Abstract 834

Top 10 Take-Home Messages For Chronic Coronary Disease 836

Preamble 836

Introduction 837

Epidemiology and General Principles 842

Evaluation, Diagnosis, and Risk Stratification 845

Treatment 849

Revascularization 891

Special Populations 896

Patient Follow-Up: Monitoring and Managing Symptoms 912

Other Important Considerations 913

References 916

Appendix 1

• Author Relationships With Industry and Other Entities 948

Appendix 2

• Reviewer Relationships With Industry and Other Entities 954

Emphasis is on team-based, patient-centered care that considers social determinants of health along with associated costs while incorporating shared decision-making in risk assessment, testing, and treatment.

Nonpharmacologic therapies, including healthy dietary habits and exercise, are recommended for all patients with chronic coronary disease (CCD).

Patients with CCD who are free from contraindications are encouraged to participate in habitual physical activity, including activities to reduce sitting time and to increase aerobic and resistance exercise. Cardiac rehabilitation for eligible patients provides significant cardiovascular benefits, including decreased morbidity and mortality outcomes.

Use of sodium glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists are recommended for select groups of patients with CCD, including groups without diabetes.

New recommendations for beta-blocker use in patients with CCD: (a) Long-term beta-blocker therapy is not recommended to improve outcomes in patients with CCD in the absence of myocardial infarction in the past year, left ventricular ejection fraction ≤50%, or another primary indication for beta-blocker therapy; and (b) Either a calcium channel blocker or beta blocker is recommended as first-line antianginal therapy.

Statins remain first line therapy for lipid lowering in patients with CCD. Several adjunctive therapies (eg, ezetimibe, PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitors, inclisiran, bempedoic acid) may be used in select populations, although clinical outcomes data are unavailable for novel agents such as inclisiran.

Shorter durations of dual antiplatelet therapy are safe and effective in many circumstances, particularly when the risk of bleeding is high and the ischemic risk is low to moderate.

The use of nonprescription or dietary supplements, including fish oil and omega-3 fatty acids or vitamins, is not recommended in patients with CCD given the lack of benefit in reducing cardiovascular events.

Routine periodic anatomic or ischemic testing without a change in clinical or functional status is not recommended for risk stratification or to guide therapeutic decision-making in patients with CCD.

Although e-cigarettes increase the likelihood of successful smoking cessation compared with nicotine replacement therapy, because of the lack of long-term safety data and risks of sustained use, e-cigarettes are not recommended as first-line therapy for smoking cessation.

Patients discharged after admission for an ACS event or after coronary revascularization procedure and after stabilization of all acute cardiovascular issues.

Patients with left ventricular (LV) systolic dysfunction and known or suspected coronary artery disease (CAD) or those with established cardiomyopathy deemed to be of ischemic origin.

Patients with stable angina symptoms (or ischemic equivalents such as dyspnea or arm pain with exertion) medically managed with or without positive results of an imaging test.

Patients with angina symptoms and evidence of coronary vasospasm or microvascular angina.

Patients diagnosed with CCD based solely on the results of a screening study (stress test, coronary computed tomography angiography [CTA]), and the treating clinician concludes that the patient has coronary disease.

Modified: formatting changes (eg, minor modifications such as PICO[TS] structure)

Adapted: substantive changes (eg, major adaptations, such as a change in COR, LOE, drug or device classification).

Observational studies reveal that patients with moderate to severe ischemia on PET and SPECT MPI have an improved outcome with early coronary revascularization.^7,21,40-43 Clinical trials of CMR imaging that included subgroups of patients with obstructive CAD, showed comparable diagnostic accuracy to stress SPECT MPI.^10,11 Several large, multicenter registries revealed that stress CMR imaging effectively risk stratifies patients with known CAD.^14-17 In a multicenter registry of 2,496 patients with a history of CAD, an abnormal stress CMR image was associated with a nearly 2-fold increased mortality hazard.¹⁴ Registry data also reported that patients with chest pain syndrome with ischemia by MPI and scarring by late gadolinium enhancement had a relative hazard of 1.5 to 2.1 for cardiovascular death or nonfatal MI.¹⁷ Prognosis worsens for patients by the extent and severity of inducible wall motion abnormalities on stress echocardiography.^44,45 Recent randomized trial evidence supports the role of stress echocardiography to guide clinical decision-making. From the ORBITA (Objective Randomized Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina) trial, a secondary outcome was a greater reduction in the stress echocardiographic wall motion score among patients with single-vessel CAD treated with percutaneous coronary intervention (PCI) compared with placebo (P<0.0001).⁴⁶ Patients with PCI and who have a wall motion score ≥1 were more often angina-free compared with those in the placebo arm.

Randomized trials of patients with CCD reveal a pattern that ischemia-guided PCI results in an improvement in angina when compared with medical therapy alone.^24-26,47,48 In the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical & Invasive Approaches) trial, 5,179 patients with stable CAD and site-determined moderate-severe ischemia on stress testing (patients with ≥50% left main stenosis on CCTA, left ventricular ejection fraction [LVEF] <35%, and unacceptable angina on medical therapy were excluded) were randomized to invasive versus conservative care strategies.²⁶ No difference in the composite primary MACE (cardiovascular death, MI, hospitalization for unstable angina, HF, or resuscitated cardiac arrest) endpoint was observed at ∼3.3 years of follow-up. Angina symptoms improved in both the conservative and invasive treatment arms, although improvements were larger in the invasive arm, particularly with more frequent angina at baseline.⁴⁸ Therefore, in patients with CCD with known anatomy and ongoing angina despite GDMT, early invasive angiography and revascularization should be considered to improve symptoms. Notably, secondary analyses of RCTs have reported no differences in major adverse cardiovascular outcomes in medical versus invasive medical treatment strategies in patient with CCD⁴⁹ when stratified by ischemia severity on noninvasive testing.

The improved diagnostic accuracy of PET MPI is helpful in patients with known CAD. In a randomized trial of 322 symptomatic patients with known CAD, the presence of low- and high-risk stress PET findings was associated with lower and higher rates of ICA when compared with SPECT MPI (P=0.001).²⁹

Observational studies of patients with CAD and stable chest pain have shown that exercise treadmill testing can be useful by evaluating the relation of symptoms to graded stress testing, thereby helping to confirm the diagnosis of angina pectoris; assessing symptom severity; and selecting appropriate management (eg, medical therapy, revascularization, cardiac rehabilitation [CR]).^26,30-32

Reduced MBFR reflects abnormalities of flow within the epicardial coronary arteries, microvasculature, or both, and independently predicts risk of major CAD events. Measurement of MBFR can be effectively accomplished using PET^18,50,51 or CMR.¹⁵ Normal MBFR may be helpful in excluding high-risk anatomy, although global reduced levels (<2) may provide a better estimate of disease extent and severity. Nonobstructive CAD with reduced MBFR is more frequently observed in women.⁵⁰

CCTA is accurate for the assessment of native vessel CAD and bypass graft patency with high accuracy (∼96%) and concordance (82% to >93%) to ICA. It may also be useful to assess patency of proximal large stents (≥3 mm) if such information is known at the time of presentation.^33-37 Other modalities may be considered in patients with CCD with smaller or more distal stents. Several controlled clinical trials have evaluated the concordance of fractional flow reserve (FFR)-CT with invasive FFR.^52-55 Diagnostic sensitivity and specificity of FFR-CT, compared with invasive FFR, is high (>90%).^19,53

Noninvasive test results alone are insufficient to adequately risk stratify patients with CCD, and the additional information improves risk prediction.⁴ In an externally validated study of patients who underwent an exercise stress testing, the Duke Treadmill Score alone had a c-index of 0.62 for all-cause death, but the addition of clinical variables into an integrated risk score improved discrimination (c-index=0.83) and reclassified 64% of low-risk Duke Treadmill Score scores to intermediate or high risk.¹ Externally validated risk scores lack some functional and anatomic testing modalities, but observational studies and secondary analyses from randomized trials consistently report that the addition of clinical and ancillary imaging variables are associated with improved risk prediction (Table 5).^3,4,15-44 A meta-analysis of 165 studies reported that in patients with a normal functional test for CCD, a negative study did not uniformly predict a <1% annual risk of cardiovascular death or nonfatal MI, suggesting that population and patient differences may be associated with prognosis.¹³ The lone exception is a normal CCTA.^45,46 Previous AHA/ACC guidelines have recommended stratifying patients with CCD as low (<1% annual risk), intermediate (1%-3% annual risk), or high (>3% annual risk) risk for MACE.^47,48 Although these cutoffs are somewhat arbitrary and may be grounded in historical Bethesda Conference recommendations based on Duke Treadmill Score risk tertiles, we suggest maintaining these categorizations for annual cardiovascular death or nonfatal MI.^47,49,50

The 2021 AHA/ACC chest pain guideline recommends the optimization of anti-ischemic and preventive therapies with the goal to reduce the patient’s angina burden and improve clinical outcomes.¹² Three major RCTs including COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation), ISCHEMIA, and BARI-2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) have shown that there is no reduction in MACE with routine cardiovascular revascularization.^5-7 The COURAGE trial, which included patients with stabilized Canadian Cardiovascular Society class IV angina and at least a 70% stenosis in at least 1 coronary artery with evidence of ischemia, reported no difference in all-cause death or nonfatal MI between revascularization with PCI and optimal medical therapy. The BARI-2D trial randomized patients with type 2 diabetes and CCD (≥70% stenosis of a major coronary artery and angina or ≥50% stenosis of a major coronary artery with a positive stress test) to revascularization or medical therapy and reported no difference in survival.

The STICH (Surgical Treatment for Ischemic Heart Failure) trial randomized 1,212 patients with an ejection fraction ≤35% with coronary disease amenable to coronary artery bypass grafting (CABG) to either medical therapy alone or medical therapy and CABG. After a median follow-up of 56 months, no significant difference was observed in the primary outcomes of all-cause death (41% versus 36%; P=0.12), but cardiovascular death (33% versus 28%; P=0.05) and all-cause death or cardiovascular hospitalization (68% versus 58%; P<0.001) were lower in the CABG arm.⁹ In a secondary analysis of the ISCHEMIA trial, 398 participants had HF or an LVEF <45%. Both the 4-year primary composite endpoint (17.2% versus 29.3%; event rate difference, −12.1% [95% CI, −22.6 to −1.6]) and cardiovascular death or MI (14.6% versus 25.9%; event rate difference −11.4% [95% CI, −21.4 to −1.4]) were lower in the invasive treatment arm.⁸ The REVIVED-BCIS2 trial randomized 700 patients with and LVEF ≤35% with CCD amenable to PCI to either medical therapy or PCI plus medical therapy and reported no difference all-cause death or health failure hospitalization (38.0% versus 37.2%).⁵¹ In addition to revascularization, ICA can also help diagnose the cause of HF and help direct medical therapies (eg, lipid lowering). We acknowledge the data are less robust for patient with HF with preserved ejection fraction.⁹ Noninvasive modalities may be appropriate to evaluate for coronary ischemia in some circumstances. Alternatively, CCTA may be considered as an initial diagnostic strategy in selected patients with suspected nonischemic cardiomyopathy.⁵²

Three multicenter trials (COURAGE, BARI 2D, ISCHEMIA) showed no improvement in clinical endpoints in patients with CCD randomized to routine revascularization plus GMDT or initial GDMT; although 21% to 42% of patients randomized to GDMT eventually underwent revascularization.^5-7 In a secondary analysis of the ISCHEMIA trial, although ischemia severity on noninvasive testing was associated with all-cause death, no treatment interaction was observed when participants were stratified by mild, moderate, or severe ischemia.¹⁰ Similarly, in a secondary analysis of the COURAGE trial limited to the 60% of patients with stress perfusion imaging and coronary angiography information available, there was no interaction between therapeutic strategy and either severity of ischemia or coronary anatomy.¹¹

Patients with CCD comprise a heterogeneous group that includes those with or without angina, a history of coronary revascularization, and previous ACS. The goals of routine clinical follow-up in these patients include: (a) to assess for new or worsened symptoms, change in functional status, or decline in QOL; (b) to assess for adherence to and adequacy of recommended lifestyle and medical interventions, including physical activity, nutrition, weight management, stress reduction, smoking cessation, immunization status, blood pressure (BP) and glycemic control, and antianginal, antithrombotic, and lipid-lowering therapies^13-15; and (c) to monitor for complications of disease or adverse effects related to therapy.^16,17 Although there are insufficient data on which to base a definitive recommendation regarding frequency, clinical follow-up evaluation at least annually is recommended and may be sufficient if the patient is stable on optimized GDMT and reliable enough to seek care with a change in symptoms or functional capacity. For select individuals, an annual in-person evaluation may be supplemented with telehealth visits when clinically appropriate.²⁶ Implementation of remote, algorithmically driven-disease management programs may provide a useful adjunctive strategy to achieve GDMT optimization in eligible patients.²⁷

Revascularization^1-3,12 and antianginal medications^4-7 primarily reduce the symptoms of CCD. The factor most strongly associated with improvement in symptoms and QOL after revascularization is the burden of ischemic symptoms before intervention.^8-12,28-30 Thus, assessment of symptoms at each clinic visit is important to identify times when additional interventions could be useful, as well as to quantify the symptomatic response to interventions. Observational studies suggest that clinicians may inaccurately estimate the burden of ischemic symptoms,^19-21 which can lead to under-²² or overtreatment.²¹ Validated patient-reported disease-specific health status measures (eg, 7-item Seattle Angina Questionnaire³¹) may help to reliably quantify the burden of CCD symptoms and reduce variation in assessment among clinicians.²³ Furthermore, patient-reported disease-specific health status instruments also measure how the patient’s angina affects their QOL, which should be an important component of the treatment decision process. Although several studies showed deficiencies with clinician estimation of patient’s symptoms, no studies show an improvement in quality of care or outcomes with routine use of patient-reported measures in clinical care.

