Guideline-directed medical therapy (GDMT) is an intrinsic part of management of patients with stable ischemic heart disease (SIHD) whether or not revascularization is performed. GDMT for patients with coronary disease is synonymous with secondary prevention and consists of pharmacologic and lifestyle interventions. This chapter synthesizes the evidence base behind guideline-recommended therapies for secondary prevention. Outside of the use of aspirin, we will not discuss strategies of antiplatelet therapy for post-percutaneous coronary intervention (PCI) patients, which are reviewed elsewhere. Additionally, management of anginal symptoms is outside the scope of this chapter, and angina management in patients with SIHD will be discussed only briefly in the context of other targets for secondary prevention and risk factor modification. We will begin by reviewing the GDMT targets for risk factor modification in the 2012 SIHD guidelines.¹ Following this, we will review the other medical therapies that have been shown to prevent death and myocardial infarction (MI) among patients with SIHD.

Lipid Management

Elevated concentration of low-density lipoprotein (LDL) cholesterol is a major risk factor for the development and progression of atherosclerosis. Therefore, the principal lipid modification strategy recommended by the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) and the recent American College of Cardiology (ACC)/American Heart Association (AHA) guideline on the treatment of blood cholesterol is to lower LDL.^2,3 All patients with coronary disease should be treated with a high-potency statin if tolerated (see below). This does not lessen the importance of nutrition, physical activity, and weight management to reduce the risk of coronary events.¹ Effective dietary strategies to lower LDL cholesterol include replacing dietary saturated fatty acids and trans-fatty acids with unsaturated fatty acids or complex carbohydrates and reducing dietary cholesterol. Specifically, the 2012 SIHD guidelines recommended limiting saturated fat to <7% of total calories; trans-fats to <1% of total; and cholesterol to <200 mg/dL of total.¹ While limiting saturated fat intake to <7% of total calories reduces both LDL cholesterol and high-density lipoprotein (HDL) cholesterol, reducing saturated fat intake lowers LDL more than HDL and has highly beneficial effects on the overall lipid profile and measures of total atherogenic particles, such as non-HDL cholesterol.⁴ Currently people in the United States derive between 11% and 15% of total calories from saturated fat. Earlier literature from randomized trials⁵ and practice guidelines² demonstrated that targeting saturated fat to <7% of total calories lowers LDL by 10% to 15% and reduces risk of ischemic heart disease. In particular, saturated fats with chain lengths of 14 (myristic) and 16 (palmitic) carbons, primarily found in dairy products and red meat, appear most potent in raising serum cholesterol. A meta-analysis by Chowdhury et al⁶ reviewed prospective observational studies of dietary fatty acids (32 studies) and fatty acid biomarkers (17 studies) along with randomized controlled trials of fatty acid supplementation (27 studies) and concluded that evidence does not support guidelines that encourage high consumption of polyunsaturated fatty acids and low consumption of saturated fatty acids. This meta-analysis required revisions of errors in the original publication and generated numerous critical letters to the editor. With the revision, the authors showed the inverse association of intake of long-chain ω-3 polyunsaturated fatty acids (PUFAs) with cardiovascular disease (CVD) risk is indeed significant. They were criticized for including the Sydney Diet Heart Study, a randomized controlled trial that replaced saturated fats with an experimental diet that included a trans-fat–based margarine. When that study was excluded, the remaining randomized controlled trials found a benefit from replacing saturated fatty acids with PUFAs. A subsequent systematic review and meta-analysis by Farvid et al⁷ summarized the evidence regarding the relation of the predominant dietary PUFA, linoleic acid (LA), with coronary heart disease (CHD) risk. They found that compared with the lowest dietary intake of LA, the highest intake of LA was associated with a 15% (95% confidence interval [CI], 0.78-0.92) and 21% (95% CI, 0.71-0.89) reduction in CHD events and mortality, respectively.⁷ They found that replacing 5% of energy from saturated fat with dietary LA was associated with a 9% (95% CI, 0.86-0.96) and 13% (95% CI, 0.82-0.94) lower risk of CHD events and mortality, respectively.⁷ Chowdhury et al⁶ reported similar findings, with a reduction in CVD risk up to 13% (95% CI, 3%-22%) when comparing the highest to lowest tertiles of intake of PUFA. Notably, the effects of PUFA intake on the secondary prevention of CVD was either not evaluated⁷ or evaluated with very few studies⁶ in these meta-analyses. Increased trans-fat intake raises serum cholesterol, lowers HDL, and increases CHD events.^1,2 The use of liquid vegetable oils, soft margarine, and trans-fatty acid–free margarine is encouraged instead of using butter, stick margarine, and shortening.²

