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Last Updated: 9/3/2014  

Coronary Heart Disease

Prevention
  • Encourage smoking cessation, regular physical activity, and a diet rich in fresh fruits and vegetables and low in cholesterol, saturated fats, and refined sugars.

  • Screen for dyslipidemia in asymptomatic, average-risk men over age 35 and women over age 45 and use a risk calculator to identify patients who may benefit from statin therapy.

  • Treat hypertension to <140/90 mm Hg in most patients and <150/90 mm Hg in patients over age 60.

  • Assess the benefits and risks of aspirin for primary prevention in patients with multiple CHD risk factors.

Screening
  • Do not screen for CHD in low-risk asymptomatic persons.

Diagnosis
  • Determine the pretest probability of CHD based on the type of pain (angina, atypical angina, noncardiac chest pain) and the presence of cardiac risk factors.

  • Examine patients for signs of CHD and comorbid diseases that may precipitate angina (e.g., hypertrophic obstructive cardiomyopathy, aortic stenosis, anemia, hyperthyroidism, cocaine use).

  • Obtain a resting ECG in all patients without an obvious noncardiac cause of chest pain.

  • Obtain a chest X-ray in all patients with HF, valvular heart disease, pericardial disease, or aortic dissection or aneurysm.

  • Obtain echocardiography in patients with possible valvular disease or outflow obstruction, HF, or history of MI.

  • Perform an exercise treadmill test in patients who are able to exercise and do not have baseline abnormalities on their resting ECG.

Therapy
  • Encourage smoking cessation, regular physical activity, and a diet rich in fresh fruits and vegetables and low in cholesterol, saturated fats, and refined sugars.

  • Prescribe β-blockers as the first-line anti-anginal therapy and calcium-channel blockers as the second-line treatment.

  • Add long-acting nitrates to β-blockers or calcium-channel antagonists or as monotherapy in patients not tolerant of first-line agents.

  • Begin all patients on aspirin and high-intensity statin therapy, and most patients on an ACE inhibitor.

  • Refer patients at high risk for death due to CHD or with persistent symptoms despite maximal medical therapy for evaluation for revascularization, including those with left-main stenoses ≥50%; severely symptomatic patients with three-vessel disease (stenoses ≥70%); high-risk exercise treadmill scores; multiple moderate or single large anterior perfusion defect on stress imaging; and LV function ≤35% to 40%.

Encourage smoking cessation in all patients who smoke. 
  • Inquire about smoking status in all patients.

  • At each visit, quantify use of tobacco products, recommend smoking cessation, and provide appropriate drug and non-drug support to all patients who want to quit smoking.

  • Consider using the following approach to encourage smoking cessation in the primary care setting:

    • Systematically identify all tobacco users

    • Recommend smoking cessation at each visit to patients who smoke

    • Identify patients who are willing to attempt to quit smoking

    • Assist patients with the development of a cessation plan

    • Encourage nicotine replacement or bupropion unless contraindicated

    • Schedule follow-up contact (in person or by telephone)

  • See module Smoking Cessation.

Evidence
  • A 1988 systematic review of features of successful smoking cessation interventions included 39 trials and found that direct, consistent reminders from physicians are an important motivation (1).

  • Epidemiologic data suggest that smokers have a two- to three-fold increased risk for death from ischemic heart disease. Compared with lifelong nonsmokers, those continuing to smoke died 10 years younger. Smoking cessation at age 60, 50, 40, or 30 years gained 3, 6, 9, or 10 years of life expectancy, respectively, compared with continuous smokers from youth (2).

  • Three randomized, controlled trials in primary prevention showed that smoking cessation reduced cardiac events by 7% to 47% (3; 4; 5).

  • A 1998 meta-analysis of 39 trials showed that among patients who quit smoking, direct, consistent reminders from physicians are an important motivation (1).

  • A review of randomized trials indicated that physician counseling is cost-effective (6).

Rationale
  • Cigarette smoking is one of the leading modifiable causes of cardiac death in the United States.

Comments
Assess asymptomatic persons without known CAD periodically for dyslipidemia.  
  • Measure a fasting lipid profile (or nonfasting total cholesterol and HDL levels) in asymptomatic standard-risk men age 35 and older and women age 45 and older without known CAD.

  • Consider screening patients with risk factors for CAD after age 20.

  • Repeat screening for hypercholesterolemia approximately every 5 years.

  • See module Lipid Disorders.

Evidence
  • A 2013 guideline from the ACC/AHA on the assessment of cardiovascular risk stated that it is reasonable to assess cardiovascular risk factors, including cholesterol, every 4 to 6 years in adults aged 20 to 79 years who do not have known cardiovascular disease (8).

  • A 2008 guideline from the U.S. Preventive Services Task Force recommended screening all men aged 35 years and older and other adults with risk factors for coronary heart disease. The guideline does not recommend routine screening in women at any age without additional risk factors.

  • Two reports from the Multiple Risk Factor Intervention Trial show that there is a continuous increase in cardiovascular events with an increasing total cholesterol level above 180 mg/dL or 4.65 mmol/L (9; 10).

  • Two studies showed that patients with the mixed dyslipidemia of elevated LDL cholesterol, low HDL cholesterol, and elevated triglyceride levels are at particularly high risk for subsequent cardiovascular events (11; 12).

Rationale
  • Hypercholesterolemia is an important identifiable and modifiable risk factor for CAD.

  • The risk for CAD is greatest in older men and women who have additional risk factors.

Comments
  • The risk for death from CAD in asymptomatic men and women without known CAD is low, even in the presence of elevated cholesterol levels; as a consequence, the estimated absolute survival benefit and cost-effectiveness of cholesterol reduction in these age groups are small (13).

  • There is no direct evidence that treatment of abnormal homocysteine or lipoprotein (a) levels reduces cardiovascular risk. Screening for these abnormalities is not recommended.

  • There is no direct evidence that treatment with vitamin E or vitamin C supplements reduces cardiovascular risk.

Use risk-targeted therapy to determine the need for statin therapy among asymptomatic patients without known CAD.  
Evidence
  • A 2013 guideline from the ACC/AHA on the assessment of cardiovascular risk recommended using the age- and race-specific pooled cohort equations to estimate each patient's risk for cardiovascular disease (8).

  • A 2013 guideline from the ACC/AHA on the treatment of blood cholesterol to reduce the risk for cardiovascular disease recommended high-intensity statin therapy for patients with known cardiovascular disease, moderate-intensity statin therapy for patients with diabetes, and therapy based on the calculated risk for cardiovascular events in the rest of the population aged 40 to 75 years (14).

  • A randomized, controlled trial done by the Oslo Study Group showed that diets low in total and saturated fat, particularly as part of multi-risk factor modification, can be effective in lowering cholesterol (5).

  • The West of Scotland Study (15) showed that among middle-aged men with elevated total cholesterol and LDL cholesterol levels, lowering of the LDL level with pravastatin reduced coronary events by 31%, MI by 31%, and coronary death by 32% during a follow-up of nearly 5 years. There was a 1.9% reduction in nonfatal MIs and a 0.5% reduction in coronary death with 5 years of therapy; this finding corresponds to an NNT of 52 to 53 to prevent one nonfatal myocardial infarction and 200 to prevent one coronary death.

  • The British Heart Protection Study showed a reduction in major vascular events in patients at high risk for CAD who were randomly assigned to receive an HMG-CoA reductase inhibitor, even among patients with a baseline LDL cholesterol level <3 mmol/L (116 mg/dL) (16). Among high-risk patients without known CAD, simvastatin, 40 mg/d, resulted in a 23% reduction in the relative risk for major vascular events (coronary death, nonfatal MI, stroke, and revascularization). The absolute risk reduction was 4.7% after 5 years of therapy (NNT, 21). High-risk patients included those with cerebrovascular disease, peripheral vascular disease, diabetes, and hypertension (>65 years). These data suggest that patients at high risk for cardiac mortality benefit from the cholesterol-lowering effects of statins, even if their baseline lipid panel is relatively normal.

  • A study showed the estimated cost-effectiveness of cholesterol lowering as primary prevention in various subgroups stratified by age and other risk factors (17). This study emphasizes the importance of targeting drug therapy at patients at highest risk for CAD (those with multiple risk factors).

  • Three separate cost-effectiveness analyses showed that drug approaches to lipid lowering are most cost-effective in persons with known CAD or multiple risk factors (17; 18; 19).

  • Observational data suggest that statin use according to NCEP guidelines reduces cardiovascular events and all-cause mortality in patients age 74 years and older without known CAD (20). The PROSPER trial showed that statins reduce cardiovascular risk in elderly patients with cardiovascular risk factors (21).

  • A prospective, randomized trial (JUPITER trial) in middle-aged, asymptomatic patients (males ≥50 years, females ≥60 years) with LDL cholesterol levels <130 mg/dL (3.36 mmol/L) and a high-sensitivity C-reactive protein of ≥2.0 mg/L compared a statin (rosuvastatin), 20 mg, with placebo. In this study, rosuvastatin therapy reduced cardiovascular events by 44% (22). Cardiovascular events were a combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes.

Rationale
  • Reduction of elevated LDL cholesterol levels reduces the risk for coronary events.

  • Age and sex markedly influence cardiac risk at any given level of LDL cholesterol.

  • Cholesterol lowering with HMG-CoA reductase inhibitors (statins) is unlikely to be cost-effective for asymptomatic men or women without known CAD who do not have other risk factors (age, hypertension, low HDL level, smoking, diabetes).

  • The benefit of cholesterol-lowering therapy is greatest in patients at highest risk for coronary events; as a consequence, statin therapy for primary prevention should be targeted at men and women who have several cardiac risk factors.

Comments
  • Use of prescribed statins declined significantly over time in an elderly cohort; fewer than 60% of patients took at least 80% of their prescribed statins after 3 months of treatment (23). It is prudent to ask about adherence to recommended therapy.

Identify and treat hypertension, using a goal blood pressure of <140/90 mm Hg for most patients.  
  • Routinely measure blood pressure in asymptomatic persons without known CAD (it is reasonable to measure blood pressure with each visit).

  • In hypertensive persons, use drug therapy if diet and exercise do not achieve desired reductions in blood pressure.

    • Use ACE inhibitors, thiazide diuretics, or calcium-channel blockers as first-line agents in most non-black patients.

    • Use calcium-channel blockers or thiazide diuretics as first-line agents in most black patients.

    • Use angiotensin receptor-antagonists as alternatives in patients who do not tolerate ACE inhibitors.

    • Use ACE inhibitors as first-line agents in patients with diabetes.

  • Target a goal blood pressure of <140/90 mm Hg in most patients, and a goal of <150/90 in patients aged over 60 years.

  • Target for earlier drug intervention those patients who have several coronary risk factors (e.g., smoking, hyperlipidemia, or diabetes mellitus) or evidence of end-organ damage (e.g., retinopathy or left ventricular hypertrophy on resting ECG).

Evidence
  • A 2014 guideline from the JNC 8 panel members recommended a target blood pressure of <140/90 mm Hg for patients aged under 60 years and <150/90 mm Hg for patients aged 60 years or older, regardless of the presence of diabetes. The guideline recommended using ACE inhibitors, ARBs, calcium-channel blockers, or thiazide diuretics as first-line agents in diabetic and non-diabetic, non-black populations, and recommended calcium-channel blockers and thiazide diuretics as first-line agents in diabetic and non-diabetic black patients (24).

  • A 2011 NICE guideline from the UK recommended using an ACE inhibitor or angiotensin-receptor blocker as the first-line agent in patients aged under 55 years, using a calcium-channel blocker as the first-line agent in patients of African or Caribbean descent and in patients over 55 years of age, and using a combination of an angiotensin and a calcium-channel blocker in patients requiring more than one drug. The guideline recommended thiazide diuretics such as chlorthalidone or indapamide as third-line agents (25).

  • A 2007 guideline from the European Society of Hypertension and the European Society of Cardiology recommended initial therapy with thiazide diuretics, calcium-channel blockers, ACE inhibitors, angiotensin-receptor blockers, or β-blockers as initial therapy, and that choice of therapy should depend on individual patient factors (26).

  • A 2012 Cochrane review of β-blockers compared with other therapies for hypertension included 13 randomized trials comparing β-blockers with placebo or other agents. Most studies used atenolol. Compared with placebo, β-blockers reduced total cardiovascular disease (RR, 0.88 [CI, 0.79 to 0.97]) and stroke (RR, 0.80 [CI, 0.66 to 0.96]) but not cardiac events. Compared with calcium-channel blockers, β-blockers were associated with higher risk for cardiovascular disease (RR, 1.18 [CI, 1.08 to 1.29]) and stroke (RR, 1.24 [CI, 1.11 to 1.40]). Compared with angiotensin agents, β-blockers were associated with higher risk for stroke (RR, 1.30 [CI, 1.11 to 1.53]) but equivalent risk for cardiovascular disease. Diuretics and β-blockers did not differ in rates of clinical outcomes. Patients on β-blockers were more likely than those on angiotensin agents to discontinue drug due to adverse events (RR, 1.14 [CI, 1.29 to 1.54]), but discontinuation rates compared with diuretics and calcium-channel blockers were similar (27).

  • A 2009 systematic review of the effect of blood pressure-lowering medications in the prevention of cardiovascular disease included 147 studies. Overall, in patients without known preexisting heart disease, each 10 mm Hg reduction in systolic blood pressure of 5 mm Hg reduction in systolic blood pressure led to a reduction in coronary heart disease events (RR, 0.78 [CI, 0.73 to 0.83]) and strokes (RR, 0.59 [CI, 0.52 to 0.57]) (28).

Rationale
  • Treatment of hypertension reduces the risk for cardiovascular events, particularly stroke.

Comments
  • Although ALLHAT, the largest antihypertensive cardiovascular outcome study, showed no difference in myocardial infarct cardioprotection between diuretic and either calcium-channel blocker or ACE inhibitor (29), the relevance in contemporary practice may be limited by multiple agents frequently being required in the management of hypertension; the availability of combination therapy as first-line treatment; and combination therapy studies.

  • The ASCOT-BPLA Study was prematurely ended because of increased mortality in high-risk hypertensive patients treated with thiazide/β-blocker combination compared with calcium-channel blocker/ACE inhibitor-based therapy (30).

  • The ACCOMPLISH study showed that a calcium-channel blocker/ACE inhibitor combination reduced cardiovascular outcomes better than an ACE inhibitor/thiazide diuretic combination in high-risk hypertensive patients (31).

  • Although β-blockers clearly reduce blood pressure, their benefit in preventing cardiovascular outcomes in hypertensive patients has been seriously questioned (32).

  • Based on the results of the ONTARGET trial, cardiovascular outcomes do not differ among high-risk hypertensive patients treated with an ACE inhibitor or angiotensin-receptor blocker, or both (33).

Consider primary prevention with aspirin for patients with multiple risk factors for cardiovascular disease.  
  • Consider treating asymptomatic persons without known CAD who have multiple coronary risk factors with medium-dose aspirin (75 to 325 mg/d), barring contraindication.

  • Consider treating men who are over age 40 and have diabetes with aspirin, barring contraindications.

  • Recognize that it is uncertain when to initiate therapy with aspirin in asymptomatic women with diabetes, although it is reasonable to recommend aspirin for postmenopausal women with diabetes who do not have known CAD.

  • Treat hypertensive adults over age 50 with aspirin, barring contraindication, provided hypertension has been adequately treated (SBP <145 mm Hg).

  • Do not recommend aspirin in asymptomatic persons of low- or average-risk for CAD.

  • See Comparative Guidelines: Aspirin for Primary Prevention.

Evidence
  • A 2009 meta-analysis from the U.S. Preventive Services Task Force found that aspirin use in women was associated with statistically significant reductions in cardiovascular events (OR, 0.88 [CI, 0.79 to 0.99]) and ischemic strokes (OR, 0.76 [CI, 0.63 to 0.93]), but no significant benefit in myocardial infarctions or cardiovascular mortality. In men, aspirin use was associated with a significant reduction in cardiovascular events (OR, 0.86 [CI, 0.78 to 0.94]) and myocardial infarctions (OR, 0.68 [CI, 0.54 to 0.86]), but no significant benefit in ischemic strokes or cardiovascular mortality. Total mortality was not significantly reduced by aspirin use in men or women (34).

  • In a meta-analysis of 145 randomized trials, treatment of patients with known coronary or vascular disease using medium-dose aspirin (75 to 325 mg qd) was associated with a 27% reduction in the odds ratio for major cardiovascular events over 5 years. The ARR was 3.3%, corresponding to an NNT of 33 (35).

  • In the Physicians' Health Study (male physicians ≥40 years), 325 mg of aspirin every other day reduced the risk for MI by 44%. No benefit was seen in participants under age 50. The ARR was 185 fewer MIs per 100,000 patient-years of observation, corresponding to an NNT of 541 persons per year to prevent one fatal or nonfatal MI (36).

  • In the British Doctors' Trial, healthy physicians were randomly assigned to receive aspirin, 500 mg/d. No difference in the incidence of MI, stroke, cardiovascular death, or total mortality was noted in 6 years of follow-up (37). However, the British Doctors' Trial was smaller than the U.S. Physicians' Health Study (and may have been underpowered), not placebo-controlled, and had a higher dropout rate (38).

  • Subgroup analysis of a Medical Research Council primary-care study found a reduction in cardiovascular events (both MI and stroke) only in the subset of patients with an SBP <145 mm Hg (39).