RCTs and systematic reviews with meta-analysis show that a patient-centered, multidisciplinary, team-based approach can improve patient self-efficacy, health-related QOL, and ASCVD risk factor management compared with usual care in patients with CCD who also may have hypertension, diabetes, or hyperlipidemia.^{1-8,11-13,15-34} Patients actively involved in their care with the medical team tend to have greater knowledge and confidence in self-management, which improves health-related QOL.^1,21,32 Team-based care also facilitates behavior change and promotes weight loss, tobacco cessation, and reduces depression.^{8,12,16,31,33,35} A team-based approach may be more cost-effective and cost-efficient compared with usual care and reduces emergency department visits, unplanned health service utilization, cardiovascular complications in patients with diabetes, and readmission costs.^{6,7,9,10,20-22,27,28,31,32,34} A large cohort study comparing health care resource utilization of >1 million patients with either diabetes or ASCVD found that, overall, health care resource utilization was comparable among patients receiving care from physicians compared with advanced practice providers, although physicians work with larger patient panels.⁹ Communication through telehealth, patient education sessions, specialty clinics, medication therapy management, and patient decision support aids are appropriate and useful methods for providing patient care.³⁶ Refer to Sections 4.1, 4.2, 4.3, and 7 for management.

A systematic review of the effect of patient education reported improvement in knowledge about medications and appropriate responses to symptoms,¹ as well as improvements in physical activity, dietary habits, and smoking cessation rates, but no convincing evidence of improvement in response to cardiac symptoms or psychosocial well-being was observed.¹ A review of 7 RCTs of Internet-based education and support found there was some supportive evidence for these interventions, but the overall effectiveness could not be determined.⁸ Education should be tailored to individual patients and their caregivers, reinforced at regular intervals, and modified as the patient’s circumstances change. Health literacy is defined as “the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions.”⁹ Verbal and written communications should be designed at the appropriate reading level, preferably in a patient’s native language, and culturally and contextually appropriate. The Agency for Healthcare Research and Quality has created a toolkit with detailed guidance on improving written and spoken communication, self-management and empowerment, and improving supportive systems.¹⁰ Internet-based self-management programs to improve access to ongoing support have been developed, but data on their efficacy are limited.⁸

Of the 68 trials and 20 intervention approaches in an Agency for Healthcare Research and Quality comparative effectiveness analysis, only 1 trial enrolled patients with CCD (those with recent MI).⁴ In that trial, patients in the treatment arm had 1.3 extra days of medication coverage per month over 9 months of follow-up and were 17% more likely to have >80% adherence compared with patients in the control arm. No significant difference in persistence of medication use was observed.¹¹ Another systematic review found no convincing evidence of improved medication adherence with educational interventions.¹ A 2020 systematic review of pharmacist-based patient education for patients on cardiovascular medications (only some with CCD) concluded that the interventions improved medication adherence but not necessarily clinical outcomes.² Another systematic review with the goal of comparing outcomes of different types of educational interventions targeting medication adherence found interventions delivered by pharmacists and nurses had the most favorable outcomes, although results were very heterogeneous.¹² A recent RCT of a pharmacist-administered intervention that used motivational interviewing to improve medication adherence among CCD patients improved medication adherence but had no effect on low-density lipoprotein cholesterol (LDL-C) levels, systolic BP, unplanned health care contact, or physical or emotional scores of the Heart Quality of Life Instrument.³

Most patients prefer to have an active role in their treatment decisions.^1-3,5 The right to information includes patients without decision-making capacity or who have chosen to defer treatment decisions to a designated caregiver. In shared decision-making, clinicians inform patients of the availability, risks, benefits, and alternatives of all medically appropriate testing or treatment options (which may include no testing or treatment), confirm patient understanding, assess patient values and treatment goals, and collaborate with patients to decide about their care. Patients may choose to include others in the shared decision-making process. Patient choices can include a treatment or therapeutic decision, an active choice to defer the decision, or a delegation of that decision to their care team or other designated individual. Patients and clinicians should engage in shared decision-making particularly when multiple medically appropriate options are available, when treatments or testing options confer increased risks, or when evidence is unclear on the optimal treatment strategy or when a risk:benefit tradeoff exists between different options. In patients with CCD, example areas for shared decision-making include duration, dose, and choice of antithrombotic therapy for secondary prevention and revascularization or medical therapy for stable angina.

Decision aids can increase patient knowledge, accuracy of risk perception, and agreement between patient values and care choices made, and may reduce decisional conflict for patients, but aids have not been developed and validated for many decisions made by patients with CCD.⁶ Before implementation of any decision aid, the decision aid should be developed according to best practice and validated in the target population.^7-9 Decision aids should augment, not replace, conversations between clinicians and patients. The decision aid PCI Choice was shown to increase knowledge about therapy options among patients with CCD choosing between optimal medical therapy alone or with PCI.⁴

Integration of SDOH is based on evidence showing the effect of SDOH on long-term cardiovascular outcomes.^9,10 Patients experiencing an MI at a young age had higher neighborhood disadvantage that was associated with 57% higher cardiovascular mortality after an 11-year period.³⁴ Women in the lower-income bracket were more likely to be under- or uninsured and had higher medication costs and higher 5-year rehospitalization rates compared with higher-income women.³⁵ Lower education and income levels were associated with lower prescribing of GDMT, as well as outcomes post-MI.^2,36-39 Further, there are disparities in CR (Section 4.2.10) referral and completion among racial and ethnic minorities, women, according to socioeconomic status, and across those living in rural and dense urban areas.^2,40-42 Neighborhood environment influences healthy lifestyle promotion and maintenance, management of traditional and nontraditional cardiovascular risk factors, and outcomes.^43-48 Telehealth and digital interventions are promising strategies to improve access to health care, management and health behaviors; however, consideration of SDOH influences is warranted.^3,29,49-51 Empirical evidence supports the use of screening tools in patients with multiple chronic diseases to efficiently assess SDOH in the clinical setting, facilitate tailoring of individualized care plans, and improve quality of care and outcomes.^{4,22,30,31,52-54} Collaborative partnerships between health care systems and community-based organizations can assist clinicians, patients, and their families in meeting unmet social needs as an extension of standard cardiovascular care for health equity.^3,55

Mediterranean-type dietary plans with higher intake of healthy plant-based foods and lean protein (eg, fish), with lower quantities of saturated fat (eg, red meat) help reduce cardiovascular risk factors, including insulin resistance, diabetes, dyslipidemia, hypertension, and obesity.^1,2,30,33-35 Multiple secondary CVD prevention studies showed lower risk of subsequent CVD events and total mortality rate with higher intake of healthy plant-based diets, including Mediterranean diets.^1-3,33 The Lyon Diet Heart Study randomized participants hospitalized with their first MI to a Mediterranean diet intervention or usual care.² After a mean intervention follow-up of 44.9 months, the Mediterranean diet showed up to a 65% reduction in composite CVD outcomes (cardiac death and nonfatal MI).² Additionally, multiple prospective cohorts showed an inverse relationship between lower all-cause death, greater adherence across multiple components of the Mediterranean diet (including fish),³⁶ and higher intake of healthier plant-based options.³⁷ Specific dietary components and serving sizes have varied across studies¹; the AHA has previously published recommendations according to energy needs and weight loss goals.³⁰ However, additional research is needed on mechanisms associated with Mediterranean-diet patterns, CVD death, and all-cause death.¹

Implementation of healthy plant-based and Mediterranean-based diets includes reducing saturated fat and optimizing caloric intake to include higher intake of monounsaturated fats, polyunsaturated fats, and complex carbohydrates.^2,34,35,38 Higher dietary fiber intake is associated with improvement in CVD risk factors, including lower BP, improved insulin sensitivity, and support of weight loss goals,^3,5 in addition to a lower risk of CVD events and all-cause death in patients with CCD.³ A meta-analysis of prospective cohorts and randomized clinical trials supports a dose-response relationship of higher quality carbohydrate intake and lower CVD-related morbidity and mortality rates.^5,39 For patients at higher CVD risk, the AHA recommends lowering saturated fatty acids to <6% of total caloric intake.³⁰ Reduction in saturated fatty acids, with healthier fat and carbohydrate intake, lowers LDL-C, which is associated with lower CVD morbidity and mortality rates.^3,30,38-40 A recent Cochrane review of randomized trials that reduced saturated fat intake, altered dietary fats, or both highlighted a 17% reduction of CVD events in patients with CCD.⁶ Among secondary prevention trials, the number needed to treat for an additional benefit was 53, by lowering saturated fat >4 years.^6,29

Dietary sodium reduction to <2,300 mg/d (optimal target of 1,500 mg/d) is important to lower BP.^8,41 Sodium reduction with a healthy diet reduces the risk of future CVD events, even in patients with CCD.^3,7 Recent analysis of the DASH (Dietary Approaches to Stop Hypertension)-Sodium study showed that sodium reduction may improve biomarkers of cardiac injury, inflammation, and cardiac strain.⁴² Dietary education should highlight potential sources of dietary sodium, including processed meat, which is a significant contributor to dietary sodium in the United States.^43,44 According to the AHA, processed meats include smoked, cured, salted meats, and/or meats with chemical preservatives.²³ Although the DASH diet supports higher potassium intake,⁸ insufficient data are available in populations with CCD to provide specific potassium recommendations.

The consumption of simple carbohydrates (eg, high-fructose corn syrup) and refined grains (eg, containing <25% whole grain by weight, including some refined cold ready-to-eat breakfast cereal, white bread, white rice)⁴ has adverse effects on lipoproteins, including LDL-C, apolipoprotein B, and plasma triglycerides.^6,38 Minimizing intake of simple carbohydrates and refined grains supports a healthier cardiometabolic profile.^4,6,39 Sugar-sweetened beverages are defined by the AHA as “manufactured carbonated and noncarbonated beverages containing caloric sweeteners or syrups and include caloric soft drinks (ie, not sugar-free), fruit drinks, sports and energy drinks, sweetened waters, and tea and coffee beverages with added sugars.”⁴⁵ Sugar-sweetened beverage consumption is associated with an increased risk of CVD events, including in patients with CCD,³ and associated with chronic conditions including diabetes, CKD, and obesity.^23,46 Overall, multiple healthy dietary components, including reduction in dietary sodium, sugar-sweetened beverages, and saturated fat reduces all-cause death among secondary prevention cohorts.³ Recommendations are unavailable for artificial sweeteners because of limited data in populations with CCD.

