Specific strategies for reducing exercise-related cardiovascu- lar events have not been evaluated. It seems prudent, how- ever, that patients at high risk of cardiac complications (ie, those with a history of multiple MIs or cardiac arrest, New York Heart Association functional class III or IV or exercise capacity ,6 METs, or significant exercise-induced ischemia on treadmill testing) participate in a medically supervised program for at least 8 to 12 weeks to establish the safety of the prescribed exercise regimen. The value of resistance exercise increasingly is recognized for improving functional capacity, independence, and quality of life in patients with and without cardiovascular disease. Although the risks and benefits of resistance therapy have not been evaluated extensively in patients with SIHD, several small studies have indicated that resistance therapy is well tolerated and is associated with improvements in quality of life, strength, and endurance when added to a program of regular aerobic exercise.611,612 Although previous guidelines have recommended that all patients undergo an exercise test before participating in a cardiac rehabilitation program, according to the World Health Organization,634 an exercise test is not considered necessary for medical and economic reasons if the patient enters a low- or moderate-intensity-level training program. 4.4.1.5. Weight Management Class I 1. BMI and/or waist circumference should be assessed at every visit, and the clinician should consistently encourage weight maintenance or reduction through an appropriate balance of lifestyle physical activity, structured exercise, caloric intake, and formal be- havioral programs when indicated to maintain or achieve a BMI between 18.5 and 24.9 kg/m2 and a waist circumference less than 102 cm (40 inches) in men and less than 88 cm (35 inches) in women (less for certain racial groups).257,449,635 642 (Level of Evidence: B) 2.


BMI and/or waist circumference should be assessed at every visit, and the clinician should consistently encourage weight maintenance or reduction through an appropriate balance of lifestyle physical activity, structured exercise, caloric intake, and formal be- havioral programs when indicated to maintain or achieve a BMI between 18.5 and 24.9 kg/m2 and a waist circumference less than 102 cm (40 inches) in men and less than 88 cm (35 inches) in women (less for certain racial groups).257,449,635 642 (Level of Evidence: B) 2. The initial goal of weight loss therapy should be to reduce body weight by approximately 5% to 10% from baseline. With success, further weight loss can be attempted if indicated. (Level of Evidence: C) Population studies consistently have demonstrated an associ- ation of increased BMI with ischemic cardiac events. In a meta-analysis of 21 cohort studies including .300 000 persons, the risks for cardiovascular events in patients who ) and obese (BMI ) compared with those of normal weight were 32% and 81% higher, respectively, after adjustment for age, sex, physical activity, and smoking.635 Cardiovascular risk is increased particularly in patients with central obesity, which can be identified by a waist circumference .102 cm (40 inches) in men or .88 cm (35 inches) in women,643,644 and in those with extreme obesity, defined as a BMI .40 kg/m2 Obesity likely contributes to increased cardiovascular risk through multiple pathophysiological pathways.


In a meta-analysis of 21 cohort studies including .300 000 persons, the risks for cardiovascular events in patients who ) and obese (BMI ) compared with those of normal weight were 32% and 81% higher, respectively, after adjustment for age, sex, physical activity, and smoking.635 Cardiovascular risk is increased particularly in patients with central obesity, which can be identified by a waist circumference .102 cm (40 inches) in men or .88 cm (35 inches) in women,643,644 and in those with extreme obesity, defined as a BMI .40 kg/m2 Obesity likely contributes to increased cardiovascular risk through multiple pathophysiological pathways. Obesity is associated with traditional cardiovascular risk factors, such as diabetes mellitus, dyslipidemia, and hypertension, but in and of itself obesity increases sympathetic tone, induces a hyper- coagulable state, and is associated with markers of inflam- mation.646 Curiously, despite the strong association of BMI with cardiovascular risk in population studies, a similar relationship between BMI and death is not observed consis- tently in cohorts with established IHD.647 This could be due to weaknesses of BMI as a measure of adiposity; confounding factors such as age, smoking, or medications; or weight loss in association with advanced chronic illness. No clinical trials have examined specifically the effects of weight loss on cardiovascular event rates in patients with SIHD. In the SOS (Swedish Obese Subjects) study, however, weight losses of 20% to 32% at 1 year achieved with bariatric surgery were associated with a 24% reduction in mortality rate.648 The association of adiposity with other cardiovascular risk factors suggests that weight reduction is indicated in all overweight or obese patients. Reducing caloric intake is a cornerstone of weight management therapy. Referral to an experienced dietitian or to a reputable weight loss program for nutritional counseling and behavioral modification ther- apy can be helpful.


Referral to an experienced dietitian or to a reputable weight loss program for nutritional counseling and behavioral modification ther- apy can be helpful. The effects of caloric restriction are potentiated by regular aerobic physical activity. Therapy with medications or bariatric surgery may be considered in se- lected patients who are unable to achieve adequate weight loss by conventional lifestyle modifications.649 4.4.1.6. Smoking Cessation Counseling Class I 1. Smoking cessation and avoidance of exposure to environmental tobacco smoke at work and home should be encouraged for all patients with SIHD. Follow-up, referral to special programs, and phar- macotherapy are recommended, as is a stepwise strategy for smoking cessation (Ask, Advise, Assess, Assist, Arrange, Avoid).650 652 (Level of Evidence: B) Observational studies over the past 4 decades have fur- nished incontrovertible evidence that smoking increases the risk of cardiovascular disease events.653,654 A dose response relationship exists between cigarettes smoked and cardiovascular risk, with an RR approaching 5.5 for cardiovascular events among heavy smokers compared with nonsmokers.654 Potential mechanisms by which smoking predisposes to cardiovascular events include ad- verse effects on fibrinogen levels,655 platelet adhesion,656 and endothelial function657; reduced HDL cholesterol lev- els658; and coronary artery vasoconstriction.659 Although RCTs have not been performed in patients with SIHD, results of observational studies strongly suggest that smoking cessation is an effective strategy for secondary prevention of coronary events. A meta-analysis of 20 pros- pective cohort studies found a 30% reduction in RR of mortality for those who quit compared with those who continued smoking, and a similar reduction was noted in nonfatal MIs.650 Some studies suggest that most of the reduction in risk occurs within 2 or 3 years of quitting.660,661 The most effective smoking-cessation therapies include both nonpharmacological and medical interventions.


A meta-analysis of 20 pros- pective cohort studies found a 30% reduction in RR of mortality for those who quit compared with those who continued smoking, and a similar reduction was noted in nonfatal MIs.650 Some studies suggest that most of the reduction in risk occurs within 2 or 3 years of quitting.660,661 The most effective smoking-cessation therapies include both nonpharmacological and medical interventions. Physi- cian advice has a significant effect on quit rates.662 Self-help programs, telephone counseling, behavioral therapy, and perhaps exercise programs also have modest efficacy in increasing cessation rates.663 667 Nicotine-replacement ther- apy (gum, patch, tablet, lozenge, or nasal spray) approxi- mately doubles the chances of success of a quit attempt.668 Similar efficacy has been demonstrated with bupropion sustained-release.669 Varenicline, a partial agonist of the a4b2 nicotinic receptor, is the most recent FDA-approved agent for smoking cessation and compares favorably with placebo and with bupropion in clinical trials.670,671 There have, however, been concerns about possible worsening of preexisting depression and the risk of suicide due to vareni- cline, and the FDA has issued an alert warning that serious neuropsychiatric symptoms can occur in patients taking this Physicians should approach smoking cessation by using the 6 A s framework: Ask each patient about tobacco use at every visit; Advise each smoker to quit; Assess each smoker s willingness to make a quit attempt; Assist each smoker in making a quit attempt by offering medication and referral for counseling; Arrange for follow-up; and Avoid exposure to environmental tobacco smoke. 4.4.1.7. Management of Psychological Factors Class IIa 1. It is reasonable to consider screening SIHD patients for depression and to refer or treat when indi- cated.237,239,323,457,463,674,675 (Level of Evidence: B) Class IIb 1.


It is reasonable to consider screening SIHD patients for depression and to refer or treat when indi- cated.237,239,323,457,463,674,675 (Level of Evidence: B) Class IIb 1. Treatment of depression has not been shown to improve cardiovascular disease outcomes but might be reasonable for its other clinical benefits.237,238,676 (Level of Evidence: C) Depression is a major cause of disability in developed countries and often coexists with SIHD.677,678 About 20% of patients with angiographic evidence of CAD and a similar percentage of those recovering from AMI have comorbid Multiple observational studies have demonstrated an asso- ciation between depression and cardiovascular events. In several studies involving $1000 outpatients with SIHD, those with symptoms of depression had more physical limi- tation, more frequent angina, and lower perceived quality of life than patients without depressive symptoms.239,683 One meta-analysis examined 21 prospective studies in healthy populations and 34 studies in patients with existing IHD.684 The studies in healthy cohorts demonstrated an 81% greater incidence of ischemic events (MI or fatal IHD) among patients with symptoms of depression over an average follow-up period of 10.8 years. A similarly increased risk was observed in patients with established IHD who had symptoms of depression. Relatively few studies, however, have reported estimates of risk that have been adjusted for traditional risk factors or severity of CAD. Although in aggregate the observational cohort studies suggest that depression confers a significant risk for adverse cardiovascular outcomes, con- founding by other risk factors or by disease severity is difficult to exclude. Moreover, most studies in patients with CAD have enrolled patients after recent MI or CABG, and the relevance to patients with SIHD is uncertain. Putative mechanisms for a contribution of depression to atherogenesis and adverse cardiovascular events include both behavioral and biological effects.


Putative mechanisms for a contribution of depression to atherogenesis and adverse cardiovascular events include both behavioral and biological effects. Depression is associated with poor compliance with risk factor modification strategies and with poor adherence to prescribed medication regi- mens.460,462 Patients diagnosed with this disorder are 2- to 4-fold less likely to adhere to medications and lifestyle recommendations, engage in self-management practices, or Fihn et al Stable Ischemic Heart Disease: Full Text e401 comply with recommendations for testing and follow- up.462,675,685 691 Alternatively, some studies suggest the pos- sibility of more direct pathophysiological links, including platelet activation,692 695 endothelial dysfunction,696 reduced heart rate variability,697 699 and inflammation.700 Despite the association of depression with adverse cardio- vascular outcomes, no clinical trials have established a reduction in cardiovascular risk with either counseling or antidepressant therapy. In the ENRICHD (Enhancing Recov- ery in Coronary Heart Disease) trial, 2481 patients with depression or low social support after MI were randomized to usual care or cognitive behavioral therapy, supplemented by a selective serotonin reuptake inhibitor when indicated. Ac- tive therapy was associated with improvements in depression and low social support but with no improvement in event-free survival after a mean 24 months of follow-up.237 A secondary analysis, however, demonstrated a significantly lower risk of death or MI in patients treated with a selective serotonin reuptake inhibitor.676 The safety and efficacy of sertraline in patients with a recent ACS were demonstrated in SADHART (Sertraline Antidepressant Heart Attack Randomized Trial). Patients were randomized to sertraline or placebo for 24 weeks. Sertraline resulted in improved depressive symptoms and no change in LVEF, ventricular ectopy, or QT interval.