Along with therapeutic lifestyle modification, all patients with SIHD should be prescribed a moderate to high dose of statin therapy (Table 65-1) in the absence of contraindications or documented adverse effects. This is a class I recommendation for management of patients with SIHD.¹ Randomized controlled trials of lipid-lowering therapy have repeatedly demonstrated that lowering LDL cholesterol with statin therapy is associated with a reduced risk of adverse cardiovascular events in patients with established ischemic heart disease (IHD) or with multiple risk factors for future IHD events.¹ Prior guidelines and commentary had focused on specific LDL thresholds to guide therapy, with a cutoff of <100 mg/dL in patients with established coronary artery disease and an LDL cholesterol goal of <70 mg/dL as a therapeutic option in patients at very high risk.^2,8 However, while a paucity of data exist to confirm the use of specific, numeric targets for LDL, the benefits of moderate- to high-dose statin therapy for secondary prevention of IHD is well established.⁹ It is in this context that the 2013 ACC/AHA guidelines on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults were published, generating significant controversy.³ In this guideline, the authors concluded there was insufficient randomized controlled trial evidence to support titrating statin or other medical therapy to achieve a specific LDL or non-HDL target in patients with or without SIHD.³ Instead of using specific LDL targets as in prior guidelines to guide cholesterol-lowering therapy,^2,8 this ACC/AHA guideline recommended measuring on-treatment levels of cholesterol only as a tool to gauge adherence with medical therapy.³ To simplify the identification of patients likely to benefit from statin therapy, the authors identified 4 “statin benefit” groups, the first of which include patients with known SIHD, such as patients after PCI. Per the guidelines, all SIHD patients should receive a high-intensity statin if ≤75 years of age (see Table 65-1) or a moderate-intensity statin if >75 years old.³ In addition to these major changes, the guideline panel could find no evidence to support the routine use of nonstatin drugs combined with statin therapy to reduce future CHD events.³ The 2013 ACC/AHA guidelines therefore suggest that the vast majority of SIHD patients undergoing percutaneous revascularization procedures should receive high-intensity statin therapy. If after 4 to 12 weeks of therapy with high-intensity statin there is a less-than-anticipated therapeutic response (anticipated LDL cholesterol reduction of ≥50% or 30%-50% for high- and moderate-intensity statin, respectively), the guidelines recommend assessing adherence to statin and lifestyle modification before additional nonstatin therapies are initiated.³ If after adherence is documented and the therapeutic response to high- or moderate-intensity statins (see Table 65-1) remains less than anticipated, the addition of nonstatin drug therapy such as bile acid sequestrants can be considered.³ For patients intolerant of statin therapy, the current ACC/AHA guidelines consider therapy with a bile acid sequestrant, niacin, or both a reasonable therapeutic option (class IIa indication).³ We refer the interested reader to the ACC/AHA guidelines for detailed recommendations on cholesterol management strategies for patients with familial hypercholesterolemia and other hypercholesterolemia syndromes.³

Blood Pressure Management

Hypertension is extremely common among patients with coronary disease and is often less than optimally treated. Lifestyle factors influence blood pressure (BP), and the 2012 SIHD guidelines give a class I indication to counseling all SIHD patients on weight management, increased physical activity, alcohol moderation, sodium reduction, and increased fruit and vegetable consumption. Significant weight loss (average of 10 kg) has been shown to reduce systolic blood pressure (SBP) by 5 to 20 mm Hg.¹⁰ A diet high in fruit, vegetables, and low-fat dairy has also demonstrated improvements in BP,¹¹ as have diets with lower sodium levels.¹² Increased physical activity¹³ and reducing alcohol intake from high to moderate consumption also has beneficial effects on BP.¹⁴