  • In the HOT study, treatment of hypertensive adults 50 to 80 years, with 75 mg/d of aspirin, in addition to treatment with antihypertensive agents, significantly reduced clinically apparent MI and major cardiovascular events (40). The absolute benefit was 1.5 MIs per 1000 patient-years (and 2.5 MIs per 1000 patient-years in persons with diabetes). This finding corresponds to an NNT of 667 for 1 year in nondiabetic patients and 400 for 1 year in diabetic patients.

  • The subset of men with diabetes in the Physicians' Health Study had a much larger ARR of 6.1% fewer fatal or nonfatal MIs over 5 years of follow-up, corresponding to an NNT of 16 (36).

  • A systematic review showed no enhanced efficacy of aspirin above the dose of 81 mg/d but an increased rate of bleeding due to gastrointestinal toxicity (41).

Rationale
  • Acute coronary events involve platelet activation and thrombosis.

  • Aspirin inhibits platelet activation by inhibiting cyclooxygenase.

  • Aspirin reduces the risk for cardiovascular events, although the ARR is highest in subgroups with multiple risk factors.

Comments
  • The absolute risk for cardiovascular events in asymptomatic persons without multiple coronary risk factors is low, regardless of whether aspirin is taken.

  • Aspirin carries a dose-related increase in the risk for gastrointestinal hemorrhage requiring transfusion (42).

Treat risk factors for CAD aggressively in persons with diabetes.  
  • Screen all patients with angina for diabetes.

  • Treat modifiable risk factors for cardiovascular disease (hypertension, smoking, hyperlipidemia) more aggressively in persons with diabetes.

    • Target blood pressure ≤130/80 mm Hg

    • Recommend smoking cessation at each visit

    • Treat with moderate- to high-intensity statin therapy

  • Consider β-blockers or ACE inhibitors as first-line antihypertensive agents in diabetic patients; thiazide diuretics are a preferable second choice to calcium-channel antagonists.

  • Treat men with diabetes who are over age 40 with aspirin, barring contraindications.

  • Consider treating postmenopausal diabetic women with aspirin, although it remains uncertain when to begin aspirin in asymptomatic women with diabetes.

Evidence
  • A 2013 guideline from the ACC/AHA on the treatment of blood cholesterol to reduce the risk for cardiovascular disease recommended high-intensity statin therapy for patients with known cardiovascular disease, at least moderate-intensity statin therapy for patients with diabetes, and therapy based on the calculated risk for cardiovascular events in the rest of the population aged 40 to 75 years (14).

  • In the UKPDS, treatment of blood pressure in persons with newly diagnosed type-2 diabetes resulted in a significant reduction in the risk for diabetes-related clinical endpoints, diabetes-related deaths, stroke, and microvascular disease. There was a nonsignificant reduction in the risk for myocardial infarction (43). Outcomes did not differ between patients treated with β-blockers or ACE inhibitors.

  • Among diabetic patients in the HOT study, the incidence of major cardiovascular events and mortality was directly correlated with the degree of diastolic decrease, down to a DBP of 80 mm Hg (40).

  • In the HOPE randomized trial, treatment of normotensive diabetic patients ≥55 years with an ACE inhibitor reduced major cardiovascular events, MI, stroke, and cardiovascular mortality, during a maximum of 6 years of follow-up (44).

  • In the SHEP study, diuretic therapy in hypertensive patients with diabetes was associated with a 44% reduction in the relative risk for major cardiovascular events per 100 patients during 5 years of follow-up. The ARR was 10.1%, corresponding to an NNT of 10 (45).

  • In both the ABCD and FACET trials, treatment of hypertensive diabetic patients with calcium-channel blockers was associated with a significantly greater risk for major cardiovascular events than treatment with ACE inhibitors (46; 47).

  • Compared with men without diabetes, men with diabetes in the Physicians' Health Study who were treated with aspirin had a much larger ARR of 6.1% fewer fatal or nonfatal MIs over 5 years of follow-up, corresponding to an NNT of 16 (36).

  • In a cohort study, the 7-year incidence of first MI among diabetic patients was as high as the incidence of MI among nondiabetic patients with a history of previous MI (20.2% vs. 18.8%) (48). A second cohort study found that diabetes mellitus was associated with a relative risk for cardiovascular death of 3.2 in men and 8.5 in women, over 7 to 8 years of follow-up (49). These findings are the basis for recommendations by the American Diabetes Association that the target LDL cholesterol level for persons with diabetes should be less than 100 mg/dL (2.59 mmol/L). There is, as yet, no evidence that aggressive reduction of cholesterol is beneficial in young adults with diabetes and no other risk factors for CAD.

Rationale
  • Cardiovascular disease accounts for 80% of mortality in patients with diabetes mellitus, and 75% of this attributable risk is due to CAD; this finding is true for both type-1 and type-2 diabetes mellitus.

  • Reduction of traditional cardiovascular risk factors significantly decreases the incidence of cardiovascular events in persons with diabetes mellitus.

Comments
  • Intensive glycemic control has not been shown to reduce major macrovascular events (50; 51), and one study has shown potential harm from this strategy (51).

  • Blood pressure control in diabetic patients has been shown to reduce macrovascular events; however, aggressive therapy to reduce systolic blood pressures below 120 mm Hg has been shown to be detrimental (52).

Encourage patients to engage in regular physical activity.  
  • Encourage persons without known CAD to incorporate at least moderate aerobic physical activity in their daily lives, such as brisk walking or other similar activity, for 30 minutes or more five to seven times per week.

Evidence
  • A 2014 guideline from the USPSTF on behavioral counseling to prevent cardiovascular disease in patients with cardiovascular risk factors recommended offering intensive behavioral counseling interventions to promote healthy eating and physical activity to overweight and obese adults with additional cardiac risk factors (53).

  • A 2013 guideline from the ACC/AHA on lifestyle management for the reduction of cardiovascular risk recommended that patients who would benefit from lowering their LDL adhere to a diet low in sweets, sugar-sweetened drinks, and red meat; high in fruits, vegetables, and whole grain; and which includes low-fat dairy, poultry, fish, nuts, and non-tropical vegetable oils. The guideline also recommended low levels of saturated and trans fats and aerobic moderate-intensity exercise for an average of 40 minutes three to four times per week (54).

  • In a cohort study of Norwegian men, the relative risk for cardiovascular death in physically fit men was one-half that of physically inactive men after adjustment for all other known cardiovascular risk factors (55).

  • In the Women's Health Initiative Observational Study, physical activity consisting of moderate (walking) or vigorous exercise was associated with reduced cardiovascular risk in postmenopausal women. Brisk walking or vigorous exercise for ≥2.5 h/wk was associated with a 30% reduced risk for cardiovascular events (56).

  • Moderately strenuous leisure-time physical activity compared with low physical activity was associated with a 40% reduction in fatal coronary heart disease events in the MRFIT study (57).

  • A prospective study showed that improvements in physical activity in both women and men with cardiovascular disease resulted in a 44% reduction in all-cause mortality over 5 years (58).

  • In a randomized, controlled trial, exercise and dietary changes reduced the risk for developing type-2 diabetes in overweight subjects with impaired glucose tolerance (59).

  • In a 6-year randomized, controlled trial in Finland, moderate exercise attenuated progression of carotid intima-media thickness, a marker of atherosclerosis, in middle-aged men not taking statins (60).

Rationale
  • Physical fitness is associated with a reduced risk for CAD and cardiovascular death.

Comments
  • Moderately strenuous exercise is a reasonable part of a multifactorial approach to reducing cardiovascular risk. It is likely to have a favorable effect on lipid profiles, hypertension, obesity, and diabetes mellitus.

Recommend a balanced diet rich in fresh fruits and vegetables and fiber, and low in cholesterol, saturated fats, and refined sugars.  
  • Advise patients to limit cholesterol and fat—particularly saturated fats—in their diets to reduce the risk for cardiovascular disease.

  • Be aware that optimal diets limit saturated fats and refined carbohydrates and include an abundance of whole grains, fruits, and vegetables.

Evidence
  • A 2014 guideline from the USPSTF on behavioral counseling to prevent cardiovascular disease in patients with cardiovascular risk factors recommended offering intensive behavioral counseling interventions to promote healthy eating and physical activity to overweight and obese adults with additional cardiac risk factors (53).

  • A 2013 guideline from the ACC/AHA on lifestyle management for the reduction of cardiovascular risk recommended that patients who would benefit from lowering their LDL adhere to a diet low in sweets, sugar-sweetened drinks, and red meat; high in fruits, vegetables, and whole grain; and which includes low-fat dairy, poultry, fish, nuts, and non-tropical vegetable oils. The guideline also recommended low levels of saturated and trans fats and aerobic moderate-intensity exercise for an average of 40 minutes three to four times per week (54).

  • In the Oslo Study Group trial of multiple risk-factor intervention, advice on dietary change and smoking cessation was associated with a reduction in the incidence of MI and sudden death (5); however, in the similar MRFIT trial, no reduction in CHD mortality was noted in the intervention group (4).

  • In the randomized, controlled Minnesota Coronary Survey, a low-fat diet that resulted in an approximately 15% reduction in serum cholesterol was not associated with a significant change in the incidence of cardiovascular event, cardiovascular deaths, or total mortality (61).

  • A pooled analysis of observational studies suggests that increased intake of dietary fiber (from fruits, vegetables, and cereal) is associated with a reduced risk for cardiovascular events and coronary death (62).

  • This topic has been reviewed (63).

Rationale
  • Hypercholesterolemia is associated with increased risk for CAD and may be reduced by dietary modification.

Comments
  • Diet is a reasonable part of a multifactorial approach to reducing cardiovascular risk. It is likely to have a favorable effect on lipid profiles, hypertension, obesity, and diabetes mellitus.

Recognize that antioxidant vitamins should not be recommended for reducing cardiovascular risk. 
  • Do not recommend antioxidant vitamins, such as β-carotene and vitamins C and E, for preventing CAD events, even among patients at high risk for cardiovascular disease.

Evidence
  • A 2003 guideline from the U.S. Preventive Services Task Force concluded that there was insufficient evidence to recommend for or against supplemental vitamin A, C, or E to prevent cardiovascular disease (64).

  • In the HOPE study, vitamin-E supplementation did not have any effect on the risk for cardiovascular events or cardiac death among more than 7000 high-risk patients randomly assigned to receive vitamin E versus placebo (65).

  • Similarly, in the Heart Protection Study that enrolled more than 20,000 subjects, supplementation with vitamin C, vitamin E, and β-carotene did not affect risk for major vascular events, nonfatal MI, stroke, cardiac death, or death from any cause (66).

  • Randomized, controlled trials have not supported evidence in favor of antioxidant supplementation from observational studies (67).

Rationale
  • Although antioxidant vitamins may theoretically reduce oxidation of LDL cholesterol and, therefore, progression of atherosclerosis, evidence from randomized, controlled trials shows that treatment with antioxidant vitamins, such as β-carotene and vitamins C and E, does not reduce cardiovascular risk.

Comments
  • Although supplementation with antioxidant vitamins is reasonably safe, one study suggests that antioxidant vitamin supplementation may actually be harmful in subsets of patients. In this study, patients with CAD and low HDL cholesterol levels randomly assigned to receive simvastatin plus niacin had stabilization or regression of angiographically measurable CAD; addition of antioxidant supplementation (vitamin C, vitamin E, β-carotene, and selenium) blunted the beneficial effects of simvastatin-niacin on HDL levels and was associated with angiographic progression of CAD (68).

  • There is no evidence that these vitamins act as antioxidants in humans.

Recognize that currently there is no direct evidence that treatment of abnormal homocysteine or lipoprotein(a) levels prevents cardiovascular disease. 
  • Recognize that there are inadequate data to recommend testing for homocysteine and/or lipoprotein(a) in asymptomatic adults.

Evidence
  • No studies to date have shown that reductions in homocysteine or lipoprotein(a) are associated with risk reduction in patients without known CAD.

  • Treatment with folic acid, vitamin B12, and vitamin B6 did reduce the rate of revascularization in patients with a history of CAD and percutaneous coronary intervention (69).

Rationale
  • Elevated levels of homocysteine and lipoprotein(a) are independent risk factors for CAD.

Do not screen for CAD in asymptomatic persons without cardiovascular risk factors. 
Evidence
  • A 2010 guideline from the ACCF/AHA does not recommend screening low-risk asymptomatic individuals with stress testing (70).

  • A 2012 guideline from the USPSTF recommends against performing a routine ECG in low-risk asymptomatic adults (71).

  • A systematic review of the literature published between 1966 and 2003 identified 13 studies examining the utility of ETT to diagnose asymptomatic coronary artery obstruction. This review concluded that previously unrecognized, clinically important coronary artery obstruction is found in 0.9% to 1.2% of screened persons with at least one risk factor and in 0.06% to 1.6% of screened persons with no risk factors (72).

  • A screening examination of 18,403 men found that abnormalities of the resting ECG are uncommon in asymptomatic middle-aged men (1% to 4%) and are not specific for CAD (73).

  • Only 29% of persons with symptomatic, angiographically proven CAD have normal baseline ECGs (74).

  • In the Coronary Artery Surgery Study, most asymptomatic persons with an abnormal exercise ECG do not have clinically significant CAD on angiography (positive predictive value of 20%) (75).

  • The U.S. Preventive Services Task Force has shown that abnormalities of resting or exercise ECG testing only modestly predict subsequent coronary events, with a pooled hazard ratio of 1.4 to 2.1 after adjustment for other risk factors (76).

  • A prospective trial found that the risk for sudden death during vigorous exercise has been estimated to be less than 1 death per 1.5 million episodes of vigorous exercise among U.S. male physicians (77).

  • Among hypercholesterolemic, middle-aged men enrolled in the Lipid Research Clinics trial, only 2% had an acute coronary event during exercise over the ensuing 7 years, and an abnormal exercise treadmill test result had a positive predictive value of only 4% (78).

Rationale
  • Abnormalities of the resting ECG are rare, not specific for CAD, and do not predict subsequent mortality from coronary disease.

  • Although exercise testing may identify persons with CAD, two factors limit the utility of routine testing in asymptomatic adults:

    • The prevalence of significant CAD is low in asymptomatic adults, rendering the predictive value of a positive exercise test low (i.e., false-positive results are common)

    • Abnormalities of exercise testing do not accurately predict major coronary events in asymptomatic persons

Comments
  • Screening for coronary heart disease in asymptomatic persons has several inherent problems. The clinical information required is the prediction of MI, and the traditional risk factors (hypertension, diabetes, smoking, hypercholesterolemia, and a family history of premature CAD) have been associated with this cardiac event. Coronary atherosclerosis (typically assessed with coronary angiography) has been used as a surrogate marker of predicting cardiac events, and noninvasive methods of detecting angiographic CAD have been developed. The problems with these studies are that angiography detects luminal narrowing rather than arterial-wall atherosclerosis, which involves a remodeling process where luminal narrowing occurs late (79); luminal narrowing does not predict MI because many infarcts occur at sites with minimal stenosis (80); and, most important, subclinical coronary atherosclerosis is highly prevalent within the community (17% of teenagers and 85% of those >50 years have coronary atherosclerosis in the absence of a history of CAD) (81). Therefore, only a small portion of persons with coronary atherosclerosis have symptomatic disease, and even fewer experience cardiac events.

  • Because the positive predictive value of an abnormal exercise test result is low, one major consequence of routine exercise testing in asymptomatic persons is the incorrect labeling of otherwise healthy individuals as having CAD.

  • In addition, a large number of these persons would have expensive and unnecessary diagnostic procedures.

  • Assessment of preoperative cardiac risk in persons without known CAD is addressed in the module Preoperative Cardiac Risk Assessment.

Consider screening for occult CHD in some asymptomatic patients at intermediate or high risk for CHD using ECG, cardiac CT, or ultrasonography for carotid intimal thickness. 
  • Screen patients in whom the results would change management.

  • Use one of several reasonable screening tests for vascular disease:

    • ECG, although it has poor sensitivity for coronary artery disease

    • Cardiac CT (for coronary calcium), for which higher scores are more predictive of cardiac events

    • Ultrasonography for carotid intimal thickness, although evidence of its independent prognostic value are unclear

    • Ankle-brachial index, to diagnose peripheral vascular disease, which is a marker of atherosclerosis

  • See module Screening for Coronary Artery Disease.

Evidence
  • ACCF/AHA guidelines for 2010 for assessment of cardiovascular risk in asymptomatic adults state that several tests are reasonable (class IIa recommendation) for risk assessment in asymptomatic adults at high or intermediate risk, including ECG, cardiac CT for coronary artery calcium, ultrasonography for carotid intima media thickness, and ankle-brachial index (70).

  • A systematic review of cohort studies found that major abnormalities, such as ST-segment or T-wave changes, conduction blocks, ventricular ectopy, and atrial fibrillation, on screening resting ECG have a sensitivity of 16% to 32% and a specificity of 87% to 96% for predicting future CHD events (82).

  • A systematic review of cohort studies performed as part of the ACCF/AHA clinical expert consensus document evaluating the predictive information gained from cardiac CT found that the summary relative-risk ratios show an incremental relationship, in which higher CAC scores are associated with higher event rates and higher relative-risk ratios. Persons with CAC scores greater than 0 had graded increases in the relative risk for CHD events after controlling for measured risk factors and demographic information. A mild-risk CAC score (with scores ranging from 1 to 112) was associated with an elevation in CHD death or MI risk with a summary relative risk ratio of 1.9 (CI, 1.3 to 2.8; P=0.001). With even higher CAC scores, the 3- to 5-year event rates increased substantially. For scores ranging from 100 to 400, the summary relative-risk ratio was 4.3 (CI, 3.1 to 6.1) when compared with patients with no detectable coronary calcium (P<0.0001). For the high-risk (CAC scores of 400 to 1000) and very-high-risk (>1000) CAC scores, pooled CHD death or MI rates were 4.6% and 7.1% at 3 to 5 years after CAC testing, resulting in relative-risk ratios of 7.2 (CI, 5.2 to 9.9; P<0.0001) and 10.8 (CI, 4.2 to 27.7; P<0.0001) when compared with the low-risk group (CAC score = 0) as reference. Persons with a CAC score of zero had remarkably low event rates over the next 3 to 5 years (less than one event per 1000 person-years follow-up) (83). Impact of testing on clinical outcomes, however, is not clear.