Consumption of trans fat has been associated with an increased risk of CVD events, including CVD mortality rate, and all-cause death in primary prevention populations and among individuals with CCD.^9,10,23,47 This association has been primarily attributed to industrially processed hydrogenated vegetable oils (eg, baked goods, fried foods), and less from ruminant trans fats (eg, meat and milk from ruminant animals, including cattle and sheep),^40,47 resulting in a higher risk of CHD.^9,10,23,47

In patients at high risk for CCD, nonprescription dietary omega-3 fatty acid supplements (eg, capsules, oil, soft gels) do not reduce CVD events or all-cause death^12,13; a Cochrane meta-analysis including 86 RCTs showed “little or no effect.”¹¹ See Section 4.2.6 (“Lipid Management”) on the role of prescription icosapent ethyl (highly purified eicosapentaenoic acid ethyl ester).⁴⁸ Despite observational studies,^49,50 insufficient evidence is available that shows vitamin D supplementation reduces CVD events.^14,15,51 In a meta-analysis of 21 RCTs (vitamin D [n=41,669] versus placebo [n=41,662]), vitamin D supplementation did not lower the risk of MACE.¹⁵ Additionally, antioxidant therapy is not associated with a decreased risk of CVD events.^17,19,22,31 Vitamin C, beta-carotene, multivitamins, or all of them do not decrease CVD event risk¹⁹ or CVD mortality rate.⁵² Insufficient data are available to support calcium supplementation (elemental calcium supplement ≥500 mg/d; carbonate, citrate, or gluconate formulation) in patients with CCD for CVD event reduction.²¹ A meta-analysis of double-blind RCTs (n=14,692 [calcium supplement intervention] versus n=14,243 [placebo-controlled]) showed an increased risk of CVD and CHD events with calcium supplementation.²¹ Mixed results on dietary calcium supplementation and CVD events suggests a U-shaped dose-response pattern.^20,21

Mental health factors, including depression, anxiety, anger or hostility, general distress and type D personality (where D stands for “distressed”), are common in diverse populations with CCD.¹² Psychological stress from environmental sources (eg, financial hardships, social isolation, discrimination) can have deleterious effects.^7,18-22 Studies consistently show that comorbid depression, anxiety, or emotional distress in patients with CCD is associated with diminished QOL,²³ atherosclerotic disease progression,²⁴ and negative effects on cardiovascular risk factors, leading to poorer cardiovascular outcomes.^6,7,25-30 An assessment of the use of depression screening found that among patients with recent ACS, screening positive for depression was associated with a 2-fold increase in MACE (adjusted hazard ratio, 2.15 [95% CI, 1.63-2.83]).² Patients randomized to antidepressants had significantly lower all-cause death than those not receiving treatment.² However, the CODIACS-QoL (Comparison of Depression Interventions After Acute Coronary Syndrome: Quality of Life) trial of patients after ACS showed no benefit of systematic depression screening (with or without subsequent treatment) on QOL or mortality.^2,3 Short, well-validated screening tools for depression or anxiety (eg, Patient Health Questionnaire-2, Generalized Anxiety Disorder Questionnaire-2) or brief questions on psychological health (eg, positive affect) are available for use in clinical settings (Tables 7 and 8).^7,31,32 It is reasonable to refer patients with positive screening for in-depth assessment by qualified mental health professionals or to accessible resources to promote mental health care.³³

Despite the preponderance of data showing the association of depression with adverse cardiovascular outcomes, treatment with antidepressants (14%) and psychotherapies (<10%) is low in patients after MI.³⁴ Studies including patients after ACS with depression found no definitive benefit of antidepressants on long-term cardiovascular outcomes.^15,17,35-37 However, the EsDEPACS (Escitalopram in Depressive Patients with Acute Coronary Artery Syndrome) study showed lower MACE after a median 8.1 years follow-up in patients with recent ACS treated with escitalopram compared with placebo (40.9% versus 53.6%; hazard ratio, 0.69 [95% CI, 0.49-0.96]).⁵ The TRIUMPH (Lifestyle Interventions in Treatment-Resistant Hypertension) trial found a higher 1-year mortality rate among patients with untreated depression compared with patients with treated depression (rates similar to those without depression).⁶ In a recent systematic review and meta-analysis, combination pharmacologic and psychotherapy, exercise, and antidepressants improved depressive symptoms among patients with CCD but had no mortality benefit.³⁸ CR (Section 4.2.10) improves depression, cardiovascular outcomes, and mortality in patients with CCD.^39,40 Mindfulness-based and psychotherapy interventions (eg, meditation, yoga, cognitive-behavioral therapy) improve depression, anxiety, stress, social support, and cardiovascular risk factors in patients with CCD but not all-cause or cardiovascular mortality, QOL, recurrent MI, or revascularization.^41-44 Pharmacological treatment of depression in patients with CCD is reasonable with consideration of adverse effects.^4,45

Most persons who smoke report they want to quit smoking, although annual quit rates among those who smoke are <10%.² Systematic assessment of tobacco and e-cigarette use is the first step to facilitating smoking cessation, but clinicians often do not screen for tobacco use.³ Routine screening for smoking status by clinicians has been shown to increase the rate of clinician intervention to promote smoking cessation. Screening for smoking can also allow clinicians to reinforce continued abstinence among those who have successfully quit and identify patients who may have relapsed. Electronic health record-based interventions that include a means to document smoking status and other tools such as clinician prompts or decision support, can improve process outcomes, such as referral to smoking cessation programs or documentation of smoking cessation counseling, although electronic health record-based documentation of smoking status alone has not improved quit rates.^27,28 Data are unavailable on the effect of screening and most other tobacco cessation interventions on quit rates for persons who use smokeless tobacco and e-cigarettes. Nicotine-containing e-cigarette use is increasing, including among never-smokers, and many cigarette smokers have become “dual users,” using both e-cigarettes and cigarettes.²⁹ Meta-analyses suggest that smokeless tobacco use is associated with increased risk of CHD events, albeit to a lesser degree than cigarette smoking.^23-25 E-cigarettes may increase the risk of CHD and cardiovascular events, and long-term risks of e-cigarettes are unknown.^8,30-37 Given these risks, screening for use as part of comprehensive risk assessment may be reasonable.

Even brief advice to quit tobacco smoking provided by a clinician increases the rate of quitting in persons who smoke (relative risk, 1.66 [95% CI, 1.42-1.94]).⁴ Other members of the care team, including nurses, community pharmacists, and oral health professionals, can also effectively provide behavioral support for smoking cessation.⁷ Messages to patients should be clear, personalized, nonjudgmental, and focus on the benefits of smoking cessation, such as: “Quitting smoking is the most important thing you can do for your heart health.”³⁸

Behavioral therapy is also effective for smoking cessation including group and individual in-person counseling, telephone-based support, interactive internet-based interventions, and text message–based interventions.⁷ A meta-analysis of 37 RCTs of behavioral interventions for smoking cessation in persons with CCD found a 22% increase in abstinence rates at 6 to 12 months.^7,39 Table 8 describes behavioral support programs available throughout the United States. NRT and varenicline have been shown to increase the success of smoking cessation in the overall population who smoke daily, including persons with CCD.^6,40-46 The effectiveness of NRT is highest when used as a combination of long- and short-acting NRT.⁴⁵ Adding behavioral therapy to pharmacotherapy increases quit rates.⁴⁷ In 2011, the FDA issued a warning for possible increased risk of cardiovascular events in persons with CVD who use varenicline. One meta-analysis of trials through 2016 found no increased cardiovascular risk in persons receiving varenicline.⁴⁸ Subsequently, a trial randomized 8,058 persons to bupropion, varenicline, or NRT and found no difference in cardiovascular events among the 3 groups.⁴⁴ Trials of pharmacotherapy and behavioral therapy for smoking cessation typically enroll persons who smoke cigarettes daily; more research is needed on the efficacy and optimal strategy for smoking cessation among those who smoke intermittently, those who use smokeless tobacco, and those who use e-cigarettes.

Varenicline is more effective than bupropion or NRT in achieving abstinence from cigarette smoking in meta-analyses of randomized trials, with a pooled estimate from 5 trials (n=5,877 persons) showing a relative risk versus bupropion of 1.39 (95% CI, 1.25-1.54), and a pooled estimate of 8 trials (N=6,264 persons) showing a relative risk versus NRT of 1.25 (95% CI, 1.14-1.37) for abstinence favoring varenicline.⁴⁹ One network meta-analysis evaluated the efficacy of RCTs of smoking cessation specifically among those with CVD and concluded that varenicline was more effective than bupropion or NRT, although no trials have compared various agents with each other in patients with CCD.⁶ The ultimate choice of pharmacotherapy for smoking cessation should incorporate patients’ previous experiences, preferences, and comorbidities (see “2018 ACC Expert Consensus Decision Pathway on Tobacco Cessation Treatment” for dosing information and information about pharmacotherapy for smoking cessation).³⁸ No data are available on the efficacy of pharmacologic therapy to support cessation of either e-cigarettes or smokeless tobacco. More research is needed on how to optimize both pharmacologic and behavioral therapy to support cessation of smokeless tobacco and e-cigarettes.

Twenty-nine RCTs evaluated the efficacy of e-cigarettes on smoking cessation, including 5 at low risk of bias.⁹ In meta-analyses, nicotine e-cigarettes appeared to be more effective than NRT for smoking cessation (relative risk, 1.69 [95% CI, 1.25-2.27]), corresponding to a 4% absolute increase in the success rates of smoking cessation compared with NRT.⁹ Persons using e-cigarettes for smoking cessation are at risk of long-term dependence. In 1 trial, 80% of those assigned to the e-cigarette group who successfully quit smoking were still using the device at 1 year (versus only 9% still using NRT in the NRT arm).¹⁰ Nicotine e-cigarettes appear to affect endothelial function, vascular stiffness, and BP less than combustible cigarettes.^33,34,36 No data are available on the long-term risks of e-cigarettes on overall health and cardiovascular risk, but physiologic and toxicology studies suggest that e-cigarettes may increase cardiovascular risk.^8,30-37 Substantial variability exists in e-cigarette additives, flavorings, and nicotine dose in e-cigarette liquid; the effect on cardiovascular risk is unknown. Because of the lack of long-term safety data and high rates of ongoing use, nicotine e-cigarettes should not be recommended as first-line therapy for smoking cessation. Patients with CCD who use e-cigarettes to support smoking cessation should be warned about the risks of developing long-term dependence and encouraged to quit use of e-cigarettes promptly to avoid potential long-term risks.

Secondhand smoke exposure has similar deleterious physiologic effects as active cigarette smoking.^50,51 Even low doses of exposure to secondhand smoke exposure are associated with a marked increase in the risk of ischemic heart disease events, including recurrent events in patients with previous MI.^11,12,50-52 Many persons are exposed to secondhand smoke exposure via their workplaces and may not individually be able to avoid exposure. For this reason, policy-level interventions are necessary to decrease occupational secondhand smoke exposure. Policies designed to reduce secondhand smoke exposure, such as smoke-free workplaces and restaurant policies, are associated with lower population-level risk of CVD.

Substance use is underrecognized and can be a significant contributor to CVD risk and outcomes.^1,3,5 Alcohol and other substances, such as cocaine, amphetamines, opioids, and marijuana can have particular adverse cardiovascular effects among patients with CCD (Table 9) and lead to premature or recurrent CVD events. A study across 2 large tertiary care centers found that drug use was observed in 10% of patients <50 years of age presenting with an MI from 2000 to 2016.² Similarly, recreational substance use of alcohol, cannabis, and amphetamines was independently associated with premature CVD in the nationwide Veterans Affairs Healthcare database and the VITAL (Veterans with Premature Atherosclerosis) registry.¹⁵ Single-question screening for unhealthy alcohol and drug use has been validated in primary care settings.⁴ These simple screening questions can also be self-administered.

There is a J-shaped relationship between alcohol consumption and death, although data on alcohol consumption is of variable quality. Proposed mechanisms supporting beneficial effects of moderate alcohol consumption include favorable effects on lipids, platelet aggregation, insulin resistance, and endothelial function.¹⁶ In the United States, 1 “standard” drink contains about 14 g of pure alcohol, which is typically found in 12 oz of regular beer (usually about 5% alcohol), 5 oz of wine (usually about 12% alcohol), and 1.5 oz of distilled spirits (usually about 40% alcohol).¹⁷ Observational studies have consistently found an inverse association between light-to-moderate alcohol consumption and vascular risk.¹⁸ In patients with CVD, a similar observation has been documented with light-to-moderate alcohol consumption (5–25 g/d) associated with lower incidence of cardiovascular and all-cause death.^6,8,7 Conversely, heavy, episodic drinking (binge drinking) is consistently associated with higher cardiovascular risk including acute myocardial infarction.