Sertraline resulted in improved depressive symptoms and no change in LVEF, ventricular ectopy, or QT interval. The study was not powered to detect a difference in cardio- vascular outcomes.238 Similarly, citalopram, a selective sero- tonin reuptake inhibitor, and mirtazapine, a dual-acting antidepressant, improved depression in postinfarction pa- tients.463,674 Thus, treatment of depression in patients with SIHD by cognitive therapy or medication is safe and contrib- utes to relief of depressive symptoms but does not have proven efficacy in reducing cardiovascular morbidity and mortality rates. Either the 2-item Patient Health Questionnaire (PHQ)-2 or the 9-item PHQ-9 can be used as a screening tool for depression701,702 (Tables 16 and 17). Patients who respond affirmatively to either item on the PHQ-2 or to item 9 on the PHQ-9 or who have a score $10 on the PHQ-9 should be referred for a more comprehensive clinical evaluation701,702 (Table 17). Patients with SIHD report high levels of psychosocial stress, and indices of stress are associated with an increased risk of cardiovascular events.245 Counseling to reduce psy- chological stress is recommended as a core component of comprehensive cardiac rehabilitation programs. Stress- management interventions use relaxation techniques and provide instruction in specific skills to reduce cognitive, behavioral, and psychological stress levels. Although stress- management programs are not of proven value in reducing the risk of cardiovascular events, they are effective in relieving anxiety and reducing depressive symptoms.461 4.4.1.8. Alcohol Consumption Class IIb 1.


Although stress- management programs are not of proven value in reducing the risk of cardiovascular events, they are effective in relieving anxiety and reducing depressive symptoms.461 4.4.1.8. Alcohol Consumption Class IIb 1. In patients with SIHD who use alcohol, it might be reasonable for nonpregnant women to have 1 drink (4 ounces of wine, 12 ounces of beer, or 1 ounce of spirits) a day and for men to have 1 or 2 drinks a day, unless alcohol is contraindicated (such as in patients with a history of alcohol abuse or dependence or with liver disease).703 705 (Level of Evidence: C) Observational studies suggest that light to moderate alcohol consumption is associated with a lower risk of IHD and all-cause mortality. Most studies report a J-shaped relation- ship between alcohol consumed and cardiovascular event rate or mortality; light to moderate drinkers have less risk than abstainers, but heavy drinkers are at greatest risk. A meta- analysis of 34 prospective studies found mortality rate reduc- tions of 17% in men and 18% in women with low levels of alcohol intake, with the lowest mortality rate at 6 g of alcohol (approximately one half drink) per day.703 Most of these studies were performed in healthy cohorts, and data in patients with IHD are limited. One study704 examined sur- vival rate among early survivors of MI and found that moderate alcohol consumption in the year before presentation was predictive of lower all-cause mortality. Similarly, among participants in the Physician s Health Study who experienced a self-reported MI, moderate drinkers had a 30% lower risk of death than abstainers.705 Light to moderate alcohol consumption might confer pro- tection against cardiovascular disease through beneficial ef- fects on the lipid profile and on insulin sensitivity.


Similarly, among participants in the Physician s Health Study who experienced a self-reported MI, moderate drinkers had a 30% lower risk of death than abstainers.705 Light to moderate alcohol consumption might confer pro- tection against cardiovascular disease through beneficial ef- fects on the lipid profile and on insulin sensitivity. Alcohol intake modestly increases HDL cholesterol in a dose- dependent fashion.706,707 Consumption of 2 drinks per day lowers fasting and postprandial insulin levels and increases insulin sensitivity in healthy subjects.708 Light to moderate alcohol consumption might also have antiinflammatory ef- Table 16. Patient Health Questionnaire-2 Over the past 2 weeks, how often have you been bothered by any of the following problems? 1) Little interest or pleasure in doing things 2) Feeling down, depressed, or hopeless Reproduced from Kroenke et al.702 Table 17. Patient Health Questionaire-9: Depression Screening Scales Over the past 2 weeks, how often have you been bothered by any of the following problems? 1) Little interest or pleasure in doing things 2) Feeling down, depressed, or hopeless 3) Trouble falling asleep, staying asleep, or sleeping too much 4) Feeling tired or having little energy 5) Poor appetite or overeating 6) Feeling bad about yourself, feeling that you are a failure, or feeling that you have let yourself or your family down 7) Trouble concentrating on things such as reading the newspaper or watching television 8) Moving or speaking so slowly that other people could have noticed.


1) Little interest or pleasure in doing things 2) Feeling down, depressed, or hopeless 3) Trouble falling asleep, staying asleep, or sleeping too much 4) Feeling tired or having little energy 5) Poor appetite or overeating 6) Feeling bad about yourself, feeling that you are a failure, or feeling that you have let yourself or your family down 7) Trouble concentrating on things such as reading the newspaper or watching television 8) Moving or speaking so slowly that other people could have noticed. Or being so fidgety or restless that you have been moving around a lot more than usual 9) Thinking that you would be better off dead or that you want to hurt yourself in some way Reproduced from Kroenke et al.702 fects, as reflected by a reduction in C-reactive protein.709,710 Alternatively, the apparent cardioprotective effects of modest alcohol consumption reported in observational studies could represent uncontrolled confounding, as many coronary risk factors are more prevalent in nondrinkers than in light to There are no RCTs in either healthy individuals or in patients with SIHD demonstrating improved clinical out- comes with alcohol consumption. Because of the many health and societal consequences of alcohol abuse, patients who do not already drink alcohol should not be encouraged to start. Patients who do consume alcoholic beverages should be counseled to do so in moderation: no more than 1 drink (4 ounces of wine or 1 ounce of spirits) per day for women and no more than 2 drinks per day for men. 4.4.1.9. Avoiding Exposure to Air Pollution Class IIa 1.


Patients who do consume alcoholic beverages should be counseled to do so in moderation: no more than 1 drink (4 ounces of wine or 1 ounce of spirits) per day for women and no more than 2 drinks per day for men. 4.4.1.9. Avoiding Exposure to Air Pollution Class IIa 1. It is reasonable for patients with SIHD to avoid exposure to increased air pollution to reduce the risk of cardiovascular events.712 715 (Level of Evidence: C) Although they are seldom an explicit focus in provision of care to individual patients, environmental influences such as exposure to air pollution can increase the risk of cardiovas- cular events, possibly because of progression of atheroscle- rosis due to oxidative stress and inflammation.715 In particu- lar, fine particulate matter, defined as particulate matter ,2.5 microns in diameter (PM2.5), is associated with a heightened risk of death due to cardiovascular causes.714 In nonsmokers, the relative odds of AMI death rise 22% for each 10 mcg increase in PM2.5.712 Short-term exposure to higher concen- trations of pollution, for example after a forest fire, also is associated with the risk for ACS and death.713 Thus, patients with SIHD may be advised to avoid exposure to increased air pollution (ie, by remaining indoors during transient elevations of air pollution). Public policy efforts to minimize small particulate matter (ie, through tighter regulations on the emissions from coal-fired power plants) have the potential to reduce cardiac complications among patients with SIHD. 4.4.2. Additional Medical Therapy to Prevent MI and Death: Recommendations 4.4.2.1. Antiplatelet Therapy Class I 1. Treatment with aspirin 75 to 162 mg daily should be continued indefinitely in the absence of contraindi- cations in patients with SIHD.716,717 (Level of Evidence: A) 2.


Treatment with aspirin 75 to 162 mg daily should be continued indefinitely in the absence of contraindi- cations in patients with SIHD.716,717 (Level of Evidence: A) 2. Treatment with clopidogrel is reasonable when as- pirin is contraindicated in patients with SIHD.718 (Level of Evidence: B) Class IIb 1. Treatment with aspirin 75 to 162 mg daily and clopidogrel 75 mg daily might be reasonable in certain high-risk patients with SIHD.719 (Level of Evidence: B) Class III: No Benefit 1. Dipyridamole is not recommended as antiplatelet therapy for patients with SIHD.720 722 (Level of Evidence: B) 4.4.2.1.1. Antiplatelet Agents. Because platelet aggregation is a key element of the thrombotic response to plaque disrup- tion, platelet inhibition is recommended in patients with SIHD unless contraindicated. Aspirin is a cyclooxygenase inhibitor that produces irreversible blockade of prostaglandin endoperoxide formation. Among 2920 patients with SIHD, a comprehensive meta-analysis of source data revealed an association of aspirin use with a 37% reduction in the risk of serious vascular events, including a 46% decrease in the risk for UA and a 53% decrease in the risk of requiring coronary angioplasty.716 Almost two thirds of the patients included in this meta-analysis were participants in SAPAT (Swedish Angina Pectoris Aspirin Trial), in which patients with SIHD were assigned randomly to aspirin 75 mg per day or placebo for a median of 15 months.717 Aspirin in a dose of 75 to 162 mg daily is equally as effective as 325 mg in secondary prevention and is associated with a lower risk of bleeding. Doses ,75 mg have less proven benefit.716,723 Aspirin is relatively contraindicated in patients with known allergies to nonsteroidal antiinflammatory drugs and in patients with the syndrome of asthma, rhinitis, and nasal polyps.


Doses ,75 mg have less proven benefit.716,723 Aspirin is relatively contraindicated in patients with known allergies to nonsteroidal antiinflammatory drugs and in patients with the syndrome of asthma, rhinitis, and nasal polyps. Clopidogrel, a thienopyridine derivative, inhibits platelet aggregation via selective and irreversible inhibition of the adenosine diphosphate P2Y12 receptor. Clopidogrel 75 mg has been compared with aspirin 325 mg in patients with previous MI, stroke, or symptomatic PAD in the prospective, randomized CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events) study.718 Although clopidogrel demonstrated superiority over aspirin in the secondary pre- vention of MI and death in this group of patients, the magnitude of difference was small. Because no additional trials comparing aspirin and clopidogrel in patients with SIHD have been conducted, clopidogrel remains an accept- able alternative agent to aspirin. In certain high-risk patients, combined treatment with aspirin and clopidogrel has been shown to be beneficial. In the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) study, patients with a recent NSTEMI were randomized to clopidogrel plus aspirin (300 mg/d and 75 mg/d) for an average of 9 months. These patients experienced fewer deaths from cardiovascular causes, nonfatal MIs, and strokes than did patients receiving placebo plus aspirin (75 to 325 mg/d).724 Similar results were found in the CREDO (Clopidogrel for Reduction of Events During Observation) study.


