterol (818). In addition, hypertriglyceridemia is often found in association with abnormalities in hemostatic factors (819).

Nonpharmacologic management of high triglycerides consists of weight loss, reduction in alcohol consumption for those in whom this mechanism may be causal, smoking cessation and physical activity. Drugs that can lower triglycerides include nicotinic acid, fibrate derivatives, and to a lesser degree HmG CoA reductase inhibitors. It is not clear whether treatment directed at high triglyceride levels will reduce risk for initial or recurrent CHD events. Data from the Helsinki study (820) indicated that among patients with elevated non-HDL cholesterol, treatment with gemfibrozil reduced risk for CHD events. This reduction in risk may be linked to the effects of treatment on lipid components other than triglyceride level. A 1992 consensus development conference defined triglycerides of 200 to 400 mg/dL as “borderline high,” 400 to 1000 mg/dL as “high,” and >1000 mg/dL as “very high” (821). The National Cholesterol Education Program Adult Treatment Panel II provides guidance for the management of elevated triglyceride levels (754).

Lipoprotein(a)

Lipoprotein(a) [Lp(a)] is a lipoprotein particle that has been linked to CHD risk in observational studies (822,823). Lipoprotein(a) levels are largely genetically determined (822). Elevated Lp(a) levels are found in 15% to 20% of patients with premature CHD (824). Among conventional lipid agents, only niacin taken in high doses lowers Lp(a) levels (822). No prospective intervention trial has specifically studied the effect of Lp(a) lowering on risk of recurrent coronary disease events.

Homocysteine

Increased homocysteine levels are associated with increased risk of CAD, peripheral arterial disease, and carotid disease (825-828). Although elevated homocysteine levels can occur as a result of inborn errors of metabolism such as homocystinuria, homocysteine levels can also be increased by deficiencies of vitamin B6, vitamin B12, and folate, which commonly occur in older persons (829,830). More than 20% of the older subjects evaluated by the Framingham Heart Study population had elevated homocysteine levels (829). In patients with coronary disease and elevated homocysteine levels, supplementation with vitamins B6, B12, and folic acid is relatively inexpensive and will usually lower homocysteine levels. Clinical trials are needed to determine whether such treatment is beneficial.

Consumption of Alcohol

Observational studies have repeatedly shown an inverse relation of moderate alcohol intake (approximately 1 to 3 drinks daily) to risk of CHD events (838-840). Excessive alcohol intake can promote many other medical problems that can outweigh its beneficial effects on CHD risk. Although some studies have suggested an association of wine consumption with a reduction in CHD risk that is greater than that observed for beer or spirits, this issue is unresolved.

The benefits of moderate alcohol consumption may be mediated through the effects of alcohol on HDL cholesterol. An alternative mechanism is the potentially beneficial effects of flavonoids. In the Zutphen Study (841), flavonoid consumption was inversely related to mortality from CHD, with risk in the lowest tertile of intake less than half that of the highest tertile. In contrast, in the Physicians’ Health Study (842), the association of flavonoid intake with risk for MI was not significant. Clinical trials are lacking on the effect of alcohol intake on CHD risk.

6. Risk Factors Associated With Increased Risk but That Cannot Be Modified or the Modification of Which Would Be Unlikely to Change the Incidence of Coronary Disease Events

Advancing age, male gender, and a positive family history of premature CHD are nonmodifiable risk factors for CHD that exert their influence on CHD risk to a large extent through other modifiable risk factors noted above. The National Cholesterol Education Program defines a family history of premature CHD as definite MI or sudden death before the age of 55 years in a father or other male first-degree relative or before the age of 65 in a mother or other female first-degree relative (20,987).

Many other risk factors for CHD have been proposed (843), and many more will be in the future. At present, there is little evidence that modification of risk factors other than those covered in categories I through III above will reduce risk for initial or recurrent CHD events.

7. Other Proposed Therapies That Have Not Been Shown to Reduce Risk for Coronary Disease Events

Diet Fish Oils and Garlic

Diet is an important contributor to multiple other risk factors discussed above, including LDL and HDL cholesterol levels, blood pressure, obesity, impaired glucose tolerance, and antioxidant and vitamin intake. Consequently, dietary modification can promote a favorable CHD risk profile by affecting multiple risk pathways. Dietary therapy has been assessed in seven randomized clinical trials performed in CHD patients. Several early trials (844-846) failed to demonstrate beneficial effects of diet on CHD risk. Of the later trials (704,847-849), three demonstrated statistically significant reductions in cardiac mortality rate associated with dietary therapy that ranged from 32% to 66% (704,847,849). These low-fat diets were high in fiber and antioxidant-rich foods (704), monounsaturated fat (849), or fish (847).

Some studies have found an inverse association between fish consumption and CHD risk (850). Meta-analyses of clinical trials have suggested that restenosis after coronary angioplasty may be reduced by fish oils (851,852); however, the results are inconclusive. Additional well-designed trials are needed.

There are no randomized trials of garlic therapy in patients with stable angina. However, garlic has been evaluated as a treatment for two risk factors of coronary artery disease (hypertension and hypercholesterolemia (Table 34). Two meta-analyses of garlic therapy for treatment of hypercholesterolemia and hypertension were published in the early 1990s (853,854). These suggested a small benefit with garlic therapy. More recently, two rigorous studies of garlic as a treatment for hypercholesterolemia have found no measurable effect (855,856). The current evidence does not suggest that there is a clinically significant benefit in cholesterol reduction or blood-pressure lowering with garlic therapy.

Oxidative Stress

Extensive laboratory data indicate that oxidation of LDL cholesterol promotes and accelerates the atherosclerosis process (831,832). Observational studies have documented an association between dietary intake of antioxidant vitamins (vitamin C, vitamin E, and beta carotene) and reduced risk for CHD (833).

Evidence from clinical trials is negative regarding the effects of supplementation with antioxidant vitamins. Although several small trials and in vitro data from basic research in vascular biology have suggested that vitamin C and/or E might interfere with formation of atherosclerotic lesions, two large randomized clinical trials have shown no benefit when vitamin E was given to patients after myocardial infarction (GISSI-P) or in those with vascular disease or diabetics with a high-risk CAD profile (992-994). Furthermore, a small coronary regression trial, the HDL Atherosclerosis Treatment Study (HATS), suggested an adverse effect of antioxidant vitamins on coronary atherosclerosis, clinical events, and HDL and apoA-1 metabolism (992,994). The use of vitamin E (administered with vitamin C and beta-carotene) was the subject of a large (20 000 participants) trial of patients at risk for CAD and with CAD (995). Antioxidant therapy had no effect on the end points of cardiovascular death, cardiovascular events, stroke, or revascularization, considered alone or in combination. Although previous observational and epidemiologic studies have suggested a benefit from dietary supplementation with antioxidants or a diet rich in antioxidants, especially vitamin E, there is currently no basis for recommending that patients take vitamin C or E supplements or other antioxidants for the express purpose of preventing or treating CAD.