All available data on the benefit of alcohol on cardiovascular risk are observational and subject to confounding. In the absence of a randomized clinical trial, data are insufficient to recommend alcohol for cardioprotection.¹¹ In fact, a recent genetic analysis found that the causal association between light-to-moderate levels of alcohol intake and lower CVD risk are likely mediated by confounding lifestyle factors.⁸ In patients with CCD, excessive alcohol is linked to hypertension, increased mortality rate, and recurrent cardiovascular events. PRIME (Prospective Epidemiological Study of Myocardial Infarction) found that binge drinking (>50 g at least once a week) was associated with a higher risk of coronary events (hazard ratio, 2.03 [95% CI, 1.41-2.94]) compared with regular drinking.¹⁰ In the Determinants of Myocardial Infarction Onset Study across 45 community and tertiary-care medical centers, binge drinking was associated with a 2-fold higher mortality rate after an acute MI.⁹ The Global Burden of Disease 2016 analysis confirmed a J-shaped relationship with alcohol and outcomes, but the benefit appeared to be offset by increasing cancer risks, concluding that the level of alcohol consumption that minimized harm was zero.¹⁹ Therefore, patients who do not drink alcohol or who have a medical reason to avoid alcohol (eg, liver dysfunction, drug-drug interactions) should not be encouraged to drink alcohol for the purposes of cardiovascular protection. Clinicians should further counsel their patients against binge drinking.

Recommendations after PCI and CABG may depend on whether femoral or radial access was performed, and whether surgery was performed in a sternal-sparing manner.^5,8 The patient should be well compensated, euvolemic, and without significant angina. Patients with CCD who are functionally well compensated or patients with no or mild angina, given the low risk of MI or sudden death, should be considered safe for sexual activity. Sexual activity represents an exercise level of approximately 3 to 5 metabolic equivalents, compared with a typical exercise treadmill test that involves approximately 4 metabolic equivalents. The risk of MI or sudden death resulting from sexual activity is very low. ³ Patients with CCD who want to engage in sexual activity should undergo a medical evaluation, similar to other forms of exercise in the presence of CCD.⁵ Because sexual activity is associated with increased metabolic requirements, patients with unstable or decompensated CCD should refrain from sexual activity.⁵

In addition to a recommendation for CR incorporating sexual counseling, in men with CCD, conservative measures such as sexual rehabilitation, consisting of 12 weeks of sexual rehabilitation with physical exercise training, pelvic floor exercise and psychoeducation, was associated with better sexual function by the International Index of Erectile Function.^9,10

Phosphodiesterase type 5 inhibitors should not be used concomitantly with nitrate medications, often used to treat CCD, because of the potential for severe hypotension.⁴ Sildenafil and vardenafil have half-lives of ∼4 hours. Tadalafil is long-acting and has a half-life of 17.5 hours. Patients on sildenafil or vardenafil should avoid taking nitroglycerine for ≥24 hours (≥48 hours for tadalafil).⁵ In patients on long-acting nitrate therapy who want to use a phosphodiesterase type 5 inhibitor, decision on the use of phosphodiesterase type 5 inhibitor should be guided by the need for continued nitrate therapy versus other alternative options available to the treating clinician.

The CTT (Cholesterol Treatment Trialists) meta-analysis of 5 RCTs showed that LDL-C lowering with high-intensity statins compared with moderate-intensity statins reduces major vascular events by 15% (Table 11).² This benefit occurred irrespective of age, even among patients >75 years of age with established ASCVD.^2,3 Greater absolute reductions in LDL-C were associated with a greater proportional reduction in MACE. The greatest absolute benefit from statin therapy is observed in those with the highest baseline LDL-C levels and at similar risk of events. Furthermore, percent reduction in LDL-C appears to provide additional prognostic value overachieved LDL-C levels.⁴³ The expected percent reduction in LDL-C levels with high-intensity statin therapy is ≥50% and should be used to assess clinical efficacy. However, baseline LDL-C levels in patients before statin initiation are not always available in clinical practice. The threshold of LDL-C ≥70 mg/dL is then useful to determine whether to intensify lipid management.

Although high-intensity statin therapy is preferred, high-intensity statin therapy may not be tolerated by some patients or may be contraindicated because of clinically significant drug-drug interactions.⁴⁴ Statin intolerance is defined as adverse effects associated with statin therapy that improve or resolve with dose modification or discontinuation of statin therapy; and requires a trial of at least 2 statins with one at the lowest approved daily dose.⁴⁵ Statin intolerance may also be complete or partial (tolerating less than the recommended statin intensity). Clinicians should also consider the possibility of a “nocebo effect”—patient expectation of harm resulting in perceived adverse effects.⁴⁶ Multiple RCTs showed that moderate-intensity statin therapy also reduces cardiovascular events and death among patients with established ASCVD, including those >75 years of age; therefore, a moderate-intensity statin should be used in patients unable to tolerate a high-intensity statin.^2,4-8 Additional strategies may also be used to identify a tolerable statin regimen (eg, low-intensity statin, alternative daily dosing) to reduce LDL-C but it is unclear if these strategies also reduce the risk of ASCVD events.⁴⁷

The goal for LDL-C lowering is defined as percentage responses in LDL-C relative to baseline levels. Although reductions in LDL-C are expected with moderate- and high-intensity statins (Table 11), individual response can vary substantially.¹¹ The maximum percentage change in LDL-C occurs within 4 to 12 weeks after initiation of or change in lipid-lowering therapy. The Friedewald equation is known to underestimate LDL-C in the setting of elevated TG levels, thus other approaches to LDL-C measurement (eg, Martin/Hopkins method) may be desirable.^48,49 Obtaining lipid profile measurements every 3 to 12 months is associated with increased adherence to therapy and identification of patients requiring further intensification of treatment.^9,10 See Sections 4.4.3 and 5 of the 2018 AHA/ACC multisociety cholesterol guideline⁵⁰ for additional information regarding efficacy and safety monitoring.

The economic value of a lipid-lowering therapy depends on the absolute benefit (in terms of the number of cardiovascular events averted or quality-adjusted life years [QALY] gained) that patients derive from receiving the treatment relative to the comparator as well as the cost of the therapy being evaluated.¹³ Because of the very low annual cost of generic formulations of statins in the United States, the use of maximally tolerated statin therapy in patients with CCD is projected to be cost-saving (ie, the lifetime savings from averted cardiovascular events more than offset the lifetime cost of statin therapy and resulting adverse effects).¹² Note that this value statement should not be extrapolated to higher-cost branded formulations of statins.

In IMPROVE-IT (Improved Reduction of Outcomes; Vytorin Efficacy International Trial), the addition of ezetimibe to moderate-intensity statin therapy among patients with ACS resulted in a significant ASCVD risk reduction (7% relative risk reduction; 2% absolute risk reduction) at a median follow-up of 6 years.¹⁵ An analysis using the TIMI (Thrombolysis in Myocardial Infarction) Risk Score for Secondary Prevention (TRS 2 P) found the addition of ezetimibe was associated with significantly greater risk reduction (19% relative risk reduction; 6.3% absolute risk reduction) among patients with ≥3 high-risk features, with more modest benefit among those with 2 high-risk features and no benefit among those with 0 or 1 additional features.¹⁴ Ezetimibe was allowed at study entry in both PCSK9 monoclonal antibody trials,^23,24 but only 3% and 5%, respectively, were on ezetimibe. No RCT has evaluated whether an ezetimibe-first strategy is preferred before adding a PCSK9 monoclonal antibody; however, clinicians should generally add ezetimibe first, then a PCSK9 monoclonal antibody, if necessary, to achieve desired LDL-C levels, given the generic availability of ezetimibe, its once-daily oral administration, and proven long-term safety and tolerability. This is supported by 2 well-designed simulation studies showing that a high proportion of patients will achieve an LDL-C level of <70 mg/dL with the addition of ezetimibe to high-intensity statin therapy.^18,19

Generic ezetimibe is an inexpensive drug, with net price of <$10 for a 1-month supply. To the extent that LDL-C lowering with ezetimibe translates to fewer lifetime MACE, the use of generic ezetimibe is likely to be improve health outcomes at modest increase in cost, especially in very high-risk patients, resulting in high value (<$50,000 per QALY gained).^12,20,21 However, the cost-effectiveness of adding generic ezetimibe to maximally tolerated statin therapy is sensitive to the assumption regarding the effect of ezetimibe on cardiovascular and all-cause death.

Very high risk ASCVD is defined in Table 10. The efficacy of alirocumab and evolocumab was shown in 2 RCTs.^22,23 The FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition Subjects with Elevated Risk) trial evaluated evolocumab among those with established ASCVD with an LDL-C level of ≥70 mg/dL or non–HDL-C level of ≥100 mg/dL on maximal statin with or without ezetimibe. Cardiovascular events were significantly reduced by 15% with evolocumab, with greater benefit observed among those with additional high-risk clinical factors. No increased risk of neurocognitive adverse effects was observed, even among those achieving the very low levels of LDL-C.²⁹ The ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab) trial evaluated alirocumab use in patients with an ACS event 1 to 12 months earlier on maximal statin with or without ezetimibe. Cardiovascular events were significantly reduced by 15% with alirocumab, especially in those with additional high-risk clinical factors.^25-27 The absolute risk reduction was relatively modest (1.5% and 0.6%, respectively) in both trials, given the ∼60% reduction in LDL-C levels. However, analyses from both FOURIER and ODYSSEY Outcomes trials subsequently showed that among several groups of patients noted in the very high-risk ASCVD category (Table 10), the absolute risk of future ASCVD events was significantly higher; therefore, the absolute risk reduction from the use of a PCSK9 monoclonal antibody was also much higher than the overall absolute risk reductions seen in the original trials.^{23,26,28,51,52} Although generally well tolerated, injection site reactions can occur, and long-term safety data are limited. Maximal LDL-C-lowering therapy should include maximally tolerated statin plus ezetimibe; however, ezetimibe may be insufficient when a ≥25% reduction in the LDL-C level is desired. Clinicians bypassing the addition of ezetimibe before adding a PCSK9 monoclonal antibody should recognize this may not be cost effective (Figure 8).

The US cost of PCSK9 monoclonal antibodies has declined by 60% since their initial market entry (from approximately $14,000 per year to $5,850 per year), which, all things being equal, has improved the cost-effectiveness of these drugs.^12,20,21 At this price point, the cost-effectiveness of the agents in very high risk patients with CCD is uncertain, with some studies projecting low economic value^12,20 and others suggesting intermediate to high economic value.^30,31 This value statement should not be extrapolated to patients with CCD who are at low to moderate risk of adverse cardiovascular events, in whom PCSK9 inhibitor monoclonal antibodies are of low economic value. The cost-effectiveness of a therapy is a function of the incremental cost of the therapy relative to the comparator, its effectiveness relative to the comparator, as well as baseline risk of cardiovascular events in the target population. Patients who have higher baseline risk are likely to derive a larger absolute health benefit from an effective drug. It follows that CVD prevention is more cost-effective in a population at higher risk of CVD events. Thus, PCSK9 inhibitors may be intermediate value in patients at higher-than-average risk of recurrent events, such as those with a recent ACS, symptomatic peripheral artery disease, or familial hypercholesteremia (FH).^12,20,21 The cost-effectiveness of PCSK9 monoclonal antibody is also likely improved in patients who are unable to tolerate statins because of severe statin-associated side effects.¹²

REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) randomized patients with established ASCVD or diabetes plus additional risk factors, triglyceride levels between 150 mg/dL and 499 mg/dL, and an LDL-C level of <100 mg/dL on background statin therapy, to either 4 g/day of icosapent ethyl (purified EPA only) or mineral oil placebo. Icosapent ethyl significantly reduced the relative risk of MACE by 25% and cardiovascular death by 20%.³² The benefit appeared driven by the increase in EPA levels and not the modest 17% reduction in triglyceride levels. RESPECT-EPA (Randomized Trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy-Statin and Eicosapentaenoic Acid) was another secondary prevention trial that showed a borderline significant reduction in MACE with icosapent ethyl 1800 mg/day (10.9% versus 14.9%; P=0.055) in 2506 participants enrolled in Japan on background statin therapy. Limitations of this trial were the lack of placebo control, and it was underpowered. Contrarily, the STRENGTH (Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia) trial found no benefit with a 4 g/day carboxylic acid formulation of omega-3 fatty acids (EPA and DHA) compared with a corn oil placebo, and no association with harm or benefit in those at the highest achieved tertiles for EPA and DHA levels. Incident AF was more common with both icosapent ethyl and the carboxylic acid formulation of omega-3 fatty acids and has been observed in other studies of omega-3 fatty acid formulations. Several factors could explain the discrepant outcomes observed in these trials; however, the use of a mineral oil placebo in REDUCE-IT is of concern given its adverse effects on lipid and inflammatory biomarkers, suggesting mineral oil may not be an inert placebo.⁵³ For patients with LDL-C levels between 70 mg/dL and <100 mg/dL, it is unclear whether further LDL-C lowering or adding icosapent ethyl is more effective. Patient preference and shared decision-making are recommended, and secondary causes of elevated triglyceride levels (eg, medications, diabetes, lifestyle) should be addressed before considering icosapent ethyl. Dietary supplements containing omega-3 fatty acids are not acceptable substitutes for icosapent ethyl.