These patients experienced fewer deaths from cardiovascular causes, nonfatal MIs, and strokes than did patients receiving placebo plus aspirin (75 to 325 mg/d).724 Similar results were found in the CREDO (Clopidogrel for Reduction of Events During Observation) study. Combined therapy for an average of 1 year signifi- cantly reduced the risk of death, MI, or stroke.725 In contra- distinction to these positive results among high-risk patients, a comparison of aspirin alone versus aspirin combined with clopidogrel in 15 603 patients with multiple cardiovascular risk factors (most of whom were without a prior cardiovas- cular event) in the CHARISMA (Clopidogrel for High Atherothrombotic Risk Ischemic Stabilization, Management, and Avoidance) trial demonstrated no differences in the rates of MI, stroke, or death.393 A post hoc analysis of this study suggested that a subgroup of patients with documented prior MI, ischemic stroke, or symptomatic PAD might have had Fihn et al Stable Ischemic Heart Disease: Full Text e403 better outcomes from dual antiplatelet therapy (DAPT) with clopidogrel plus aspirin.719 In a meta-analysis of 5 RCTs comparing clopidogrel plus aspirin to aspirin alone in patients with IHD, the incidence of all-cause mortality, MI, and stroke was found to be reduced in the clopidogrel-plus-aspirin group, whereas the risk of major bleeding increased signifi- cantly.726 Overall, it appears that the addition of clopidogrel to aspirin could be beneficial in certain high-risk groups of patients with SIHD, but data on specific subgroups are lacking,727 and further research will be required to identify the ideal target population. The effectiveness of clopidogrel depends on generation of the active metabolite in 2 steps that are catalyzed by enzymes of the cytochrome P450 system, principally CYP2C19.


The effectiveness of clopidogrel depends on generation of the active metabolite in 2 steps that are catalyzed by enzymes of the cytochrome P450 system, principally CYP2C19. Vari- ants of the CYP2C19 gene have been identified that are associated with impaired antiplatelet effects, as measured by ex vivo platelet aggregation assays, and with higher cardio- vascular event rates after ACS and percutaneous revascular- ization procedures.728 731 Poor metabolizers of clopidogrel can be identified by clinically available tests, but optimal dosing strategies for these individuals have not been estab- lished in clinical outcome trials.732,733 Other drugs that are metabolized by CYP2C19 could competitively inhibit the enzyme and impair metabolism of clopidogrel. Several stud- ies have demonstrated a pharmacodynamic interaction be- tween proton pump inhibitors and clopidogrel.734,735 Obser- vational studies have suggested that use of a proton pump inhibitor in combination with clopidogrel is associated with an approximately 25% increased RR of adverse cardiovascu- lar events,736,737 although post hoc analyses of several clinical trials and a recent observational study have failed to demon- strate a clinically significant interaction.738,739 Pantoprazole is less likely than other proton pump inhibitors to inhibit CYP2C19 and does not impair the pharmacodynamic re- sponse to clopidogrel740 742; alternatively, treatment with an H2 antagonist or antacid could be sufficient in some patients. The combination of clopidogrel with a statin can be pre- scribed safely on the basis of a secondary analysis of the CHARISMA trial in 10 078 patients with cardiovascular disease or multiple high-risk coronary risk factors.743 There was no difference in the composite endpoint of MI, stroke, or cardiovascular death between the agents, independent of the metabolism pathway of the statin.


The combination of clopidogrel with a statin can be pre- scribed safely on the basis of a secondary analysis of the CHARISMA trial in 10 078 patients with cardiovascular disease or multiple high-risk coronary risk factors.743 There was no difference in the composite endpoint of MI, stroke, or cardiovascular death between the agents, independent of the metabolism pathway of the statin. Clopidogrel requires a loading dose to accelerate the onset, intensity, and consisten- cy of inhibition.744,745 Prasugrel is a third-generation thienopyridine that has more potent antiplatelet effects and is associated with less interpatient variability in response than clopidogrel. In TRITON-TIMI (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel Thrombolysis In Myocardial Infarction) 38, there was a 19% reduction in RR of the primary efficacy endpoint (cardiovas- cular death, nonfatal MI, or nonfatal stroke) but an increased risk of bleeding with prasugrel compared with clopidogrel in ACS patients scheduled for percutaneous revasculariza- tion.746 Clinical trials evaluating prasugrel in patients with SIHD have not been conducted. It has not been tested or approved for use in patients with SIHD. Ticagrelor is a newly approved agent that has been shown to be beneficial in patients with ACS but has not been tested in patients with Ticlopidine is a thienopyridine derivative that also inhibits platelet aggregation but compares less favorably to clopi- dogrel as an alternative to aspirin, because it has limited evidence for cardiovascular event reduction among patients with SIHD and an associated risk of blood dyscrasias.720,721 For these reasons, its use is quite limited for secondary prevention among patients with SIHD. The pyrimido-pyrimidine derivative, dipyridamole, pos- sesses antiplatelet effects but does not have a proven role in patients with SIHD.


The pyrimido-pyrimidine derivative, dipyridamole, pos- sesses antiplatelet effects but does not have a proven role in patients with SIHD. The combination of aspirin and dipyri- damole was not clearly superior to aspirin alone in preventing reinfarction in the PARIS (Persantine-Aspirin Reinfarction Study).722 Because dipyridamole vasodilates coronary resis- tance vessels and can provoke exercise-induced myocardial ischemia, it is not recommended for secondary prevention in patients with SIHD.748,749 4.4.2.1.2. Oral Anticoagulant Therapy. Fibrinolytic function can be disturbed in patients with IHD, particularly related to activation of the extrinsic coagulation pathway leading to formation of thrombin. Thrombin, in turn, generates fibrin and promotes platelet activation and aggregation, thereby amplifying the activity of both the coagulation and platelet pathways.750 752 These observations have provided a poten- tial rationale for antithrombotic therapy in patients with SIHD. A systematic review of randomized trials of oral anticoagulants with and without antiplatelet therapy among 20 000 patients with IHD, however, failed to provide evi- dence of benefit from anticoagulation, and it is not recom- mended.753 Similarly, there is no evidence that individuals with defects in the coagulation system, such as G1691A factor V Leiden, G20201A prothrombin, G455A fibrinogen chain, G10976A factor VII, or the plasminogen activator inhibitor-1 4G/5G polymorphisms, are at higher risk of cardiac events, and they should not receive anticoagulation therapy solely to prevent such events.754 756 4.4.2.2. Beta-Blocker Therapy Class I 1. Beta-blocker therapy should be started and continued for 3 years in all patients with normal LV function after MI or ACS.757 759 (Level of Evidence: B) 2. Beta-blocker therapy should be used in all patients with LV systolic dysfunction (EF <40%) with heart failure or prior MI, unless contraindicated. (Use should be limited to carvedilol, metoprolol succinate, or bisoprolol, which have been shown to reduce risk of death.)


(Use should be limited to carvedilol, metoprolol succinate, or bisoprolol, which have been shown to reduce risk of death.)571,760 763 (Level of Evidence: A) Class IIb 1. Beta blockers may be considered as chronic therapy for all other patients with coronary or other vascular disease. (Level of Evidence: C) Beta-receptor activation is associated with increases in heart rate, accelerated AV nodal conduction, and increased con- tractility, which contribute to increased myocardial oxygen demand. Decreases in the rate BP product, AV nodal con- duction, and myocardial contractility from beta blockers reduce myocardial oxygen demand, counteracting beta- receptor activity and contributing to a reduction in angina onset, with improvement in the ischemic threshold during exercise and in symptoms.764 769 These agents significantly reduce deaths and recurrent MIs in patients who have suffered a MI and are especially effective when a STEMI is complicated by persistent or recurrent ischemia or tachyarrhythmias early after the onset of infarction.757 How- ever, no large trials have assessed effects of beta blockers on survival or coronary event rates in patients with SIHD. Many clinically important differences exist between beta blockers. These differences relate to cardioselectivity, pres- ence of intrinsic sympathomimetic activity or vasodilating properties, and relative lipid solubility in the presence of renal or hepatic impairment. Despite these differences, all beta blockers seem to be equally efficacious in SIHD.765 767,770,771 Two large long-term follow-up studies investigating the prognostic importance of heart rate showed that all-cause mortality rate progressively increases with higher resting heart rate after adjustment for exercise capacity, age, diabetes mellitus, systolic arterial pressure, BMI, and level of physical activity.772,773 Therefore, it is recommended that beta-blocker dosing be adjusted to limit the heart rate to 55 to 60 beats per minute at rest.


Despite these differences, all beta blockers seem to be equally efficacious in SIHD.765 767,770,771 Two large long-term follow-up studies investigating the prognostic importance of heart rate showed that all-cause mortality rate progressively increases with higher resting heart rate after adjustment for exercise capacity, age, diabetes mellitus, systolic arterial pressure, BMI, and level of physical activity.772,773 Therefore, it is recommended that beta-blocker dosing be adjusted to limit the heart rate to 55 to 60 beats per minute at rest. In large prospective studies, bisoprolol, carvedilol, and metoprolol, when administered on a background of ACE inhibitors and diuretics with or without digoxin, have been shown to reduce the risk of death and to improve symptoms, clinical status, and quality of life in patients with chronic systolic heart failure. Importantly, these benefits were seen in patients with and without IHD.571,760,761 Studies on multiple polymorphisms in the gene encoding for the beta-adrenergic receptor have variously shown asso- ciations with physiological responses to exercise.774 781 Clin- ical studies with a variety of beta blockers in different patient populations with hypertension have, however, yielded diver- gent results in terms of associations with BP and heart rate,782 785 but it remains to be studied whether this variation is mainly a function of beta-adrenergic receptor genotype and whether genotype influences the clinical outcome of beta- blocker use in patients with SIHD. Beta blockers have been compared with and combined with dihydropyridine calcium channel blockers in controlled clinical trials.