Probucol is a lipid-lowering drug with antioxidant properties. In a recent clinical trial, patients with coronary disease undergoing angioplasty were treated with placebo, probucol, or multivitamins (beta carotene, vitamin E, and vitamin C). A reduction in restenosis was observed only with probucol (836). In the PQRST trial, however, treatment with probucol had no effect on femoral artery atherosclerosis (837).

Although dietary supplementation with antioxidants or a diet rich in foods with antioxidant potential, especially vitamin E, may be of benefit to patients with chronic stable angina, the benefits are still unresolved.

Anti-Inflammatory Agents

It is now recognized that inflammation is a common and critical component of atherothrombosis. High sensitive C-reactive protein has been the most extensively studied marker. However, routine measurement of any of the emerging risk factors, such as hs-CRP, is not recommended. It would appear to have the most potential usefulness for risk assessment in middle-aged or older persons in whom standard risk factors decline in predictive power (987). Although statins have been advocated as they modify the CRP measurement, there is as yet no evidence that they modify inflammation.

Postmenopausal Hormonal Replacement Therapy

Both estrogenic and androgenic hormones produced by the ovary have appeared to be protective against the development of atherosclerotic cardiovascular disease. When hormonal production decreases in the perimenopausal period over several years, the risk of CAD rises in postmenopausal women. By age 75 years, the risk of atherosclerotic cardiovascular disease among men and women is equal. Women have an accelerated risk of developing CAD if they experience an early menopause or abrupt onset of menopause through surgical removal or chemotherapeutic ablation of the ovaries. Loss of estrogen and onset of menopause result in an increase in LDL cholesterol, a small decrease in HDL cholesterol, and therefore an increased ratio of total to HDL cholesterol (787). Numerous epidemiologic studies have suggested a favorable influence of estrogen replacement therapy on the primary prevention of CAD in postmenopausal women (792-794). Furthermore, prospective studies of the effects of estrogen administration on cardiac risk factors demonstrate an increase in HDL cholesterol, a decrease in LDL cholesterol (788-791), and positive physiologic effects on the vascular smooth muscle and the endothelium.

Based on the above, postmenopausal estrogen replacement has previously been advocated for both primary and secondary prevention of CAD in women. However, the first published randomized trial of estrogen plus progestin therapy in postmenopausal women with known CAD did not show any reduction in cardiovascular events over four years of followup (799), despite an 11% lower LDL cholesterol level and a 10% higher HDL-cholesterol level in those women receiving hormone replacement therapy. In addition, women receiving hormone replacement therapy had higher rates of cardiovascular events during the first two years, more thromboembolic events, and more gallbladder disease (996). A subsequent angiographic study also revealed no benefit from hormonal replacement therapy (997). Another prospective randomized controlled trial using hormone replacement therapy in women with a history of stroke found no benefit in reducing mortality or stroke after 2.8 years (998). The Women’s Health Initiative, a randomized controlled primary prevention trial of estrogen plus progestin, found that the overall health risks of this therapy exceeded its benefits (999). Thus, current information suggests that hormone replacement therapy in postmenopausal women does not reduce risk for major vascular events or coronary deaths in secondary prevention. Women who are taking hormone replacement therapy and who have vascular disease can continue this therapy if it is being prescribed for other well-established indications and no better alternative therapies are appropriate. There is, however, at the present time no basis for adding or continuing estrogens in postmenopausal women with clinically evident CAD or cerebrovascular disease in an effort to prevent or retard progression of their underlying disease (1000).

If a woman develops an acute CAD event while undergoing hormone replacement therapy, it is prudent to consider discontinuance of the therapy (1000). In women who are immobilized, hormone replacement therapy should be discontinued or venous thromboembolism prophylaxis should be used.

Other randomized trials of hormone replacement therapy in primary and secondary prevention of CAD in postmenopausal women are being conducted. As their results become available over the next several years, this recommendation may require modification.

Chelation Therapy

There is no evidence to support the use of chelation therapy to treat atherosclerotic cardiovascular disease. Four randomized clinical trials in patients with atherosclerotic cardiovascular disease (intermittent claudication) found no evidence of a beneficial effect of chelation therapy on progression of disease or clinical outcome (858). These results, combined with the potential for harm from chelation therapy, indicate that chelation therapy has no role in the treatment of chronic stable angina.

8. Asymptomatic Patients

In asymptomatic patients with documented CAD on the basis of noninvasive testing or coronary angiography, the treatment of risk factors outlined above is clearly appropriate. The same recommendations should apply to these patients.

In the absence of documented CAD, asymptomatic patients should also undergo treatment of risk factors according to primary prevention standards. Therapy should be directed toward hypertension, smoking cessation, diabetes, exercise training, and weight reduction in the presence of other risk factors. In the absence of documented CAD, lipid-lowering therapy should be administered according to the primary prevention standards outlined in the ATP III guidelines (987).

E. Revascularization for Chronic Stable Angina

Recommendations for Revascularization With PCI (or Other Catheter-Based Techniques) and CABG in Patients With Stable Angina

Class I

1. Coronary artery bypass grafting for patients with significant left main coronary disease. (Level of Evidence: A)

2. Coronary artery bypass grafting for patients with three-vessel disease. The survival benefit is greater in patients with abnormal LV function (ejection fraction less than 50%). (Level of Evidence: A)

3. Coronary artery bypass grafting for patients with two-vessel disease with significant proximal LAD CAD and either abnormal LV function (ejection fraction less than 50%) or demonstrable ischemia on noninvasive testing. (Level of Evidence: A)

4. Percutaneous coronary intervention for patients with two- or three-vessel disease with significant proximal LAD CAD, who have anatomy suitable for catheterbased therapy and normal LV function and who do not have treated diabetes. (Level of Evidence: B)

5. Percutaneous coronary intervention or CABG for patients with one- or two-vessel CAD without significant proximal LAD CAD but with a large area of viable myocardium and high-risk criteria on noninvasive testing. (Level of Evidence: B)

6. Coronary artery bypass grafting for patients with one- or two-vessel CAD without significant proximal LAD CAD who have survived sudden cardiac death or sustained ventricular tachycardia. (Level of Evidence:C)

7. In patients with prior PCI, CABG or PCI for recurrent stenosis associated with a large area of viable myocardium or high-risk criteria on noninvasive testing (Level of Evidence: C)