  • A small number of cohort studies show evidence that carotid ultrasonography (84) and ankle-brachial index (18) provide risk information, but there are questions about whether or not traditional CHD risk factors were adequately controlled. Other studies have demonstrated that carotid intimal thickness (RR, 2.1) is associated with increased risk for CHD events and mortality (85).

Rationale
  • In asymptomatic adults at high or intermediate risk for cardiovascular disease, prognostic tests may help direct more aggressive therapy. In patients already receiving maximal medical therapy, these tests may have little utility.

Comments
  • Cardiovascular tests in asymptomatic persons can be used to diagnose unsuspected coronary artery lesions that could be treated with antiatherosclerotic therapies (i.e., statins, aspirin) to prevent imminent cardiovascular events. This strategy is likely to be most effective in low- to intermediate-risk persons (6% to 20% risk for cardiovascular disease event in 10 years); providing revascularization to asymptomatic persons has not been shown to improve outcomes and is generally considered inappropriate. Revascularization has only been shown to be helpful in the setting of symptoms of heart disease or an acute coronary syndrome.

  • The principal tests for detecting asymptomatic CHD include CAC testing, resting ECG, and ETT. These tests can provide evidence of atherosclerosis, unrecognized previous MI, silent or inducible myocardial ischemia, or other cardiac abnormalities.

  • Cardiovascular screening tests could also be used to provide further information about future risk for CHD beyond that of traditional risk-factor assessment and to guide the use of risk-reducing treatments, such as lipid-lowering or aspirin therapies.

  • The addition of cardiovascular screening tests is likely to be most helpful in patients whose risk for future cardiovascular events is not clear and when better risk stratification would change patient management, such as adding aspirin or initiating or titrating statin therapy for primary prevention. If a patient is considered low risk as determined by such instruments as the Framingham Risk Score calculator, additional screening tests rarely will change that risk. Likewise, if a patient is considered high risk, additional testing is unlikely to change the management plan. The intermediate-risk patient may derive the most benefit from additional tests to better stratify risk. Further studies are needed to determine whether treatment based on cardiovascular screening tests improves outcomes.

Consider screening for CAD in selected asymptomatic persons whose occupations may affect public safety or who engage in new or intermittent high-intensity physical activity. 
  • Consider exercise testing or baseline ECGS in occupations that require physical fitness or high-intensity physical activity, such as airline pilots, air traffic controllers, police, and firefighters.

  • Consider exercise testing in patients beginning an intensive exercise program.

  • See module Screening for Coronary Artery Disease.

Evidence
  • There is no adequate evidence for or against screening in these occupations (86; 87) or screening patients before initiation of a new exercise program.

Rationale
  • Persons whose occupations involve public safety may be held to a higher standard of physical fitness than the average individual.

  • Persons who engage in occupations that involve bursts of high-intensity physical activity, such as police or firefighters, may be at increased risk for cardiovascular events.

Comments
  • Policies regarding screening for CAD in certain occupations are frequently codified by local and national regulatory agencies.

Assess the probability of significant CAD based on the clinical history. 
  • Assess the pretest probability of significant CAD in all patients with chest pain based on:

    • Type of pain (typical angina, atypical angina, or noncardiac chest pain). See table Clinical Classification of Chest Pain.

      • Typical angina has three components: 1) location: substernal, jaw, neck, back, epigastrium, or arm; 2) quality: squeezing, heavy, suffocating; 3) exacerbation by exertion or stress and relieved with rest or nitroglycerine. The presence of typical angina has a sensitivity of 91% in men and 89% in women and a specificity of 87% in men and 63% in women for the diagnosis of CAD.

      • Atypical angina meets any two of the three characteristics of typical angina and is still moderately predictive of CAD. The positive predictive value for atypical angina is reported to be 26% to 65% for the presence of significant CAD.

    • Cardiac risk factors (age, gender, smoking history, hyperlipidemia, diabetes mellitus, hypertension, and family history of premature coronary disease)

  • See table Diagnostic Accuracy of Elements of the History and Physical Examination for Coronary Disease.

Evidence
  • A 2012 guideline from the American College of Physicians, American College of Cardiology Foundation, American Heart Association, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, and the Society of Thoracic Surgeons for the diagnosis of stable ischemic heart disease recommends using the history and physical exam to assess the likelihood of ischemic heart disease before further diagnostic testing (88).

  • The sensitivity of typical angina for the diagnosis of CAD is 91% in men and 89% in women, and the specificity is 87% in men and 63% in women. Data were derived from an angiography referral population (89) and may overestimate the accuracy of the history.

  • The positive predictive value for atypical angina is reported to be 26% to 65% for the presence of significant CAD (87).

  • The clinical history is the cornerstone in the diagnosis of coronary heart disease, and the features of “angina pectoris” remain the same as when first described by William Osler (90).

  • In a retrospective review of several studies done in the 1960s and 1970s, Diamond and Forrester calculated pretest probabilities of significant CAD based on age, gender, and type of chest pain (typical angina, atypical angina, or nonanginal chest pain) (91).

  • This simple model was validated in comparisons of clinical and angiographic findings in the >20,000 participants of the multicenter Coronary Artery Surgery Study (92).

  • A prospective study of patients referred to a single center for angiography shows the importance of additional cardiac risk factors in modifying the pretest probabilities of significant CAD based on type of pain, age, and gender alone (93).

Rationale
  • The diagnosis of CAD is based on the gold-standard diagnostic test of invasive coronary angiography, which has inherent limitations.

  • Estimates of the probability of significant angiographic CAD (low, intermediate, or high) may be made from limited clinical information.

  • The predictive value of further diagnostic testing is influenced by the pretest probability of disease.

  • In general, persons with a high pretest probability of disease require no further testing to establish the diagnosis of CAD and, instead, stratification according to risk becomes the primary goal.

  • The positive predictive value of an exercise treadmill test is low in patients with a low pretest likelihood of CAD.

  • Exercise treadmill tests or other noninvasive tests provide the most diagnostic information about persons with an intermediate probability of CAD (e.g., 20% to 80% pretest probability).

Comments
  • Type of pain, age, and gender are the most important predictors of angiographically significant CAD.

  • Smoking history (defined as smoking ≥ half a pack per day or at least 25 pack-years), hyperlipidemia, and diabetes mellitus are also independent predictors of significant CAD.

  • Hypertension and family history are less predictive, although a family history of premature CAD (before the age of 45 years) or strong family history (two or more first-degree relatives with CAD) more strongly predicts CAD (94).

Examine patients for signs of cardiovascular disease and comorbid diseases that may precipitate angina.  
Evidence
  • A 2012 guideline from the American College of Physicians, American College of Cardiology Foundation, American Heart Association, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, and the Society of Thoracic surgeons for the diagnosis of stable ischemic heart disease recommends using the history and physical exam to assess the likelihood of ischemic heart disease before further diagnostic testing (88).

Rationale
  • Findings at physical examination suggesting peripherovascular or cerebrovascular disease increase the likelihood of CAD.

  • Conditions that increase myocardial oxygen demand (uncontrolled hypertension, hyperthermia in the setting of hypovolemia, tachyarrhythmias, left ventricular outlet obstruction, hyperthyroidism, sympathomimetic toxicity), diminish tissue oxygenation (anemia and hypoxemia), or cause hyperviscosity (polycythemias or hypergammaglobulinemia) may precipitate angina in the setting of nonsignificant CAD.

  • The treatment of angina is best directed at the underlying cause in this setting.

Test patients for diabetes mellitus. 
  • Measure serum glucose, preferably in the fasting state, to evaluate for diabetes mellitus.

  • See module Diabetes Mellitus, Type 2.

Evidence
  • A cohort study found that the 7-year incidence of MI among diabetic patients without previous MI was as high as the incidence of MI among nondiabetic patients with a history of previous MI (20.2% vs. 18.8%) (48).

  • A second cohort study found that diabetes mellitus conferred a relative risk for cardiovascular death of 3.2 in men and 8.5 in women, over 7 to 8 years of follow-up (49).

Rationale
  • Persons with diabetes are at an elevated risk for and mortality from CAD.

  • Treatment of hypercholesterolemia reduces mortality in patients with CAD.

  • Statin therapy reduces mortality in patients with CAD, regardless of initial LDL cholesterol level.

Comments
  • One study suggests that antioxidant vitamin therapy attenuated the benefit of lipid-lowering therapy (68).

Obtain a resting ECG in patients with angina.  
  • Obtain a resting ECG in all patients without an obvious noncardiac cause of chest pain.

  • Obtain a resting ECG during an episode of chest pain when possible.

  • Obtain a chest X-ray in all patients with signs or symptoms of HF, valvular heart disease, pericardial disease, or aortic dissection or aneurysm.

  • Note that the usefulness of a chest X-ray in other settings is not well established.

  • See table Laboratory and Other Studies for the Diagnosis and Risk Stratification of Patients with Angina.

Evidence
  • A 2012 guideline from the American College of Physicians, American College of Cardiology Foundation, American Heart Association, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, and the Society of Thoracic Surgeons for the diagnosis of stable ischemic heart disease recommends a resting ECG in patients with chest pain (88).

  • One study showed that the resting ECG is normal in ≥50% of patients with chronic stable angina (95).

  • According to ACC/AHA/ACP guidelines, evidence of previous Q-wave MI on the resting ECG makes CAD very probable (87).

  • Many abnormalities of depolarization, repolarization, rhythm, or conduction are more common in patients with CAD, but are nonspecific (87; 96).

  • ACC/AHA/ACP guidelines state that approximately 50% of patients with angina will have an abnormal ECG during an episode of chest pain and that chest x-ray results are frequently normal (87); this finding is highly suggestive of CAD and suggests ischemia at low workloads, portending high-risk coronary anatomy (87).

  • A cohort study showed that calcification of the aorta on chest X-ray increases the probability of CAD and is associated with an increased relative risk for subsequent coronary events (97).

Rationale
  • A resting ECG may show signs of ischemia, abnormalities of conduction, abnormalities of rhythm, or left ventricular hypertrophy.

  • An ECG obtained during chest pain is most useful.

  • Chest X-ray results may show signs of HF (e.g., pulmonary edema, vascular redistribution, pleural effusions, or cardiomegaly) or arterial calcification, or may suggest causes of chest pain other than angina.

Obtain standard echocardiography in patients with a suspicion of significant valvular disease, signs or symptoms of HF, history of myocardial infarction, or history of HF.  
  • Obtain standard echocardiography in patients with a systolic murmur suggesting aortic stenosis or hypertrophic cardiomyopathy.

  • Obtain echocardiography (or radionuclide imaging) to assess left ventricular function in several subsets of patients:

    • Patients with a documented history of myocardial infarction

    • Patients with pathologic Q-waves on resting ECG

    • Patients with signs or symptoms suggesting heart failure

  • Do not routinely obtain echocardiography in patients with suspected angina who have a normal ECG, no history of myocardial infarction, and no signs or symptoms of HF.

  • Note that patients with aortic stenosis are at increased risk for mortality during exercise treadmill testing.

  • See table Laboratory and Other Studies for the Diagnosis and Risk Stratification of Patients with Angina.

Evidence
  • A 2012 guideline from the American College of Physicians, American College of Cardiology Foundation, American Heart Association, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, and the Society of Thoracic Surgeons for the diagnosis of stable ischemic heart disease recommends Doppler echocardiography in patients with signs or symptoms of HF, pathologic Q-waves on ECG, ventricular arrhythmias, or heart murmurs (88).

  • According to ACC/AHA/ACP guidelines, echocardiography allows accurate diagnosis of patients with significant aortic stenosis or hypertrophic cardiomyopathy (87).

  • The 10-year results from randomized, controlled trials of CABG showed that reduced LV function is associated with a worse prognosis in patients with stable angina (98).

    • In long-term follow-up from the CASS registry, 72% of deaths occurred in the 38% of the population with LV dysfunction (LVEF = 40%) or severe CAD (99).

    • A resting ejection fraction of <35% is associated with an annual mortality rate of >3% (99).

    • In three randomized, controlled trials, patients with three-vessel disease and LV dysfunction derive a clear survival benefit after CABG (100; 101; 102).

  • The guidelines state that patients with normal resting ECGs are likely to have normal LV function (92% to 96%) and an excellent prognosis (87).

Rationale
  • Echocardiography is useful in identifying patients with functional angina related to valvular lesions and to identify patients with reduced LV function.

  • LV function is one of the major determinants of survival among patients with chronic stable angina.

Perform an exercise treadmill test or other diagnostic noninvasive study in patients with an intermediate probability of CAD. 
Evidence
  • A 2012 guideline from the American College of Physicians, American College of Cardiology Foundation, American Heart Association, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, and the Society of Thoracic Surgeons for the diagnosis of stable ischemic heart disease (88) recommends:

    • Standard exercise ECG in patients with an intermediate likelihood of CAD, an interpretable ECG, and at least moderate ability to exercise

    • Exercise stress testing with either radionucleotide imaging or echocardiography in patients with intermediate to high pre-test probability of CAD, an uninterpretable ECG, and at least moderate ability to exercise

    • Pharmacologic stress testing with radionucleotide imaging or echocardiography in patients with intermediate or high pre-test probability of CAD who are unable to exercise

    • Against the use of standard exercise ECG testing in patients with uninterpretable ECGs or the inability to exercise, exercise stress testing with either radionucleotide imaging or echocardiography or cardiac MRI in patients with interpretable ECGs who are able to exercise

  • A 2014 AHA consensus statement on noninvasive testing in the evaluation of women with suspected ischemic heart disease recommended exercise stress testing for the assessment of symptomatic women at intermediate risk for CAD who are able to exercise, and recommended imaging only for women with abnormalities on the resting ECG or for those unable to adequately exercise. For women with resting ECG abnormalities or inability to exercise or for those with indeterminate exercise stress test results, the guideline recommended stress echocardiography or stress myocardial perfusion imaging with PET or SPECT, and stated that it may be reasonable to use stress cardiac MRI or coronary CT angiography (103).

  • A 2010 systematic review of the accuracy of stress echocardiography and myocardial perfusion imaging for the diagnosis of left main and three-vessel CAD included 32 studies. Stress echocardiography had pooled sensitivity of 94% and pooled specificity of 40%; myocardial perfusion imaging had pooled sensitivity of 75% and pooled specificity of 48% (104).

  • The ACC/AHA Guidelines for Exercise Testing state that a positive exercise ECG is defined as ≥1 mm of horizontal or down-sloping ST-segment depression or elevation for ≥60 to 80 ms after the end of the QRS complex, either during or after exercise (105).

  • One study found that the Duke treadmill score accurately predicts prognosis and combines information about the patient's exercise capacity, exercise-induced ECG changes, and exercise-induced symptoms of angina (106).

  • A retrospective analysis showed that exercise ECG has a sensitivity of 40% and specificity of 96% in men for detecting obstructive CAD on angiography (107).

  • ACC/AHA/ACP guidelines state that exercise thallium (201Tl) testing has a sensitivity of 45% to 82% and specificity of 59% to 78% for detecting obstructive CAD on angiography (87).

  • Exercise echocardiography has a sensitivity of 32% and specificity of 86% for detecting obstructive CAD on angiography (108).

  • A meta-analysis found that pharmacologic stress imaging had a sensitivity of 87% and specificity of 64% for detecting obstructive CAD on angiography, unadjusted for potential referral bias. Dobutamine echocardiography has a sensitivity of 85% and specificity of 77% for detecting obstructive CAD on angiography (109).

  • MI or death is extremely rare during ETT (110). In a retrospective review, persistent tachyarrhythmia occurred in approximately 0.01% of tests (111).

Rationale
  • Exercise ECG is safe and relatively inexpensive, and accurately predicts prognosis.

  • Exercise is preferred to pharmacologic stress in most instances.

  • Myocardial perfusion imaging or echocardiography is preferred in settings where exercise ECG alone will probably be difficult to interpret.

  • Noninvasive stress testing is most useful in the setting of an intermediate pretest probability of CAD.

Comments
  • Myocardial perfusion imaging may allow localization of CAD to the distribution of individual coronary arteries.

  • Dipyridamole and adenosine may cause bronchospasm in patients with asthma or bronchospastic COPD.

  • Morbid obesity reduces the sensitivity of scintigraphy and echocardiography.

  • Men and women with suspected angina should be evaluated according to the same approach. The combined ACC/AHA/ACP expert panel on the diagnosis of angina concluded there was inadequate evidence to recommend a particular diagnostic strategy in women (87).

  • Combining pretest probability of disease with the sensitivity and specificity of noninvasive diagnostic testing allows calculation of post-test probability of disease and facilitates management.

Stratify patients with an intermediate or high post-test probability of CAD following diagnostic stress testing according to their risk for future major coronary events (death or MI).  
  • Assess anginal pattern (atypical, stable, progressive, or unstable), noting that progressive angina or unstable angina patterns are associated with increased risk for major coronary events.

  • Assess comorbidities (peripheral or cerebrovascular disease, diabetes, previous MI, hypertension, and signs or symptoms of HF).