Beta blockers have been compared with and combined with dihydropyridine calcium channel blockers in controlled clinical trials. The results of the APSIS (Angina Prognosis Study in Stockholm), TIBBS (Total Ischemic Burden Biso- prolol Study), and IMAGE (International Multicenter Angina Exercise) studies showed that a beta blocker was more effective than a calcium channel blocker in control of angina, reduction of cardiovascular events, and need for revascular- ization.786 788 A rationale for combining these agents is a reduction of dihydropyridine-induced tachycardia by beta- blockade. When combined, beta blockers and dihydropyri- dine calcium channel blockers have increased exercise time and shown a trend toward a lower rate of cardiovascular outcomes.788,789 Caution is warranted when a beta blocker is combined with verapamil or diltiazem because of the poten- tial for development of bradycardia, AV block, or excessive fatigue. The combination of a beta blocker with a nitrate could be an additive combination in patients with SIHD. Nitrates increase sympathetic tone, which can lead to reflex tachycardia, which is attenuated by the beta blocker. Beta blockers can increase LV wall tension associated with de- creased heart rate, which is counteracted by the concomitant use of nitroglycerin. Clinical trials have validated this ratio- nale, showing that the combination is more effective in controlling angina than is either monotherapy alone.790,791 Absolute contraindications to beta blockers are severe bradycardia, preexisting high-degree AV block, sick sinus syndrome (without a pacemaker in place), and refractory heart failure. Relative contraindications include bronchospas- tic disease or active PAD (beta blockers without vasodilating properties or selective agents at low doses may be used). Because they can mask symptoms of hypoglycemia, beta blockers should be used with caution in patients with insulin- dependent diabetes mellitus.


Because they can mask symptoms of hypoglycemia, beta blockers should be used with caution in patients with insulin- dependent diabetes mellitus. Abrupt beta-blocker withdrawal should be avoided because heightened beta-receptor density and sensitivity can result in a rebound phenomenon associ- ated with an increased risk for AMI and sudden death. If withdrawal is necessary, beta blockers should be tapered over a 1- to 3-week period, with consideration given to use of sublingual nitroglycerin or substitution with a nondihydro- pyridine calcium channel blocker during the withdrawal period. The principle adverse effects of beta blockers are fatigue, exercise intolerance, lethargy, insomnia, nightmares, and impotence. 4.4.2.3. Renin-Angiotensin-Aldosterone Blocker Therapy Class I 1. ACE inhibitors should be prescribed in all patients with SIHD who also have hypertension, diabetes mellitus, LVEF 40% or less, or CKD, unless contra- indicated.295 298,301 (Level of Evidence: A) 2. ARBs are recommended for patients with SIHD who have hypertension, diabetes mellitus, LV systolic dysfunction, or CKD and have indications for, but are intolerant of, ACE inhibitors.792 794 (Level of Evidence: A) Class IIa 1. Treatment with an ACE inhibitor is reasonable in patients with both SIHD and other vascular dis- ease.795,796 (Level of Evidence: B) 2. It is reasonable to use ARBs in other patients who are ACE inhibitor intolerant.797 (Level of Evidence: C) (Table 15) A substantial body of evidence supports the concept that ACE inhibitors have cardiovascular protective effects, reducing the risks of future ischemic events. ACE inhibitors result in a reduction in angiotensin II with an increase in bradykinin.


ACE inhibitors result in a reduction in angiotensin II with an increase in bradykinin. These changes in the physiological balance between angio- tensin II and bradykinin could contribute to the reductions in LV and vascular hypertrophy, atherosclerosis progression, plaque rupture, and thrombosis; the favorable changes in cardiac hemodynamics; and the improved myocardial oxygen supply/demand that result from treatment with ACE inhibi- tors and ARBs.798 801 Clinical studies have demonstrated significant reductions in the incidence of AMI, UA, and the need for coronary revascularization in patients after MI with LV dysfunction, independent of etiology.559,561,801 The benefits of ACE inhibitors extend to patients with IHD in the absence of LV dysfunction. In patients with Fihn et al Stable Ischemic Heart Disease: Full Text e405 atherosclerotic vascular disease or diabetes mellitus and at least 1 other IHD risk factor, the HOPE (Heart Outcomes Prevention Evaluation) study301 showed that compared with placebo, ramipril significantly decreased the primary composite endpoint of cardiovascular death, AMI, and stroke by 22%.301 MICRO-HOPE (Microalbuminuria, Car- diovascular, and Renal Outcomes), a substudy of HOPE, additionally showed, in middle-aged patients with diabetes mellitus who were at high risk for cardiovascular events, significant reductions in MI by 22%, stroke by 33%, cardiovascular death by 37%, and the combined primary event outcome by 25%.802 Furthermore, the need for revascularization and incidence of worsening angina also were significantly reduced.


In patients with Fihn et al Stable Ischemic Heart Disease: Full Text e405 atherosclerotic vascular disease or diabetes mellitus and at least 1 other IHD risk factor, the HOPE (Heart Outcomes Prevention Evaluation) study301 showed that compared with placebo, ramipril significantly decreased the primary composite endpoint of cardiovascular death, AMI, and stroke by 22%.301 MICRO-HOPE (Microalbuminuria, Car- diovascular, and Renal Outcomes), a substudy of HOPE, additionally showed, in middle-aged patients with diabetes mellitus who were at high risk for cardiovascular events, significant reductions in MI by 22%, stroke by 33%, cardiovascular death by 37%, and the combined primary event outcome by 25%.802 Furthermore, the need for revascularization and incidence of worsening angina also were significantly reduced. The EUROPA (European trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease) trial provided added support to the HOPE trial results in patients with SIHD without clinical evidence of heart failure.296 In 12 218 patients followed up for a mean of 4.2 years, there was a 20% relative increase in the time to the primary composite endpoint of cardiovascular death, nonfatal MI, or cardiac arrest with perindopril compared with placebo.296 Perindo- pril was further tested in the PEACE (Prevention of Events with Angiotensin-Converting Enzyme Inhibitor) trial, which enrolled 4158 patients with SIHD and normal or slightly reduced LV function (ie, absence of LV wall- motion abnormalities).295 The incidence of the primary endpoint of death from cardiovascular causes, MI, or coronary revascularization was equivalent between perin- dopril and placebo, but the overall rate of cardiovascular events was lower than in the HOPE and EUROPA trials. Equivalent results were seen in HOPE and EUROPA when examined by age, sex, known IHD, LV function, previous MI, hypertension, or diabetes mellitus.


Equivalent results were seen in HOPE and EUROPA when examined by age, sex, known IHD, LV function, previous MI, hypertension, or diabetes mellitus. In QUIET (Quinapril Ischemic Event Trial), there was also no sig- nificant reduction with quinapril in ischemic events and progression of CAD in coronary angioplasty patients without systolic LV dysfunction (RR: 13%; P0.49), although this finding has been attributed to study design limitations.797 Similarly, the IMAGINE (Ischemia Man- agement With Accupril Post-Bypass Graft via Inhibition of the Converting Enzyme) study demonstrated no reduction in clinical outcomes in low-risk patients (LVEF with quinapril after surgical revascularization.803 In a meta-analysis of ACE-inhibitor therapy versus placebo in 31 555 patients from HOPE, EUROPA, PEACE, and QUIET, ACE-inhibitor therapy produced 14% reductions in all-cause mortality and MI (both P0.0004), a 23% reduction in stroke (P0.0004), and a 7% reduction in revascularization procedures (P0.025) compared with Although the cited studies involved a variety of ACE inhibitors that differ with regard to structure, bioavailability, potency, receptor-binding characteristics, tissue distribution, metabolism, and excretion properties, there is little evidence that these differences are associated with therapeutic advan- tages. Because the benefits of ACE inhibitors seem to reflect a class effect, the selection of a particular agent can be based on such factors as availability in local formularies, cost, and tolerability. ACE inhibitors are recommended for all patients with SIHD and hypertension, diabetes mellitus, LV dysfunction (EF 40%), or CKD. Also included in the HOPE301 or EUROPA296 trials were participants who did not have one of these conditions but did have multiple cardiac risk factors, and it seems that they also benefited from use of ACE ARBs also play an important role in vascular protection.


Also included in the HOPE301 or EUROPA296 trials were participants who did not have one of these conditions but did have multiple cardiac risk factors, and it seems that they also benefited from use of ACE ARBs also play an important role in vascular protection. They bind in a competitive or insurmountable manner to the type 1 angiotensin II receptor, increasing plasma renin activity, plasma renin, and angiotensin I and II concentra- tions. In patients with hypertension or cardiovascular disease, ARBs produce reductions in BP equivalent to those achieved with ACE inhibitors.804 These agents significantly reduce LV mass and stroke incidences compared with beta blockers and improve outcomes in diabetic nephropathy and heart fail- ure.563,565,792,805 A meta-regression analysis of 26 trials com- pared the effects of ACE inhibitors and ARBs on major vascular events by BP effects.804 Treatment with ACE inhib- itor based regimens was associated with a reduction in the risk for stroke (by 19%), IHD (by 16%), and heart failure (by 27%) for each 5 mm Hg reduction in BP; corresponding figures for the reduction in risk for ARBs were 26%, 17%, and 12%, respectively. There were no significant differences between ARB- and ACE inhibitor based regimens in the risk of stroke, IHD, and heart failure for each 5 mm Hg reduction in BP. When these outcomes were assessed at zero BP reduction, the risk reduction for IHD was significantly greater for ACE inhibitors than for ARBs (P0.002). Furthermore, unlike ARBs, ACE inhibitors were associated with a signif- icant additional risk reduction for IHD of 9% (P0.004), without differences seen for stroke or heart failure versus ARBs. It is therefore recommended that ARBs be substituted for ACE inhibitors in patients with SIHD and hypertension who are intolerant of ACE inhibitors.563,565,792,804,805 4.4.2.4. Influenza Vaccination Class I 1.


It is therefore recommended that ARBs be substituted for ACE inhibitors in patients with SIHD and hypertension who are intolerant of ACE inhibitors.563,565,792,804,805 4.4.2.4. Influenza Vaccination Class I 1. An annual influenza vaccine is recommended for patients with SIHD.806 810 (Level of Evidence: B) In patients with chronic medical conditions such as cardio- vascular disease, influenza contributes to a higher risk for mortality and hospitalization and exacerbates underlying medical conditions. The World Health Organization and the AHA/ACCF recommend annual vaccination with inactivated vaccine (administered intramuscularly) against seasonal in- fluenza to prevent all-cause mortality and morbidity in patients with underlying cardiovascular conditions.806,807 A cohort study in 1340 elderly (ie, 65 years of age) patients with heart failure or IHD showed that annual influenza vaccinations reduced the risk of mortality by 37% during the winter period (January through April), but not the summer period (June through September), resulting in a number needed to treat to prevent 1 death during 1 influenza period of 122 annual vaccinations.808 Further mechanistic and confir- Trandolapril was further tested in the PEACE (Prevention of Events matory studies in heart failure and other cardiovascular disease are needed to confirm these findings. Evidence from 2 prospective randomized clinical studies in patients $65 years of age who were medically stable supports increasing influenza vaccine doses to achieve higher serum antibody titers and potentially improved protection from influenza infection.809,810 This dosing scheme was associated with higher injection site reactions, including pain and myalgias. Currently, it is recommended that patients with SIHD receive an annual influenza vaccination in the standard dose. 4.4.2.5. Additional Therapy to Reduce Risk of MI and Death Class III: No Benefit 1.