In patients not at very high risk, there may be instances where high-intensity statin therapy is insufficient to achieve desired LDL-C levels or not tolerated. Although moderate-intensity statin therapy effectively reduces cardiovascular risk, it is inferior to high-intensity statin therapy.² Additional LDL-C lowering may also be necessary in patients on moderate-intensity statin therapy with LDL-C levels ≥70 mg/dL. Adding ezetimibe to moderate-intensity statin therapy may compensate for the reduced LDL-C lowering observed with moderate-intensity statin therapy alone. Although the net benefit of ezetimibe may be less robust among patients not at very high risk, it is preferred before a PCSK9 monoclonal antibody for reasons provided in Recommendation 5.

Bempedoic acid is a first-in class therapy adenosine triphosphate-citrate lyase⁵⁴ inhibitor that reduces LDL-C levels by 15% to 25% depending on the type and dose of background statin therapy and is associated with fewer muscle-related adverse effects.^33,34 It is also available in a combination product with ezetimibe that reduces LDL-C levels by ∼35%. Although it can be combined with statins, bempedoic acid should be avoided when using doses of simvastatin >20 mg daily or pravastatin 40 mg daily because of an ∼2-fold increase in serum levels of both statins. Elevation in uric acid levels may occur with bempedoic acid use, and rare cases of tendon rupture have been reported. Inclisiran is a first-in-class small interfering RNA directed to break down PCSK9 mRNA, resulting in reduced synthesis of PCSK9.³⁵ Inclisiran reduces LDL-C levels by approximately 50% and is administered as a single subcutaneous dose, with a second dose at 3 months, then every 6 months. Inclisiran administration must be performed by a health care professional, which may limit accessibility. It is generally well tolerated, but injection site reactions can occur. The effect of bempedoic acid and inclisiran on MACE is currently under investigation; therefore, nonstatin therapies with proven efficacy (ie, ezetimibe, PCSK9 monoclonal antibody) should be prioritized over these 2 therapies. Preliminary modeling studies project that the use of bempedoic acid or inclisiran in patients unable to tolerate statin therapy because of severe statin-associated side effects is of intermediate value ($50,000–$150,000 per QALY gained), as is the use of inclisiran in patients with CCD and heterozygous FH.⁵⁵ However, the cost-effectiveness of these novel therapies is sensitive to assumptions regarding the effect of each drug on cardiovascular and all-cause death and should be updated when long-term outcomes data become available.

Dietary supplements containing omega-3 fatty acids (ie, fish oil) are widely used for presumed cardioprotective benefits. However, low-dose omega-3 fatty acid supplementation does not reduce MACE in patients with CCD.^39-41 The only omega-3 fatty acid formulation that can be recommended in patients with CCD is icosapent ethyl (EPA only) as described in Recommendation 9. The AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health) trial found no benefit with the addition of extended-release niacin to background statin therapy.³⁶ Another niacin trial in secondary prevention, HPS2-THRIVE (Treatment of HDL to Reduce the Incidence of Vascular Events), also found no benefit with a combination product of niacin and laropiprant, a prostaglandin receptor antagonist; however, this product is no longer available.³⁷ ACCORD-LIPID (Action to Control Cardiovascular Risk in Diabetes-Lipid Trial)⁵⁶ found no benefit with the addition of fenofibrate to background statin therapy. Although this trial was conducted in patients with type 2 diabetes, more than half of the trial participants had established CVD at baseline, and no benefit was observed in this subgroup of patients. A selective PPARα modulator, pemafibrate, was investigated in the PROMINENT (Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Diabetic Patients) trial in high-risk patients with diabetes, but this trial was stopped early for futility.⁵⁷ Fenofibrate should only be considered for severe hypertriglyceridemia (triglycerides, ≥500 mg/dL) to reduce the risk of acute pancreatitis.

Lifestyle-related factors influence BP levels, and lifestyle modifications are effective strategies to help lower elevated BP. These factors include weight loss,^1,5 a heart-healthy diet that is rich in fruits and vegetables,^2,3 reduced dietary sodium,^29,30 physical activity,^4,8 and reduction or elimination of alcohol intake.⁶

Among patients with increased cardiovascular risk, reduction of systolic BP to <130 mm Hg has been shown to reduce CVD complications by 25% and all-cause death by 27%.¹³ Optimal diastolic BP for clinical outcomes appears to be in the range of 70 to 80 mm Hg.^10,14

In the HOPE (Heart Outcomes Prevention Evaluation) trial, ramipril therapy in patients with CVD or at high risk for CVD reduced the risk of MI, stroke, or CVD by 22% compared with placebo.¹⁶ In patients with CAD and hypertension who were randomized into the INVEST (International Verapamil SR/Trandolapril Study) trial, CCB and ACE inhibitors and beta-blocker/thiazide diuretic therapy had similar cardiovascular morbidity and death outcomes.³¹ In the EUROPA (Exclusive Endocrine Therapy or Partial Breast Irradiation for Women ≥70 Years Early Stage Breast Cancer) study involving patients with CCD, ACE inhibitor therapy produced a 20% reduction in risk of CVD death, MI, or cardiac arrest compared with placebo.¹⁵ Beta blockers are particularly effective in patients with CCD, especially those with recent MI and those with ongoing angina, given their ability to reduce angina, improve angina-free exercise tolerance, reduce exertion-related myocardial ischemia, and reduce risk of CVD events.^{17,23,27,32,33} Because of the significant benefits from beta blockers and ACE inhibitors and ARB agents in patients with CCD, these medications are recommended as a first-line therapy in the treatment of hypertension in such individuals. GDMT beta blockers for CCD and for lowering BP include carvedilol, metoprolol tartrate, metoprolol succinate, nadolol, bisoprolol, propranolol, and timolol.¹⁹ Outcomes with atenolol appear to be inferior compared with other antihypertensive drugs in the treatment of hypertension.³⁴ When beta blockers, ACE inhibitors, and ARB therapies do not sufficiently control BP, additional GDMT BP-lowering therapies can be added, including thiazide diuretics, CCB, and mineralocorticoid receptor antagonists.¹⁹

In patients with CCD and type 2 diabetes, both SGLT2 inhibitors and GLP-1 receptor agonists significantly reduce the risk of MACE, with additional benefits in terms of weight loss⁴⁹ and progression of kidney disease.^7,16,17 SGLT2 inhibitors do not appear to primarily reduce atherosclerosis as much as they reduce incident and worsening HF (for which patients with CCD and type 2 diabetes who are at risk).^1-8 In contrast, GLP-1 receptor agonists appear to primarily reduce the risk of atherosclerotic events, such as MI and stroke. Although there has been some inconsistency across the cardiovascular outcomes trials,^9-15 meta-analyses have shown no statistically significant heterogeneity in cardiovascular risk reduction across different GLP-1 receptor agonists.^16,17 Currently, no compelling evidence is available that either medication reduces cardiovascular risk in patients with CCD but without type 2 diabetes,^50,51 or in the case of SGLT2 inhibitors, without concomitant HF. Given their distinct mechanisms, the cardiovascular risk reduction may be greater using both classes of medications compared with either medication alone. Data on concurrent use are mostly limited to safety and metabolic endpoints,⁵² but available studies showed benefit in BP and weight reduction with dual therapy.^53,54 Whether the effects on cardiovascular outcomes are additive, or even synergistic, is not yet known.

In a systematic review of cost-effectiveness analyses examining the addition of GLP-1 agonists compared with alternative therapies (including insulin or other classes of diabetes medications) among patients with diabetes, the use of a GLP-1 agonist is projected to be of high value (cost-saving or incremental cost-effectiveness ratio of <$50,000 per QALY gained).¹⁸ Although these analyses were performed in all patients with type 2 diabetes rather than specifically in patients with CCD, these results appear to be robust to a range of assumptions regarding underlying risk and are likely applicable to patients with CCD.

In a systematic review of cost-effectiveness analyses examining the addition of SGLT2 inhibitors to standard of care among patients with diabetes, the use of an SGLT2 inhibitor is projected to be of intermediate value ($50,000 to <$150,000 per QALY gained) compared with standard of care.¹⁸ As noted previously, these analyses were performed in all patients with type 2 diabetes rather than specifically in patients with CCD, but these results appear to be robust to a range of assumptions regarding underlying risk and are likely applicable to patients with CCD.

Among patients with HF with reduced ejection fraction (with or without type 2 diabetes), SGLT2 inhibitors reduce the risk of cardiovascular death and HF hospitalization^19-22 and improve functional capacity and QOL.^23,24 These effects were independent of cause of cardiomyopathy, because approximately half of enrolled patients across the trials had CCD. SGLT2 inhibitors should be avoided or used with caution in patients with type 1 diabetes or with advanced CKD (eg, eGFR <30 mL/min/1.73 m²).

Among patients with HF with reduced ejection fraction (with or without type 2 diabetes), the use of SGLT2 inhibitors is projected to be of intermediate value ($50,000 to <$150,000 per QALY gained) from a US health care sector perspective and a lifetime horizon. One modeling-based study compared dapagliflozin and GDMT with GDMT alone in a hypothetical cohort of adults in the United States with similar clinical characteristics as participants of the DAPA-HF (Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction) trial.²⁵ Assuming the cost of dapagliflozin to be $4,192 annually, dapagliflozin was projected to add 0.63 (95% uncertainty interval, 0.25-1.15) QALYs at an incremental lifetime cost of $42,800 (95% uncertainty interval, $37,100-$50,300), for an incremental cost-effectiveness ratio of $68,300 per QALY gained (95% uncertainty interval, $54,600-$117,600 per QALY gained; cost-effective in 94% of probabilistic simulations at a threshold of $100,000 per QALY gained).²⁵ Findings were similar among individuals with or without diabetes but were sensitive to drug cost. Similar findings were independently reported by another group of investigators.²⁶

Among patients with HF with preserved ejection fraction (with or without type 2 diabetes), SGLT2 inhibitors reduced the risk of HF hospitalization or cardiovascular death in the EMPEROR-PRESERVED (Evaluation of the effects of sodium-glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction) trial²⁷ and the risk of worsening HF or cardiovascular death in the DELIVER trial (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure), with the primary endpoints driven by significant reductions in HF hospitalization in both trials. SGLT2 inhibitors also improved functional capacity and QOL in the PRESERVED-HF and DELIVER trials.^28,29 CCD was diagnosed in 35% of enrolled patients in EMPORER-PRESERVED and 20% of enrolled patients in PRESERVED-HF (Effects of Dapagliflozin on Symptoms and Functional Status in Patients with Heart Failure and Preserved Ejection Fraction), with no significant difference in risk of HF hospitalization (subgroup was not tested in the QOL study); the CCD rate was not reported in DELIVER.