  • Determine whether evaluation of LV function is warranted (history of previous MI or signs and symptoms of HF).

  • Use the Duke Treadmill Score to evaluate patients <75 years old:

    • Minutes of exercise − (5 × maximal mm ST deviation) − (4 × angina score)

    • Angina score: 0 for no chest pain, 1 for angina with exertion, 2 if angina is the reason for stopping the exercise test

  • Use stress imaging or coronary angiography in patients with intermediate exercise treadmill results (Duke treadmill scores of -10 to +4) to identify patients who have high-risk CAD (estimated annual mortality >3%).

  • Identify high-risk clinical features and noninvasive test results that would favor proceeding directly to coronary angiography:

    • LV dysfunction

    • Class III or IV angina despite adequate medical therapy

    • High-risk exercise treadmill score (< -10)

    • Large single or multiple moderate-size, stress-induced perfusion defects on myocardial perfusion imaging

    • Stress-induced LV dilation

    • Stress echocardiographic evidence of extensive areas of stress-induced wall-motion abnormalities

  • See table Risk of Mortality at 1 Year: Clinical History Variables.

Evidence
  • The 27th Bethesda Conference reported that the probability of death at 1 year may be estimated from several readily obtainable clinical variables, including age, type of angina (nonanginal, atypical, stable typical angina, progressive angina, and unstable angina), and comorbidities (peripheral or cerebrovascular disease, diabetes, previous MI, hypertension, and mitral regurgitation) (112).

  • The conference also reported that risk estimates may be refined with the results of functional studies (treadmill, stress myocardial perfusion imaging, or stress echocardiography), or coronary angiography (112).

  • One study of 2200 consecutive patients found that those with low-risk exercise treadmill scores generally need no further risk stratification. Fewer than 5% of patients with a low-risk exercise treadmill score are identified as having high-risk CAD after stress imaging (113).

  • Another study of 1159 consecutive patients showed that among those with an intermediate Duke treadmill score (≥-10 and <+5), myocardial perfusion imaging helped stratify patients into low-risk and high-risk groups (114). For example, a normal or mild perfusion defect on scintigraphy confers a 0.7% to 0.8% risk for cardiac death and a 1.1% to 4.4% risk for nonfatal MI over 2 years of follow-up. Patients with moderate or severe perfusion defects on scintigraphy had a 10.5% risk for cardiac death and a 6.3% risk for nonfatal MI over 2 years of follow-up.

  • According to the 10-year results from randomized, controlled trials of CABG, subsets of patients with CAD and high short-term risk for mortality (≥3% per year) have improved survival after CABG. Patients with left ventricular dysfunction (LVEF ≤40%) and three-vessel CAD have improved survival after CABG (98).

Rationale
  • Patients with CAD may be divided according to short-term risk for cardiac death and nonfatal MI on the basis of clinical parameters and the results of noninvasive functional testing.

  • Patients with low-risk exercise treadmill scores (≥+5) have an estimated cardiac mortality rate of less than 1% per year and usually do not require further risk stratification.

  • Patients with high-risk exercise treadmill scores (<-10) have an estimated cardiac mortality rate of ≥3% per year and should be referred for coronary angiography and possible revascularization.

  • Patients with intermediate exercise treadmill scores (≥-10 and <+ 5) may be stratified into low-risk (appropriate for medical management) and high-risk (consider revascularization) groups.

  • Patients with LV dysfunction (LVEF ≤40%) or severe coronary disease (left-main or three-vessel disease) are at particularly high risk for death and should be evaluated for possible revascularization.

Comments
  • The Duke treadmill score does not accurately predict prognosis in patients >75 years. More than two thirds of elderly patients are classified as intermediate risk, and risk category does not predict cardiac death or nonfatal MI. It is not clear whether other noninvasive functional studies are better in elderly patients (115).

  • Patients with a low post-test probability of CAD (≤ 10% to 20%) generally have a favorable prognosis, eliminating the need for further risk stratification.

Recommend coronary angiography for patients with an uncertain diagnosis after noninvasive testing or probable high-risk CAD.  
  • Recommend coronary angiography in several subsets of patients with suspected angina:

    • Patients with a high pretest probability of left-main or three-vessel CAD

    • Patients with an uncertain diagnosis after noninvasive testing when the benefit of a more certain diagnosis outweighs the risk and cost of angiography

    • Patients who have survived sudden cardiac death

    • Patients in whom coronary spasm is strongly suspected

    • Selected patients with an occupational requirement for a definitive diagnosis (e.g., pilots, firefighters, or police)

  • Refer patients with high-risk CAD for possible revascularization, including patients with:

    • High-risk treadmill scores (<-10)

    • Moderate or severe perfusion defects on scintigraphy and LV dysfunction at rest (LVEF ≤40%)

    • Stress-induced wall motion abnormalities on stress echocardiography and LV dysfunction at rest

    • Intermediate- or high-risk treadmill score and LV dysfunction at rest

    • A history of aborted sudden cardiac death

  • See figure Coronary Angiogram.

Evidence
  • A 2014 guideline update from the American College of Physicians, American College of Cardiology Foundation, American Heart Association, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, and the Society of Thoracic Surgeons on the diagnosis and management of stable coronary artery disease stated that coronary angiography is reasonable to define the extent of disease in patients with a high likelihood of severe ischemic heart disease who are candidates for revascularization, and in those who cannot undergo stress testing or who have nondiagnostic results of noninvasive testing (116).

  • A 2012 guideline from the American College of Physicians, American College of Cardiology Foundation, American Heart Association, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, and the Society of Thoracic Surgeons for the diagnosis of stable ischemic heart disease recommends coronary angiography in patients with a high likelihood of severe CAD in whom potential benefits outweigh potential harms. The guideline recommends against coronary angiography in patients with stable CAD who are not candidates for revascularization, or in low-risk patients who have not undergone noninvasive testing (88).

  • A comparative analysis found that in patients with a high pretest probability of severe CAD (e.g., abnormalities on the resting ECG associated with chest pain), direct referral for coronary angiography may be more cost-effective than an initial noninvasive study followed by coronary angiography (117).

  • In an overview of 10-year results from randomized trials, subsets of patients with CAD whose survival was improved after CABG include those with left-main disease, and three-vessel disease, particularly if LV function was diminished (118).

  • In one long-term follow-up study done among survivors of out-of-hospital sudden cardiac death, 71% had three-vessel disease and 6% had one-vessel CAD (119).

Rationale
  • Coronary angiography provides detailed information about coronary anatomy that cannot be obtained by other means.

  • Invasive coronary angiography is associated with significant risks, including death (0.1%), myocardial infarction (0.05%), stroke (0.07%), contrast reactions (0.37%), and vascular complications (0.4%) (120); therefore, the risks of this procedure need to be balanced against its potential benefits.

  • Risk stratification allows identification of patients at high risk (>3% annual mortality rate) who may have improved survival after revascularization.

  • Coronary angiography is considerably more expensive and invasive than other diagnostic methods.

Comments
  • Coronary angiography does not provide information about the physiologic significance of stenotic lesions (121).

  • Coronary angiography is a poor predictor of plaque stability and subsequent myocardial infarction (122).

  • Invasive coronary angiography is associated with significant risks, including death (0.1%), myocardial infarction (0.05%), stroke (0.07%), contrast reactions (0.37%) and vascular complications (0.4%) (120); therefore, the risks of this procedure need to be balanced against its potential benefits.

Consider a broad differential diagnosis in patients with chest pain. 
  • Consider potentially life-threatening causes of chest pain, such as myocardial ischemia, pericardial tamponade, aortic dissection, pulmonary embolism, and pneumothorax.

    • Measure blood pressure in both arms.

    • Assess neck veins.

    • Assess respiratory status.

    • Perform pulmonary auscultation.

    • Evaluate cardiac risk factors.

    • Obtain a resting electrocardiogram and a chest X-ray.

  • Evaluate patients with suspected angina for the presence of comorbid conditions that may exacerbate angina in the presence of CAD that would otherwise not cause symptoms (functional or secondary angina).

    • Assess for tachyarrhythmia.

    • Auscultate for the presence of murmurs consistent with aortic stenosis or subaortic hypertrophic cardiomyopathy.

    • Measure hemoglobin to evaluate for anemia.

    • Consider testing for hyperthyroidism.

  • See table Differential Diagnosis of Chest Pain.

Evidence
  • A systematic approach to the initial evaluation of chest pain may be found in 123.

  • An approach to evaluating patients with angina for the presence of comorbid conditions is outlined in a 1999 clinical guideline (87).

Rationale
  • Although chest pain may have a benign cause, it is appropriate to initially exclude a life-threatening cause.

  • Functional angina is best treated by correcting the underlying condition.

  • A systematic approach to suspected nonischemic chest pain includes evaluation of the integument, nervous system, musculoskeletal system, gastrointestinal system, pulmonary system, and the great vessels.

Consider consultation with a cardiologist for patients with suspected angina and intermediate results on noninvasive testing, or for patients with suspected angina in whom noninvasive testing is contraindicated. 
  • Consult a cardiologist for coronary angiography to establish the diagnosis of CAD in patients with indeterminate results on noninvasive testing, or in whom noninvasive testing is contraindicated, when the benefit of confirming the diagnosis exceeds the risk and cost of coronary angiography.

Evidence
  • Recommendation of the ACP guidelines on the diagnosis and treatment of chronic stable angina (124).

Rationale
  • Diagnostic and prognostic information may be obtained by coronary angiography, although it is more expensive and riskier than noninvasive functional studies.

Refer patients at high risk for death due to CAD or with persistent symptoms despite maximal medical therapy for evaluation for revascularization.  
  • Refer for evaluation for CABG:

    • Patients with left-main stenoses ≥50%, regardless of ventricular function

    • Severely symptomatic patients with three-vessel disease (stenoses ≥70%), regardless of ventricular function (patients with reduced LV function benefit more than patients with normal LV function)

  • Consider either PCI or CABG in patients with known stenosis (≥70%) in at least one major coronary artery who have insufficient relief of angina symptoms despite maximal medical therapy.

  • Use the Duke Treadmill Score to evaluate patients:

    • Minutes of exercise − (5 × maximal mm ST deviation) − (4 × angina score)

    • Angina score: 0 for no chest pain, 1 for angina with exertion, 2 if angina is the reason for stopping the exercise test

  • Refer for evaluation for revascularization:

    • Patients with high-risk exercise treadmill scores (≤-11)

    • Patients with multiple moderate or single large anterior perfusion defect on stress imaging

    • Patients with LV function ≤35% to 40%

  • Individualize decisions to refer patients for evaluation for revascularization in light of a given patient's comorbid illnesses, competing mortality risks, and preferences.

Evidence
  • A 2012 guideline from the American College of Physicians, American College of Cardiology Foundation, American Heart Association, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, and the Society of Thoracic Surgeons for the management of stable ischemic heart disease recommends CABG in patients with left main coronary disease, with three coronary arteries with ≥70% stenosis in the proximal left anterior descending artery plus one additional artery. The guideline recommends PCI or CABG in patients with at least one major coronary artery with ≥70% stenosis and unacceptable symptoms despite maximal medical therapy. The guideline recommends against stenting in patients who would be unable to tolerate dual antiplatelet therapy (125).

  • In two studies of outpatients with suspected CAD, the 4% of patients with high-risk exercise treadmill scores (< -10) had an average annual mortality of 5% (106; 126).

  • By comparison, the two thirds of patients with low-risk exercise treadmill scores (> +5) had an average annual mortality of 0.25% (106; 126).

  • One study found that the average annual risk for cardiac death in patients with moderately or severely abnormal exercise myocardial perfusion studies is 2.1% to 4.2% (127).

  • The same study also showed that patients with suspected CAD and normal exercise myocardial perfusion studies have a very low annual risk for cardiac death and myocardial infarction (<0.5% per year) (127).

  • Three large, multicenter, randomized trials show improved survival in patients with left-main disease or three-vessel CAD with reduced LV function (100; 101; 102).

  • The landmark COURAGE trial randomly assigned patients with symptomatic chronic stable angina to optimal medical therapy alone or in combination with percutaneous coronary intervention (94% stented) and found no difference in death, myocardial infarction, or other major cardiovascular events between the therapeutic approaches. Of note, this study included high-risk CAD patients, including those with previous myocardial infarct (38%), diabetes (34%), multivessel disease (69%), left-anterior descending artery disease (68%), and class IV angina that was responsive to medical therapy (128).

  • The COURAGE study not only compared medical and percutaneous revascularization therapy in relation to cardiovascular events but also in health status. Surprisingly, health status improved in both treatment groups following angiography, although the PCI-treated patients showed an greater initial benefit (128). Although some critics speculated that this reflected the artificial clinical trial setting, a clinical registry study reported similar findings (129). The initial incremental health-status benefits reported with percutaneous coronary intervention in the COURAGE trial had dissipated by 36 months when there was no difference between the two treatments.

  • A randomized trial of CABG vs. angioplasty vs. medical management for patients with proximal left-anterior descending disease showed no difference in survival between any of the three strategies (130).

Rationale
  • Patients at high-risk for subsequent death from CAD may benefit from revascularization.

Comments
  • Although a number of studies have shown increased cardiovascular risk in patients with chronic stable angina with certain clinical criteria (e.g., noninvasive studies), revascularization therapy does not appear to confer additional protection from cardiovascular events except for those with left-main CAD or triple-vessel disease with LV dysfunction.

Consider referral to a cardiologist for evaluation for revascularization (PTCA or CABG) in patients with functionally limiting angina who, despite adequate medical therapy, have lifestyle-limiting symptoms. 
  • Consider CABG in patients with chronic stable angina with triple-vessel disease and LV dysfunction or left-main CAD.

  • Consider revascularization therapy in those whose symptoms are not controlled with optimal medical therapy.

Evidence
  • In the BARI and EAST trials, among patients with one- or two-vessel CAD and normal LV function, there was no significant difference in survival between PTCA and CABG (131; 132).

  • Diabetic patients with multi-vessel disease had significantly improved survival after CABG vs. PTCA in the BARI trial (131). This difference was not noted in the comparable EAST study (132).

  • Patients randomly assigned to PTCA had less initial morbidity and cost versus patients randomly assigned to CABG (131).

  • Patients randomly assigned to CABG had less angina, required less antianginal medication, and required fewer subsequent revascularization procedures during 5-years of follow-up (131).

Rationale
  • In patients with normal LV function and without high-risk coronary lesions, CABG and PTCA are reasonable alternatives for patients with chronic stable angina who despite adequate medical therapy have lifestyle-limiting symptoms.

Comments
  • Patients enrolled in these studies had coronary anatomy amenable to both PTCA and CABG.

  • These studies do not include technical advances in the use of intracoronary stents in PTCA and the aggressive use of arterial grafts in CABG.

  • Follow-up in these trials has been relatively short and the adverse effects of secondary occlusion of vein grafts have not yet become apparent.

  • Elderly patients, women, and patients with previous CABG have been underrepresented in these studies.

  • The COURAGE trial showed no difference between percutaneous coronary intervention and medical therapy on the rate of major cardiovascular events in patients with stable disease (128).

  • The BARI-2 study reported no difference in major cardiovascular events or mortality in diabetic patients with chronic stable angina managed with either optimal medical therapy or revascularization therapy (133).

Refer patients with significant CAD who have survived sudden cardiac death or sustained ventricular tachycardia to a cardiologist.  
  • Refer patients who have survived sudden cardiac death for coronary angiography and possible CABG.

Evidence
  • Long-term follow-up of 49 survivors of out-of-hospital sudden cardiac death showed that 71% had three-vessel disease and 6% had one-vessel disease (119).

  • Survival of patients treated with CABG was superior to medically managed historical controls (119).

Rationale
  • Persons who have survived sudden cardiac death have a high pretest probability of high-risk coronary lesions.

Consider consultation with a cardiologist for patients hospitalized with unstable coronary syndromes. 
  • Admit patients with suspected MI to a telemetry unit or coronary intensive care unit.

  • Barring contraindication, recommend that persons with acute MI associated with ST-segment elevation ≥2 mm in consecutive leads undergo emergent revascularization (thrombolysis or PTCA).

  • Admit patients with suspected unstable angina to a telemetry unit or coronary care unit with any of the following features:

    • Nocturnal angina or pain at rest

    • Pulmonary edema, new or worsening mitral regurgitation, or S3 gallop

    • Angina at rest with dynamic ST changes ≥1 mm

    • Angina with hypotension

    • Angina with dynamic T-wave changes

    • New onset class III or IV angina in the past 2 weeks

    • Pathologic Q-waves or resting ST depression ≤1mm in multiple lead groups (anterior, inferior, lateral)

    • Age older than 65 years

Evidence
  • Management of unstable coronary syndromes is summarized in 1994 Agency for Health Care Policy and Research guidelines (134; 135; 136).

  • Features of intermediate- or high-risk unstable angina are shown in the Agency for Health Care Policy and Research practice guideline for unstable angina (135).

  • Studies of the outcomes of patients with unstable coronary syndromes treated by cardiologists vs. internists have shown conflicting results (137; 138).

Rationale
  • Emergent hospitalization allows monitoring for arrhythmias and early interventions of proven benefit (aspirin, β-blockade, ACE inhibitors, anticoagulation, thrombolysis, or PTCA).

  • Early consultation with a cardiologist is appropriate in settings where emergent interventional revascularization is an option.

Comments
  • The decision to seek consultation with a cardiologist for the management of hospitalized patients is appropriately influenced by an internist's level of experience and confidence in the management of unstable coronary syndromes.