Additional Therapy to Reduce Risk of MI and Death Class III: No Benefit 1. Estrogen therapy is not recommended in postmeno- pausal women with SIHD with the intent of reducing cardiovascular risk or improving clinical out- comes.811 814 (Level of Evidence: A) 2. Vitamin C, vitamin E, and beta-carotene supplemen- tation are not recommended with the intent of reducing cardiovascular risk or improving clinical outcomes in patients with SIHD.398,527,815 818 (Level of Evidence: A) 3. Treatment of elevated homocysteine with folate or vitamins B6 and B12 is not recommended with the intent of reducing cardiovascular risk or improving clinical outcomes in patients with SIHD.819 822 (Level of Evidence: A) 4. Chelation therapy is not recommended with the intent of improving symptoms or reducing cardio- vascular risk in patients with SIHD.823 826 (Level of Evidence: C) 5. Treatment with garlic, coenzyme Q10, selenium, or chromium is not recommended with the intent of reducing cardiovascular risk or improving clin- ical outcomes in patients with SIHD. (Level of Evidence: C) 4.4.2.5.1. Hormone Replacement Therapy. Numerous obser- vational studies have suggested that estrogen therapy might provide protection against the development of IHD in post- menopausal women.827 829 Beneficial effects of exogenous estrogen include an increase in HDL cholesterol, a decrease in LDL cholesterol, and enhanced endothelial function.830 833 In light of the epidemiological data and evidence of salutary physiological effects, postmenopausal estrogen replacement previously was advocated for the primary and secondary prevention of CAD in women. Clinical trials in women with and without established CAD, however, have failed to con- firm a decrease in cardiovascular events with hormone therapy.


Clinical trials in women with and without established CAD, however, have failed to con- firm a decrease in cardiovascular events with hormone therapy. In HERS (Heart and Estrogen/progesterone Replace- ment Study), 2763 postmenopausal women with CAD were randomized to therapy with 0.625 mg of conjugated estrogen plus 2.5 mg of medroxy progesterone acetate or placebo and were followed up for an average of 4.4 years. Despite an 11% lower level of LDL cholesterol and a 10% higher level of HDL cholesterol in the hormone therapy group, there was no difference in the composite primary endpoint of MI or IHD death, and an early increase in cardiovascular events was observed.811 In HERS-II, an unblinded follow-up study of HERS, the lack of benefit with estrogen/progestin therapy persisted at an average of 6.8 years.834 A subsequent angio- graphic study demonstrated a nonsignificant worsening of coronary stenoses in patients prescribed estrogen therapy.835 The Women s Health Initiative, a randomized controlled primary prevention trial, also found no evidence that estrogen protects against IHD.812 814 Thus, the weight of current scientific evidence suggests that estrogen/progestin therapy in postmenopausal women does not reduce the risk of vascular events or coronary deaths in secondary prevention. Women who are taking estrogen therapy and who have vascular disease can continue this therapy if it is prescribed for other well-established indications and if no better alternative ther- apies are appropriate, although the FDA recommends use in the lowest dose and shortest duration acceptable. There is, however, no basis for adding or continuing estrogens in postmenopausal women with clinically evident SIHD in an effort to prevent or retard progression of their atherosclerotic disease. 4.4.2.5.2. Vitamin C, Vitamin E, and Beta-Carotene.


There is, however, no basis for adding or continuing estrogens in postmenopausal women with clinically evident SIHD in an effort to prevent or retard progression of their atherosclerotic disease. 4.4.2.5.2. Vitamin C, Vitamin E, and Beta-Carotene. Epide- miological and population studies have suggested that anti- oxidant vitamins, such as vitamin E, vitamin C, and beta- carotene, could lower cardiovascular risk.836,837 Controlled clinical trials, however, have failed to demonstrate a benefi- cial effect of antioxidant supplements on risk of cardiovas- cular morbidity and mortality.398,527,815 817 A meta-analysis of antioxidant vitamin studies examined 7 trials of vitamin E treatment and 8 trials of beta-carotene treatment with .1000 subjects in each. Most of these studies were performed in patients with CAD or at risk of CAD. Vitamin E had no effect on all-cause mortality or cardiovascular death.838 Beta- carotene led to a small but statistically significant increase in all-cause mortality and cardiovascular death. Thus, existing scientific evidence does not justify routine use of antioxidant supplements for the prevention or treatment of cardiovascular disease. 4.4.2.5.3. Folate and Vitamins B6 and B12. Prospective observational studies have demonstrated that the serum ho- mocysteine level is a strong, independent risk factor for ischemic events.839 841 Homocysteine levels can be lowered with folic acid or B-vitamins. Trials of folate and vitamin B supplementation, however, consistently have failed to dem- onstrate a decrease in cardiovascular morbidity or mortality rates. The VISP (Vitamin Intervention for Stroke Prevention) trial randomized patients with prior nondisabling stroke to varying doses of folic acid, B6, and B12.


The VISP (Vitamin Intervention for Stroke Prevention) trial randomized patients with prior nondisabling stroke to varying doses of folic acid, B6, and B12. Despite a reduction in homocysteine that was 2 mmol/L greater in the group allocated to the high dose of supplementation, there were no differences in the incidence of recurrent stroke, IHD, or death.822 Similarly, the HOPE 2 (Heart Outcome in Preven- tion) trial found no benefit of folate and vitamins B6 and B12 in patients with vascular disease or diabetes mellitus.821 The NORVIT (Norwegian Vitamin Trial) examined 3 combina- tions of folate and B vitamins in patients who had an AMI and observed no decrease in the risk of cardiovascular events.820 A meta-analysis of these and 9 other smaller trials also found no reduction in cardiovascular events or mortality with folate supplementation.819 These studies indicate that routine use of folate and B vitamins for the prevention or treatment of cardiovascular disease should not be recommended. 4.4.2.5.4. Chelation Therapy. Chelation therapy, which con- sists of a series of intravenous infusions of disodium ethylene diamine tetraacetic acid (EDTA) in combination with other substances, has been promoted as a noninvasive means of Fihn et al Stable Ischemic Heart Disease: Full Text e407 improving blood flow in atherosclerotic vessels. EDTA combines with polyvalent cations, such as calcium ions, to form soluble complexes that can be excreted. Advocates maintain that this process can result in regression of athero- sclerotic plaques and relief of angina and that EDTA reduces oxidative stress in the vascular wall. Anecdotal reports have suggested that EDTA chelation therapy can result in relief of angina in patients with SIHD. In general, however, the efficacy of chelation therapy in athero- sclerotic disease is not supported by clinical trials.


In general, however, the efficacy of chelation therapy in athero- sclerotic disease is not supported by clinical trials. Studies in patients with intermittent claudication have failed to demon- strate improvements in exercise measures,823,824 ankle- brachial index,823,824 or digital subtraction angiograms with chelation.825 The only RCT examining the effectiveness of chelation therapy on SIHD826 studied 84 patients with stable angina and a positive treadmill test for ischemia. Those randomized to active therapy received weight-adjusted diso- dium EDTA chelation therapy for 3 hours per treatment, twice weekly for 15 weeks and then once monthly for an additional 3 months. There were no differences between groups in changes in exercise time to ischemia, exercise capacity, or quality-of-life scores. The National Center of Complementary and Alternative Medicine and the National Heart, Lung, and Blood Institute have sponsored TACT (Trial to Assess Chelation Therapy),842 an RCT comparing chela- tion to placebo in patients who had experienced an MI. There is insufficient evidence to support chelation therapy for improving symptoms or preventing adverse outcomes in patients with SIHD. Moreover, this therapy is costly and time consuming, can result in harm, and could result in patients failing to pursue proven treatment strategies. 4.4.2.5.5. Garlic, Coenzyme Q10, Selenium, and Chromium. Nu- tritional supplements for the prevention and treatment of cardiovascular disease have grown increasingly popular in the United States. These alternative therapies often are promoted with anecdotal claims of efficacy but have not been studied rigorously. When data are available, they often conflict and consist of results of small, open-label trials. At present, there is no definitive evidence to recommend treat- ment with garlic, coenzyme Q10, selenium, or chromium for improving cardiovascular outcomes in patients with SIHD. 4.4.3. Medical Therapy for Relief of Symptoms 4.4.3.1. Use of Anti-ischemic Medications: Recommendations Class I 1.


Medical Therapy for Relief of Symptoms 4.4.3.1. Use of Anti-ischemic Medications: Recommendations Class I 1. Beta blockers should be prescribed as initial therapy for relief of symptoms in patients with SIHD.757,765,766 (Level of Evidence: B) 2. Calcium channel blockers or long-acting nitrates should be prescribed for relief of symptoms when beta blockers are contraindicated or cause unaccept- able side effects in patients with SIHD.420,768,769 (Level of Evidence: B) 3. Calcium channel blockers or long-acting nitrates, in combination with beta blockers, should be pre- scribed for relief of symptoms when initial treatment with beta blockers is unsuccessful in patients with SIHD.420 (Level of Evidence: B) 4. Sublingual nitroglycerin or nitroglycerin spray is recommended for immediate relief of angina in patients with SIHD.843 845 (Level of Evidence: B) Class IIa 1. Treatment with a long-acting nondihydropyridine calcium channel blocker (verapamil or diltiazem) instead of a beta blocker as initial therapy for relief of symptoms is reasonable in patients with SIHD.420 (Level of Evidence: B) 2. Ranolazine can be useful when prescribed as a substitute for beta blockers for relief of symptoms in patients with SIHD if initial treatment with beta blockers leads to unacceptable side effects or is ineffective or if initial treatment with beta blockers is contraindicated.846 (Level of Evidence: B) 3. Ranolazine in combination with beta blockers can be useful when prescribed for relief of symptoms when initial treatment with beta blockers is not successful in patients with SIHD.847,848 (Level of Evidence: A) 4.4.3.1.1. Beta Blockers. Beta blockers are recommended as the initial agents to relieve symptoms in most patients with SIHD. Beta blockers reduce myocardial oxygen consumption by reducing heart rate, myocardial contractility, and afterload, with attenuation of cardiovascular remodeling by decreasing LV wall tension with long-term use.