Among patients with HF with preserved ejection fraction (with or without type 2 diabetes), the economic value of SGLT2 inhibitors is sensitive to the effect of SGLT2 inhibitors on cardiovascular mortality. The reduction in cardiovascular mortality was not statistically significant in the EMPEROR-PRESERVED or DELIVER trials, or in a pooled analysis of the 2 trials. If one were to assume no reduction in cardiovascular mortality and minimal improvement in QOL among patients with HF with preserved ejection fraction, the use of empagliflozin is of low value (incremental cost-effectiveness ratio $437,000).³⁰ However, if one were to assume a 9% reduction in cardiovascular mortality (as consistent with the point-estimate of EMPEROR-PRESERVED), the incremental cost-effectiveness ratio is lowered to $ 174,000 (which the authors defined as intermediate value after adjusting the ACC/AHA thresholds for interval change in per capita GDP). Although the trials included patients with and without CCD, it is likely that patients with CCD have a higher risk of events (including cardiovascular mortality) and therefore derive a larger-than-average benefit from SGLT2 inhibitors. Additional clinical studies that examine the effect of SGLT2 inhibitors on cardiovascular and noncardiovascular mortality, and additional economic evaluations that synthesize the available clinical evidence and consider a range of costs and risks, are needed to ascertain the value of SGLT2 inhibitors in patients with CCD and HF with preserved ejection fraction.

Patients with CCD should undergo routine measurement of BMI with or without waist circumference for initial evaluation and as a guide to efficacy of weight loss intervention.^1-6 Although not a measure of body composition, BMI remains the most practical way to evaluate for overweight and obesity, defined as a BMI 25 to 29.9 kg/m² and ≥30 kg/m², respectively.²⁴ Waist circumference, a surrogate estimate of visceral adiposity, may be a better indicator of risk than BMI in some patients and populations,^25,26 with central obesity defined as a waist circumference >102 cm (40 in) in men and >88 cm (35 in) in women.²⁴ As with BMI, racial and ethnic differences in waist circumference thresholds associated with cardiometabolic risk have been reported.²⁷ Recognizing that weight assessment in some individuals may represent a deterrent to seeking care, gender- and culturally sensitive approaches to assessing weight are recommended in all patients, with an option for patients to self-report values where appropriate.

Lifestyle modification (see Section 4.2.1, “Nutrition” and Section 4.2.11, “Physical Activity”) with associated weight loss improves obesity-related CCD comorbidities. With lifestyle measures alone, a weight loss of 5% to 7% of body weight is typical but often difficult to sustain. Multicomponent interventions including dietary modification, exercise, and behavioral counseling are more effective than interventions targeting single components.^7,8 A meta-analysis of 122 RCTs and 2 observational studies compared an intensive, multicomponent behavior-based weight loss intervention with a comparison group receiving usual care. At 12 to 18 months, patients receiving multicomponent behavior-based interventions were more likely to achieve a ≥5% weight loss (relative risk, 1.94 [95% CI, 1.70-2.22]).⁷ In patients with CCD, regular physical activity with increased lean mass may be more important for improving survival than achieving a normal BMI.¹⁰ Patients with CCD and overweight or obesity should be counseled to lose weight, especially if accomplished with increases in physical activity and improvements in cardiorespiratory fitness.⁹

Candidates for weight-loss drug therapy include individuals with a BMI ≥30 kg/m² or a BMI of 27 to 29.9 kg/m² with weight-related comorbidities who have not met weight-loss goals (eg, loss of ≥5% of total body weight at 3–6 months) with a comprehensive lifestyle intervention alone. The decision to initiate drug therapy in patients with CCD should be individualized, considering associated risks and benefits. The cardiovascular safety of certain weight-loss drugs, such as naltrexone/bupropion, has not been established and remains controversial.²⁸ Use of a GLP-1 receptor agonist (Section 4.2.8) is beneficial when pharmacologic therapy is warranted for further weight reduction.^11,12,14 Among eligible adults without diabetes, the STEP 8 (Semaglutide Treatment Effect in Patients with Obesity) randomized controlled trial (N=338, 3.3% with known CCD) found that once-weekly subcutaneous semaglutide 2.4 mg added to counseling for diet and physical activity resulted in significantly greater weight loss at week 68 compared with once-daily subcutaneous liraglutide 3.0 mg or placebo (mean weight change, –15.8% [95% CI, –17.6 to –13.9] versus –6.4% [95% CI, –8.2 to –4.6] versus –1.9% [95% CI, –4.0 to 0.2] for semaglutide versus liraglutide versus placebo, respectively).¹³ Both semaglutide (0.5–1.0 mg weekly) and liraglutide (1.2–1.8 mg daily) were associated with reduced MACE in patients with type 2 diabetes and CCD.^29,30 Recently, the double-blind randomized controlled trial SURMOUNT-1 (A Study of Tirzepatide [LY3298176] in Participants with Obesity or Overweight) also showed a dose-dependent weight loss benefit (mean weight change up to –20.9% [95% CI, –21.8 to –19.9]) with once-weekly subcutaneous tirzepatide (at 5 mg, 10 mg, or 15 mg) relative to placebo in eligible obese adults without diabetes (N=2539, 3.1% with ASCVD) over 72 weeks.³¹

Patients with CCD and severe obesity (BMI ≥40 kg/m² or BMI 35-39.9 kg/m² with a weight-related comorbidity) who have not met weight loss goals with lifestyle and pharmacologic intervention may benefit from a bariatric procedure such as gastric bypass surgery. Bariatric procedures appear to be relatively safe and effective among patients with CCD, at least in those <65 years of age.^15,17,18 In the nonrandomized prospective SOS (Swedish Obese Subjects) study, bariatric surgery was associated with prevention of type 2 diabetes and fewer cardiovascular deaths and lower incidence of MI or stroke compared with matched obese controls (hazard ratio, 0.47 [95% CI, 0.29-0.76] for death, and hazard ratio, 0.67 [95% CI, 0.54-0.83] for MI or stroke).^16,32 These benefits do not appear to occur with liposuction, suggesting that the negative energy balance associated with bariatric intervention may be necessary for achieving the metabolic benefits of weight loss.³³ Specifically among patients with obesity and type 2 diabetes, bariatric surgery is an effective strategy for achieving weight loss, glycemic control, and reducing cardiovascular risk factors.³⁴ More recently, 2 retrospective observational studies of patients with CCD showed significant reductions in MACE among those undergoing bariatric surgery compared with matched controls.^17,18

Sympathomimetic drugs (eg, phentermine, diethylproprion, benzphetamine, phendimetrazine) can increase heart rate and BP and are not recommended in patients with CCD. In a trial of sibutramine versus placebo in >10,000 patients with or at high risk for CCD, sibutramine was associated with a higher risk of nonfatal MI (4.1% versus 3.2%; hazard ratio, 1.28 [95% CI, 1.04-1.57]) and nonfatal stroke (2.6% versus 1.9%; hazard ratio, 1.36 [95% CI, 1.04-1.77]).¹⁹ As a result, the FDA removed sibutramine from the US market in 2010, but it can still be found illicitly in dietary supplements marketed for weight loss and in other parts of the world.³⁵ Clinicians are encouraged to ask patients about potential use of dietary supplements for weight management.

Patients with CCD with a recent MI, PCI, or CABG procedure who participate in CR have significantly better outcomes compared with those who do not participate,^39-41 including lower all-cause and cardiovascular mortality rates,^27,41,42 lower rehospitalization rates (total, cardiovascular, and noncardiovascular),^43-45 and superior QOL.^{27,41,42,44,45} Participation in CR appears to improve symptom control, functional capacity, and QOL in patients with stable angina.^2,40

CR is also associated with improved outcomes in special populations with CCD. CR improves exercise capacity in heart transplant recipients,⁸ including those in maintenance (1–8 years after heart transplant) as well as de novo (7–16 weeks after heart transplant).^9,10 In maintenance of patients with heart transplant with or without cardiac allograft vasculopathy, high-intensity interval training versus usual care resulted in significantly lower rates of cardiac allograft vasculopathy progression at 1 year,¹¹ but these effects were no longer present on long-term (3–5 years) follow-up, suggesting that continued intermittent periods of high-intensity interval training may be necessary to maintain the initial benefits.^12,46,47 One observational study showed an association between the dose of CR sessions and survival in patients with heart transplant.⁴⁸

Similarly, patients with spontaneous coronary artery dissection (SCAD) who participated in CR, compared with those who did not, had lower MACE and lower rates of recurrent MI with favorable trends in physical, emotional, and mental domains.^14-17 For patients with CCD and concomitant HF, CR is also recommended as a Class 2a recommendation, LOE B-NR (see 2022 ACC/AHA/HFSA heart failure guideline).³⁸

Moderate-to-higher intensity exercise training in individuals with CCD, which is done in CR programs, improves functional capacity, health-related QOL, cardiovascular risk factor control, and mortality rates.^2,3,13,14 In addition to continuous, moderate-intensity exercise training, high-intensity interval training also appears to be an effective and safe approach to aerobic exercise training in individuals with CCD.^15,16 US guidelines recommend that adults who do not have contraindications to exercise should do at least 150 to 300 minutes per week of moderate-intensity aerobic physical activity, or at least 75 to 150 minutes per week of vigorous (higher)-intensity aerobic physical activity, or an equivalent combination of moderate- and vigorous-intensity aerobic activity.

Muscle-strengthening (resistance training) activities are recommended on ≥2 days a week.¹⁷ Resistance training to safely improve muscular strength improves functional capacity and QOL.^5,6,18 Resistance training may also reduce mortality rates in individuals with CCD.¹⁹

Compared with a sedentary lifestyle, lower-intensity lifestyle activities (eg, gardening), office-based physical activities, and climbing stairs improve energy expenditure, functional capacity, and cardiometabolic risk, especially in previously sedentary individuals who are not exercising on a regular basis.^20-25 Interventions, such as the use of step counters and walking prompts, may be helpful in decreasing sedentary time and increasing lifestyle activities in individuals with CCD.^{9-11,20-23,26}

Ambient air pollution, especially small particulate matter with an aerodynamic diameter ≤2.5 microns (also referred to as “PM2.5”), is associated with worse cardiovascular outcomes.^1-7 Most outdoor and indoor PM2.5 pollutants are produced by combustion (eg, car engines, coal- or natural gas-fired power plants, woodstoves, or wildfires). Proximity to automobile traffic or fossil fuel-dependent industries and use of poorly ventilated stoves are key predictors of exposure to increased PM2.5 levels. Long-term exposure to PM2.5 levels >10 micrograms per cubic meter (μg/m³) is associated with a >10% increase in the odds of having CCD, progression of CCD, and suffering an acute MI or cardiovascular mortality.^1-5 Even short-term exposure (<7 days) to elevated levels is associated with increased hospitalization and cardiovascular death.^6,7 There are insufficient data to support regular use of in-home high-efficiency air purifiers or N95 filters to improve cardiovascular outcomes.¹⁹ Other pollutants, such as ground-level ozone, are associated with a small increase in risk of cardiovascular death, but additional studies are needed to quantify the magnitude of risk.²⁰ Information regarding air pollutants and their relation to air quality in a specific geography can be found via the US Environmental Protection Agency at AirNow.gov.²¹

Exposure to extreme ambient heat or several consecutive days of extreme heat (“heat wave”) is associated with increased death from ischemic heart disease.⁸ Older adults, individuals with outdoor jobs, and patients receiving certain medications such as loop diuretics are at increased risk.^8,9 The effects of extreme heat are exacerbated in urban areas because of the “urban heat island effect,” wherein dense concentrations of pavement and buildings absorb and retain heat.¹³ Individualized assessment should include risk of exposure (ie, regional temperature and occupational exposure), clinical susceptibility (ie, age, comorbidities, and medications used), and capacity for adaptation (ie, cognitive skills, housing quality, and community resources).¹⁴ Similarly, exposure to wildfire smoke has been associated with increased hospitalizations for acute MI, ischemic heart disease, and cardiac arrest.¹² Wildfire smoke can be carried long distances, exposing individuals thousands of miles from the source.¹¹ The population health impact of wildfires is projected to increase in the coming years because of climate change–related increases in temperature and changes in precipitation patterns, as well as increased human habitation in wildland-urban interfaces.²² Minimizing exposure to these environmental extremes may improve outcomes for individuals with CCD.