8. Percutaneous coronary intervention or CABG for patients who have not been successfully treated by medical therapy (see text) 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 LAD. It may be appropriate to use PCI for focal saphenous vein graft lesions or multiple stenoses in poor candidates for reoperative surgery. (Level of Evidence: C)

2. Use of PCI or CABG for patients with one- or two-vessel CAD without significant proximal LAD disease but with a moderate area of viable myocardium and demonstrable ischemia on noninvasive testing. (Level of Evidence: B)

3. Use of PCI or CABG for patients with one-vessel disease with significant proximal LAD disease. (Level of Evidence: B)

Class IIb 1. Compared with CABG, PCI for patients with two- or three-vessel disease with significant proximal LAD CAD, who have anatomy suitable for catheter-based therapy, and who have treated diabetes or abnormal LV function. (Level of Evidence: B)

2. Use of PCI for patients with significant left main coronary disease who are not candidates for CABG. (Level of Evidence: C)

3. PCI for patients with one- or two-vessel CAD without significant proximal LAD CAD who have survived sudden cardiac death or sustained ventricular tachycardia. (Level of Evidence: C)

Class III

1. Use of PCI or CABG for patients with one- or twovessel CAD without significant proximal LAD CAD, who have mild symptoms that are unlikely due to myocardial ischemia, or who have not received an adequate trial of medical therapy and

a. have only a small area of viable myocardium or

b. have no demonstrable ischemia on noninvasive testing. (Level of Evidence: C)

2. Use of PCI or CABG for patients with borderline coronary stenoses (50% to 60% diameter in locations other than the left main coronary artery) and no demonstrable ischemia on noninvasive testing. (Level of Evidence: C)

3. Use of PCI or CABG for patients with insignificant coronary stenosis (less than 50% diameter). (Level of Evidence: C)

4. Use of PCI in patients with significant left main coronary artery disease who are candidates for CABG. (Level of Evidence: B)

There are currently two well-established revascularization approaches to treatment of chronic stable angina caused by coronary atherosclerosis. One is CABG, in which segments of autologous arteries or veins are used to reroute blood around relatively long segments of the proximal coronary artery. The other is PCI, a technique that uses catheter-borne mechanical or laser devices to open a (usually) short area of stenosis from within the coronary artery. Since the introduction of bypass surgery in 1967 and PCI (as 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. A major problem in trying to assess the role of these invasive treatments is that demonstration of their effectiveness requires long-term follow-up. Although these long-term follow-up studies are being accomplished, treatments have changed, usually for the better. Revascularization is also potentially feasible with transthoracic (laser) myocardial revascularization. However, this technique, which is still in its infancy, is primarily used as an alternative when neither CABG nor PCI is feasible.

1. Coronary Artery Bypass Surgery

Coronary bypass surgery has a 30-year history. For most patients, the operation requires a median sternotomy incision and cardiopulmonary bypass. At present, there are alternative, less invasive forms of bypass surgery under investigation, and some limited “mini” operations may acquire the status of standard clinical treatment. However, at this point, only fairly simple bypass operations are consistently possible with less invasive techniques, and all the studies that have documented the long-term effectiveness of bypass surgery in terms of graft patency, symptom relief, and lower death rate have involved patients operated on with standard techniques. With these standard approaches to bypass surgery, extensive revascularization of complex CAD can be accomplished with relative safety.

Bypass grafts are constructed with saphenous vein or arterial grafts, most commonly the internal thoracic (mammary) artery (ITA). One disadvantage of bypass grafting with the saphenous vein is that there is an attrition of vein grafts with time due to intrinsic changes that may occur in the grafts. Data from the 1970s showed occlusion rates of saphenous vein grafts of 10% to 15% within one week to one year after operation and 20% to 25% by five years after surgery. Beyond five postoperative years, the development of vein graft atherosclerosis further compromised grafts so that by 10 postoperative years, approximately 40% of saphenous vein grafts were occluded, and approximately half of the patent grafts showed atherosclerotic changes (859-861). Fortunately, progress has been made in preventing vein graft attrition. Randomized prospective studies have shown that perioperative and long-term treatment with platelet inhibitors have significantly decreased the occlusion rate of saphenous vein grafts at one year after surgery to 6% to 11% (862-864), and long-term occurrence and progression of vein graft atherosclerosis appear to be significantly decreased by aggressive lipid-lowering strategies (865). However, despite these advances, vein graft atherosclerosis is still the greatest problem compromising long-term effectiveness of CABG.

Arterial grafts, most notably the ITA, have a much lower early and late occlusion rate than vein grafts, and in the case of the left ITA to the LAD bypass graft (LITA-LAD), more than 90% of grafts are still functioning more than 10 years after surgery (859,866,867). Furthermore, the occurrence of late atherosclerosis in patent ITA grafts is extremely rare, and even at 20 postoperative years, the occlusion rate of these grafts is very low. The use of the LITA-LAD graft has also been shown to improve long-term clinical outcome in terms of survival and freedom from reoperation, and this strategy is now a standard part of bypass surgery at most institutions (866,868). The right ITA has also been used for bypass grafts at some centers, and excellent long-term results have been noted, but that strategy has not become widespread. Other arterial grafts, including the right gastroepiploic artery, the radial arteries, and inferior epigastric arteries, have all shown promise, and excellent early results in terms of graft patency have been documented. However, the strategy of extensive arterial revascularization has not become widespread, and long-term outcomes are as yet unknown.

2. Coronary Artery Bypass Grafting Versus Medical Management

The goals of coronary bypass surgery are to alleviate symptoms and prolong life expectancy. Early in the history of CABG, it became clear that successful bypass surgery relieved angina or lessened symptoms. To investigate the question of whether bypass surgery prolonged survival, three large multicenter randomized trials, the Veterans Administration Cooperative Study (VA Study) (869), the European Coronary Surgery Study (ECSS) (870), and CASS (871), were undertaken. These trials compared the strategy of initial bypass surgery with initial medical management with regard to long-term survival and symptom status for patients with mild or moderate symptoms. Severely symptomatic patients were excluded from the randomized portions of these trials, and crossover from medical to surgical therapy was allowed. The lessons learned from these trials concerning survival rate were that the subsets of patients for whom bypass surgery improved the survival rate the most were patients who were at high risk of death without surgery. The characteristics that defined high-risk groups include the angiographic characteristics of left main coronary artery stenosis, three-vessel disease with abnormal LV function, two- or three-vessel disease with a greater than 75% stenosis in the proximal LAD, and the clinical descriptors of an abnormal baseline ECG and a markedly positive exercise test.