Beta blockers reduce myocardial oxygen consumption by reducing heart rate, myocardial contractility, and afterload, with attenuation of cardiovascular remodeling by decreasing LV wall tension with long-term use. The reduction in myo- cardial oxygen demand is directly proportional to the level of adrenergic tonic stimulation. Furthermore, the reduction in heart rate also shifts the cardiac cycle, permitting more diastolic time and greater coronary perfusion, thereby im- proving myocardial oxygen supply. Long-term beta-blocker treatment is well tolerated, has proven benefit in SIHD by reducing ischemic burden and threshold, and improves survival in patients with LV dys- function or history of MI.757,765,766 When prescribed in com- bination with agents that block the renin-angiotensin-aldoste- rone system, beta blockers are the preferred agents for the treatment of angina in patients with LV dysfunction after MI and in patients with heart failure, on the basis of documented improvements in survival and ventricular A meta-analysis of comparison trials between beta block- ers and calcium channel blockers (dihydropyridine and non- dihydropyridine agents) showed negligible differences in the rate of death or MI over relatively brief durations of admin- istration (ie, 6 wk to 6 mo), although patients with heart failure, heart block, or significant pulmonary disease were excluded from the meta-analysis.420 Beta blockers were found to exhibit an advantage with regard to control of angina and withdrawals from therapy due to adverse events, a problem that was most pronounced with nifedipine.420 Calcium chan- nel blockers, however, have not been shown to improve survival after MI, as beta blockers have, but have been shown to offer protection against severe angina and to reduce the risk of reinfarction after MI.849 851 Adherence to beta-blocker therapy can be influenced by the occurrence of adverse effects such as fatigue, lethargy, sexual dysfunction, or sleep disturbances.


Long-term beta-blocker treatment is well tolerated, has proven benefit in SIHD by reducing ischemic burden and threshold, and improves survival in patients with LV dys- function or history of MI.757,765,766 When prescribed in com- bination with agents that block the renin-angiotensin-aldoste- rone system, beta blockers are the preferred agents for the treatment of angina in patients with LV dysfunction after MI and in patients with heart failure, on the basis of documented improvements in survival and ventricular A meta-analysis of comparison trials between beta block- ers and calcium channel blockers (dihydropyridine and non- dihydropyridine agents) showed negligible differences in the rate of death or MI over relatively brief durations of admin- istration (ie, 6 wk to 6 mo), although patients with heart failure, heart block, or significant pulmonary disease were excluded from the meta-analysis.420 Beta blockers were found to exhibit an advantage with regard to control of angina and withdrawals from therapy due to adverse events, a problem that was most pronounced with nifedipine.420 Calcium chan- nel blockers, however, have not been shown to improve survival after MI, as beta blockers have, but have been shown to offer protection against severe angina and to reduce the risk of reinfarction after MI.849 851 Adherence to beta-blocker therapy can be influenced by the occurrence of adverse effects such as fatigue, lethargy, sexual dysfunction, or sleep disturbances. Although beta blockers have the potential to worsen symptoms in patients with significant depressive illness or PAD, these effects are observed rarely in clinical practice. For patients with severe PAD or those with vasospastic (Prinzmetal s) angina, wors- ening symptoms due to vasoconstriction from unopposed alpha-adrenergic activity can be avoided by using beta blockers with alpha-adrenergic blocking (eg, labetalol or carvedilol) or direct vasodilator (eg, nebivolol) properties. 4.4.3.1.2. Calcium Channel Blockers.


For patients with severe PAD or those with vasospastic (Prinzmetal s) angina, wors- ening symptoms due to vasoconstriction from unopposed alpha-adrenergic activity can be avoided by using beta blockers with alpha-adrenergic blocking (eg, labetalol or carvedilol) or direct vasodilator (eg, nebivolol) properties. 4.4.3.1.2. Calcium Channel Blockers. If adverse effects or contraindications limit the use of beta blockers, calcium channel blockers are recommended for relief of anginal symptoms. These agents noncompetitively limit calcium ion influx through voltage-dependent L-type calcium channels, resulting in negative inotropic effects, cardiac pacemaker depression, slowing conduction, and smooth muscle relax- ation. There are 3 classes of calcium channel blockers: the dihydropyridines (eg, nifedipine) and 2 types of nondihydro- pyridines, the phenylalkylamines (eg, verapamil) and the benzothiazepines (eg, diltiazem). All classes improve myo- cardial oxygen supply by decreasing coronary vascular resis- tance and augmenting epicardial conduit vessel and systemic arterial blood flow. Myocardial demand is decreased by a reduction in myocardial contractility, systemic vascular resis- tance, and arterial pressure. However, the phenylalkylamines and, to a lesser extent, the benzothiazepines also depress cardiac pacemaker rate and slow conduction. This depressant effect can cause sinus bradycardia or can worsen preexisting conduction defects, leading to heart block. Myocardial con- tractile depression also is a common feature, although the degree is variable according to drug class.


Myocardial con- tractile depression also is a common feature, although the degree is variable according to drug class. As a result of these pharmacological properties, the calcium channel blockers are effective anti-ischemic drugs, but their use must be All classes of calcium channel blockers reduce anginal episodes, increase exercise duration, and reduce use of sublingual nitroglycerin in patients with effort-induced an- gina.854 856 Because all 3 classes also reduce the frequency of Prinzmetal s variant angina, they are the drugs of choice, along with nitrates, used alone or in combination.857 859 Because the 3 classes seem to be equally efficacious in treating angina, the choice of a particular agent should be based on potential drug interactions and adverse events. The dihydropyridine class is preferred over other calcium channel blockers in patients with cardiac conduction defects such as sick sinus syndrome, sinus bradycardia, or significant AV conduction disturbances. Dihydropyridines should be used with caution in patients with severe aortic valve stenosis. Short-acting dihydropyridines in patients with fixed lesions can exacerbate angina, possibly by excessive lowering of arterial pressure with reflex tachycardia, and therefore should be avoided. Short-acting nifedipine seems to increase mortal- ity in patients with hypertension,860 but there is currently no evidence that these concerns apply to extended-release prep- arations.861,862 Because of their effects on contractility, none of the calcium channel blockers are recommended for routine treatment of patients with current or prior symptoms of heart failure and a reduced LVEF.21 Many drug interactions associated with calcium channel blockers occur because of rapid absorption or low bioavail- ability due to high first-pass metabolism by the cytochrome P450 (ie, CYP3A4) system. These pharmacokinetic properties result in high intraindividual and interindividual variability, necessitating dosage adjustment.


These pharmacokinetic properties result in high intraindividual and interindividual variability, necessitating dosage adjustment. These drugs should be used with caution when combined with cyclosporine, carbamaz- epine, lithium carbonate, amiodarone, or digoxin (ie, 50% to 70% increase in digoxin concentrations in first week of therapy). Combining verapamil or diltiazem with beta block- ers generally should be avoided because of potentially pro- found adverse effects on AV nodal conduction, heart rate, or cardiac contractility. Overall, calcium channel blockers, particularly diltiazem, are well tolerated. The major adverse effects of dihydropyr- idines are related to vasodilation and systemic hypotension, including headache, dizziness, palpitations, and flushing. Many patients experience peripheral edema because of ex- cessive arterial vasodilation unmatched to venous dilation. Verapamil can cause constipation that can be severe, partic- ularly in the elderly. 4.4.3.1.3. Nitrates. Nitrates are effective in the treatment of all forms of angina. They relax vascular smooth muscle in the systemic arteries, inclusive of the coronary arteries, and veins (predominant effect at lower doses) in patients with SIHD. Short-term continuous nitroglycerin delivery by the intrave- nous or transdermal route for only 2 to 4 hours protects the endothelium from experimental ischemia in healthy volun- teers and reduces ischemia during coronary angioplasty and physical exercise in IHD patients.863 865 Oxygen free radical release seems to be associated with these protective out- comes.


Short-term continuous nitroglycerin delivery by the intrave- nous or transdermal route for only 2 to 4 hours protects the endothelium from experimental ischemia in healthy volun- teers and reduces ischemia during coronary angioplasty and physical exercise in IHD patients.863 865 Oxygen free radical release seems to be associated with these protective out- comes. Nitroglycerin causes dilation of the artery wall not affected by plaque, but independent of an intact endothelium, leading to reduced resistance across the obstructed lumen.866 Furthermore, nitroglycerin contributes to coronary blood flow redistribution, by augmenting collateral flow and lowering ventricular diastolic pressure, from areas of normal perfusion to ischemic zones.867 Preload is reduced, leading to reduc- tions in myocardial wall tension and myocardial oxygen demand, although this effect is offset by increased heart rate and myocardial contractile state due to reflex sympathetic activity. Nitroglycerin also has demonstrated antithrombotic and antiplatelet effects.868,869 Long-term nitrate therapy, however, could offset the beneficial short-term ischemic preconditioning effects. Long- term nitroglycerin therapy is associated with endothelial dysfunction via accumulation of the same oxygen free radi- cals that seem to be beneficial in short-term administra- tion.870,871 The oxygen free radical accumulation increases arterial sensitivity to vasoconstrictors such as angiotensin II, which can be counteracted by concomitant treatment with an ACE inhibitor or hydralazine.872 875 Importantly, these phys- iological changes are independent of dose or the presence or absence of a nitrate-free interval and can result in a decrease in the anginal threshold during the nitrate-free interval.876 Further research to better understand the balance between the long-term benefits and safety concerns of these compounds is warranted in patients with SIHD.


Long- term nitroglycerin therapy is associated with endothelial dysfunction via accumulation of the same oxygen free radi- cals that seem to be beneficial in short-term administra- tion.870,871 The oxygen free radical accumulation increases arterial sensitivity to vasoconstrictors such as angiotensin II, which can be counteracted by concomitant treatment with an ACE inhibitor or hydralazine.872 875 Importantly, these phys- iological changes are independent of dose or the presence or absence of a nitrate-free interval and can result in a decrease in the anginal threshold during the nitrate-free interval.876 Further research to better understand the balance between the long-term benefits and safety concerns of these compounds is warranted in patients with SIHD. Despite these physiological observations, nitrates improve exercise tolerance, time to ST-segment depression, and time to onset of angina in patients with SIHD, albeit in small patient studies conducted for relatively short periods.876 878 Comparisons of nitrates to beta blockers or calcium channel blockers have not shown significant differences with regard to weekly anginal episodes, time to ST-segment depression, total exercise time, or sublingual nitroglycerin use.420 With- drawal for adverse effects was also not statistically different between the drug classes. All patients with SIHD should be prescribed sublingual nitroglycerin tablets or nitroglycerin spray for immediate relief of angina. Most patients respond within 5 minutes of taking 1 to 2 sublingual dose(s) of 0.3 to 0.6 mg. Nitroglyc- erin spray is available in a 0.4-mg metered-dose canister that dispenses 200 doses. The tablets should be placed under the tongue and not swallowed. If the spray is used, it should be applied to the tongue and not swallowed or inhaled. If additional doses are necessary, they should be taken at 5-minute intervals, for a maximum dose of #1.2 mg within 15 minutes.


