However, as discussed above, although the presence of data confirming the use of a specific, numeric target LDL cholesterol level for all patients with SIHD has been challenged, the benefit of therapy with moderate- to high-dose statin therapy is well established.458 For this reason, the recommendations in this guideline stress the importance of prescribing a statin in at least a moderate dose. The ATP-IV report is anticipated later in 2012 and is expected to provide guidance for the treatment of LDL cholesterol levels on the basis of the results of an extensive systematic review. Factors that identify patients at very high risk in the ATP-III update include the presence of established coronary vascular disease, plus 1) multiple major risk factors, especially diabetes mellitus; 2) severe and poorly controlled risk factors, especially continued tobacco use; and 3) multiple risk factors for the metabolic syndrome. Again, it should be acknowledged that no studies have assessed the benefits of titrating lipid- lowering drugs to achieve a specific LDL cholesterol target. In addition, trials of intensive lipid lowering for secondary prevention have used statins alone. Although the addition of other agents could lower LDL cholesterol in patients in whom a target level cannot be achieved with a statin, the utility of this approach in reducing risk of cardiovascular morbidity and mortality has not been firmly established. A secondary target of therapy introduced by ATP-III is non HDL cholesterol in patients with elevated triglycer- ides.18,24 Non HDL cholesterol is defined as the difference between total cholesterol and HDL cholesterol. It includes all cholesterol and lipoprotein particles that are considered atherogenic, including LDL cholesterol, lipoprotein, intermediate-density lipoprotein, and very-low-density lipo- protein, and is a predictor of cardiovascular death.523 Because statins lower LDL cholesterol and non HDL cholesterol to a similar extent, the relative benefits of lowering these 2 lipid measures cannot be distinguished from recent clinical trials. Fibrates could reduce the risk of coronary events in patients with high triglycerides and low HDL cholesterol levels and could have an adjunctive role in these patients in combination with statins.503,524 Nicotinic acid raises HDL cholesterol, and several trials support the efficacy of niacin when used alone or in combination with statins.504,505,525 Observational studies and treatment trials suggest that consumption of omega-3 fatty acids reduces cardiovascular risk. Cohort and case control studies have found an RR reduction of about 15% for fish consumption versus little or no fish consumption.526 In the GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell Infarto Miocardico) Preven- tion study in patients with prior MI, 1 g daily of fish oil supplement resulted in a 20% reduction in mortality at 42 months.527 Pharmacological treatment with fish oil at higher doses (2 to 4 g daily) is effective in reducing triglyceride 4.4.1.2. Blood Pressure Management Class I 1. All patients should be counseled about the need for lifestyle modification: weight control; increased physical activity; alcohol moderation; sodium reduc- tion; and emphasis on increased consumption of fresh fruits, vegetables, and low-fat dairy prod- ucts.17,529 537 (Level of Evidence: B) 2. In patients with SIHD with BP 140/90 mm Hg or higher, antihypertensive drug therapy should be instituted in addition to or after a trial of lifestyle modifications.538 543 (Level of Evidence: A) 3. The specific medications used for treatment of high BP should be based on specific patient characteris- tics and may include ACE inhibitors and/or beta blockers, with addition of other drugs, such as thiazide diuretics or calcium channel blockers, if needed to achieve a goal BP of less than 140/ 90 mm Hg.544,545 (Level of Evidence: B) Hypertension is an important independent risk factor for ischemic cardiovascular events. Observational studies have demonstrated a continuous and graded relationship between BP and cardiovascular risk. In a collaborative meta-analysis of prospective studies of nearly 1 million adults without preexisting vascular disease, the risk of a vascular death increased linearly over the BP range of 115/75 mm Hg to 185/115 mm Hg, without a threshold effect. Each increment of 20 mm Hg in systolic BP or 10 mm Hg in diastolic BP was associated with a doubling of risk.546 RCTs indicate that treatment results in a reduction of cardiovascular risk consistent with predictions Treatment of high BP should begin with lifestyle measures. Maintenance of an appropriate body weight (BMI ,25 ) is a key element of the nonpharmacological strategies recommended to improve BP control; weight loss of 10 kg typically results in a decrease in BP of 5 to 20 mm Hg.529 531,548,549 Consumption of a diet rich in fruits, vegeta- bles, and low-fat dairy products532,533; reduction of dietary sodium intake529,531,533,534,550; regular physical activity535; and moderation of alcohol consumption536 also result in signifi- cant lowering of BP. In many patients with SIHD, therapy with medications will be required to lower BP to the desired level. Treatment trials have definitively demonstrated a beneficial effect of antihy- pertensive drug therapy on cardiovascular disease risk. An overview of 17 placebo-controlled trials, most of which focused on lowering diastolic BP, showed that reducing diastolic BP 5 to 6 mm Hg (or an estimated 10 to 20 mm Hg in systolic BP) within a population was associated with a significant reduction in vascular mortality, with approxi- mately 40% reduction in stroke and 20% reduction in coronary events.547 This benefit of treatment also has been observed in studies of older adult patients with isolated Despite the plethora of clinical studies, the appropriate BP threshold for initiating medical therapy and specific treatment goals for patients with chronic IHD remain controversial. RCTs have demonstrated a benefit from antihypertensive therapy in patients with a diastolic BP .90 mm Hg547 and also in patients with isolated systolic hypertension and a systolic BP .160 mm Hg.539,551,552 The Seventh Report of the Joint National Committee on Prevention, Detection, Evalua- tion, and Treatment of High Blood Pressure recommends a target BP of ,140/90 mm Hg in patients with uncomplicated hypertension and of ,130/80 mm Hg in patients with diabetes mellitus or CKD.17 Observations from epidemiolog- ical studies and the relatively high absolute risk of cardiovas- cular events in patients with vascular disease have led some to suggest that a lower BP target might also be appropriate in individuals with SIHD.553 On the other hand, excessive reduction in diastolic BP could compromise coronary perfusion in SIHD patients, and some studies have demonstrated a J-shaped relationship between diastolic BP and coronary events.554 The ACCORD (Action to Control Cardiovascular Risk in Diabetes) BP trial,555 which enrolled patients with type 2 diabetes mellitus at high risk of cardiovascular events, found no benefit of targeting a systolic BP of 120 mm Hg compared with a systolic BP of 140 mm Hg in reducing a composite endpoint of MI, stroke, or death from cardiovascular causes. In a related vein, in AASK (African-American Study of Kidney Diseases and Hypertension),556 1094 black patients with hypertensive kidney disease (diastolic pressure .95 mm Hg and glomerular filtration rate of 20 to 60 mL/min) and no diabetes mellitus were randomly assigned to achieve a mean arterial pressure target #92 mm Hg (corresponding to 130/ 80 mm Hg) or to a target of 102 to 107 mm Hg (correspond- ing to 140/90 mm Hg). Overall, there was no advantage to more intensive BP control with regard to progression to end-stage kidney disease or death.556 Although in patients with uncomplicated hypertension there are a variety of considerations in selecting a medication, effective BP lowering is the most important factor in prevent- ing stroke and MI. Clinical trials have failed to convincingly demonstrate superiority of any single antihypertensive drug class in preventing cardiovascular events.544,545 In many patients with SIHD, the choice of medications is guided by compelling indications for specific classes of drugs, as discussed elsewhere in this guideline (Table 15).557 ACE inhibitors improve outcomes in most patients with CAD, especially those with a history of MI, LV dysfunction and heart failure, or CKD or diabetes mellitus.295,296,301,558 562 Angiotensin-receptor blockers (ARBs) are beneficial in the same spectrum of patients.563 566 Beta blockers are recom- mended in patients with angina pectoris, a history of MI, or LV dysfunction.567 571 Aldosterone antagonists improve prognosis in patients with LV dysfunction and heart fail- ure.572,573 Calcium antagonists are useful in the treatment of angina. Many patients with SIHD will require a combination of drugs, including a diuretic, to achieve optimal BP control. Fihn et al Stable Ischemic Heart Disease: Full Text e397 The role of emotional stress in relationship to hypertension has yet to be fully elucidated. It might be important to acknowledge the potential relationship of stress to many of the cardiovascular risk factors, particularly hypertension, when counseling patients. 