Recently, a meta-analysis of these three major randomized trials of initial surgery versus medical management and other smaller trials has confirmed the survival benefit achieved by surgery at 10 postoperative years for patients with three-vessel disease, two-vessel disease, or even one-vessel disease that included a stenosis of the proximal LAD (489). The survival rate of these patients was improved by surgery whether they had normal or abnormal LV function (489). For patients without a proximal LAD stenosis, bypass surgery improved the mortality rate only for those with three-vessel disease or left main stenosis.

It is important to note that the largest and most pertinent of the trials (ECSS and CASS) contained only patients with mild or moderate symptoms; severely symptomatic patients were excluded from randomization. In CASS, these symptomatic patients excluded from randomization were monitored in the CASS registry. Analysis of this prospective but nonrandomized database showed that initial bypass surgery dramatically improved the survival rate of severely symptomatic patients with three-vessel disease regardless of ventricular function and regardless of the presence or absence of proximal stenoses (872).

Coronary bypass surgery consistently improves the symptoms of patients with angina. Observational studies have noted freedom from angina for approximately 80% of patients at five postoperative years (72). In the randomized trials of surgery versus medical therapy, patients receiving initial surgery experienced superior relief of angina at five postoperative years. The advantage for the group initially treated with surgery became less by 10 postoperative years, in part because during this time many patients initially assigned to medical therapy crossed over to receive bypass surgery (873). In the studies included in the meta-analysis (489), 41% of the patients assigned to the medical treatment group had crossed over and undergone bypass surgery by 10 postoperative years. This crossover effect is important to recognize in any study of long-term outcome in which invasive studies are compared with medical management. Conversely, patients who underwent initial surgery also had a progressive increase in the incidence of reoperation with the passage of time, although less of an incidence than that of patients crossing over from medical to surgical therapy.

The crossover effect, however, does not totally explain the observations that the survival advantage and improved symptoms for patients treated with initial surgery decreased with time beyond five postoperative years. It is probable that much of this deterioration was related to late vein graft failure. It is also important to note that these trials were performed in the relatively early years of bypass surgery, and outcomes of the procedure have improved over time. Few patients received ITA grafts or were treated with either platelet inhibitors or lipid-lowering agents, strategies that have all been clearly shown to improve the long-term outcome of patients undergoing bypass surgery. The improvements in short- and long-term survival rates after bypass surgery that have occurred since the randomized studies were conducted have been documented by observational studies (866,868,874), but further CABG-medical treatment randomized trials have not been conducted. Another weakness of the randomized trials that must be kept in mind when interpreting their current implications is that tremendous advances in imaging techniques have allowed a more accurate definition of ischemia and thus allowed identification of patients at high risk of events with medical treatment alone that did not exist during the years of the randomized trials. The randomized trials were based on angiographic anatomy and baseline ventricular function. However, improved imaging techniques have allowed a more accurate definition of groups that can potentially benefit from revascularization. In elderly patients, revascularization appears to improve quality of life and morbidity compared with medical therapy (1001).

3. Percutaneous Coronary Intervention

Percutaneous coronary intervention began in 1977 as PTCA, a strategy in which a catheter-borne balloon was inflated at the point of coronary stenosis. Alternative mechanical devices for percutaneous treatments have been developed and have included rotating blades or burrs designed to remove atheromatous material, lasers to achieve photoablation of lesions, and metal intracoronary stents designed to structurally maintain lumen diameter. The advantages of PCI for the treatment of CAD are many and include a low level of procedure-related morbidity, a low procedure-related mortality rate in properly selected patients, a short hospital stay, early return to activity, and the feasibility of multiple procedures. The disadvantages of PCI are that it is not feasible for many patients, there is a significant incidence of restenosis in lesions that are successfully treated, and there is a risk of acute coronary occlusion during PCI. The risk of acute coronary occlusion during PCI was a serious problem in the early years of percutaneous treatments, but the advent of intracoronary stents, improved selection of vessels for treatment, and improved pharmacologic therapies have greatly decreased the risk of acute occlusion and procedure-related cardiac morbidity, as well as emergency coronary bypass surgery associated with PCI. The other disadvantages of PCI are that many patients do not have an anatomy suitable for percutaneous treatment and that restenosis occurs in 30% to 40% of treated lesions within six months (875-877).

Despite some disadvantages, the efficacy of PCI in producing symptom relief for some patient subsets has become rapidly apparent, and the number of PCI procedures performed has grown so rapidly that today PCI is performed more commonly than bypass surgery. Initially used to treat only proximal one-vessel CAD, the concepts of percutaneous treatment have been extended to more complex situations.

Recommendations for Alternative Therapies for Chronic Stable Angina in Patients Refractory to Medical Therapy Who Are Not Candidates for Percutaneous Intervention or Surgical Revascularization

Class IIa

Surgical laser transmyocardial revascularization. (Level of Evidence: A)

Class IIb

1. Enhanced external counterpulsation. (Level of Evidence: B)

2. Spinal cord stimulation. (Level of Evidence: B)

Other Therapies in Patients With Refractory Angina

Since the previous draft of these guidelines (1002), evidence has emerged regarding the relative efficacy, or lack thereof, of a number of techniques for the management of refractory chronic angina pectoris. These techniques should only be used in patients who cannot be managed adequately by medical therapy and who are not candidates for revascularization (interventional and/or surgical). In this section, data are reviewed regarding three techniques: spinal cord stimulation, enhanced external counterpulsation, and laser transmyocardial revascularization (see Recommendations).

SPINAL CORD STIMULATION. Since approximately 1987, spinal cord stimulation (SCS) has been proposed as a method for providing analgesia for patients with chronic angina pectoris refractory to medical, catheter interventional, or surgical therapy. The efficacy of SCS depends on the accurate placement of the stimulating electrode in the dorsal epidural space, usually at the C7-T1 level. A review of the literature has revealed two small randomized clinical trials involving implanted spinal cord stimulators, one of which directly tested its efficacy (see Table 34a). One report studied the efficacy of SCS in 13 treated patients versus 12 control subjects; both groups with chronic intractable angina pectoris were studied for six weeks (1003). In the SCS group, compared with the control group, exercise duration, time to angina, and perceived quality of life all increased. Furthermore, the number of anginal attacks, sublingual nitrate consumption, prevalence of ischemic episodes on 48-h ECG, and degree of STsegment depression on the exercise ECG all decreased. The authors concluded that SCS was effective in the treatment of chronic intractable angina pectoris and that its effect was exerted through an anti-ischemic action (1003).