If additional doses are necessary, they should be taken at 5-minute intervals, for a maximum dose of #1.2 mg within 15 minutes. During this timeframe, if relief does not occur, Fihn et al Stable Ischemic Heart Disease: Full Text e409 the patient should seek immediate medical attention. These products are also effective for prevention of effort-induced angina when administered 5 to 10 minutes before activity, with relief lasting approximately 30 to 40 minutes. The tablets must be kept in the manufacturer s bottle (loss of potency can occur in a few hours if out of the bottle) and should be stored in a cool, dry place but should not be refrigerated. The tablets should not be used 6 to 12 months after opening the bottle. Patients usually are able to detect when tablets have lost potency by the absence of a burning sensation beneath the tongue. Nitroglycerin ointment also may be used for short-term relief of angina. Applied to the chest in doses of 0.5 to 2.0 inches, with a delay in relief of 30 minutes, this preparation can be effective for 4 to 6 hours. Absorption can be increased by rotating the application sites, covering the paste with plastic, or not applying the ointment continuously (ie, maintenance of a nitrate-free interval).879 881 All short-acting nitrate preparations can cause hypotension, sometimes severe, and headaches that limit adherence to these agents. Patients should be counseled about these ad- verse effects and advised to seek medical treatment if syncope or resistant chest pain occurs. The ointment can cause permanent discoloration of clothing.


Patients should be counseled about these ad- verse effects and advised to seek medical treatment if syncope or resistant chest pain occurs. The ointment can cause permanent discoloration of clothing. Long-acting nitrate preparations (eg, nitroglycerin, isosor- bide dinitrate, isosorbide-5-mononitrate) are recommended for treatment of angina when initial therapy with a beta blocker or nondihydropyridine calcium channel blocker is contraindicated or poorly tolerated or when additional ther- apy to control angina is necessary. Isosorbide dinitrate undergoes rapid high first-pass metabolism, resulting in low bioavailability. However, substantial interpatient variability exists in the metabolic enzyme systems responsible for isosorbide dinitrate conversion. Isosorbide mononitrate, the active metabolite of the dinitrate formulation, is 100% bio- available. Nitroglycerin also can be delivered through sili- cone gel or polymer matrix release patch systems. The rate of release varies between these systems, necessitating individu- alization of dosing. With all formulations, titration of dose is important to gain adequate anginal control with the lowest possible dose to limit the occurrence of headaches, avoid nitrate tolerance, and facilitate long-term adherence. The effectiveness of all of these formulations seems to be roughly equivalent despite differences in the preparation and dosing schedules.843,882 With all of them, it is necessary to maintain a daily nitrate-free interval of 10 to 14 hours to avoid development of nitrate tolerance.843 Nitrate tolerance does not develop with the sublingual route of administration. Use of long-acting nitrates also does not result in tolerance to the use of sublingual products. Nitrates are relatively well tolerated if a titration schedule is used at initiation and with discontinuation. The most common side effects are headache, flushing, and hypotension. Patients should be instructed to remain seated when taking rapid-acting nitrate products as a safety precaution to avoid syncope from vasodilation.


Patients should be instructed to remain seated when taking rapid-acting nitrate products as a safety precaution to avoid syncope from vasodilation. Tolerance to the headaches could develop after a few weeks of continuing the medication. Prophylactic analgesics can be helpful until headache toler- ance develops. Methemoglobinemia is a rare adverse effect, usually seen only with large doses. Nitrates are relatively contraindicated in hypertrophic obstructive cardiomyopathy because of the potential to increase the outflow tract obstruc- tion and mitral regurgitant flow. They should be avoided in patients with severe aortic valvular stenosis. Coadministra- tion of the phosphodiesterase inhibitors sildenafil, tadala- fil, or vardenafil with long-acting nitrates should be strictly avoided within 24 hours of nitrate administration because of the risk of profound hypotension (eg, 25 mm Hg drop in systolic BP). Patients should be advised not to take phosphodiesterase inhibitors within 24 hours of long- acting nitrates, and nitrates should not be taken for 24 hours after use of sildenafil or 48 hours after tadalafil; a suitable time interval after vardenafil has not been deter- mined. Patients should be made aware of the possibility of intensification of their angina if nitrates are discontinued abruptly. This effect could be reduced by concomitant administration of other antianginals or by tapering of the long-acting nitrate dosage. 4.4.3.1.4. Ranolazine. Ranolazine inhibits the late inward sodium current, indirectly reducing the sodium-dependent calcium current during ischemic conditions and leading to improvement in ventricular diastolic tension and oxygen consumption. Minimal changes in mean heart rate (,2 beats per minute) and systolic BP (,3 mm Hg) occur in controlled studies.


Minimal changes in mean heart rate (,2 beats per minute) and systolic BP (,3 mm Hg) occur in controlled studies. At maximal exercise, the rate pressure product is not increased, independent of age, or in the presence of diabetes mellitus, reactive airway disease, or heart failure.883 Ranola- zine is currently indicated for the treatment of chronic angina and may be used in combination with beta blockers, nitrates, dihydropyridine calcium channel blockers, ACE inhibitors, ARBs, and antiplatelet and lipid-lowering therapy. It should be prescribed only in low doses in combination with verap- amil or diltiazem, as described later. The lack of an effect on BP and heart rate makes ranolazine an attractive alternative in patients with bradycardia or low BP. Although ranolazine has been well studied in SIHD, the agent was not administered in the COURAGE (Clinical Outcomes Utilizing Revasculariza- tion and Aggressive Drug Evaluation) study,366 and further clinical evaluation is needed, especially of ranolazine as an element of intensive interventions for multiple risk factors.


Although ranolazine has been well studied in SIHD, the agent was not administered in the COURAGE (Clinical Outcomes Utilizing Revasculariza- tion and Aggressive Drug Evaluation) study,366 and further clinical evaluation is needed, especially of ranolazine as an element of intensive interventions for multiple risk factors. The ranolazine extended-release preparation reduces the frequency of angina, improves exercise performance, and delays the development of exercise-induced angina and ST- segment depression.847,884 In one study, ranolazine reduced weekly anginal frequency by 36% and nitroglycerin use by 43% in comparison with placebo.848 Other studies indicated that among patients with ACS, ranolazine did not reduce the incidence of MI or death885 but did reduce recurrent ischemia in the postinfarction period.886 In patients with preexisting angina, it was superior to placebo in improving patients angina and quality of life.887 Ranolazine could exert a beneficial effect on glycemic control and has demonstrated consistent reductions in HbA1c in patients with diabetes Ranolazine blocks the delayed rectifier potassium current and prolongs the QTc interval in a dose-related manner, resulting in a mean increase in QTc of approximately 6 msec at maximal recommended dosing. Currently, there is limited experience with concomitant administration of ranolazine and other drugs that prolong the QT interval, including Class IA and III antiarrhythmics and certain antipsychotics (thiorida- zine and ziprasidone). In 3162 patients with ACS, there was no increased risk of proarrhythmia or sudden death. In this study, there was a significantly lower incidence of arrhyth- mias, including ventricular tachycardia, bradycardia, su- praventricular tachycardia, and new atrial fibrillation, in patients treated with ranolazine (80%) versus placebo Ranolazine does not require dose adjustment for age, sex, New York Heart Association class I IV heart failure, or diabetes mellitus.


In this study, there was a significantly lower incidence of arrhyth- mias, including ventricular tachycardia, bradycardia, su- praventricular tachycardia, and new atrial fibrillation, in patients treated with ranolazine (80%) versus placebo Ranolazine does not require dose adjustment for age, sex, New York Heart Association class I IV heart failure, or diabetes mellitus. Plasma concentrations of ranolazine are increased by up to 50% in patients with Stage 4 CKD (creatinine clearance ,30 mL/min).892 The drug is contrain- dicated in patients with clinically significant hepatic impair- ment because of increased plasma concentrations and QT prolongation. In general, dosing in the elderly should start at the low end of the dosing range.883 Ranolazine is contraindicated in combination with potent inhibitors of the CYP3A4 pathway, including ketoconazole (3.2-fold increase in ranolazine plasma levels) and other azole antifungals, macrolide antibiotics, HIV (human immunodefi- ciency virus) protease inhibitors, grapefruit products or juice, diltiazem (1.8- to 2.3-fold increase in ranolazine plasma levels), itraconazole, clarithromycin, and certain HIV protease inhibi- tors. When administered with moderate inhibitors of CYP3A such as diltiazem, verapamil, aprepitant, erythromycin, flucona- zole, or grapefruit juice, the dose of ranolazine should be limited to 500 mg twice daily because of an approximately 2-fold increase in ranolazine plasma levels. No dose adjustment is required in patients treated with cimetidine or paroxetine. Co- administration of ranolazine (1000 mg twice daily) with simva- statin increases the plasma concentration of simvastatin and its active metabolite 2-fold. Digoxin plasma concentrations are increased 1.5-fold, but this interaction might not be clinically relevant with lower digoxin dosing (0.125 mg daily). Coadmin- istration of ranolazine with drugs that inhibit CYP2D6, with the exceptions of tricyclic antidepressants and some antipsychotics, does not require dosage adjustment. Ranolazine is well tolerated; the major adverse effects are constipation, nausea, dizziness, and headache.


Ranolazine is well tolerated; the major adverse effects are constipation, nausea, dizziness, and headache. The incidence of syncope is ,1%. 4.4.3.1.5. Antianginal Agents Not Currently Available in the United States 4.4.3.1.5.1. Nicorandil. Nicorandil is a nicotinamide ester with a dual mechanism of action. It activates adenosine triphosphate sensitive potassium channels and promotes sys- temic venous and coronary vasodilation through a nitrate moiety.893 This dual action increases coronary blood flow, with reductions in afterload, preload, and oxidative injury.893 The agent does not exhibit effects on contractility or conduc- tion.894,895 The antianginal efficacy and safety of nicorandil are similar to those of oral nitrates, beta blockers, and calcium channel blockers.893,896,897 In a prospective, randomized, study of 5126 patients with chronic stable angina, the addition of nicorandil to standard therapy was found to produce a 17% RR reduction in the composite endpoint of IHD death, nonfatal MI, or unplanned hospital admission for cardiac chest pain.898 There was, however, no difference between nicorandil and placebo with regard to death from IHD or nonfatal MI.894 Tolerance can develop with long-term dos- ing.899 Common side effects include flushing; palpitation; weakness; headache; ulceration of the mouth, perianal, ileal, and peristomal areas; nausea; and vomiting. The agent is not currently available in the United States. 4.4.3.1.5.2. Ivabradine. Ivabradine is a specific inhibitor of the If current of pacemaker cells in the sinoatrial node at concentrations that do not inhibit other cardiac currents.900 This action results in heart rate reduction, prolonging diastole and thereby improving myocardial oxygen balance.