The use of aspirin for secondary ASCVD prevention is well established for reduction in MACE.^2,45 More recently, the ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term) trial used a large (N=15,076), open-label design to assign patients with established ASCVD to either 81 mg or 325 mg of aspirin.³ No significant differences were observed in the primary composite of death from any cause, hospitalization for MI, or hospitalization for stroke by aspirin dose. No differences in major bleeding were observed. However, substantial dose switching was observed (41.6% of patients assigned to take 325 mg daily switched to 81 mg daily and 7.1% assigned to take 81 mg daily switched to 325 mg daily). As an alternative to low-dose aspirin, clopidogrel may be used in individuals who cannot tolerate aspirin therapy, and many of the contemporary trials have used clopidogrel monotherapy after a short course of DAPT.^46,47

To assess optimal duration of antiplatelet therapy, a meta-analysis of RCTs (n=31,666 patients) comparing shorter DAPT with longer DAPT showed that shorter DAPT was associated with lower all-cause mortality.⁴ Patients treated with DAPT for ≤6 months had similar mortality rates, MI, and stent thrombosis, but lower rates of major bleeding than patients treated with 1-year DAPT.⁴ Data supporting the use of DAPT for 6 months with continued use of aspirin after 6 months come from several trials. The largest trial was ISAR-SAFE (Randomized, Double Blind Trial of 6 Versus 12 Months of DAPT After DES-Implantation; N=4,005 patients, of which 60% had stable CAD).⁷ In these trials, aspirin use continued for the duration of the 12-month trial design.^5,12 Data are limited on which antiplatelet agent—aspirin or clopidogrel—is best for indefinite therapy after a 12-month period after PCI. The HOST-Exam (Harmonizing Optimal Strategy for Treatment of coronary artery diseases-Extended Antiplatelet Monotherapy) trial enrolled 5,530 East Asian participants if they tolerated DAPT for 6 to 18 months without any ischemic or major bleeding complication and randomized them to receive clopidogrel 75 mg daily or aspirin 100 mg daily for 24 months.⁴⁶ The benefit of clopidogrel over aspirin was observed in both thrombotic and bleeding complications. This study used an open-label design in a homogenous East Asian population known to have lower rates of thrombotic complications, and the observed event rate was lower than expected. Therefore, further clinical trials would be useful to guide recommendations regarding the long-term use of clopidogrel versus aspirin as SAPT in CCD.^46,48,49

Multiple clinical trials (SMART CHOICE [Comparison Between P2Y12 Antagonist Monotherapy and Dual Antiplatelet Therapy after DES], STOP-DAPT2 [Short and Optimal Duration of Dual Antiplatelet Therapy after Everolimus-Eluting Cobalt-Chromium Stent-2 Acute Coronary Syndrome], TWILIGHT [Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention], and GLOBAL LEADERS [A Clinical Study Comparing Two Forms of Antiplatelet Therapy After Stent Implantation]) found reduced bleeding complications without increased ischemic complications when DAPT was used for 1 to 3 months followed by P2Y12 monotherapy.^8,9,47,50-52 These trial populations comprised 35% to 62% in stable patients with stable CAD. In a network meta-analysis that included 29,089 patients randomized to short-term DAPT followed by P2Y12 inhibitor monotherapy versus standard duration DAPT, a net clinical benefit was seen that favored short-term DAPT followed by P2Y12 inhibitor monotherapy with less MI and bleeding.⁸ A meta-analysis showed discontinuation of aspirin after 1 to 3 months with continuation of a P2Y12 agent (mostly prasugrel or ticagrelor) reduced the risk of major bleeding by 40% without an increased risk of MACE.¹⁰ These trials were not powered to assess ischemic events, particularly stent thrombosis. Therefore, longer duration DAPT may be needed for patients with higher thrombotic risk (eg, several lesions, long stent length, bifurcation location, atherectomy use, lesion location [left main], bypass graft, or chronic occlusion).

A systematic review and meta-analysis of prospective RCTs of secondary prevention examined data from 33,435 participants. Of these, 20,203 were treated with DAPT and 13,232 were given only aspirin. Patients were considered high risk and almost half had previous MI. Comorbidities also included diabetes, previous PCI, and CKD. Extended DAPT for >1 year reduced MACE (relative risk, 0.78 [95% CI, 0.67-0.90]; P=0.001) and absolute risk difference of 1.09%, or a number needed to treat for benefit of 91 to prevent 1 MACE over 31-month follow up. This came with an increased absolute 0.8% risk of major bleeding without significant intracranial or fatal bleeding.¹³ Similarly, a systematic review conducted for the 2016 ACC/AHA guidelines on DAPT³⁴ examined the incidence of death, major hemorrhage, MI, stent thrombosis, and major adverse cardiac events in 33,051 patients in 11 RCTs of prolonged versus short-course DAPT after stenting with DES and in secondary prevention after MI. Among those treated with DES, prolonged DAPT reduced stent thrombosis and MI but increased major hemorrhage. Patients with previous MI had evidence of reduced cardiovascular events at the expense of increased bleeding.^53-55 The PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54) trial enrolled 21,162 patients who had MI 1 to 3 years before being given ticagrelor 90 mg or 60 mg twice daily compared with placebo on a background of low-dose aspirin.⁵⁶ Treatment with ticagrelor 60 mg reduced the risk of cardiovascular death, MI, or stroke by 16% and increased the risk of major bleeding at 33-month follow up.¹⁴

Given multiple pathways of platelet activation, options for additional suppression of platelet activity have been studied. PAR-1 is a key receptor for thrombin activation. Vorapaxar selectively inhibits PAR-1 on platelets, thereby potently inhibiting thrombin-induced platelet aggregation. The TRAP 2P TIMI 50 (Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients with Atherosclerosis) trial randomized 26,449 patients with history of MI, ischemic stroke, or peripheral artery disease to either 2.5 mg of vorapaxar daily or placebo on a background of aspirin therapy. At a mean follow up of 3 years, patients who received vorapaxar experienced an ischemic event less often or died from cardiovascular causes; however, they had more major and intracranial bleeding.¹⁵ In a prespecified subgroup analysis of 17,779 patients who had previous MI, there was a reduced incidence of cardiovascular death, MI, or stroke in the vorapaxar group compared with placebo; however, moderate or severe bleeding was increased.¹⁶ In a prespecified analysis of 16,897 patients with previous MI without a history of stroke or TIA and on thienopyridine therapy, vorapaxar reduced the composite of cardiovascular death, MI, or stroke compared with thienopyridine use; however, GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) moderate or severe bleeding was increased. Three-year rates of fatal bleeding were 0.2% versus 0.1% in patients receiving vorapaxar versus thienopyridine. Intracranial hemorrhage rates were 0.5% versus 0.4% in that cohort. Vorapaxar had net clinical benefit with a combined risk of all-cause death, MI, stroke, or GUSTO severe bleeding decreased by 13% compared with placebo. Of note, thienopyridine use was not randomized in this study; therefore, formal comparison is limited. The thienopyridine used was clopidogrel therefore extrapolation to more potent P2Y12 agents is not possible.¹⁷

In a systematic review and meta-analysis of observational and RCTs (N=20,315 patients) comparing DAPT with SAPT after urgent or elective CABG,¹⁸ investigators performed a pooled sensitivity analysis of studies with stable ischemic heart disease–predominant patients (>50% of study population), and found no difference between SAPT and DAPT after CABG in overall mortality (odds ratio, 0.83 [95% CI, 0.63–1.10]; P=0.20), cardiovascular mortality (odds ratio, 0.66 [95% CI, 0.34–1.29]; P=0.23), MI (odds ratio, 1.15 [95% CI, 0.66–1.99]; P=0.63), stroke (odds ratio, 0.58 [95% CI, 0.32–1.06]; P=0.08), combined incidence of cardiovascular death, MI, and stroke (odds ratio, 0.81 [95% CI, 0.57–1.16]; P=0.25), and arterial graft occlusions (odds ratio, 1.13 [95% CI, 0.73–1.73]; P=0.59). In the studies that had predominantly stable patients with CAD, the rate of saphenous vein graft occlusion was lower among those receiving DAPT (odds ratio, 0.74 [95% CI, 0.60–0.90]; P<0.01).

Clopidogrel plus aspirin is not more effective than aspirin alone in reducing the rate of MI, stroke, or death from cardiovascular causes in patients at high risk for atherothrombotic events.¹⁹

In the TRAP 2P–TIMI 50 trial, after 2 years the data and safety monitoring board recommended discontinuation of study treatment in patients with a history of stroke because of the risk of intracranial hemorrhage. Significant reduction in cardiovascular death, MI, stroke, or recurrent ischemia leading to revascularization was observed; however, the primary driver of benefit was in lower risk of MI, at a cost of increased moderate to severe bleeding along with increased intracranial bleeding.^15,57 Vorapaxar is FDA approved for use in patients with previous MI for the reduction in cardiovascular death, MI, stroke, or recurrent ischemia leading to revascularization; however, it carries a 55% increase in moderate or severe bleeding and is contraindicated with a history of stroke, TIA, or intracranial hemorrhage.

In the TRITON-TIMI 38 (Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis In Myocardial Infarction 38) trial, patients with previous TIA or stroke had increased risk of intracranial hemorrhage leading to an FDA warning: Prasugrel can cause significant, sometimes fatal, bleeding and should not be used in patients with active pathological bleeding or with a history of TIA or stroke. Patients ≥75 years of age and weighing <60 kg had less clinical efficacy with prasugrel use.^21,58

Investigators have assessed the vascular and gastrointestinal side effects in patients with vascular disease and have found major vascular events were increased by about a third by a coxib (relative risk, 1.37 [95% CI, 1.14–1.66]; P=0.0009) or diclofenac (relative risk, 1.41 [95% CI, 1.12–1.78]; P=0.0036), because of an increase in major coronary events (coxibs relative risk, 1.76 [95% CI, 1.31–2.37]; P=0.0001; diclofenac relative risk, 1.70 [95% CI, 1.19–2.41]; P=0.0032). Ibuprofen also significantly increased major coronary events (relative risk, 2.22 [95% CI, 1.10–4.48]; P=0.0253). Vascular death was increased significantly by coxibs (relative risk, 1.58 [99% CI, 1.00–2.49]; P=0.0103) and diclofenac (relative risk, 1.65 [95% CI, 0.95–2.85], P=0.0187). HF risk was doubled by all nonsteroidal anti-inflammatory drugs.²² However, at moderate doses, celecoxib was found to be noninferior to naproxen or ibuprofen regarding increased cardiovascular risk in patients with arthritis who were considered high cardiovascular risk (stable angina, history of MI, unstable angina, status post CABG or PCI, TIA, or cerebrovascular accident within 3 months, >50% stenosis, carotid disease, peripheral artery disease, diabetes, age >55 years in men, age >65 years in women, hyperlipidemia, hypertension, early family history of CAD, smoking). These trials involved celecoxib, rofecoxib, etoricoxib, and lumiracoxib and 3 high-dose nonsteroidal anti-inflammatory regimens: diclofenac 150 mg, ibuprofen 2,400 mg, and naproxen 1,000 mg daily.