Another small randomized trial involved 24 patients with refractory angina who had implanted spinal cord stimulators (1004). After randomization to the study, the withdrawal-of-SCS group (n = 12) had their SCS set active during the first four weeks, followed by four weeks of withholding stimulation. In the control group (n = 12), SCS was switched off during the four weeks before the end of the study. The authors found no increase in anginal complaints or ischemia after withholding stimulation. Neurohormonal levels and aerobic capacity were also not altered. The authors concluded that there was no adverse clinical rebound phenomenon after withholding neurostimulation in patients with refractory angina pectoris.

In a more recent randomized, prospective, open comparison of CABG surgery (n = 51 patients) and SCS (n = 53 patients) in patients with no a priori prognostic benefit from CABG and with an increased risk for surgical complications, anginal symptoms decreased in the SCS group despite discontinued stimulation. Also noted was a lack of effect of SCS on ischemic ST changes (1005). These authors suggested that their results could indicate a long-term primary analgesic effect of SCS.

Nine other studies, either retrospective (1006-1008) or prospective (1003,1009-1013) cohort studies, were identified in the literature. These studies have purported to show that SCS is effective in decreasing the number of anginal episodes and in preventing hospital admissions, apparently without masking serious ischemic symptoms or leading to silent ischemia (1008,1013). A significant increase in the average exercise time on the treadmill has also been reported during SCS (1003). However, analgesic effects of SCS may be observed despite discontinuation of CPS and in the absence of changes in myocardial ischemia. In summary, although most published reports appear promising, there is still a paucity of data on the intermediate- and long-term benefit of these devices.

ENHANCED EXTERNAL COUNTERPULSATION. Another nonpharmacologic technique that has been described for treatment of patients with chronic stable angina is known as enhanced external counterpulsation (EECP). This technique uses a series of cuffs that are wrapped around both of the patient’s legs. Using compressed air, pressure is applied via the cuffs to the patient’s lower extremities in a sequence synchronized with the cardiac cycle. Specifically, in early diastole, pressure is applied sequentially from the lower legs to the lower and upper thighs, to propel blood back to the heart. The procedure results in an increase in arterial blood pressure and retrograde aortic blood flow during diastole (diastolic augmentation).

EECP was evaluated in a randomized, placebo-controlled multicenter trial to determine its safety and efficacy (1014). As shown in Table 34a, 139 patients with chronic stable angina, documented CAD, and a positive exercise treadmill test were randomly assigned to receive EECP (35 hours of active counterpulsation) or inactive EECP over a four- to sevenweek period. The authors concluded that EECP decreased angina frequency (p less than 0.05) and improved time to exercise-induced ischemia (p = 0.01). In addition, treatment was relatively well tolerated and free of limiting side effects in most patients. However, the sample size in this study was relatively small.

Two multicenter registry studies that included 978 patients from 43 centers (1015) and 2289 patients from more than 100 centers (1016) evaluated the safety and effectiveness of EECP in treating chronic stable angina. These studies found the treatment to be generally well tolerated and efficacious; anginal symptoms were improved in approximately 75% to 80% of patients. However, additional clinical trial data are necessary before this technology can be recommended definitively.

LASER TRANSMYOCARDIAL REVASCULARIZATION. Another emerging technique that has been studied for the treatment of more severe chronic stable angina refractory to medical or other therapies is laser transmyocardial revascularization (TMR). This technique has either been performed in the operating room (using a carbon dioxide or holmium:YAG laser) or by a percutaneous approach with a specialized (holmium:YAG laser) catheter. Eight prospective randomized clinical trials have been performed, two using the percutaneous technique and the other six using an epicardial surgical technique (942,945,1017-1021). The goal in both approaches is to create a series of transmural endomyocardial channels to improve myocardial revascularization.

PERCUTANEOUS TMR. The two randomized percutaneous TMR trials, enrolling about 550 patients, reported symptomatic improvement among 45% and 66% of patients compared with 13% for best medical therapy (942); one of these has not yet been published (http://www.eclipsesurg.com/professionals/professionals.cfm). The studies have generally assessed parameters such as angina class, freedom from angina, exercise tolerance, and quality of life score. In general, these studies have shown improvement in severity of angina class, exercise tolerance, and quality of life, as well as increased freedom from angina. However, percutaneous TMR technology has not been approved by the Food and Drug Administration; therefore, percutaneous TMR should still be considered an experimental therapy.

SURGICAL TMR. The surgical TMR technique has also generally been associated with improvement in symptoms in patients with chronic stable angina. The mechanism for improvement in angina symptoms is still controversial. Possible mechanisms for this improvement include increased myocardial perfusion, denervation of the myocardium, stimulation of angiogenesis, or perhaps some other unknown mechanism (1022-1024). On the other hand, there are conflicting data regarding improvement in exercise capacity; two studies demonstrated no improvement (1017,1021), whereas a third study demonstrated improvement (945). Three studies also assessed myocardial perfusion using thallium scans (945,1018,1019). Only one of these studies demonstrated an improvement in myocardial perfusion in patients who underwent TMR versus those continuing to receive only medical therapy (1019). Despite the apparent benefit in decreasing angina symptoms, no definite benefit has been demonstrated in terms of increasing myocardial perfusion.

In the Society of Thoracic Surgeons database for surgical TMR (1025), 80% of surgical TMR cases had been performed in conjunction with CABG. In a recent multicenter, randomized controlled trial comparing TMR plus CABG to CABG alone in patients not amenable to complete revascularization by CABG alone, one-year survival was better in the combination therapy group (95% vs. 89%, p = 0.05) (1020). In general, angina relief and exercise treadmill improvement were no different at 12-month follow-up. Furthermore, there are currently no published studies to document the long-term efficacy of surgical TMR. Nonetheless, this technique appears to provide symptomatic relief for endstage chronic angina in the short term. Additional follow-up studies are necessary to evaluate procedural efficacy in patients who have undergone surgical laser TMR alone, as well as coronary bypass surgery plus TMR.

PERCUTANEOUS CORONARY INTERVENTION VERSUS MEDICAL TREATMENT. The initial randomized study that compared PTCA with medical management alone for the treatment of chronic stable angina was the Veterans Affairs Angioplasty Compared to Medicine (ACME) Trial, which involved patients with one-vessel disease and exercise-induced ischemia. In a six-month follow-up, the death rate was expectedly low for both the PTCA and medically treated groups, and 64% of the PTCA group were free of angina versus 46% of the medically treated group (p less than 0.01) (878).