Ivabradine is a specific inhibitor of the If current of pacemaker cells in the sinoatrial node at concentrations that do not inhibit other cardiac currents.900 This action results in heart rate reduction, prolonging diastole and thereby improving myocardial oxygen balance. Ivabra- dine has no effect on BP, myocardial contractility, or intra- cardiac conduction parameters.901 903 Ivabradine improves exercise capacity and reduces anginal frequency in compar- ison to atenolol among patients with chronic stable an- gina.904,905 In 5479 patients with IHD and LV systolic dysfunction, however, ivabradine added to standard treatment had no effect, when compared with placebo, on the composite endpoint of cardiovascular death, admission to the hospital for AMI, and admission to the hospital for new-onset or worsening heart failure.906 The most common adverse event, reported in 14.5% of patients, is phosphenes, described as a transient enhanced brightness in a limited area of the visual field that typically occurs within the first 2 months of treatment. Most of these luminous visual-field disturbances (77%) resolve without discontinuing treatment. The drug is approved in Europe (not currently available in the United States) for the symptomatic treatment of chronic stable angina in patients with normal sinus rhythm with a contrain- dication or intolerance to beta blockers. 4.4.3.1.5.3. Trimetazidine. Trimetazidine seems to improve cellular tolerance to ischemia by inhibiting fatty acid metab- olism and secondarily by stimulating glucose metabolism, although the exact anti-ischemic mechanisms are un- known.907 In patients with chronic stable angina, this agent increases coronary flow reserve, delaying the onset of ische- mia associated with exercise and reducing the number of weekly angina episodes and weekly nitroglycerin consump- tion.908,909 The anti-ischemic effects are not associated with changes in heart rate or systolic BP. Few data exist on the effect of trimetazidine on cardiovascular endpoints, mortality, or quality of life.


Few data exist on the effect of trimetazidine on cardiovascular endpoints, mortality, or quality of life. The most frequently reported adverse events are gastrointestinal disorders, but the incidence is low. The agent is not available in the United States but is available in Europe and reportedly in .80 countries worldwide. 4.4.4. Alternative Therapies for Relief of Symptoms in Patients With Refractory Angina: Recommendations Class IIb 1. Enhanced external counterpulsation (EECP) may be considered for relief of refractory angina in patients with SIHD.910 (Level of Evidence: B) 2. Spinal cord stimulation may be considered for relief of refractory angina in patients with SIHD.911,912 (Level of Evidence: C) 3. Transmyocardial revascularization (TMR) may be considered for relief of refractory angina in patients with SIHD.913 915 (Level of Evidence: B) Class III: No Benefit 1. Acupuncture should not be used for the purpose of improving symptoms or reducing cardiovascular risk in patients with SIHD.916,917 (Level of Evidence: C) TMR has been used as either a percutaneous or a surgical procedure concomitant with CABG or as sole therapy in patients with angina refractory to medical therapy,913 915,918 although the mechanism by which it might be efficacious is unknown.919,920 Early studies of the percutaneous approach demonstrated no therapeutic benefit, and it was promptly abandoned.921 When used as sole therapy by a surgical approach, TMR is reserved for the patient with incapacitat- ing, medically refractory angina and no other feasible thera- Fihn et al Stable Ischemic Heart Disease: Full Text e411 peutic options. Proposed mechanisms of action include stim- ulation of microcirculation, creation of myocardial scarring, and denervation of ischemic myocardium.922 Various energy sources have been used, including carbon dioxide XeCl excimer and holmium:YAG lasers.923 925 There is no con- vincing evidence that one energy source is superior to the others.


Proposed mechanisms of action include stim- ulation of microcirculation, creation of myocardial scarring, and denervation of ischemic myocardium.922 Various energy sources have been used, including carbon dioxide XeCl excimer and holmium:YAG lasers.923 925 There is no con- vincing evidence that one energy source is superior to the others. TMR also has been combined with cardiac denerva- tion by thoracic sympathectomy.926 Numerous single-center and a few multicenter randomized trials have been published that compare TMR with medical therapy for relief of refractory angina.927 930 Most have shown better angina relief with TMR but no survival benefit. The exception is a single multicenter trial that shows a survival benefit as well as better relief of angina at 5 years.931 A 5-year follow-up of a multicenter, prospectively random- ized trial reported not only sustained angina relief but also improved survival in CCS Class IV angina, and patients with no additional options for therapy who were randomized to sole-therapy TMR.931 A meta-analysis of 7 RCTs involving 1053 patients evaluated the effect of TMR on survival and angina relief.932 The conclusion was that at 1 year, TMR improved angina class but not survival when used as the sole procedural intervention compared with medical therapy alone. A number of other series also have reported sustained angina relief and improved quality of life in randomized patients receiving TMR at 3 to 5 years after treatment (Section 5.10 for additional information on TMR in revascularization). A growing number of patients with SIHD have refractory angina, defined as multivessel CAD with ischemia and symptoms that cannot be controlled with medical therapy or surgical or percutaneous revascularization.


A growing number of patients with SIHD have refractory angina, defined as multivessel CAD with ischemia and symptoms that cannot be controlled with medical therapy or surgical or percutaneous revascularization. The prevalence of this syndrome is not well established, but data from registries suggest that about 10% of patients referred for angiography for symptomatic SIHD have coronary anatomy that is not amenable to revascularization.933 935 Other nonpharmacologi- cal therapies may be considered in these patients in an effort to improve quality of life. 4.4.4.1. Enhanced External Counterpulsation EECP is a technique that uses inflatable cuffs wrapped around the lower extremities to increase venous return and augment diastolic BP. The cuffs are inflated sequentially from the calves to the thigh muscles during diastole and are deflated instantaneously during systole. The resultant diastol- ic augmentation increases coronary perfusion pressure, and the systolic cuff depression decreases peripheral resistance. Treatment is associated with improved LV diastolic filling and improved endothelial function936 938; other putative mechanisms for improvement in symptoms include recruit- ment of collaterals, release of proangiogenic cytokines, and a peripheral training effect. A treatment course typically con- sists of 35 hour-long treatment sessions, given 5 days a week. Contraindications include decompensated heart failure, se- vere PAD, and severe aortic regurgitation. The efficacy of EECP in treating stable angina pectoris has been evaluated in a single RCT and several observational registry studies.


The efficacy of EECP in treating stable angina pectoris has been evaluated in a single RCT and several observational registry studies. In MUST-EECP (Multicenter Study of En- hanced External Counterpulsation), 139 patients with angina, documented CAD, and evidence of ischemia on exercise testing were randomized to 35 hours of active counterpulsa- tion or to inactive counterpulsation.910 Time to $1-mm ST-segment depression increased significantly in patients treated with active counterpulsation (from 337618 s to 379618 s) compared with placebo (from 326621 s to 330620 s; P50.01), although there was no difference be- tween the groups in exercise duration. More active counter- pulsation patients experienced a decrease in anginal episodes. Of patients receiving EECP, 55% reported adverse events, including leg and back pain and skin abrasions, compared with 26% in the control group, with approximately half of these events categorized as device related. In a meta-analysis of 13 observational studies that tracked 949 patients, anginal class as categorized by the CCS classi- fication was improved by $1 class in 86% (95% CI: 82% to 90%).939 The EECP Consortium reported results in 2289 consecutive patients undergoing EECP therapy at 84 partic- ipating centers, including a subgroup of 175 patients from 7 centers who underwent radionuclide perfusion stress tests before and after therapy.940 Treatment was associated with improved perfusion images and increased exercise duration. Similarly, the International EECP Registry reported improve- ment of $1 angina class in 81% of patients immediately after the last treatment.941 In general, existing data, largely from uncontrolled studies, suggest a benefit from EECP in patients with angina refrac- tory to other therapy. Additional data from well-designed RCTs are needed to better define the role of this therapeutic strategy in patients with SIHD.942 4.4.4.2.


Additional data from well-designed RCTs are needed to better define the role of this therapeutic strategy in patients with SIHD.942 4.4.4.2. Spinal Cord Stimulation Spinal cord stimulation at the T1 to T2 level has been advocated as a therapeutic option for patients with angina pectoris that is refractory to medical therapy and coronary revascularization. The stimulation lead is inserted into the epidural space and is connected to a pulse generator im- planted subcutaneously. A paresthetic stimulus is delivered in a continuous, cyclic, or intermittent manner. The mechanisms by which spinal cord stimulation leads to reduced angina are not well established. Although inhibition of pain transmission plays a role, some studies suggest that spinal cord stimulation also might reduce myocardial ischemia.943 945 The efficacy of spinal cord stimulation has been evaluated in several observational and cohort studies. The Prospective Italian Registry described outcomes in 104 patients with severe angina refractory to medical therapy over an average of 13 months after initiation of spinal cord stimulation.946 A .50% reduction in anginal symptoms was observed in 73% of patients. CCS class improved by $1 class in 80% and by $2 classes in 42% of patients. Similarly, in a cohort of 51 patients with refractory CCS Class III or IV angina, spinal cord stimulation was associated with a significant reduction in anginal episodes in 88% of subjects at 24 months of follow-up.947 There were no significant complications of therapy in either series. The published RCTs of spinal cord stimulation were small.


Similarly, in a cohort of 51 patients with refractory CCS Class III or IV angina, spinal cord stimulation was associated with a significant reduction in anginal episodes in 88% of subjects at 24 months of follow-up.947 There were no significant complications of therapy in either series. The published RCTs of spinal cord stimulation were small. One study tested the efficacy of spinal cord stimulation in 13 patients with chronic, intractable angina compared with 12 controls over 6 weeks.912 Patients with spinal cord stimulation demonstrated greater exercise duration and time to angina during treadmill testing and fewer bouts of angina and fewer episodes of ST depression on ambulatory echocardiographic monitoring. A subsequent trial com- pared spinal cord stimulation to CABG.911 Subjects included 104 patients with severe angina who would not be expected to derive survival benefit from revascularization, were at increased risk of surgical complications, and were unsuitable for PCI. Patients in both groups had significant symptom relief. Those assigned to bypass surgery had greater increases in exercise capacity and less ST depression on treadmill testing than did those treated with spinal cord stimulation. Mortality and cardiovascular morbidity rates were lower in the spinal cord stimulation group. In summary, studies of spinal cord stimulation suggest that this technique might have some use as a method to relieve angina in patients with symptoms that are refractory to standard medical therapy and revascularization. There is a paucity of data on the mechanisms and long-term risks and benefits of this therapeutic approach, however. Acupuncture is used by some practitioners for the relief of acute and chronic pain. The efficacy of acupuncture in the treatment of angina pectoris has not been studied rigorously, however. In part this is due to the difficulty of blinding both patients and healthcare providers.