Consider consultation with a cardiologist for patients with angina due to valvular heart disease. 
  • Refer patients with hemodynamically significant aortic stenosis or subaortic hypertrophic cardiomyopathy for coronary angiography and consideration of surgical repair.

Evidence
  • Survival is increased in patients with critical aortic stenosis who have aortic valve replacement (139).

Rationale
  • Critical aortic stenosis and subaortic hypertrophic cardiomyopathy are associated with an increased risk for mortality.

  • Fixed ventricular outflow obstruction from aortic stenosis limits the usefulness of commonly used medications for angina or reduced ventricular function.

Hospitalize patients with unstable coronary syndromes and features that confer an intermediate or high risk for death or MI.  
  • Admit persons with suspected MI to a telemetry unit or coronary intensive care unit.

  • Barring contraindication, order emergent revascularization (thrombolysis or PTCA) for persons with acute MI associated with ST-segment elevation ≥ 2 mm in consecutive leads.

  • Admit persons with suspected unstable angina to a telemetry unit or coronary care unit if any of the following features are present:

    • Nocturnal angina or prolonged (>20 minutes) pain at rest

    • Pulmonary edema, new or worsening mitral regurgitation, or S3 gallop

    • Angina at rest with dynamic ST changes ≥1 mm

    • Angina with hypotension

    • Angina with dynamic T-wave changes

    • New onset class III or IV angina in the past 2 weeks

    • Pathologic Q-waves or resting ST depression ≤1mm in multiple lead groups (anterior, inferior, lateral)

    • Age >65 years

  • Consider consulting with a cardiologist for recommendations for management of patients hospitalized for an unstable coronary syndrome.

Evidence
  • Management of unstable coronary syndromes is summarized in the 1994 Agency for Health Care Policy and Research guidelines (134; 135; 136).

Rationale
  • Emergent hospitalization allows monitoring for arrhythmias and early interventions of proven benefit (aspirin, β-blockade, ACE inhibitors, anticoagulation, thrombolysis, or PTCA).

  • Early consultation with a cardiologist is appropriate in settings where emergent interventional revascularization is an option.

Choose β-blockers as the first-line anti-anginal therapy in most patients with angina.  
  • Treat patients with β-blockers to reduce angina severity and frequency.

  • Adjust the β-blocker dose to achieve a resting heart rate of approximately 55 to 60 beats/min and approximately 75% of the heart rate that produces angina with exertion.

  • Use β-blockers in combination with calcium-channel blockers (particularly long-acting dihydropyridines) or long-acting nitrates in the treatment of angina refractory to a single agent.

  • See table Drug Treatment for Angina.

Evidence
  • A 2012 guideline from the American College of Physicians, American College of Cardiology Foundation, American Heart Association, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, and the Society of Thoracic Surgeons for the diagnosis of stable ischemic heart disease recommended β-blocker therapy as the initial treatment for symptoms of stable angina and for patients who have had acute coronary syndrome (125).

  • ACC/AHA/ACP guidelines state that β-blockers are effective at reducing angina severity and frequency (87).

  • An overview of randomized trials found that treatment with β-blockers after MI results in a 25% reduction in the risk for death (140).

  • According to one systematic review and meta-analysis, β-blockers improve survival and reduce the risk for stroke in patients with hypertension (141).

  • A meta-analysis showed that use of β-blockers slows progression of coronary atherosclerosis (142).

  • Expert panels recommend titrating β-blockers to a resting heart rate of 55 to 60 beats/min and approximately 75% of the heart rate that typically produces angina with exertion (87).

  • The same panels noted that there is no consistent difference in the incidence of death and nonfatal MI between β-blockers and calcium-channel blockers in the treatment of patients with chronic stable angina (87).

Rationale
  • β-blockers reduce myocardial oxygen demand by reducing heart rate, conduction, and contractility, and they improve survival in patients with hypertension after MI.

Comments
  • β-blockers are contraindicated in patients with severe bradycardia, sick sinus syndrome, high-degree AV block, and decompensated HF.

  • Asthma, bronchospasm, depression, and peripheral vascular disease are relative contraindications.

  • β-blockers are generally tolerated in persons with diabetes, even persons with type-1 diabetes mellitus; however, β-blocker therapy may mask warning symptoms of hypoglycemia in patients on insulin therapy.

Counsel smokers to quit smoking to reduce their cardiac risk. 
  • Systematically identify all tobacco users.

  • Recommend smoking cessation at each clinic visit to patients who smoke.

  • Identify patients who are willing to attempt to quit smoking.

  • Assist patients with the development of a cessation plan.

  • Encourage nicotine replacement and/or bupropion unless contraindicated.

  • Encourage participation in a smoking-cessation program.

  • Schedule follow-up contact (in person or by telephone).

Evidence
  • A 2012 guideline from the American College of Physicians, American College of Cardiology Foundation, American Heart Association, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, and the Society of Thoracic Surgeons for the diagnosis of stable ischemic heart disease recommended advising all patients with CAD to stop smoking (if they smoke) and to avoid environmental exposure to smoke (125).

  • A randomized trial of an intensive smoking cessation intervention vs. standard counseling in patients with acute coronary syndromes showed that the intensive intervention prevented all-cause mortality, with NNT of 11 over 2 years (143).

  • A surgeon general's report states that there is a 50% increase in cardiovascular disease mortality in smokers (144).

  • A second report from the surgeon general found that the risk for MI declines rapidly in the first several months after smoking cessation (145).

  • Patients who continue to smoke after MI have a 22% to 47% increased risk for death (145).

  • In a randomized, controlled trial, patients with symptomatic CAD were particularly receptive to treatment directed at smoking cessation (146).

  • According to a meta-analysis, consistent, direct physician reminders to stop smoking significantly increase smoking cessation (1).

  • Drug and non-drug approaches are both important elements of successful smoking-cessation interventions (1; 7).

Rationale
  • Among patients with CAD, continued smoking is associated with an increase in cardiovascular mortality, while cessation reduces that risk.

Consider calcium-channel blockers as the second-line treatment. 
  • Treat patients with chronic stable angina with calcium-channel blockers if they are unable to tolerate β-blockers or if symptoms are inadequately controlled with β-blockers.

  • Do not use short-acting calcium-channel blockers in the treatment of patients with angina pectoris.

  • Consider decompensated HF as a contraindication to the use of calcium-channel blockers.

  • Consider bradycardia, sinus node dysfunction, and AV nodal block as contraindications to non-dihydropyridine calcium-channel blockers.

  • See table Drug Treatment for Angina.

Evidence
  • A 2012 guideline from the American College of Physicians, American College of Cardiology Foundation, American Heart Association, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, and the Society of Thoracic Surgeons for the diagnosis of stable ischemic heart disease recommended calcium-channel blockers or long-acting nitrites for symptom relief in patients who cannot tolerate β-blockers or in patients for whom β-blockers or in patients for whom β-blockers do not provide adequate relief (125).

  • The 1997 ACC/AHA Guidelines for Exercise Testing reported that calcium-channel blockers are as effective as β-blockers in reducing symptoms of angina in several small, randomized trials and that short-acting preparations of calcium-channel blockers have been associated with an increased risk for myocardial infarction and perhaps mortality (105).

Rationale
  • Calcium-channel blockers cause vasodilation, increase coronary blood flow, and reduce myocardial contractility.

  • Non-dihydropyridine agents, such as verapamil and diltiazem, have a greater effect on myocardial contractility and conduction; dihydropyridine agents, such as nifedipine, amlodipine, felodipine, and isradipine, exert relatively more effect on vasodilation.

  • The combination of non-dihydropyridine calcium-channel antagonists (verapamil and diltiazem) with β-blockers is relatively contraindicated considering their additive effect in reducing myocardial contractility and cardiac conduction.

Consider treatment with long-acting nitrates in combination with or instead of β-blockers or calcium-channel antagonists. 
  • Treat patients with long-acting nitrates in combination with β-blockers or calcium-channel antagonists, or both, or as monotherapy in patients not tolerant of other agents.

  • Note that treatment of patients with long-acting nitrates alone may result in reflex tachycardia.

  • Do not administer nitrates and sildenafil together because of the risk for life-threatening hypotension.

  • Provide an 8- to 12-hour nitrate-free period daily to prevent tachyphylaxis.

  • See table Drug Treatment for Angina.

Evidence
  • A 2012 guideline from the American College of Physicians, American College of Cardiology Foundation, American Heart Association, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, and the Society of Thoracic Surgeons for the diagnosis of stable ischemic heart disease recommended calcium-channel blockers or long-acting nitrites for symptom relief in patients who cannot tolerate β-blockers or in patients for whom β-blockers or in patients for whom β-blockers do not provide adequate relief (125).

  • The 1997 ACC/AHA Guidelines for Exercise Testing reported that nitrates improve exercise tolerance and diminish symptoms of angina either alone or in combination with β-blockers or calcium-channel antagonists (105).

Rationale
  • Nitrates alleviate anginal symptoms by dilation of epicardial coronary vessels and increasing capacitance of the venous system, resulting in diminished cardiac preload and myocardial oxygen demand.

Comments
  • Nitrates are relatively contraindicated in the setting of left ventricular outflow obstruction, e.g., hypertrophic obstructive cardiomyopathy or aortic stenosis.

Consider novel anti-anginal therapies in patients suboptimally controlled on conventional triple therapy (nitrates, β-blockers, calcium-channel blockers) or unable to tolerate these various agents. 
  • Consider novel anti-anginal therapies in patients who are not optimally controlled or unable to tolerate conventional triple therapy with nitrates, β-blockers, and calcium-channel blockers.

  • Consider use of enhanced external counterpulsation in patients with refractory angina.

  • Do not use chelation therapy in patients with angina.

  • See table Drug Treatment for Angina.

Evidence
  • A 2014 guideline update from the American College of Physicians, American College of Cardiology Foundation, American Heart Association, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, and the Society of Thoracic Surgeons on the diagnosis and management of stable coronary artery disease recommended against chelation therapy in patients with angina and stated that enhanced external counterpulsation can be considered for treatment of refractory symptoms (116).

  • In two randomized, placebo-controlled trials, ranolazine was shown to reduce angina frequency when combined with background atenolol, diltiazem, or amlodipine therapy (147; 148).

  • A randomized, controlled trial found that ivabradine slows resting heart rate by inhibiting the “funny current” (If current) within the sinoatrial node. By reducing heart rate, it is an effective agent for exertional angina (149). Another randomized, controlled trial reported that ivabradine can be combined with β-blockers and can be safely used in patients with left ventricular dysfunction (150).

  • Nicorandil has both nitrate and potassium channel-opening properties that mediate its anti-anginal effects. The IONA study showed that nicorandil reduced cardiovascular events in patients with chronic stable angina (151).

Rationale
  • Clinical studies have shown efficacy for additional therapies.

Comments
  • Although the exact mechanism of action of ranolazine has not been fully elucidated, it alters the late transcellular sodium current and thus influences cellular calcium overload, which is detrimental during ischemia. Hence this agent exerts its antianginal effects by metabolic mechanisms since it does not significantly influence heart rate or blood pressure.

  • Perhexiline is another metabolic antianginal agent that does not significantly influence heart rate or blood pressure. It is thought to exert its antianginal benefit via shifting myocardial metabolism from fatty acid to glucose utilization.

Treat patients with angina with aspirin (or other antiplatelet therapy), barring contraindication. 
  • Prescribe aspirin, 75 to 325 mg, for all patients with angina, unless they have a history of significant gastrointestinal bleeding or aspirin allergy.

  • Prescribe clopidogrel in patients in whom aspirin is contraindicated.

  • See table Drug Treatment for Angina.

Evidence
  • In several randomized trials, aspirin reduces the risk for death and/or MI by approximately one third in patients with stable angina (35; 152; 153).

  • In the CAPRIE study, clopidogrel showed a statistically significant, although small, reduction in the incidence of the combined endpoint of stroke, MI, or vascular death, compared with aspirin (154). The study population in the CAPRIE study consisted of patients with a history of recent MI, stroke, or symptomatic vascular disease.

  • A 2012 guideline from the American College of Physicians, American College of Cardiology Foundation, American Heart Association, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, and the Society of Thoracic Surgeons for the diagnosis of stable ischemic heart disease recommends aspirin at a dose of 75 to 162 mg/d in patients with CAD who have no contraindication (125).

Rationale
  • Aspirin reduces platelet aggregation and acute coronary events.

  • Aspirin reduces the risk for MI and death in patients with angina.

Comments
  • Clopidogrel is a reasonable alternative to aspirin for patients with contraindications to aspirin, but much less is known about its potential risks and benefits.

Treat all patients with angina with a high-intensity statin.  
  • Treat patients with angina with a high-intensity statin.

  • Try lower intensity statins in patients who cannot tolerate high-intensity statins.

  • Consider alternative agents, such as niacin or a cholesterol-binding resin, in patients who cannot tolerate any statin.

Evidence
  • A 2013 guideline from the ACC/AHA on the treatment of blood cholesterol to reduce the risk for cardiovascular disease recommended high-intensity statin therapy for patients with known cardiovascular disease, moderate-intensity statin therapy for patients with diabetes, and therapy based on the calculated risk for cardiovascular events in the rest of the population aged 40 to 75 years (14).

  • A 2012 guideline from the American College of Physicians, American College of Cardiology Foundation, American Heart Association, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, and the Society of Thoracic Surgeons for the diagnosis of stable ischemic heart disease recommended low-fat diet and lifestyle modification, and moderate- or high-dose statins for patients with CAD without contraindication or side effects (125).

  • A 2013 individual patient meta-analysis of the effects of high-dose atorvastatin compared to low-dose atorvastatin or simvastatin in patients with coronary disease included 15,056 patients. High-dose atorvastatin decreased cardiovascular events (NNT, 66 [CI, 43 to 165]) and increased the incidence of diabetes (NNT varied from 95 [CI, 51 to 505] to 39 [CI, 22 to 113]), depending on diabetes risk factors (155; 156).

  • A 2007 meta-analysis of intensive compared to moderate lipid lowering included six trials. In patients with acute coronary syndromes, intensive statin therapy reduced mortality over 2 years (OR, 0.75 [CI, 0.61 to 0.93]). In patients with stable coronary disease, intensive statin therapy did not reduce mortality over 4.7 years (OR, 0.99 [CI, 0.89 to 1.11]) (157).

  • In the 4S trial, a 35% reduction in LDL cholesterol levels in patients with hyperlipidemia with CAD treated with simvastatin reduced mortality and major coronary events 30% to 35% (158).

  • In the CARE study, patients with mild-to-moderate elevations in total and LDL cholesterol levels and a history of MI were treated with a statin; this was associated with a 24% risk reduction for fatal and nonfatal MI (159).

  • Two randomized, controlled trials support the benefit of statin therapy in patients with CAD, even if their baseline LDL cholesterol level is in a normal range. In the LIPID trial, all-cause mortality was reduced in patients with a baseline LDL cholesterol level <135 mg/dL (3.5 mmol) randomly assigned to receive treatment with pravastatin, 40 mg/d (160). In the Heart Protection Study, a significant reduction in all-cause mortality, cardiac death, and major vascular events (coronary death, nonfatal MI, stroke, or revascularization) was observed in patients randomly assigned to simvastatin, 40 mg/d. Although total and cardiac mortality were not reported in patients with low baseline LDL cholesterol, patients with LDL cholesterol levels <115 mg/dL (3.0 mmol) who were randomly assigned to simvastatin had significantly fewer major vascular events over 5 years of follow-up (16).

  • In a prospective, randomized, double-blind, placebo-controlled trial, gemfibrozil reduced the risk for major cardiovascular events by 22% after approximately 5 years among patients with CAD, low HDL (≤40 mg/dL or 1.03 mmol/L), and an LDL ≤140 mg/dL or 3.62 mmol/L (161).

  • Two prospective, randomized, controlled trials found that ezetimibe, an inhibitor of intestinal cholesterol absorption, augments the reduction of LDL cholesterol attained by statin therapy alone (162; 163).

  • A 2000 cost-effectiveness analysis found that treatment with statins is cost-effective for patients with known CAD, with incremental cost-effectiveness ratios of <$50,000/QALY (17).

  • In the Treating to New Targets Study, high-dose statin therapy lowered the incidence of cardiovascular events by 22%. This benefit was extended to the subgroup older than 65 years (164; 165).

Rationale
  • Statin therapy in patients with known CAD improves survival and reduces the risk for major coronary events.

Treat patients with chronic stable angina with ACE inhibitors, barring contraindications. 
  • Treat patients with reduced LVEF (less than 35%) with an ACE inhibitor.

  • Treat patients with angina and one or more additional cardiovascular risk factors (diabetes, hypertension, dyslipidemia, cigarette smoking, or microalbuminuria) with an ACE inhibitor.

  • See table Drug Treatment for Angina.

Evidence
  • A 2012 guideline from the American College of Physicians, American College of Cardiology Foundation, American Heart Association, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, and the Society of Thoracic Surgeons for the diagnosis of stable ischemic heart disease recommended ACE inhibitors in patients with CAD who also have hypertension, diabetes, ejection fraction ≤40%, or chronic kidney disease unless there are contraindications. The guideline recommends angiotensin-receptor blockers for patients qualifying for ACE inhibitors who are unable to tolerate them (125).

  • Several large randomized, controlled trials show a mortality benefit in patients with HF and LVEF less than 35% treated with an ACE inhibitor (166; 167; 168).

  • In the CONSENSUS trial, enalapril titrated to 40 mg/d in patients with class IV HF reduced mortality by 18% at 6 months (NNT, 5.5) (166).