A second randomized trial comparing initial PTCA versus initial medical management (Randomized Intervention Treatment of Angina [RITA-2]) included a majority of patients with one-vessel disease (60%) and some angina (only 20% without angina) monitored over a 2.7-year median follow-up interval. There was a slightly greater risk of death or MI for the PTCA group (p = 0.02), although those risks were low for both groups. The greater risk of MI in the PTCA group was due to enzyme elevations during the procedure. The PTCA patients had less angina three months after randomization, although by two years, the differences between the two groups were small (879). (7.6% more medically treated patients had angina). Some of that narrowing of the difference in symptom status was due to the crossover of medically treated patients to PTCA or bypass surgery. By one year, 15% of the medically treated group had crossed over to PTCA or CABG and 14.9% of the initial PTCA group had undergone repeat PTCA or CABG. Thus, compared with medically treated patients, the PTCA group had improved symptoms, although reintervention was often needed to maintain that symptomatic improvement In the Atorvastatin Versus Revascularization Treatment trial (AVERT), 341 patients with mild stable angina and normal LV function were randomized to medical therapy including atorvastatin 80 mg or to PTCA. Angina relief was superior in the PTCA groups, but at 18 months, this group had more ischemic events, primarily hospitalizations and repeat revascularization (21% vs 13%, p = 0.048) (1026). These results parallel a meta-analysis of the 953 patients with mild or no symptoms entered into randomized comparison of PTCA and medical therapy (see Figure 12) (1027). It is important to note, however, that lipid-lowering therapy in AVERT was different in the two groups of patients. There was a markedly lower LDL cholesterol in the medical therapy group. These studies suggest that an initial medical approach with aggressive lipid lowering is appropriate in minimally symptomatic patients with stable angina.

These randomized studies of PTCA versus medical management have involved patients who were at a low risk of mortality even with medical management. The use of PCI to treat patients with chronic stable angina and characteristics that define a high risk of mortality has not been testedis currently being tested in the COURAGE trial.

Medical Management Versus PCI or CABG

The most current study of medical management versus revascularization is the Asymptomatic Cardiac Ischemia Pilot (ACIP) study. This study included patients with CAD who were either free of angina or had symptoms that were well controlled with medical management but at least one episode of asymptomatic ischemia documented during 48-h ambulatory ECG monitoring. The three arms of the study were medical management guided by angina, medical management conducted by ambulatory ECG monitoring, and revascularization (either CABG or PTCA, depending on the judgment of the investigators). At a two-year follow-up, the 170 patients randomized to revascularization (PTCA in 92 patients, CABG in 78) had a significantly lower death rate (p less than 0.005) than those in either of the medically managed groups. Furthermore, 29% of the patients randomized to medical management underwent nonprotocol (crossover) revascularization during the two-year follow-up. Patients with at least 50% LAD stenosis appeared to derive the most benefit from revascularization (880). Patients with ischemia on ambulatory ECG monitoring frequently had multivessel disease, severe proximal stenoses, and complex plaque (881).

Use of PCI Versus Medical Management Versus CABG

One randomized three-arm trial (the Medicine, Angioplasty or Surgery Study [MASS]) (882) compared PTCA, medical treatment, and CABG (LITA-LAD) for the treatment of isolated, severe, proximal LAD stenosis in patients with lesions ideal for treatment with PTCA. With 214 patients randomized and monitored for three years, there was no difference in mortality or MI rate among the three groups. Both revascularization strategies resulted in more asymptomatic patients (CABG, 98%; PTCA, 82%) compared with medical treatment (32%) (p less than 0.01), but no patient in any treatment group had severe angina at follow-up. Patients assigned to PTCA and medicine had more revascularization procedures during the follow-up period than did the patients assigned to surgery. The primary end point of the study was the combined incidence of cardiac death, MI, or refractory angina requiring revascularization. That combined end point occurred more often for patients assigned to PTCA (17 [24%]) and medical therapy (12 [17%]) than for those assigned to bypass surgery (2 [3%], p less than 0.006).

Use of PCI Versus Use of CABG

Multiple trials have compared the strategy of initial PTCA with initial CABG for treatment of multivessel CAD. In general, the goal of these trials has been to try to answer the question of whether or not there are subsets of patients who pay a penalty in terms of survival for initial treatment with PTCA. The two U.S. trials of PTCA versus CABG are the multicenter Bypass Angioplasty Revascularization Investigation (BARI) trial (883) and the single-center Emory Angioplasty Surgery Trial (EAST) (884).

Both trials included patients with both stable and unstable angina who were considered suitable candidates for either PTCA or CABG. There are no PTCA versus CABG trials of patients with only chronic stable angina, and the results of the trials that were conducted did not appear to vary according to whether the patients had stable or unstable angina. Therefore, in trying to understand the invasive treatment of patients with chronic stable angina, these trials represent the best data available. It is important to note that because of the requirement that the patients be good candidates for PTCA, the PTCA versus surgery trials included a minority of the total spectrum of patients with multivessel disease who are considered for revascularization. For example, in the EAST trial, 16% of the patients who were screened were considered eligible for inclusion, and in the BARI trial, 60% of the patients considered possible clinical and angiographic candidates were thought to be anatomically unsuitable for PTCA when subjected to careful angiographic review (885). In both trials, a majority of patients had two- rather than three-vessel disease and normal LV function (ejection fraction greater than 50%); a history of CHF was rare (fewer than 10%). 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, but the definition of an LAD lesion allowed more distal stenoses to be considered. Therefore, these trials did not include large numbers of patients who were at high risk for death without revascularization.

The results of both these trials at an approximately 5sevento eight-year follow-up interval have shown that early and late survival rates have been equivalent for the PTCA and CABG groups (1028,1029). 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 (886). In the EAST trial, persons with diabetes had an equivalent survival rate with CABG or PTCA at three 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). Longer-term follow-up data from the BARI and EAST trials have not yet been published.

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 antianginal medications.

The latest randomized trial comparing percutaneous and surgical coronary revascularization was the European Arterial Revascularization Therapies Study (ARTS) (1030). A total of 1205 patients with multivessel disease suitable for either therapy were randomly assigned to coronary stenting or bypass surgery. At one year, there was no significant difference between the two groups with respect to mortality, stroke, or MI. Event-free survival was higher in the surgery group (87.8% vs 73.8%, p less than 0.001), but surgery was more expensive by $2973 per patient in spite of more repeat revascularizations in the stent group (16.8% vs 3.5%) (1030). At 12 months, surgery patients had an improved perception of mobility, usual activity, and freedom from anxiety or depression than patients in the stent group, although overall quality-of-life evaluation was similar.

