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-provokin