  • In the SOLVD treatment trial, enalapril titrated to 20 mg/d in patients with class II and III HF reduced mortality by 4.5% at 3 years (NNT, 22) (167).

  • In the SOLVD prevention trial, enalapril titrated to 20 mg/d in patients with asymptomatic LV dysfunction (LVEF < 35%) reduced death from HF, hospitalization for HF, and the composite outcome of death or development of HF (169).

  • A prospective, randomized, controlled trial showed that angiotensin-receptor antagonists may offer comparable benefit to ACE inhibitors in patients with HF (170).

  • In the landmark HOPE trial, a prospective, randomized, double-blind, placebo-controlled study, subjects with vascular disease or diabetes and at least one additional cardiovascular risk factor who were treated with ramipril, 10 mg/d, for an average of 4.5 years had significantly reduced risk for composite cardiovascular events (the primary outcome), total mortality, cardiovascular mortality, MI, stroke, heart failure, diabetic complications, revascularization procedures, and cardiac arrest (171). The relative risks for each of these outcomes ranged from 0.63 to 0.84 across a range of predefined subgroups. The ARR of the composite outcome (MI, stroke, or cardiovascular death) was 3.8% (NNT, 26), and the ARR in total mortality was 2.8% (NNT, 36) patients treated for 4.5 years. The absolute benefit in patients with diabetes was slightly higher than the overall reported benefit (44).

  • Using a prospective, randomized, double-blind design, the ONTARGET study compared the efficacy of ramipril with telmisartan and the combination of the two in patients with vascular disease or high-risk diabetes. They reported that telmisartan alone or in combination with ramipril was equivalent to ramipril alone in preventing cardiovascular events, although the combined therapy was associated with more adverse effects (33).

  • Several large trials have shown improved survival with ACE inhibitor treatment in the immediate peri-infarction period. A systematic review comprising more than 100,000 patients from four trials suggests there was a 7% relative reduction in 30-day mortality in patients with acute MI treated with ACE inhibitor, initiated within 36 hours of the onset of chest pain (172). The ARR in 30-day mortality was 4.8 deaths per 1000 patients treated (NNT, 208), and 80% of this benefit accrued during the first week after MI. The absolute benefit is greatest in persons at highest risk for short-term mortality after MI (persons with anterior MI, clinically evident congestive heart failure, tachycardia at entry, or Killip class 2 or 3).

  • The ACE Inhibitor Myocardial Infarction Collaborative Group and the ACC/AHA Committee on Management of Acute Myocardial Infarction recommend treatment with an ACE inhibitor during the first 24 hours in patients with acute anterior MI and acute MI with HF (172; 173).

Rationale
  • Treatment with an ACE inhibitor reduces mortality in patients with HF and reduced LV function.

  • Treatment with an ACE inhibitor reduces mortality, composite cardiovascular events, MI, and stroke in patients with documented vascular disease or diabetes and at least one additional cardiovascular risk factor.

Comments
  • Major side effects include hypotension (particularly in the setting of hypovolemia, diuretic use, or acute MI), hyperkalemia (particularly in patients with renal insufficiency and those taking potassium-sparing diuretics or potassium supplementation), and renal insufficiency (particularly in patients with renal artery stenosis, severe HF, or volume depletion).

  • ACE inhibitors are also indicated in subsets of patients with acute MI. See module Acute Coronary Syndromes.

  • Reduced mortality in the HOPE trial may have been partly due to lower ambulatory blood pressure in the ramipril group.

Recognize that regular aerobic exercise is an important part of a multifactorial approach to cardiac risk reduction. 
  • Encourage persons with chronic stable angina to incorporate at least moderate aerobic physical activity in their daily lives.

  • Note that moderate physical activity consists of walking briskly for 30 minutes or more, or a similar activity, five to seven times per week.

Evidence
  • A 2013 guideline from the ACC/AHA on lifestyle management for the reduction of cardiovascular risk recommended that patients who would benefit from lowering their LDL adhere to a diet low in sweets, sugar-sweetened drinks, and red meat; high in fruits, vegetables, and whole grains; and which includes low-fat dairy, poultry, fish, nuts, and nontropical vegetable oils. The guideline also recommended low levels of saturated and trans fats and aerobic moderate-intensity exercise for an average of 40 minutes three to four times per week (54).

  • Three randomized trials of the effects of regular aerobic exercise in patients with chronic stable CAD have shown reduction in symptoms or markers for myocardial ischemia (174; 175; 176).

  • ACC/AHA/ACP guidelines from 1999 state that regular exercise is safe during cardiac rehabilitation after CABG; it is inferred to be safe in chronic stable angina (87).

Rationale
  • Regular aerobic exercise reduces cardiac risk.

Comments
  • There were fewer than 250 subjects, all men, in the three randomized studies listed above.

Recognize that dietary modification is an important component of multifactorial cardiac risk reduction. 
  • Recommend a diet low in cholesterol and fat, particularly saturated fats, in patients with stable angina.

  • Emphasize that consumption of diets rich in fresh fruits and vegetables and replacement of saturated fats with monounsaturated fats is particularly desirable.

Evidence
  • A 2013 guideline from the ACC/AHA on lifestyle management for the reduction of cardiovascular risk recommended that patients who would benefit from lowering their LDL adhere to a diet low in sweets, sugar-sweetened drinks, and red meat; high in fruits, vegetables, and whole grains; and which includes low-fat dairy, poultry, fish, nuts, and nontropical vegetable oils. The guideline also recommended low levels of saturated and trans fats and aerobic moderate-intensity exercise for an average of 40 minutes three to four times per week (54).

  • A 2012 guideline from the American College of Physicians, American College of Cardiology Foundation, American Heart Association, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, and the Society of Thoracic Surgeons for the diagnosis of stable ischemic heart disease recommended low-fat diet and lifestyle modification, and moderate- or high-dose statins for patients with CAD without contraindications or side effects (125).

  • Randomized studies of diet therapy for patients with CAD have had conflicting results (87).

  • A study of the so-called Mediterranean diet evaluated the effect of a diet low in saturated fats and rich in fresh fruits, vegetables, whole grains, and monounsaturated fats in patients with a history of MI. This study showed significant reductions in death and nonfatal MI, as well as major cardiovascular endpoints (177). A similar diet reduced cardiovascular events in a south Asian population at high risk for CAD (178).

Rationale
  • Diet contributes to other cardiac risk factors, including dyslipidemia, hypertension, obesity, and diabetes mellitus.

  • Diets low in fat, particularly saturated fats and cholesterol, may help reduce serum cholesterol and cardiovascular risk.

Treat anemia in patients with heart disease, using a restrictive blood transfusion strategy. 
  • Treat anemia in patients with heart disease, with specific therapy depending upon the underlying cause.

  • Use a restrictive blood transfusion strategy in hospitalized patients with heart disease, considering transfusion in patients with hemoglobin <7 to 8 mg/dL.

  • See module Microcytic Anemia.

  • See module Normocytic Anemia.

Evidence
  • A 2013 ACP guideline on the treatment of anemia in patients with heart disease recommended a restrictive blood transfusion strategy in hospitalized patients with heart disease at a hemoglobin level <7 or 8 mg/dL. The guideline recommended against erythropoietin-stimulating agents (179).

  • A 2012 guideline from the AABB recommends that decisions about transfusion be influenced by both symptoms and hemoglobin level. In general, they recommend a restrictive transfusion strategy, with a goal hemoglobin of 7 to 8 g/dL in stable hospitalized patients and 8 g/dL (in the absence of symptoms) in hospitalized patients with known cardiovascular disease. The guideline does not make recommendations for patients with acute coronary syndromes due to lack of evidence (180).

  • A 2012 Cochrane review compared restrictive and liberal transfusion strategies and included 19 trials involving a total of 6264 patients. Restrictive strategies lowered hospital mortality (RR, 0.77 [CI, 0.62 to 0.95]) but not 30-day mortality (RR, 0.85 [CI, 0.70 to 1.03]); the groups had similar rates of adverse events, including cardiac events, stroke, pneumonia, and thromboembolism. There was no difference in hospital or intensive care length of stay. Included studies did not involve patients with acute coronary syndromes (181).

  • A 1999 multicenter, randomized, controlled trial randomly assigned over 800 patients in intensive care with hemoglobin levels of less than 9 g/dL within 72 hours of admission to a restrictive strategy (transfusion if hemoglobin dropped below 7.0 g/dL) or a liberal strategy (transfusion if hemoglobin dropped below 10 g/dL). Patients randomly assigned to the restrictive strategy had lower in-hospital mortality (NNT, 17; P=0.05) but no reduction in 30-day mortality. However, patients who were younger and less ill did have significantly lower 30-day mortality with the restrictive strategy (182).

Rationale
  • Severe anemia can worsen ischemia in patients with coronary heart disease.

Refer patients at high risk for death due to CAD or with persistent symptoms despite maximal medical therapy for evaluation for revascularization.  
  • Refer for evaluation for CABG:

    • Patients with left-main stenoses ≥50%, regardless of ventricular function

    • Severely symptomatic patients with three-vessel disease (stenoses ≥70%), regardless of ventricular function (patients with reduced LV function benefit more than patients with normal LV function)

  • Consider either PCI or CABG in patients with known stenosis (≥70%) in at least one major coronary artery who have insufficient relief of angina symptoms despite maximal medical therapy.

  • Use the Duke Treadmill Score to evaluate patients:

    • Minutes of exercise − (5 × maximal mm ST deviation) − (4 × angina score)

    • Angina score: 0 for no chest pain, 1 for angina with exertion, 2 if angina is the reason for stopping the exercise test

  • Refer for evaluation for revascularization:

    • Patients with high-risk exercise treadmill scores (≤-11)

    • Patients with multiple moderate or single large anterior perfusion defect on stress imaging

    • Patients with LV function ≤35% to 40%

  • Individualize decisions to refer patients for evaluation for revascularization in light of a given patient's comorbid illnesses, competing mortality risks, and preferences.

Evidence
  • A 2012 guideline from the American College of Physicians, American College of Cardiology Foundation, American Heart Association, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, and the Society of Thoracic Surgeons for the management of stable ischemic heart disease recommended CABG in patients with left main coronary disease, with three coronary arteries with ≥70% stenosis in the proximal left anterior descending artery plus one additional artery. The guideline recommends PCI or CABG in patients with at least one major coronary artery with ≥70% stenosis and unacceptable symptoms despite maximal medical therapy. The guideline recommends against stenting in patients who would be unable to tolerate dual antiplatelet therapy (125).

  • A randomized trial compared PCI to CABG in 1800 patients with three-vessel coronary disease or left-main disease. After 5-years follow-up, patients in the surgery group had a lower rate of the combined primary endpoint of long-term major adverse coronary and cerebrovascular events (PCI NNH, 10) (183; 184).

  • Three large, multicenter, randomized trials show improved survival in patients with left-main disease or three-vessel CAD with reduced LV function (100; 101; 102).

  • The COURAGE trial randomly assigned patients with symptomatic chronic stable angina to optimal medical therapy alone or in combination with percutaneous coronary intervention (94% stented) and found no difference in death, myocardial infarction, or other major cardiovascular events between the therapeutic approaches. Of note, this study included high-risk CAD patients, including those with previous myocardial infarct (38%), diabetes (34%), multivessel disease (69%), left-anterior descending artery disease (68%), and class IV angina that was responsive to medical therapy. The COURAGE study also evaluated health status and found improvements in both treatment groups following angiography, although patients treated with PCI showed a greater initial benefit (128).

  • A randomized trial of CABG vs. angioplasty vs. medical management for patients with proximal left-anterior descending disease showed no difference in survival between any of the three strategies (130).

  • In two studies of outpatients with suspected CAD, the 4% of patients with high-risk exercise treadmill scores (< -10) had an average annual mortality of 5% (106; 126).

  • By comparison, the two thirds of patients with low-risk exercise treadmill scores (> +5) had an average annual mortality of 0.25% (106; 126).

  • One study found that the average annual risk for cardiac death in patients with moderately or severely abnormal exercise myocardial perfusion studies is 2.1% to 4.2% (127).

  • The same study also showed that patients with suspected CAD and normal exercise myocardial perfusion studies have a very low annual risk for cardiac death and myocardial infarction (<0.5% per year) (127).

Rationale
  • Patients at high-risk for subsequent death from CAD may benefit from revascularization.

Comments
  • Although a number of studies have shown increased cardiovascular risk in patients with chronic stable angina with certain clinical criteria (e.g., noninvasive studies), revascularization therapy does not appear to confer additional protection from cardiovascular events except for those with left-main CAD or triple-vessel disease with LV dysfunction.

Develop an individualized and systematic approach to patient education. 
  • Assess the patient's baseline understanding of his or her condition.

  • Elicit the patient's desire for information.

  • Use epidemiologic and clinical evidence; quantify risk in terms that are understandable to the patient.

  • Use ancillary personnel and patient educators when appropriate.

  • Use professionally prepared resources when available.

  • Engage the patient in the development of a realistic and attainable therapeutic plan.

  • Involve family members in educational efforts.

  • Reinforce patient education frequently.

Evidence
  • A 2012 guideline from the American College of Physicians, American College of Cardiology Foundation, American Heart Association, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, and the Society of Thoracic Surgeons for the management of stable ischemic heart disease recommends education for patients with CAD including personalized education about medication adherence, risk reduction strategies, therapeutic options, exercise, and self-monitoring. Specific recommended topics include weight management, lipid and blood pressure management, and avoidance of cigarette smoke (125).

Rationale
  • Educational efforts need to be tailored to individual patients, congruent with their desire to adopt changes in medications or lifestyle, and reinforced over time in order to be effective.

Discuss with the patient modifiable cardiac risk, treatment, prognosis, and physical activity, and how to contact the medical system in the setting of progressive symptoms or an acute coronary event. 
  • Review important risk factors, emphasizing potentially modifiable risk factors.

  • Review potential complications (unstable angina, MI, heart failure, arrhythmia, and sudden death).

  • Review individual prognosis.

  • Review the benefits and potential side effects of medications.

  • Review the proper method of administration of medications (doses, timing, precautions).

  • Review any limitations on physical activity, including sexual activity.

  • Carefully instruct the patient on how and when to contact the medical system (progressive symptoms vs. unstable coronary syndromes).

  • Instruct patients on:

    • Warning signs and symptoms of MI

    • Prompt use of aspirin and nitroglycerin

    • How to contact emergency medical personnel

    • Location of the nearest hospital with 24-hour emergency cardiovascular services

  • Consider advising CPR training for family members.

Evidence
  • A 2012 guideline from the American College of Physicians, American College of Cardiology Foundation, American Heart Association, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, and the Society of Thoracic Surgeons for the management of stable ischemic heart disease recommends education for patients with CAD including personalized education about medication adherence, risk reduction strategies, therapeutic options, exercise, and self-monitoring. Specific recommended topics include weight management, lipid and blood pressure management, and avoidance of cigarette smoke (125).

Rationale
  • Individualized, systematic patient education is likely to improve adherence to medical therapy and patient satisfaction and may improve functional status and survival.

Schedule periodic follow-up according to the stability of clinical status and the establishment of consistent communication with patients and other physicians involved in the care of the patient. 
  • See patients with successfully treated chronic stable angina every 4 to 12 months.

  • See patients every 4 to 6 months during the first year of treatment.

  • Consider longer visit intervals for patients with stable symptoms who are reliable enough to call or make an appointment when they have new or changing symptoms.

  • Realize that communication among physicians is paramount for patients comanaged by their primary-care physician and cardiologist.

Evidence
  • There is little evidence to support specific visit intervals (87).

  • A 2012 guideline from the American College of Physicians, American College of Cardiology Foundation, American Heart Association, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, and the Society of Thoracic Surgeons for the management of stable ischemic heart disease recommends periodic follow-up to assess symptoms, complications, risk factors, and adherence to therapy (125).

Rationale
  • Follow-up visits are appropriately more frequent after the initiation and titration of medical management.

Comments
  • Changes in clinical status may result from comorbid disease, medication side effects, nonadherence with recommended drug therapy, or social factors, as well as progression of coronary heart disease.

Obtain a follow-up history, focusing on angina symptoms, medication use, and modifiable cardiac risk factors. 
  • Has the patient decreased his or her level of physical activity since the last visit?

  • Have the patient's anginal symptoms increased in frequency or become more severe since the last visit?

    • Obtain detailed information about the exacerbating and alleviating conditions

    • If the symptoms have worsened or the patient has decreased his or her physical activity to avoid precipitating angina, evaluate and treat according to either the unstable angina or chronic stable angina guideline

  • Assess the patient for adherence to therapy and adverse drug effects.

  • How successful has the patient been in modifying risk factors and improving knowledge about ischemic heart disease?

  • Has the patient developed any new comorbid illnesses or has the severity or treatment of known comorbid illnesses worsened the patient's angina?

  • Review with the patient his or her action plan for a myocardial infarction or other acute coronary event.

Evidence
  • A 2012 guideline from the American College of Physicians, American College of Cardiology Foundation, American Heart Association, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, and the Society of Thoracic Surgeons for the management of stable ischemic heart disease recommends periodic follow-up to assess symptoms, complications, risk factors, and adherence to therapy (125).

  • The efficacy and side effects of commonly used medications are reviewed in the table Drug Treatment for Chronic Stable Angina.

Rationale
  • Changes in angina severity or frequency may indicate worsening CAD, changes in comorbid conditions, or changes in social factors (e.g., personal finance) that may affect disease severity.

  • Changes in angina symptoms may warrant changes in medication or risk stratification to evaluate whether revascularization is now appropriate.

  • Review of medical therapy is important in the elderly who may be particularly prone to drug side effects and polypharmacy.