These and other randomized trials have provided important insights into the choice of interventional therapy for some patient subgroups, but there are also some clear limitations of these trials in terms of current recommendations for treatment of a broad spectrum of patients with multivessel CAD. First, because the patients included in the trials were a select minority of acceptable-risk patients with multivessel disease who were good angiographic candidates for PTCA, the long term outcome benefit of PTCA in the treatment of subsets of high-risk patients, particularly those in whom CABG has been shown to prolong survival most, has not been definitely established. Second, the results of these trials should not be applied to patients who are not good angiographic candidates for PTCA. Third, few patients, except in ARTS, the PTCA-CABG randomized trials received intracoronary stents, a change in percutaneous technique that has decreased the rate of emergency bypass surgery and may decrease the incidence of restenosis (1030) but has not yet been subjected to long-term scrutiny. Fourth, the follow-up period of the PTCA-CABG studies extends only fiveeight years at this writing, a point at which the adverse effect of vein graft atherosclerosis has not yet become apparentbeen fully realized. Fifth, none of these trials used aggressive lipid-lowering therapy or IIb/IIIa platelet receptor inhibitors. FifthSixth, although most of the patients in the surgical groups received LITA-LAD grafts, few patients underwent extensive arterial revascularization or off-pump bypass surgery. All these changes in technique may conceivably change the relative benefit ratios of CABG and PCI for some patient subgroups. Sixth, none of these trials used aggressive lipid-lowering therapy.

Finally, it is critical to understand that important patient subgroups (elderly patients, women, and patients with previous bypass surgery) were either not represented or were underrepresented in the randomized trials discussed. None of these trials included patients with previous bypass surgery. The trials of initial medical versus initial surgical management excluded patients greater than 65 years old and contained very few women. In the trials of PTCA versus surgery, women were included and reasonably well represented, but few patients greater than 70 years old and none greater than 80 years old were included. The committee believes that patients with significant CAD who have survived sudden cardiac death or sustained ventricular tachycardia are best treated with CABG rather than PCI. This subject is discussed in detail elsewhere (887). Use of CABG reduces sudden cardiac death compared with medical therapy (888) and appears to be beneficial in uncontrolled series of patients with prior cardiac arrest (889). There are few available data on this issue for PCI. The risk of sudden death or ventricular arrhythmias recurring is likely to be greater with PCI than CABG because of the known risk of restenosis after PCI.

Recommendations for Revascularization in Patients With Native-Vessel CAD

Advances have been made in medical therapy that reduce MI and death and decrease the rate of progression of coronary stenoses. However, there is still no evidence that medical treatment alone sufficiently improves the life expectancy of the high-risk subgroups that were defined by the trials of medical treatment versus bypass surgery.

The randomized trials of initial medical treatment versus initial surgery showed that patients with left main stenoses greater than or equal to 70% and those with multivessel CAD with a proximal LAD stenosis greater than or equal to 70% and abnormal LV function have a better late survival rate if they have coronary bypass surgery. Because the randomized trials of PCI versus bypass surgery included an inadequate number of patients in these high-risk subsets, it cannot be assumed that the alternative strategy of PCI produces equivalent late survival in such patients.

Meta-analysis (489) of the randomized trials of medical management versus CABG has further indicated that patients without severe symptoms but with a proximal LAD lesion have a better survival rate with surgery, even if they have normal LV function and only one-vessel disease. For these patients, data from the PTCA versus CABG trials appear to show that, at least for the first five years, the alternative revascularization strategy of PCI does not compromise survival for patients with normal LV function who are good angiographic candidates for PCI. Severely symptomatic patients with three-vessel disease have a better survival rate with surgery than medical management even in the absence of a proximal LAD lesion and the presence of good LV function. Severely symptomatic patients with abnormal LV function should have surgery. For good angiographic candidates who have normal LV function, PCI may be considered an alternative to CABG if the patient is a favorable angiographic candidate for PCI.

Caution should be used in the treatment of diabetic patients with PCI, particularly in the setting of multivessel, multilesion severe CAD, because the BARI trial showed that patients with diabetes had a better survival rate with CABG than with PTCA (886).

Most patients with chronic angina have not been shown to have an increased survival rate with invasive treatment but may require invasive treatment for control of their symptoms. For patients with two-vessel disease, PCI and surgery are both acceptable, and patients and physicians can select therapies based on an analysis of the advantages and disadvantages of the two forms of treatment. For patients with multivessel disease who are candidates for both surgery and PCI, the current advantages and disadvantages of both procedures have been defined by the randomized trials. Both procedures had a low initial mortality rate (1% to 1.5%), but PCI involved less initial morbidity cost and a shorter hospital stay. On the other hand, recurrent angina and repeat procedures (either CABG or PCI) were much more common after PCI. By five postoperative years, the total costs of both procedures appeared to be equivalent.

Most patients with symptoms and ischemia based on onevessel disease can be treated effectively with PCI. For symptomatic patients with lesions unfavorable for PCI or who wish to decrease the risk of undergoing subsequent procedures, CABG is an acceptable alternative and produces excellent long-term outcomes.

An important observation of the EAST trial was that the patients in the EAST registry (those deemed appropriate for randomization but not randomized and whose therapy was determined by patient-physician choice) appeared to have slightly better outcomes than either of the randomized groups (890). In particular, the PTCA registry patients had better long-term outcome than the randomized PTCA patients did. These observations appear to suggest that even within a group of patients with similar baseline clinical and angiographic characteristics, the judgments of experienced interventional cardiologists and surgeons as to the best therapy may produce better outcomes than therapy by protocol or random choice. Furthermore, those judgments often appear to be based on the angiographic characteristics that influence the likelihood of a successful outcome with PCI.

4. Patients With Previous Bypass Surgery

The previous sections apply only to patients with native-vessel CAD. The randomized studies of invasive therapy for chronic angina have all excluded patients who developed recurrent angina after previous bypass surgery. Patients with previous bypass surgery differ in many ways from those who have never had the surgery. First, their pathology is different. For patients with previous surgery, myocardial ischemia and jeopardy may be produced not only by progression of native vessel CAD but also by stenoses in vein grafts produced by intimal fibroplasia or vein graft atherosclerosis, pathologies that are distinct from native-vessel CAD. Few existing data define outcomes for risk-stratified groups of patients who develop recurrent angina after bypass surgery. Those that do indicate that patients with ischemia produced by late atherosclerotic stenoses in vein grafts are at higher risk with medical treatment alone than those with ischemia produced by native-vessel disease (510). Second, the risks of coronary reoperation are increased relative to the risks of primary coronary bypass procedures. Third, the risks of percutaneous treatment of vein graft stenoses are also increased, and longterm outcome is not as good as that documented for treatment of native-vessel lesions. Only one observational study contains data comparing medical and surgical treatments of risk-stratified groups of patients with previous bypass surgery. That study shows that patients with late (greater than 5 years after operation) stenoses in saphenous vein grafts had a better survival rate with reoperation than initial medical management, particularly if a stenotic vein graft supplied the LAD (509). Patients with early (less than 5 years after operation) stenoses in vein grafts did not appear to have a better survival rate with reoperation, although their symptom status improved.