4.4.1.3. Diabetes Management Class IIa 1. For selected individual patients, such as those with a short duration of diabetes mellitus and a long life expectancy, a goal hemoglobin A1c (HbA1c) of 7% or less is reasonable.574 576 (Level of Evidence: B) 2. A goal HbA1c between 7% and 9% is reasonable for certain patients according to age, history of hypo- glycemia, presence of microvascular or macrovascu- lar complications, or presence of coexisting medical conditions.577,578 (Level of Evidence: C) Class IIb 1. Initiation of pharmacotherapy interventions to achieve target HbA1c might be reasonable.456,579 588 (Level of Evidence: A) Class III: Harm 1. Therapy with rosiglitazone should not be initiated in patients with SIHD.589,590 (Level of Evidence: C) Diabetes mellitus is an important independent risk factor for cardiovascular disease. Type 1 diabetes mellitus is associated with at least a 10-fold increase in cardiovascular events,591,592 and patients with type 2 diabetes mellitus have a risk of death from cardiovascular causes that is 2 to 6 times that of persons without diabetes mellitus.593 595 The complications of athero- sclerosis account for 80% of deaths among patients with diabetes mellitus, and IHD is responsible for the majority of deaths.574,596 Diabetes mellitus is associated with a poor outcome in patients with SIHD, even after the extent of disease and other clinical characteristics are taken into ac- count. In the CASS registry, for example, patients with diabetes mellitus had a 57% greater risk of death after adjustment for other risk factors.597 Clinical trials have demonstrated a salutary effect of intensive glycemic control on the development of microvas- cular complications of diabetes mellitus, such as retinopathy, nephropathy, and peripheral and autonomic neuropa- thy,574,575,598 with secondary analyses suggesting a benefit extending into the normal range of HbA1c. However, the efficacy of intensive diabetes therapy in reducing cardiovas- cular disease is less well established. In the DCCT (Diabetes Control and Complications Trial), patients with type 1 dia- betes mellitus were randomized to intensive (mean achieved therapy. During the mean 6.5 years of observation, fewer cardiovascular events occurred in the intensive-treatment group, but the number of events was small, and the difference between groups did not reach statistical significance.574 In a long-term follow-up study of this population, however, inten- sive therapy reduced the risk of cardiovascular events by 42%.579 Intensive glycemic controlled to a reduction in microvascular complications (primarily the need for retinal laser photocoagulation) but not cardiovascular events in the patients with type 2 diabetes mellitus who participated in the UKPDS (UK Prospective Diabetes Study).575 In a secondary analysis, treatment with metformin seemed to confer most of the benefit, whereas treatment with a sulfonylurea was not associated with a significant improvement in any endpoint.599 Patients in UKPDS treated with metformin had a lower median HbA1c (7.4% versus 8.0%) and a 37% reduction in $1 diabetes endpoints compared with those in the conven- tional therapy (diet alone) group.580 In the PROactive (Pros- pective Pioglitazone Clinical Trial in Macrovascular Events) study, patients with type 2 diabetes mellitus and evidence of vascular disease were randomized to pioglitazone or placebo. HbA1c averaged 7.8% at baseline and decreased by 0.3% in the placebo group and by 0.8% in those on active therapy. There was no significant difference between treatment groups in the primary study endpoint, although pioglitazone resulted in a statistically significant 16% relative reduction in a secondary endpoint of mortality, nonfatal MI, and stroke.581 Three studies in patients with type 2 diabetes mellitus suggest that even more intensive glucose lowering fails to reduce the incidence of cardiovascular events and could cause harm.576,578,600 The ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial tested a strategy of intensive glucose control with a target HbA1c of 6.5%, with the Table 15. Indications for Individual Drug Classes in the Treatment of Hypertension in Patients With SIHD* Indication Recommended Drugs Diuretic Beta Blocker ACE Inhibitor ARB Calcium-Channel Blocker Aldosterone Antagonist Heart failure LV dysfunction After myocardial infarction Angina Diabetes mellitus Chronic kidney disease *Table indicates drugs that should be considered and does not indicate that all drugs should necessarily be prescribed in an individual patient (eg, ACE inhibitors and ARB typically are not prescribed together). ACE indicates angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; and LV, left ventricular. sulfonylurea gliclazide (modified release) and other drugs used as required.576 After a median 5 years of follow-up, HbA1c averaged 6.5% in the intensive-control group and 7.3% in the standard-control group. Intensive control reduced the incidence of microvascular events but had no effect on a composite of macrovascular events that included nonfatal MI, nonfatal stroke, or death from cardiovascular causes.576 In the ACCORD study, patients were assigned to receive intensive therapy with a goal of normalizing the HbA1c (to ,6%) or standard therapy targeting a level of 7.0% to 7.9%.600 Median achieved HbA1c levels at 1 year were 6.4% and 7.5% in the 2 groups, respectively. Over 3.5 years, the use of intensive therapy did not significantly reduce major cardiovascular events (nonfatal MI, nonfatal stroke, and death from cardio- vascular causes) but was associated with a 22% greater all-cause mortality.578,600 The VADT (Veterans Affairs Dia- betes Trial) examined macrovascular complications in pa- tients randomized to standard glycemic control or to intensive therapy (goal HbA1c of ,6%), with a planned HbA1c separation of $1.5%.578 Median HbA1c levels were 8.4% and 6.9% in the standard- and intensive-therapy groups, respectively. There were no differences in the primary end- point of time to occurrence of a cardiovascular event or all-cause mortality in the 2 groups over a median follow-up of 5.6 years. In summary, the most appropriate goal level for HbA1c in patients with diabetes mellitus has not been established definitively by clinical trials. A goal HbA1c ,7% a level approximating that achieved in the intensive-therapy arms of the DCCT, UKPDS, and PROactive studies is reasonable for many younger patients, depending on their duration of diabetes mellitus, comorbidities, adherence, and personal preferences. Secondary analyses of the DCCT and UKPDS and microvascular data from the ADVANCE trial suggest that even lower HbA1c levels could be beneficial in selected individuals. On the other hand, treatment to achieve a HbA1c ,7% might not be safe or practical for some patients, and factors such as life expectancy, advanced microvascular or macrovascular complications, cognitive function, comorbidi- ties, and risk of hypoglycemia should be considered in every patient before intensifying the therapeutic regimen. Regardless of the degree of glycemic control, treatment of other modifiable risk factors that often accompany diabetes mellitus, such as hypertension and dyslipidemia, results in a substantial reduction in cardiovascular risk. The benefits of a target-driven, multifactorial intervention in patients with type 2 diabetes mellitus were demonstrated in the Steno-2 study.601 Behavioral modification and pharmacological ther- apy targeting hyperglycemia, hypertension, dyslipidemia, and microalbuminuria lowered the risk of cardiovascular disease When the patient and provider elect to use pharmacological therapy to improve glycemic control, several factors should be considered in selecting an agent, including acceptability and safety. Although head-to-head comparisons of different pharmacological regimens are largely lacking, limited evi- dence suggests that all agents are not equivalent. For exam- ple, long-term follow-up from the UKPDS indicates that patients receiving metformin, particularly those who were overweight, had a lower incidence of diabetic complications, MI, and death than those who received insulin plus a sulfonylurea.588 In addition, available information suggests that certain agents lack an acceptable safety profile. The FDA, for example, has imposed restrictions on use of rosiglitazone, a thiazolidinedione, because of data that sug- gest an increased risk of cardiovascular complications. Pre- scriptions for rosiglitazone should not be initiated for patients with SIHD. Patients who are already receiving this agent and whose blood glucose is well controlled should be counseled about the potential hazards, and switching to a different agent should be strongly considered. In this light, when deciding whether to prescribe newer hypoglycemic agents, providers should bear in mind the potential for safety concerns that could emerge when these drugs are adopted into wider use. 4.4.1.4. Physical Activity Class I 1. For all patients, the clinician should encourage 30 to 60 minutes of moderate-intensity aerobic activity, such as brisk walking, at least 5 days and preferably 7 days per week, supplemented by an increase in daily lifestyle activities (eg, walking breaks at work, gardening, household work) to improve cardiorespi- ratory