  • Attention to modifiable risk factors (e.g., smoking) at each visit increases the likelihood of successful risk reduction.

Perform a careful physical exam, focusing on the cardiovascular system and directed by changes in symptoms. 
  • Conduct the physical exam according to the patient's history.

    • Measure weight, blood pressure, and pulse at each visit.

    • Assess jugular venous pressure and waveforms, carotid pulsation magnitude and upstroke, and the presence or absence of carotid bruits.

    • Conduct a thorough pulmonary exam, focusing on the presence of crackles, wheezes, rhonchi, diminished breath sounds, and dullness to percussion.

    • Conduct a cardiac exam and note any presence of gallops, new or changing murmurs, and location and size of the apical impulse.

    • On abdominal exam, note hepatomegaly, abdominojugular reflux, and the presence of abdominal pulsations consistent with an aortic aneurysm.

    • Conduct a vascular exam, including evaluation of peripheral pulses and the presence of any bruits.

    • Evaluate for new or worsening peripheral edema.

Evidence
  • A 2012 guideline from the American College of Physicians, American College of Cardiology Foundation, American Heart Association, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, and the Society of Thoracic Surgeons for the management of stable ischemic heart disease recommends periodic follow-up to assess symptoms, complications, risk factors, and adherence to therapy (125).

Rationale
  • Hypertension should be controlled in patients with CAD.

  • Signs of HF identify patients with CAD at high risk (average annual mortality rate >3%).

  • Persons with CAD may be at risk for peripheral vascular and cerebrovascular disease.

Use laboratory evaluation to monitor reduction of modifiable risk factors (cholesterol and diabetes). 
  • Perform a fasting lipid panel and obtain transaminase levels 8 to 12 weeks after initiating or adjusting lipid-lowering therapy, with an LDL goal of less than 100.

  • Measure creatine phosphokinase in the setting of muscle weakness or pain.

  • Monitor glycosylated hemoglobin at least twice per year in patients with stable, treated diabetes mellitus.

  • Consider monitoring lipid levels periodically in patients who did not tolerate high-intensity statin therapy.

  • Do not routinely measure serum electrolytes, renal function, hemoglobin, or thyroid function, but obtain these as indicated by the patient's history, physical exam, or clinical course.

Evidence
  • A 2012 guideline from the American College of Physicians, American College of Cardiology Foundation, American Heart Association, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, and the Society of Thoracic Surgeons for the management of stable ischemic heart disease recommends periodic follow-up to assess symptoms, complications, risk factors, and adherence to therapy (125).

  • Evaluation of diabetes mellitus is according to the American Diabetes Association recommendation (185).

  • Elevations of hepatic transaminase levels in excess of three times the upper limit of normal are seen in approximately 2% of patients (186).

  • Elevations of creatine phosphokinase levels in excess of ten times the upper limit of normal occur in 0.1% to 0.5% of patients (186).

Rationale
  • Statins may cause elevations of hepatic transaminases, most commonly ALT; these elevations are most common in the first 3 to 16 months of therapy.

  • Myopathy or myositis are less common complications of statins.

Do not perform routine, periodic resting ECGs. 
  • Do not perform routine, periodic resting ECGs in the absence of changes in medications, symptoms, or physical exam.

  • Consider doing an ECG when medications affecting cardiac conduction (e.g., digoxin) are initiated or changed.

  • Do a repeated ECG for a change in the anginal pattern, symptoms of HF, or symptoms or findings suggesting a dysrhythmia or conduction abnormality, and near or frank syncope.

Evidence
  • There is no clear evidence that periodic resting ECGs are useful in the absence of changes in the clinical history or physical exam.

  • Recommendations for use of the resting ECG are according to the 1999 ACC/AHA/ACP guideline for the treatment of chronic stable angina (87). Follow-up resting ECG is not addressed in the 2012 guidelines.

Rationale
  • An ECG is essential to evaluate new or worsening angina, HF, or dysrhythmia.

  • Many medications commonly used in the treatment of angina, dysrhythmia, or HF have the potential to affect cardiac conduction (e.g., β-blockers, calcium-channel antagonists, digoxin, or antiarrhythmics).

Obtain a repeated stress test in patients if changes in symptoms warrant risk stratification or if the outcome is likely to influence a decision to proceed with revascularization. 
  • In the absence of a change in clinical status, do not perform repeated stress testing in low-risk patients with an estimated annual mortality rate of <1% for at least 3 years after the initial evaluation.

  • Consider repeated stress testing in stable, high-risk patients with an estimated annual mortality rate of >3% only if the initial decision not to proceed with revascularization is likely to change if the patient's estimated risk worsens.

  • In stable, intermediate-risk patients with an estimated annual mortality rate ≥1% and ≤3%, consider repeated stress testing at an interval of 1 to 3 years, although there are few data to recommend a particular approach.

  • Perform a repeated noninvasive stress test in patients with new angina or worsening anginal symptoms, provided the patient is a candidate for revascularization.

Evidence
  • Studies on risk stratification of patients with angina with exercise treadmill or stress imaging studies include patients with known CAD, as well as patients with suspected CAD (106; 114; 126; 127). It is therefore appropriate to use repeated stress testing to risk-stratify patients with known CAD who have changes in their anginal symptoms.

Rationale
  • The intermediate-term prognosis and natural history of various patient cohorts with chronic stable angina is well documented.

  • Risk stratification of patients with stable angina allows patients to be grouped into low, intermediate, and high risk for death from CHD during the ensuing 3 years.

  • Aside from patients who have intermediate- or high-risk unstable angina, little is known about what defines clinically important changes in anginal symptoms in patients with known CAD.

Comments
  • Choose a repeated stress test according to the considerations outlined above on the diagnosis and risk stratification of patients with angina.

Table Grahic Jump Location
 Diagnostic Accuracy of Elements of the History and Physical Examination for Coronary Disease

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CategoryElementSensitivity (%)Specificity (%)Likelihood Ratio PositiveLikelihood Ratio NegativeNotes
HistoryTypical angina91 (male)
89 (female)
87 (male)
63 (female)
7.0 (male)
2.4 (female)
0.1 (male)
0.2 (female)
Typical angina has three components. (1) Location: substernal, jaw, neck, back, epigastrium, or arm. (2) Quality: squeezing, heavy, suffocating. (3) Exacerbated by exertion or stress and relieved with rest or nitroglycerine. Data were derived from an angiography referral population (89) and may overestimate the accuracy of the history.
HistoryPressure-like pain65591.60.6Test characteristics are for the prediction of MI among patients with normal ECG or only nonspecific ECG who presented to emergency departments with chest pain (187). The sensitivity and specificity for the diagnosis of CAD are uncertain
HistoryRadiation to the arm or jaw48681.50.8(187)
HistoryDiaphoresis32771.40.9(187)
HistorySubsternal chest pain85331.30.5Test characteristics are for the prediction of MI among patients who presented to emergency departments with chest pain, including patients with ECGs diagnostic of acute MI (188). The sensitivity and specificity for the diagnosis of CAD are uncertain
HistoryReproduced with palpation3830.21.2(188)
HistoryReproduced with deep inspiration4820.21.2(188)
HistoryReproduced with change in position3860.21.1(188)
HistoryRadiation to the left arm47853.10.6Test characteristics were reported for the diagnosis of MI or coronary disease among 278 patients who presented to an emergency department with chest pain (189). The diagnosis of coronary disease in this study was questionable
HistoryRadiation to the anterior jaw49853.20.6(189)
HistoryRadiation to the right arm28979.70.7Persons with radiation to the right arm typically had radiation across the precordium and down the left arm (189).

CAD = coronary artery disease; ECG = electrocardiography; MI = myocardial infarction.

Table Grahic Jump Location
 Laboratory and Other Studies for Diagnosis and Risk Stratification of Patients with Angina

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TestSensitivity (%)Specificity (%)Likelihood Ratio PositiveLikelihood Ratio NegativeNotes
Resting ECG<50More than 50% of patients with CAD have normal resting ECGs (190). The presence of pathologic Q waves or ST-T wave abnormalities consistent with ischemia increases the likelihood of CAD (87)
Resting ECG with nonspecific ST-segment or TW abnormalities21-3321%-33% of middle-aged men with angina have nonspecific ST-segment or T-wave abnormalities (73)
Resting ECG with Q-waves2727% of middle-aged men with angina have Q waves (73).
Abnormal resting ECG during an episode of chest pain~50Approximately 50% of patients with CAD will have some abnormality on an ECG obtained during an episode of chest pain. This finding suggests probable angina at a low workload and is associated with a worse prognosis (87)
Fasting lipid panel, including total cholesterol, HDL cholesterol, triglycerides, and calculated LDL cholesterolRecommended laboratory evaluation (87)
HemoglobinRecommended laboratory evaluation (87)
Fasting glucoseRecommended laboratory evaluation (87)
Chest X-rayEvaluate for signs of congestive heart failure or non-anginal causes of chest pain (87)
Abnormal ETT40 (men)
33 (women)
96 (men)
89 (women)
10 (men)
3 (women)
0.6 (men)
0.75 (women)
Diagnostic ETTs, controlling for referral bias (107)
Abnormal exercise echocardiography42 (men)
32 (women)
83(men)
86 (women)
2.5 (men)
2.3 (women)
0.70 (men)
0.79 (women)
Diagnostic exercise echocardiography, controlling for referral bias (108)
Abnormal ETT with SPECT thallium perfusion imaging825920.31Diagnostic ETTs with SPECT thallium imaging, controlling for referral bias (191)
Abnormal exercise or dipyridamole stress with SPECT sestamibi perfusion imaging88 (men)
87 (women)
96 (men)
91 (women)
22 (men)
9.7 (women)
0.1 (men)
0.1 (women)
Diagnostic ETTs with SPECT sestamibi, controlling for referral bias (192)
Abnormal dipyridamole stress myocardial perfusion imaging88908.80.1Summary of 3 studies involving 243 patients, not corrected for referral bias; this may overestimate the magnitude of the positive and negative LRs (87)
Abnormal dobutamine echocardiography79773.50.3Summary of 20 studies involving 2582 patients, not corrected for referral bias; this may overestimate the magnitude of the positive and negative LRs (87)
Electron-beam computed tomography85-100 (avg. 94)41-76 (avg. 50)1.90.1Summary of 7 studies involving 1501 patients (193). Uncertain diagnostic and prognostic accuracy, and few studies separated men from women

CAD = coronary artery disease; ECG = electrocardiography; ETT = exercise treadmill test; HDL = high-density lipoprotein; LDL = low-density lipoprotein; SPECT = single photon emission computed tomography.

Table Grahic Jump Location
 Differential Diagnosis of Chest Pain

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DiseaseCharacteristics
Non-ischemic cardiovascular disease; arrhythmiasMay cause typical angina related to increased myocardial oxygen demand and/or diminished diastolic filling of the coronary arteries
Tachycardia
Non-ischemic cardiovascular disease; valvular heart diseaseMay cause typical angina related to left ventricular outflow obstruction and increased myocardial wall stress
Auscultation typically shows a sustained systolic murmur at the base of the heart. Aortic stenosis commonly radiates to the carotids and is associated with a weak and delayed carotid upstroke. Murmurs of subaortic hypertrophic cardiomyopathy typically increase with the Valsalva maneuver
Non-ischemic cardiovascular disease; aortic dissectionClassically described as a tearing pain of abrupt onset that may radiate to the back
In a large registry of patients with aortic dissection, abrupt onset was reported in 85%, severe pain in 91%, sharp pain in 64% (194). Blood pressure measured in both arms may show differences > 10 mm Hg (this finding is neither sensitive nor specific). Chest X-ray may show a widened mediastinum or abnormal aortic contour in approximately 80% (194)
Non-ischemic cardiovascular disease; pericarditisPain is often pleuritic, but may resemble angina. Classically relieved by sitting up and leaning forward
May be associated with the presence of a friction rub on auscultation and diffuse ST-segment elevation on electrocardiogram (or PR-segment depression)
Pulmonary disease; pulmonary embolusPain is often sharp and pleuritic, and associated with dyspnea
The presence of pulsus paradoxus, decreased oxygen saturation, and risk factors for thromboembolic disease increase the likelihood of pulmonary embolism. Syncope, hypotension, elevated neck veins, and characteristic findings on electrocardiogram are more commonly seen with large, central pulmonary embolisms
Pulmonary disease; pneumothoraxAcute onset; associated with dyspnea, pleuritic chest pain, and hyperresonance of the affected hemithorax
Hypotension, elevated neck veins, and/or deviation of the trachea are found in hemodynamically significant tension pneumothorax
Pulmonary disease; pneumoniaFrequently associated with fever, pleuritic pain, and a productive cough
Pulmonary disease; pleuritisPleuritic chest pain
Gastrointestinal disease; esophageal (esophagitis, spasm, reflux)May be indistinguishable from angina
Often diagnosed after a negative workup for ischemic heart disease
Gastrointestinal disease; biliary (colic, cholecystitis, choledocholithiasis, cholangitis)Right upper-quadrant pain that radiates to the back or scapula
Typically worse following meals. Cholangitis is suspected in the setting of fever, right upper-quadrant pain, and jaundice
Gastrointestinal disease; acid peptic diseaseMay be indistinguishable from angina, but often is related to meals
Gastrointestinal disease; pancreatitisPain is classically described as boring epigastric pain that may radiate to the back
May be associated with systemic illness (fever, pleural effusions, hypotension, acidemia)
Chest wall or dermatologic pain; costochondritis (Tietze's syndrome)Characteristically reproduced with palpation or movement
Reproduction with palpation does not exclude angina
Chest wall or dermatologic pain; fibrositis, rib fractureAntecedent cough or trauma
Chest wall or dermatologic pain; sternoclavicular arthritis; herpes zosterPain may precede the rash
Psychiatric disorders; anxiety disordersMay be indistinguishable from angina
Often diagnosed after a negative workup for ischemic heart disease. Often associated with palpitations, sweating, anxiety
Psychiatric disorders; affective disorders (e.g., depression); somatoform disorders; thought disorders (e.g., fixed delusion); factitious disorder (Munchausen's syndrome)
Table Grahic Jump Location
 Drug Treatment for Angina

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Drug or Drug ClassDosingSide EffectsPrecautionsClinical Use
FirstLineIconBeta-blockersBradycardia, hypotension, AV block, bronchospasm dizziness, drowsiness, diarrhea, nauseaAvoid with: advanced AV block, sick sinus syndrome, acute HF. Avoid abrupt withdrawal. Caution with: CKD, asthma, depression, elderly, hyperthyroidism
blackboxiconMetoprolol (Lopressor, Toprol-XL)Regular-release: 50-200 mg bid. Extended-release: 100-400 mg qdblackboxicon Avoid abrupt withdrawal. Decrease dose with hepatic disease. Substrate of CYP2D6
Carvedilol (Coreg, Coreg CR)Regular-release: 25-50 mg bidHyperglycemia, weight gainAvoid with hepatic disease. Substrate of CYP2D6
Acebutolol (Sectral)200-600 mg bidDecrease dose with CrCl<50. Caution with hepatic disease
Pindolol15-40 mg total daily dose, dosed tid-qidDecrease dose with severe hepatic disease
Dihydropyridine calcium-channel blockersHeadache, edema, hypotensionCaution with: severe bradycardia, HF, hepatic disease, reflux esophagitis, aortic stenosisSecond-line
Amlodipine (Norvasc)5-10 mg qd
Nifedipine (Adalat CC, Procardia XL)Extended-release: 30-90 mg qdDizziness, nausea, heartburn
Non-dihydropyridine calcium-channel blockersBradycardia, hypotension, AV block, edema, dizziness, headacheAvoid with: advanced AV block, sick sinus syndrome, acute HF, advanced aortic stenosis. Caution with: hepatic disease, reflux esophagitis, elderly. Substrates and inhibitors of CYP3A4 and P-gpSecond-line
Diltiazem (Cardizem, Cardizem CD, Dilacor XR)Regular-release: 180-360 mg total daily dose, dosed tid-qid. Extended-release: 120-360 mg qdNausea
Verapamil (Calan, Covera-HS)Regular-release: 80-160 mg q8hr. Extended-release: 180-480 mg qhsConstipationCaution with: CKD, neuromuscular disease. Substrate of CYPs: 1A2, 2C8, 2C9, 2C18
NitratesHeadache, flushing, hypotension, bradycardia, tachycardia, syncope, toleranceAvoid with: severe anemia, increased intracranial pressure, closed-angle glaucoma, sildenafil. Caution with hepatic disease. Elderly should start with low doseCombined of beta-blockers or CCBs or as monotherapy in patients intolerant of other agents
Nitroglycerin (Nitrostat, NitroMist, Nitrolingual Pumpspray, Minitran, Nitrodur)Sublingual: 1 tablet (0.3 mg, 0.4 mg, or 0.6 mg) SL. May repeat q5min prn, up to 3 doses. Lingual spray or aerosol: 1-2 sprays (400-800 mcg) SL. May repeat q5min prn, up to 3 doses. 2% ointment: 15-30 mg q6-8hr. Transdermal patch: 1 patch (0.1-0.8 mg/hr) q24hr. Remove patch for 10-12 hr before next patchDermatologic reactions, methemoglobinemiaExtreme caution with suspected right ventricular infarction. Caution with: constrictive pericarditis, restrictive cardiomyopathy, cardiac tamponadeAll patients should have a short-acting nitrate
Isosorbide dinitrate (Isordil, Dilatrate-SR)Immediate-release: 5-40 mg bid-tid. Sustained-release: 40-160 mg qd. SL: 2.5-5 mg prior to activityNausea
Isosorbide mononitrate (Monoket)Immediate-release: 10-20 mg bid, 7 hr apart. Extended-release: 30-60 mg qd in the AM. Maximum 120 mg qd
Other anti-anginal therapy
Ranolazine (Ranexa)500-1000 mg bidQT prolongation, headache, dizziness, hypotension, nausea, constipation,Avoid with: hepatic cirrhosis, severe CKD, CYP3A inducers or potent inhibitors. Caution with: mild-moderate CKD, hepatic disease. Use low dose with moderate CYP3A inhibitors. Substrate and inhibitor of CYP2D6 and P-gpInadequate response or intolerance to other agents
Platelet inhibitors
Aspirin75-325 mg qdNausea, dyspepsia, abdominal pain, hypersensitivity reactions, bleedingAvoid with severe hepatic disease or severe CKD. Caution with: asthma, GI diseaseAll patients without a contraindication
blackboxiconClopidogrel (Plavix)75 mg qdBleeding, diarrhea, rare TTPblackboxicon Diminished effect in poor metabolizers. Avoid use of omeprazole or esomeprazole. Caution with hepatic diseaseFor patients with aspirin contraindication
HMG-CoA reductase inhibitors (statins)Generally more effective if given at bedtimeConstipation, abdominal pain, nausea, rhabdomyolysis, nephrotoxicity, myalgia, myopathy, hepatotoxicity, diabetes. Rare: hypersensitivity reactions, neuropathyAvoid with: hepatic disease, pregnancy, cyclosporine, gemfibrozil. Caution with: fenofibrate, niacin, elderly. Most statins have additional CYP450 drug interactions. Avoid >1 quart/day grapefruit juiceAll patients who tolerate
Atorvastatin (Lipitor)10-80 mg qdIf taking a CYP3A4 inhibitor, maximum dose 20 mg qd
Lovastatin (Mevacor, Altoprev)Regular-release: 10-80 mg qd with PM meal. Extended-release (Altoprev): 10-60 mg qhsIf CrCl<30, maximum dose 20 mg qd. Avoid CYP3A4 inhibitors
Rosuvastatin (Crestor)5-40 mg qd. Can be taken in AM or PMIf CrCl<30, maximum dose 10 mg qd. Undergoes minimal hepatic metabolism. Use 5 mg starting dose with Asians
Simvastatin (Zocor)10-40 mg qhs. Up to 80 mg qhs in select patientsIf CrCl<20, start with 5 mg qhs. Avoid CYP3A4 inhibitors. Caution with >20 mg in Chinese
blackboxiconAngiotensin- converting enzyme inhibitorsHypotension, cough, hyperkalemia, angioedema, anaphylactoid reactionsblackboxicon Pregnancy. Avoid if history of angioedema. Caution with aortic stenosisAll patients without contraindications
blackboxiconEnalapril (Vasotec)2.5 mg qd-20 mg bidRequires hepatic activation. Decrease dose with CrCl<30
blackboxiconLisinopril (Prinivil, Zestril)5-40 mg qdDecrease dose with: elderly, CrCl<30
blackboxiconRamipril (Altace)1.25-20 mg total daily dose, dosed qd-bidDecrease dose with CrCl<40
blackboxiconQuinapril (Accupril)5-80 mg total daily dose, dosed qd-bidDecrease dose with CrCl<90