The heterogeneity of patients with previous bypass surgery makes treatment protocols difficult to establish. Patients with multiple vein grafts with late stenoses or late stenoses in an LAD vein graft should have reoperation in the absence of major contraindications to surgery. Despite improvement in the procedure-related complications of PCI for vein graft stenoses by the use of coronary stents, stenting has not significantly decreased the incidence of restenosis in vein grafts (511) and is not an equivalent form of revascularization for patients with late vein-graft stenoses. However, many symptomatic patients whose angina is caused by native-vessel stenoses or focal and early (less than 5 years after operation) stenoses in saphenous vein grafts can be treated successfully with percutaneous techniques.

These guidelines are only general principles for patients with previous bypass surgery, and there are many gray areas.

As indicated in Section III.D, a low threshold for angiographic evaluation is indicated for patients who develop chronic stable angina more than five years after surgery, especially when ischemia is documented noninvasively (473-475). Decisions about further therapy should be made with experienced invasive cardiologists and cardiac surgeons.

5. Asymptomatic Patients

Recommendations for Revascularization with PCI and CABG in Asymptomatic Patients

Class I (These recommendations are identical to those for symptomatic patients.)

1. Coronary artery bypass grafting for patients with significant left main coronary disease. (Level of Evidence: B)

2. Coronary artery bypass grafting for patients with three-vessel disease. The survival benefit is greater in patients with abnormal LV function (ejection fraction less than 50%). (Level of Evidence: C)

3. Coronary artery bypass grafting for patients with two-vessel disease with significant proximal LAD CAD and either abnormal LV function (ejection fraction less than 50%) or demonstrable ischemia on noninvasive testing. (Level of Evidence: C)

4. Percutaneous coronary intervention for patients with two- or three-vessel disease with significant proximal LAD CAD who have anatomy suitable for catheter based therapy and normal LV function and who do not have treated diabetes. (Level of Evidence: C)

5. Percutaneous coronary intervention or CABG for patients with one- or two-vessel CAD without significant proximal LAD CAD but with a large area of viable myocardium and high-risk criteria on noninvasive testing. (Level of Evidence: C)

6. Coronary artery bypass grafting for patients with one- or two-vessel CAD without significant proximal LAD CAD who have survived sudden cardiac death or sustained ventricular tachycardia. (Level of Evidence: C)

7. In patients with prior PCI, CABG or PCI for recurrent stenosis associated with a large area of viable myocardium or high-risk criteria on noninvasive testing. (Level of Evidence: C)

Class IIa (This recommendation is identical to the Class IIa recommendation for symptomatic patients.) Percutaneous coronary intervention or CABG for patients with one-vessel disease with significant proximal LAD CAD. (Level of Evidence: C)

Class IIb (Recommendations 1, 2, and 3 are identical to the recommendations for symptomatic patients. Recommendations 4 and 5 are identical to Class IIa recommendations for symptomatic patients.)

1. Compared with CABG, PCI for patients with 2- or 3-vessel disease with significant proximal LAD CAD who have anatomy suitable for catheter-based therapy and who have treated diabetes or abnormal LV function. (Level of Evidence: B)

2. Use of PCI for patients with significant left main coronary disease who are not candidates for CABG. (Level of Evidence: C)

3. Percutaneous coronary intervention for patients with one- or two-vessel CAD without significant proximal LAD CAD who have survived sudden cardiac death or sustained ventricular tachycardia. (Level of Evidence: C)

4. Repeat CABG for patients with multiple saphenous vein graft stenoses, with high-risk criteria on noninvasive testing, especially when there is significant stenosis of a graft supplying the LAD. Percutaneous coronary intervention may be appropriate for focal saphenous vein graft lesions or multiple stenoses in poor candidates for reoperative surgery. (Level of Evidence: C)

5. Percutaneous coronary intervention or CABG for patients with one- or two-vessel CAD without significant proximal LAD CAD but with a moderate area of viable myocardium and demonstrable ischemia on noninvasive testing. (Level of Evidence: C)

Class III (These recommendations are identical to the Class III recommendations for symptomatic patients.)

1. Use of PCI or CABG for patients with one- or two vessel CAD without significant proximal LAD CAD and

a. only a small area of viable myocardium or

b. no demonstrable ischemia on noninvasive testing. (Level of Evidence: C)

2. Use of PCI or CABG for patients with borderline coronary stenoses (50% to 60% diameter in locations other than the left main coronary artery) and no demonstrable ischemia on noninvasive testing. (Level of Evidence: C)

3. Use of PCI or CABG for patients with insignificant coronary stenosis (less than 50% diameter). (Level of Evidence: C)

4. Use of PCI in patients with significant left main CAD who are candidates for CABG. (Level of Evidence: B)

In asymptomatic patients, revascularization cannot improve symptoms. The only appropriate indication for revascularization with either PCI or CABG is therefore to improve prognosis. Most of the recommendations for revascularization that appear earlier in this section for patients with stable angina also apply to asymptomatic patients, because their underlying rationale is to improve prognosis. The single recommendation for revascularization in patients who have not been successfully treated by medical therapy is the exception and obviously does not apply to asymptomatic patients. However, the level of evidence in support of these recommendations in asymptomatic patients is clearly weaker than in symptomatic patients. Most of the available randomized trial data have focused on symptomatic patients. Their extrapolation to asymptomatic patients appears reasonable but is based on far more limited evidence.

In the CASS registry, asymptomatic patients with left main CAD who underwent CABG had a better outcome than those patients treated with medical therapy, but this was not a randomized trial (1031). The most compelling randomized trial data on asymptomatic patients comes from the previously mentioned ACIP study (880,881). In patients with CAD who were either free of angina or had well-controlled symptoms, patients randomized to revascularization had a lower cardiac event rate than patients who were randomized to medical management guided by angina or medical management guided by noninvasive ischemia. The patients entered in this study, who were required to have ischemia during ambulatory monitoring and exercise testing, as well as significant CAD, were more likely to have extensive CAD and prior MI. In the overall study group, 39% of the patients had three-vessel disease, 40% had prior MI, and 22% had prior revascularization, and 59% had angina within the previous 6 weeks. Many of the patients enrolled in this trial presumably came to medical attention because of symptoms or prior MI. The degree to which the results of ACIP can be applied to patients who have never been symptomatic and have less severe asymptomatic CAD is uncertain.