fitness and move patients out of the least-fit, least-active, high-risk cohort (bottom 20%).602 604 (Level of Evidence: B) 2. For all patients, risk assessment with a physical activity history and/or an exercise test is recom- mended to guide prognosis and prescription.605 608 (Level of Evidence: B) 3. Medically supervised programs (cardiac rehabilita- tion) and physician-directed, home-based programs are recommended for at-risk patients at first diag- nosis.602,609,610 (Level of Evidence: A) Class IIa 1. It is reasonable for the clinician to recommend complementary resistance training at least 2 days per week.611,612 (Level of Evidence: C) Physical activity counseling is an integral component of a comprehensive coronary risk factor modification strategy in patients with SIHD. Consistent with the American College of Sports Medicine and AHA recommendations for healthy adults,603 most patients with CAD should be encouraged to engage in 30 to 60 minutes of moderate-intensity aerobic activity, such as brisk walking, on most, and preferably all, days of the week. Similar recommendations (2 hours and 30 minutes of moderate-intensity aerobic activity and muscle- strengthening activities on $2 days a week) have been advanced by the Centers for Disease Control and Preven- tion.18,613 Many patients benefit from participation in a cardiac rehabilitation program that incorporates super- vised exercise into a comprehensive secondary prevention Multiple controlled clinical trials have examined the ben- efits of exercise training and cardiac rehabilitation in patients with IHD. Most of these studies have been relatively small, Fihn et al Stable Ischemic Heart Disease: Full Text e399 but in aggregate they demonstrate that regular exercise reduces mortality in patients with IHD. A systematic review and meta-analysis published in 2004 examined 48 RCTs of exercise interventions in a total of 8940 patients with IHD.602 The median intervention duration was 3 months (range, 0.25 to 30 months), and the median duration of follow-up was 15 months (range, 6 to 72 months). Exercise training resulted in a 20% reduction in all-cause mortality and a 26% reduction in total cardiac mortality; favorable but nonsignificant trends were noted in nonfatal MI, CABG, and percutaneous coro- nary revascularization procedures. There was no difference between the mortality rate effects of exercise-only and more comprehensive cardiac rehabilitation interventions, and the benefits were independent of actual amount and intensity of exercise. Many of the studies demonstrating the efficacy of exercise- based cardiac rehabilitation enrolled patients after an AMI or coronary revascularization procedure. Clear benefits of exer- cise training also have been shown in patients with stable angina. Controlled trials consistently have demonstrated an improvement in functional capacity and a delay in the onset of ischemia in anginal patients who complete an exercise training program.444,615 620 Exercise-based cardiac rehabilita- tion could also reduce subjective evidence of ischemia and could ameliorate symptoms.615,619,621,622 The reduction in mortality rate associated with exercise interventions might be explained partially by modification of traditional cardiovascular risk factors. Controlled trials have demonstrated reductions in total cholesterol, triglycerides, and BP, although these findings have not been uniform. Exercise also can enhance smoking quit rates. Other potential mechanisms include decreased fibrinogen and coagulabil- ity,623 moderation of inflammation,624 improved endothelial function,625 627 and improved autonomic regulation.628,629 Several studies have documented the safety of exercise- based cardiac rehabilitation in patients with documented SIHD.630 633 The 2007 AHA Scientific Statement on Exer- cise and Acute Cardiovascular Events estimates the risk of a major adverse cardiac event (MACE) at 1 in 80 000 patient- hours.447 This low event rate applies to medically supervised programs that evaluate patients before participation, provide serial surveillance, and are equipped to handle emergencies. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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 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. 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. 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. 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. 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 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.)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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 