FirstLineIcon = first-line agent; blackboxicon = black box warning; AM = morning; AV = atrioventricular; bid = twice daily; CCBs = calcium-channel blockers; CKD = chronic kidney disease; CNS = central nervous system; CrCl = creatinine clearance; CYP = cytochrome P450 isoenzyme; GI = gastrointestinal; HF = heart failure; HMG-CoA = hydroxymethylglutaryl-coenzyme A; IM = intramuscular; IV = intravenous; P-gp = P-glycoprotein; PM = evening; PO = oral; prn = as needed; q6-8hr = every 6-8 hours; qd = once daily; qhs = every day at bedtime; qid = four times daily; SC = subcutaneous; SL = sublingual; tid = three times daily; TTP = thrombotic thrombocytopenic purpura.

ACP Smart Medicine provides key prescribing information for practitioners but is not intended to be a source of comprehensive drug information.

Table Grahic Jump Location
 Choice of Diagnostic Stress Test

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Exercise ECG without imaging
Obtain in patients with an intermediate probability of CAD who are able to exercise, including patients with <1 mm ST depression or complete right bundle-branch block on a resting ECG
Exercise ECG is accurate in patients with complete right bundle-branch block (a positive test is indicated by exercise-induced ST-segment depression in the inferior leads or lateral precordium) or <1 mm of baseline ST-segment depression on the resting ECG
Left ventricular hypertrophy with repolarization abnormality on the resting ECG reduces the specificity of exercise treadmill testing
Digoxin often causes ST-segment depression and reduces the specificity of exercise treadmill testing
Hold β-blockers and nitrates for approximately 48 hours (4-5 half-lives) when feasible before diagnostic exercise treadmill testing
Exercise ECG with myocardial perfusion imaging or exercise echocardiography
Obtain in patients with an intermediate probability of CAD who are able to exercise and have one of the following baseline ECG abnormalities:
Pre-excitation (Wolff-Parkinson-White) syndrome
More than 1 mm of ST depression
Also appropriate in patients who are able to exercise with an intermediate pretest probability of CAD and have a history of previous revascularization (PTCA or CABG)
May be preferable studies in patients who take digoxin or have LVH with less than 1 mm of ST depression at rest
Exercise echocardiography is an acceptable choice in patients with left bundle-branch block on resting ECG
Pharmacologic stress myocardial perfusion imaging or dobutamine echocardiography
Obtain in patients with an intermediate pretest probability of CAD and:
An electronically paced ventricular rhythm; or
Left bundle-branch block (exercise stress testing is associated with an increase in false-positive test results)
Also appropriate in patients with an intermediate pretest probability of CAD who are unable to exercise
Notes:
Stress imaging is recommended to further stratify patients with intermediate risk diagnostic exercise treadmill test results
Exercise (treadmill or bicycle ergometer) is preferred to pharmacologic stress in most instances; it provides the most information regarding symptoms, cardiovascular reserve, and hemodynamic response during activity
Exercise or pharmacologic stress testing is safe in low-risk outpatients with unstable angina and in low- or intermediate-risk inpatients with unstable angina who have had an acute MI ruled out, are angina-free at rest, and do not have symptomatic heart failure (87)

CABG = coronary artery bypass grafting; CAD = coronary artery disease; ECG = electrocardiography; LVH = left ventricular hypertrophy; MI = myocardial infarction; PTCA = percutaneous transluminal coronary angiography.

Table Grahic Jump Location
 Example of Estimation of Mortality Risk Using the Duke Treadmill Score

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A 55-year-old man with atypical angina and no other risk factors has a 50% pretest probability of significant CAD and a post-test probability of 37.5%
Although this result does not exclude the possibility of significant CAD, the treadmill results convey important prognostic information; on exercise treadmill testing, he exercised for 12 minutes and developed 1 mm ST-segment depression in his lateral precordium. He had no chest pain. His DTS = 12 [minutes of exercise] - 5 [5 × the ST-deviation] - 0 [4 × angina score] = +7. This is a low-risk score that corresponds to an estimated annual mortality of 0.25% over the following 4 years
It is therefore possible to avoid additional testing for the purposes of risk stratification
Had the same patient exercised for 7 minutes before developing 2 mm ST-segment depression and angina that resulted in stopping the test, his DTS would = 7 - (5 × 2) - (4 × 2) = -11. This is a high-risk score that corresponds to an estimated annual mortality of 5% over the following 4 years
This result would warrant referral for coronary angiography and evaluation for possible revascularization
Similarly, a 55-year-old man with typical angina and no other risk factors has a pretest probability of CAD of 80%. A normal result on an exercise treadmill test would not exclude the diagnosis of CAD (the post-test probability would be approximately 70%, but would be important in determining whether to recommend proceeding directly to coronary angiography

CAD = coronary artery disease; DTS = Duke treadmill score.

Table Grahic Jump Location
 Examples of Diagnostic Usefulness of Noninvasive Functional Studies

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For example, a 55-year-old man with atypical angina and no other risk factors has a 50% pretest probability of significant CAD (i.e., ≥70% stenosis in one or more major epicardial arteries) (93). The pretest odds of significant CAD are 0.5/0.5 = 1
An abnormal exercise treadmill test (LR+ = 10) would result in post-test odds of 10 or a posterior probability of 10/11 = 91% probability of CAD
A normal exercise treadmill test (LR- = 0.6) would result in post-test odds of 0.6 in a posterior probability of 0.6/1.6 = 37.5% probability of CAD
An abnormal exercise treadmill test with SPECT sestamibi scintigraphy (LR+ = 22) would result in post-test odds of 22 or a posterior probability of 22/23 = 96% probability of CAD
A normal exercise treadmill test with SPECT sestamibi scintigraphy (LR- = 0.13) would result in post-test odds of 0.13 or a posterior probability of 0.13/1.13 = 11% probability of CAD
Noninvasive functional studies are of little value for diagnosing CAD in patients with a high pretest probability of CAD. In this circumstance, a negative test is more likely to be falsely than truly negative. For example, a 55-year-old man with typical angina and no other risk factors has an 80% pretest probability of significant CAD (93). The pretest odds of significant CAD are 0.8/0.2 = 4
An abnormal exercise treadmill test would result in a posterior probability of 98% probability of CAD
A normal exercise treadmill test would result in a posterior probability of 71% probability of CAD
An abnormal exercise treadmill test with SPECT sestamibi scintigraphy would result in a posterior probability of 99% probability of CAD
A normal exercise treadmill test with SPECT sestamibi scintigraphy would result in a posterior probability of 33% probability of CAD
Noninvasive functional studies are of little value for diagnosing CAD in patients with a low pretest probability of CAD. In this circumstance, a positive test result is often more likely to be falsely than truly positive. For example, a 45-year-old woman with atypical angina and no other risk factors has a 5% pretest probability of significant CAD (93). The pretest odds of significant CAD are 0.05/0.95 = 0.05
An abnormal exercise treadmill test would result in a posterior probability of 14% probability of CAD
A normal exercise treadmill test would result in a posterior probability of 4% probability of CAD
An abnormal exercise treadmill test with SPECT sestamibi scintigraphy would result in a posterior probability of 33% probability of CAD
A normal exercise treadmill test with SPECT sestamibi scintigraphy would result in a posterior probability of < 1% probability of CAD

CAD = coronary artery disease; SPECT = single photon emission computed tomography.

Table Grahic Jump Location
 Post-test Probability of Significant Coronary Artery Disease After Various Functional Studies, Corrected for Referral Bias Unless Indicated

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ResultPretest Probability (%)
205080
Abnormal exercise treadmill test, men (107)719198
Abnormal exercise treadmill test, women (107)437592
Normal exercise treadmill test, men (107)133871
Normal exercise treadmill test, women (107)164375
Abnormal exercise treadmill test with SPECT thallium scintigraphy (191)336789
Normal exercise treadmill test with SPECT thallium scintigraphy (191)72355
Abnormal exercise or dipyridamole stress test with SPECT sestamibi scintigraphy, men (192)859699
Abnormal exercise or dipyridamole stress test with SPECT sestamibi scintigraphy, women (192)719198
Normal exercise or dipyridamole or stress test with SPECT sestamibi scintigraphy, men (192)31133
Normal exercise or dipyridamole or stress test with SPECT sestamibi scintigraphy, women (192)41336
Abnormal exercise echocardiography, men (108)387191
Abnormal exercise echocardiography, women (108)377082
Normal exercise echocardiography, men (108)154174
Normal exercise echocardiography, women (108)174476
Abnormal dipyridamole stress myocardial perfusion imaging. Unadjusted for referral bias; this may overestimate the predictive value of an abnormal test (87)699097
Normal dipyridamole stress myocardial perfusion imaging. Unadjusted for referral bias; this may overestimate the predictive value of a normal test (87)31235
Abnormal dobutamine echocardiography. Unadjusted for referral bias; this may overestimate the predictive value of an abnormal test (87)467793
Normal dobutamine echocardiography. Unadjusted for referral bias; this may overestimate the predictive value of a normal test (87)31132

SPECT = single photon emission computed tomography.

Table Grahic Jump Location
 Post-test Probability of Significant Coronary Artery Disease After Electron-beam CT in Adults

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ResultPretest Probability (%)
205080
Abnormal electron-beam CT (193)326688
Normal electron-beam CT (193)31132

CT = computed tomography

Table Grahic Jump Location
 Post-test Probabilities of Significant Coronary Artery Disease Based on Exercise Electrocardiogram Results

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ResultPretest Probability (%)
205080
ST depression <0.5 mm51944
ST depression 0.5-0.99 mm194879
ST depression 1.0-1.49 mm346889
ST depression 1.5-1.99 mm518194
ST depression 2.0-2.49 mm739298
ST depression ≥2.5 mm9198>99
Table Grahic Jump Location
 Contraindications and Reasons to Terminate Stress Tests

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Absolute contraindications for exercise testing include:
Acute MI within the past 2 days
Arrhythmias causing symptoms or hemodynamic compromise
Symptomatic and severe asymptomatic aortic stenosis
Symptomatic heart failure
Acute pulmonary embolus or pulmonary infarction
Acute myocarditis or pericarditis
Acute aortic dissection
Relative contraindications for exercise testing include:
Left-main coronary stenosis
Moderate aortic stenosis
Electrolyte abnormalities
Systolic blood pressure >200 mm Hg or diastolic blood pressure >110 mm Hg
Tachyarrhythmias or bradyarrhythmias
Hypertrophic cardiomyopathy or other forms of ventricular outflow obstruction
Mental or physical impairment resulting in an inability to exercise
High-degree atrioventricular block
Absolute indications for stopping an exercise treadmill test:
Drop in systolic blood pressure >10 mm Hg when accompanied by other signs of ischemia
Moderate to severe angina
Increasing ataxia, dizziness, or near syncope
Signs of poor perfusion, such as pallor or cyanosis
Technical difficulties monitoring the ECG or systolic blood pressure
The subject's desire to stop
Sustained ventricular tachycardia
ST elevation ≥1 mm in leads without diagnostic Q waves (other than V1 or aVR)
Relative indications for stopping include:
Drop in systolic blood pressure >10 mm Hg in the absence of other evidence of ischemia
2 mm of horizontal or downsloping ST-segment depression
Marked axis deviation
Arrhythmias, such as multifocal PVCs, triplets of PVCs, supraventricular tachycardia, heart block or bradyarrhythmias
Fatigue, shortness of breath, wheezing, leg cramps, or claudication
Exercise-induced bundle-branch block or intraventricular conduction delay that cannot be distinguished from ventricular tachycardia (e.g., fast wide rhythm)
Increasing chest pain
Systolic blood pressure >250 mm Hg or diastolic blood pressure >115 mm Hg

ECG = electrocardiography; MI = myocardial infarction; PVC= premature ventricular contraction.

Table Grahic Jump Location
 Risk of Mortality at 1 Year: Clinical History Variables

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1. Find points for each risk factor:
Age (yr)PointsPain typePointsComorbid FactorPoints*
200Nonanginal pain3CVD20
3013Atypical angina25PVD23
4025Typical anginaDiabetes20
5038Stable41Previous MI17
6050Progressive46Hypertension8
7062Unstable51Mild mitral regurgitation19
8075Severe mitral regurgitation38
9088
100100
2. Sum points for all risk factors:
Age + Pain score + Comorbidity = Point total
3. Look up risk corresponding to point total:
Total PointsProbability of 1-year Death
841%
1062%
1203%
1365%
16010%
18420%
19930%
21140%
22050%
22960%

From 112

CVD = cerebrovascular disease; MI = myocardial infarction; PVD = peripheral vascular disease.

* Zero points for each “no”.

Clinical examples: 60-year-old man with stable angina: 1%-2% mortality at 1 year; 60-year-old man with stable angina and a history of MI: <3% mortality at 1 year; 60-year-old man with progressive angina, a history of MI, peripheral vascular disease, hypertension, and diabetes: 10%-20% mortality at 1 year

Table Grahic Jump Location
 Clinical Classification of Chest Pain

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Typical (Definite) Angina
1.Substernal chest discomfort with a characteristic quality and duration that is,
2.Provoked by exertion or emotional stress and
3.Relieved by rest or nitroglycerin
Atypical (Probable) Angina
Meets 2 of the above criteria
Typical (Definite) Angina
Meets ≤1 of the typical angina criteria

Adapted from Diamond (1979 and 1983) (91; 195).

  • Coronary Angiogram Radiocontrast dye is injected via catheter (arrow) during coronary angiography, demonstrating 85% to 90% occlusion of the mid right coronary artery (asterisk).
  • CT (SPECT) Stress Study Selected images from a nuclear perfusion single-photon emission CT (SPECT) stress study. Short axis views (panel A) of the heart with stress (top row) and at rest (bottom row) show a radiotracer defect in the septum and anterior wall that is filled on the rest image. Long axis views (panel B) demonstrate an apical filling defect with stress (top row) that is perfused on rest images (bottom row).
  • Stress Echocardiogram with Microbubble Transpulmonary Contrast In the top panel, the heart is shown at baseline (rest) with the left (LV) and right (RV) ventricles opacified by bubble echocontrast. The interventricular septum and LV apex are also indicated. Following administration of dobutamine (bottom panel), there is a decrease in inward systolic motion of the apex and distal half of the septum, suggestive of myocardial ischemia (small arrows). The remainder of the ventricle contracts normally, with inward endocardial motion and decrease in ventricular size.
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