Despite lifestyle modifications, many patients with SIHD require medical therapy for adequate BP control. There is a large body of literature demonstrating that, on average, a reduction in diastolic blood pressure (DBP) of 5 to 6 mm Hg (10-20 mm Hg SBP) within a population is associated with a 40% reduction in stroke risk and a 20% reduction in risk of IHD.¹⁵ Despite the abundance of clinical studies, the appropriate BP threshold for initiating medical therapy and specific treatment goals for patients with SIHD remains controversial. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends a target of <140/90 mm Hg in patients with uncomplicated hypertension and of <130/80 mm Hg in patients with diabetes or chronic kidney disease (CKD).¹⁶ Observations from epidemiologic studies have led some to suggest that a target lower than <130/80 mm Hg might be appropriate for patients with SIHD or multiple IHD risk factors.¹⁷ However, excessive reduction in DBP may compromise coronary perfusion in SIHD patients, leading to a “J-shaped” relationship of increased risk of CVD with DBP <70 to 80 mm Hg.¹⁸ Randomized data from the ACCORD trial also demonstrated no benefit from targeting normal BP (<120 mm Hg) versus SBP <140 mm Hg on fatal and nonfatal CVD events among patients with type 2 diabetes (T2D).¹⁹ On the other hand, a lower SBP in ACCORD was associated with a lower risk of stroke, albeit with a higher risk of serious adverse events attributed to antihypertensive medications.¹⁹ It is in this setting that the Eighth Joint National Committee 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults (JNC 8) was released.²⁰ While JNC 8 does not specifically address BP control in patients with SIHD, it does recommend treating to BP <140/90 mm Hg, a target given a class I recommendation in the 2012 SIHD guidelines.^1,20

In patients with uncomplicated hypertension, effective BP lowering is the most important factor in preventing stroke and MI. Clinical trials have failed to demonstrate superiority of any single antihypertensive drug in preventing CVD events.¹ In many patients with SIHD, the choice of medications to control BP is guided by other compelling clinical indications such as the presence of left ventricular dysfunction, T2D, or CKD (Table 65-2), for which specific medication classes have demonstrated clear evidence of benefit. In recognition of this, the 2012 SIHD guidelines gave a class I recommendation to support the treatment of high BP based on specific patient characteristics and may include angiotensin-converting enzyme inhibitors (ACEi) and/or β-blockers, with the addition of other drugs, such as thiazide diuretics or calcium channel blockers, if needed to achieve a goal BP of <140/90 mm Hg.¹

Diabetes Management

Management of diabetes mellitus continues to pose a quandary with regard to CVD risk. Diabetes is an important risk factor for CVD events and mortality.¹ Diabetes is also associated with poor outcomes in patients with SIHD, even after adjustment for disease extent and other clinical characteristics.²¹ However, despite multiple randomized trials and observational studies, the efficacy of intensive diabetes therapy in reducing CVD is not well established.²² Three seminal trials of intensive glucose control in patients with T2D (ACCORD, VA Diabetes Trial, and ADVANCE) failed to demonstrate an improvement in macrovascular complications or composite outcomes of cardiovascular events and mortality with targeting a hemoglobin A1c (HbA1c) of <7% compared to less stringent control of HbA1c >7%.^1,23 While intensive glucose control has not demonstrated reductions in macrovascular risk, it has demonstrated notable reductions in morbidity associated with microvascular disease, including retinopathy, nephropathy, and microalbuminuria.^1,23 Subgroup analyses from the aforementioned trials have also suggested a macrovascular benefit of intensive glycemic control may exist for patients with type 1 diabetes or T2D of short duration and long life expectancy.²³ Therefore, the 2012 SIHD guidelines classified an HbA1c target of <7% as reasonable (class IIa) for patients with a shorter duration of diabetes and a longer life expectancy.¹ Complementing this recommendation, the 2012 SIHD guidelines acknowledge that an HbA1c target of 7% to 9% is reasonable (class IIa recommendation) for older patients, patients with a history of hypoglycemia, and/or patients with microvascular or macrovascular complications.¹ Regardless of degree of glycemic control, treatment of other modifiable risk factors common in SIHD patients with diabetes, such as hypertension, dyslipidemia, physical inactivity, and smoking, is of paramount importance to reduce cardiovascular risk.^23,24 If patients and physicians decide to use pharmacologic treatment to improve glycemic control, SIHD guidelines support the use of metformin to reduce diabetic complications, especially for overweight patients.¹ Available evidence also indicates that rosiglitazone is associated with an excess risk of cardiovascular complications and should not be initiated in patients with SIHD. The US Food and Drug Administration (FDA) has imposed restrictions on the use of this medication, and it has received a class III (harm) indication in the 2012 SIHD guidelines.¹

Physical Inactivity

The SIHD guidelines recommend 30 to 60 minutes of physical activity 5 to 7 days per week for all patients (class I) and support increasing physical activity, particularly for the most inactive patients.¹ Virtually all post-PCI patients would benefit from participation in a cardiac rehabilitation program that incorporates supervised exercise into a comprehensive program of secondary CVD prevention.¹ Despite this benefit, cardiac rehabilitation referral rates remain low, particularly for patients age ≥65 years.²⁵ A meta-analysis of 48 randomized controlled trials of exercise interventions of a median of 3 months on duration (95% CI, 0.25-30 months) and with 15 months of follow-up (95% CI, 6-72 months) demonstrated an overall 20% reduction in all-cause mortality; a 26% reduction in total cardiac mortality; and favorable but nonsignificant trends in the occurrence of MI, coronary artery bypass grafting (CABG), and PCI.²⁶ The benefits of exercise and cardiac rehabilitation are independent of the actual amount or intensity of exercise and have clear benefits in SIHD patients with and without angina.²⁶ The effects of exercise on CVD risk reduction are multifactorial. Exercise does not lower LDL, but it facilitates weight loss and has other beneficial cardiometabolic effects. Exercise in patients with SIHD is safe, with a rate of major adverse cardiac events (MACE) of approximately 1 in 80,000 patient-hours.¹ Previous SIHD guidelines have recommended that all patients undergo an exercise test before participating in a cardiac rehabilitation program. However, in line with recent recommendations from the World Health Organization, the 2012 SIHD guidelines state that a physical activity history and/or an exercise test is recommended to guide prognosis and exercise prescription.¹

Weight Management

Effective weight management complements many of the secondary prevention targets for patients with SIHD. Regular assessment of patient weight, body mass index (BMI), and/or waist circumference is a class I recommendation in the 2012 SIHD guidelines.¹ Physicians should encourage weight maintenance or reduction through a balance of physical activity and caloric intake to maintain a BMI between 18.5 and 24.9 kg/m² and a waist circumference <40 inches in men and 35 inches in women.¹ Population studies have repeatedly demonstrated an association between increased BMI and IHD events. Specifically, a large meta-analysis of over 300,000 participants in 21 cohort studies demonstrated that IHD risk increased by 30% and 81% for overweight (BMI 25.0-29.9 kg/m²) and obese (BMI >30 kg/m²) participants, respectively, compared to those of normal weight. This relationship was independent of age, sex, smoking status, and physical activity. After additional adjustment for hypertension and hyperlipidemia, the relationship between BMI and IHD risk was attenuated, but remained statistically significant.²⁷ These findings suggest that while a portion of the IHD risk of overweight and obesity is conditional on the development of hypertension, hyperlipidemia, and T2D, overweight and obesity also increase risk of IHD through heightened sympathetic tone, hypercoagulability, and inflammation.¹ Interestingly, a similar relationship between BMI and death and CVD events is not consistently observed in cohorts with established IHD.²⁸ This altered relationship between BMI and IHD risk in patients with established IHD may be due to confounders such as smoking or age or due to the weight loss and lower BMI associated with chronic illness.^1,28 To date, no clinical trials have examined the effects of weight loss on cardiovascular event rates in patients with SIHD. However, the association of adiposity, overweight, and obesity with other cardiovascular risk factors suggests that weight reduction is indicated in all overweight or obese patients.¹

Smoking Cessation

The detrimental effects of smoking are clear for patients with IHD. The 2012 SIHD guidelines recommend smoking cessation and avoidance of exposure to tobacco at work and at home (class I).¹ The mechanisms of CVD risk from tobacco exposure are well known and include enhanced platelet activity, increased endothelial dysfunction, heightened vasoconstriction, and decreased HDL.¹ Although randomized controlled trials have not been performed in patients with SIHD, observational studies strongly suggest that smoking cessation is an important strategy for the secondary prevention of IHD. A meta-analysis of 20 prospective cohort studies in patients with known coronary artery disease (CAD) found a 30% relative risk reduction in mortality for those who quit smoking compared to those with CAD who continued to smoke.²⁹ A similar risk reduction was observed for the occurrence of nonfatal MI.²⁹ The most effective smoking-cessation therapies include both nonpharmacologic and medical interventions. Most of the recommendations to improve quit rates in patients with SIHD are extrapolated from literature in patients without SIHD. Notably, physician advice has a significant effect on smoking quit rates, and the SIHD guidelines recommend physicians inquire about plans for smoking cessation at each visit with patients who continue to smoke. Other useful interventions to improve smoking cessation include self-help programs, behavioral therapy, and possibly exercise interventions.¹ Nicotine replacement therapy, sustained-release bupropion, and varenicline all approximately double quit rates. There have been recent concerns of enhanced suicidality and depression in patients prescribed varenicline, which may be an issue for patients with SIHD in whom depression is frequently a comorbid disorder.¹ The 2012 SIHD guideline recommends that physicians should use a standardized approach to smoking cessation counseling by using the “6 A’s” framework: Ask, Advise, Assess, Assist, Arrange, and Avoid.¹ By applying the 6 A’s framework, physicians can more systematically address principles important to smoking cessation.