A systematic review and network meta-analysis of 4 RCTs, including 10,026 patients (39%–72% with stable CAD)^23,59 showed that the combination of a DOAC with a P2Y12 inhibitor was associated with less bleeding compared with vitamin K agonists and DAPT. The omission of aspirin led to less bleeding, including intracranial bleeding, without differences in MACE, compared with strategies including aspirin.⁵⁹ In an updated network meta-analysis including these trials and a fifth trial (ENTRUST-AF PCI [Edoxaban Treatment Versus Vitamin K Antagonist in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention]; N=11,542), fewer bleeding complications were observed with preserved antithrombotic efficacy when aspirin was discontinued within a few days (3–14 days) after PCI. The authors concluded that an antithrombotic regimen of vitamin K agonists plus DAPT should generally be avoided. The use of a DOAC (apixaban 5 mg twice daily or 2.5 mg twice daily in those with 2 of 3 criteria for high bleeding risk; rivaroxaban 15 mg daily; edoxaban 60 mg daily or 30 mg if creatinine clearance 15-50 mL/min, weight <60 kg, or concurrent use of specific potent P-glycoprotein inhibitors; and dabigatran 110 mg or 150 mg twice daily) plus a P2Y12 inhibitor without aspirin may be the most favorable treatment option and the preferred antithrombotic regimen for most patients with AF undergoing PCI. The AUGUSTUS trial (A Study of Apixaban in Patients with AF, not Caused by a Heart Valve Problem, who are at Risk for Thrombosis due to having had a Recent Coronary Event, such as a Heart Attack or a Procedure to Open the Vessels of the Heart) examined randomized treatment effects of low-dose aspirin (compared with placebo) and apixaban (compared with vitamin K antagonist [VKA]) on the risk of stent thrombosis and found a 2-fold increase in bleeding with aspirin while the incidence of stent thrombosis was low, occurring in <1% over 6 months. However, the study had limited power to detect a difference in stent thrombosis. Rates of stent thrombosis were lower with aspirin compared with placebo and with apixaban compared with VKA. Among patients with a high risk of stent thrombosis and an acceptable bleeding risk, the use of aspirin up to 30 days after PCI should be considered.²⁵

Triple therapy after PCI in patients with AF increases bleeding risk without significant reduction in ischemic risk.⁵⁹ A recent expert consensus document recommends triple therapy with aspirin, a P2Y12 inhibitor, and an oral anticoagulant for up to 30 days after PCI for patients at particularly high risk for coronary thrombosis such as previous MI, complex lesions, presence of select traditional cardiovascular risk factors, or extensive CVD but with bleeding risk that is judged to be low.²⁹ A subgroup analysis of the REDUAL PCI trial (Dual Therapy with Dabigatran/Ticagrelor Versus Dual Therapy with Dabigatran/Clopidogrel in ACS Patients with Indication for NOAC Undergoing PCI) examined effect of lesion complexity and clinical risk factors. This trial found that dabigatran dual therapy after PCI was associated with reduced bleeding risk compared with warfarin triple therapy, independent of the presence of procedural or clinical complexity factors. However, patients in the highest lesion complexity and clinical risk factor group had the highest hazard ratio (1.43 [95% CI, 0.74-2.77]) for death, thromboembolic event, or unplanned revascularization in the dabigatran 110 mg dual therapy compared with dabigatran 150 mg dual therapy (hazard ratio, 0.88 [95% CI, 0.33-2.36]) both compared with warfarin triple therapy.^60-63

The AFIRE (Atrial Fibrillation and Ischemic Events With Rivaroxaban) trial was a multicenter, open-label trial that randomized 2,236 patients with AF who had previous PCI or CABG >1 year earlier or who had CCD to rivaroxaban versus rivaroxaban plus a single antiplatelet agent (70.2% received aspirin, and 26.8% received a P2Y12 inhibitor). The primary endpoint was a composite of stroke, systemic embolism, MI, unstable angina requiring revascularization, or death from any cause, with a safety endpoint of major bleeding. Rivaroxaban monotherapy was noninferior to combination therapy for efficacy and superior for safety among patients with AF and stable CAD. In patients with stable CCD and AF, the addition of antiplatelet therapy to a VKA does not reduce the risk of recurrent coronary events or thrombosis; furthermore, this combination leads to significantly increased bleeding risk.^26,64,65

Several studies have evaluated triple therapy with a DOAC and DAPT as well as a DOAC and SAPT in patients with AF and recent ACS.^27,28,38-44 Although these trials showed a lower risk of bleeding with a DOAC combined with a single antiplatelet agent compared with triple therapy, none of the studies were powered to clearly show differences in reducing ischemic events. Additionally, data are limited comparing either of these therapies for secondary prevention in patients with AF. This recommendation is based on historical data with warfarin as well as data extrapolated from more recent studies evaluating various combination therapies versus monotherapy in patients with a recent ACS.^38-44,66-70

The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial evaluated the efficacy and safety of low-dose rivaroxaban 2.5 mg twice daily, with or without low-dose aspirin therapy, in reducing CVD events in patients with stable ASCVD.³⁰ The primary outcome of cardiovascular death, stroke, or MI occurred in 4.1% of the aspirin plus rivaroxaban group, 4.9% of the rivaroxaban alone group, and 5.4% for aspirin monotherapy. The study was terminated early because of the observed benefit of rivaroxaban plus aspirin compared with aspirin alone. Evaluation of high-risk patients (multivessel CAD and at least one of the following: diabetes requiring medication, recurrent MI, peripheral artery disease, HF, or CKD with an eGFR of 15-59 mL/min/m^{2 69}) showed an absolute net clinical benefit with combination therapy, with substantial reductions in ischemic events and all-cause death.³¹ The high-risk population also derived a larger absolute risk reduction, resulting in an even lower number needed to treat.^30-32 The combination of rivaroxaban plus aspirin resulted in a higher risk of major bleeding compared with aspirin monotherapy (3.1% versus 1.9%; hazard ratio, 1.70 [95% CI, 1.40–2.05]; P<0.001]). The use of DAPT was an exclusion criteria.

Increased bleeding including gastrointestinal bleeding is a common side effect of DAPT; the mitigation of this risk has been an area of clinical investigation. SAPT (aspirin or clopidogrel) compared with DAPT leads to lower gastric or small intestinal mucosal injury.⁷¹ Aspirin increases gastroduodenal ulcer formation. When combined with aspirin therapy, P2Y12 inhibitors can promote gastric ulcer bleeding. Clopidogrel is a prodrug that requires cytochrome CYP P450 2C19 for metabolism to its active form. PPIs are also metabolized by the P450 system, thereby leading to concern for inadequate clopidogrel therapy in those on both PPIs and DAPT. The FDA has added a boxed warning to avoid use of omeprazole with clopidogrel as well as other potent CYP 2C19 inhibitors, including esomeprazole. Several studies assessed the safety and efficacy of PPI in the context of DAPT. A meta-analysis of 6 RCTs (6,930 patients) showed that the use of PPIs is associated with a reduced risk of gastrointestinal bleeding in patients treated with DAPT after PCI. No significant differences were observed in the incidence of MACE, MI, and all-cause death in patients with CAD on DAPT and PPIs.³³

Multiple well-conducted RCTs from the precontemporary as well as modern era showed the efficacy of beta-blocker therapy in reducing cardiovascular death and MACE among patients with LV systolic dysfunction.^1-4,7,25 This benefit was found among patients with previous MI and those without history of MI.^1,2,4,5,25 Furthermore, data from the KAMIR-NIH (Korea Acute Myocardial Infarction Registry-National Institute of Health) registry suggest that the clinical benefits of beta-blocker therapy may extend beyond patients with reduced LVEF (≤40%) and even toward patients with mid-range LVEF (40%–49%).² Given unequivocal benefit of beta-blocker therapy, widespread use of these agents in this subset of patients has been recommended. For detailed discussion of beta-blocker use in heart failure patients, see the “2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.”²⁰

Different beta blockers have been at the center of multiple clinical investigations evaluating their effectiveness among patients with HF with LV systolic dysfunction.^3,4,8,30-32 CIBIS-II (Cardiac Insufficiency Bisoprolol Trial II), COPERNICUS (Carvedilol Prospective Randomized Cumulative Survival Study), and MERIT-HF (Metoprolol Randomized Intervention Trial in Congestive Heart Failure) RCTs have shown clinical efficacy of bisoprolol, carvedilol, and metoprolol succinate among patients with LV systolic dysfunction in reducing cardiovascular death and MACE.^3,4,30 Continued dose titration was performed within these trials to target doses of 10 mg per day for bisoprolol, 200 mg per day for metoprolol succinate, and 25 mg twice daily for carvedilol (or 50 mg twice daily for patients weighing >84 kg).

Although previous iterations of the ACC/AHA guidelines on patients with stable ischemic heart disease recommended the use of beta-blocker therapy in patients with previous MI and preserved LV systolic function, this recommendation was based on data gathered from the noncontemporary era.³³ In the contemporary era of timely reperfusion/revascularization and progressive pharmacotherapy (including antithrombotic and lipid-lowering therapy) among patients with MI, the recommendation for long-term use (>1 year) of beta-blocker therapy in the absence of LV systolic dysfunction has been challenged.^13,14 Observational studies from the current era evaluating post-MI patients with preserved LV systolic function showed discrepant results with some studies suggesting clinical benefit while others showed lack of clinical benefit with long-term use of beta-blocker therapy.^9-15,34 Long-term use of beta-blocker therapy may also confer potential clinical risks including fatigue, depression, and drug-drug interactions, thereby necessitating future high-quality data to ascertain the need for and duration of beta-blocker use among this population. Several ongoing large randomized controlled clinical trials including REBOOT-CNIC (Treatment with Beta-blockers after MI without Reduced Ejection Fraction), REDUCE-SWEDEHEART (Evaluation of Decreased Usage of Beta-blockers After MI in the Swedeheart Registry), BETAMI (Beta-blocker Treatment after Acute MI in Revascularized Patients without Reduced LVEF), and DANBLOCK (Danish Trial of Beta-blocker Treatment after MI Without Reduced LVEF) aim to provide more clarity on the efficacy, safety, and QOL associated with beta-blocker therapy in patients with CCD, including post-MI patients with preserved LV systolic function.

Protective clinical benefits of beta-blocker therapy in reducing cardiovascular death have not been shown among CCD patients without previous MI or LV systolic dysfunction. The REACH (Reduction of Atherothrombosis for Continued Health) registry evaluated patients with CAD without history of MI and studied the effect of beta-blocker therapy on the primary endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke.¹⁸ Among patients with CAD without a history of MI, the use of beta-blocker therapy was not associated with a significant reduction in event rates for the primary endpoint. Similarly, a recent analysis from the National Cardiovascular Data Registry CathPCI registry evaluated the clinical benefit of beta blockers among patients with stable angina without a history of MI, LV systolic dysfunction, or systolic HF who were undergoing PCI.¹⁹ The authors showed that the use of beta blockers was not associated with improvement in cardiovascular morbidity or mortality rates at 30 days or at 3-year follow-up. Similar results were seen in a post-hoc analysis from the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance) trial in which no reduction in cardiovascular events was observed with the use of beta blockers among patients without previous MI or HF.¹⁷

In RCTs,^1-5 RAASi improved symptoms, reduced hospitalizations, prolonged survival, or all 3 among high-risk patients with CCD. In patients with hypertension and diabetes, RAASi reduce the incidence of moderate albuminuria and end-stage renal disease.^16-18 For patients with CCD and LVEF ≤40% who are clinically symptomatic beyond stage B, refer to the 2022 AHA/ACC/HFSA heart failure guideline.¹⁹

In the HOPE trial,¹⁰ high-risk patients with CCD and preserved LVEF assigned to ramipril 10 mg daily had significant reductions in the composite of death, cardiovascular events, and stroke, although the concurrent use of other risk reduction medications was low compared with other trials.¹⁰ The EUROPA trial compared perindopril 8 mg daily to placebo in a lower risk population.⁹ In the PEACE trial,²⁰ which compared trandolapril versus placebo in populations with CCD and normal LVEF, RAASi were not associated with reduced total mortality rate; however, there was a benefit in a subset of patients with reduced renal function (eGFR, <60 mL/min/m²).¹¹ In QUIET,¹³ quinapril had no effect on progression of atherosclerosis in patients with CCD and preserved LVEF, except in those with CKD. The CAMELOT study⁸ found no reduction in MACE among patients with CCD and normal BP. The lack of overall benefit of RAASi in lower risk populations likely reflects both baseline comorbidities and levels of concurrent pharmacotherapies with other evidence-based therapies for CCD.^20,21

The LoDoCo2 (Colchicine Reduces Risk of Major Cardiovascular Events in CCD) trial aimed to validate the LoDoCo (Low Dose Colchicine for Secondary Prevention of Cardiovascular Disease) results among patients with clinically stable ASCVD who had shown a reduced risk of recurrent cardiovascular events in patients taking colchicine 0.5 mg daily compared with placebo.^2,5 The primary endpoint was a composite of cardiovascular death, spontaneous MI, ischemic stroke, or ischemic-driven revascularization, which occurred in 6.8% of patients in the colchicine group compared with 9.6% in the placebo group (P<0.001). Despite the positive results, the study showed a trend toward increased risk of death from noncardiovascular causes in the colchicine group. The first trial to evaluate the efficacy of colchicine in secondary prevention in patients with ACS was the COLCOT trial.^8,9 Of patients treated with colchicine, the primary endpoint of death from cardiovascular causes, MI, resuscitated cardiac arrest, stroke, or urgent hospitalization for angina leading to coronary revascularization occurred in 5.5% of patients compared with 7.1% in the placebo group (P=0.02). These results were driven primarily by reductions in the incidence of strokes and urgent hospitalizations for angina leading to coronary revascularization. Although studies evaluating colchicine in secondary prevention excluded patients with creatinine clearance of <50 mL/min, these studies were also limited to a duration of just over 2 years.^1,2 Given its long half-life, narrow therapeutic window, and degree of dependence on renal function for clearance, use should be avoided in patients with advanced renal disease (eGFR, <30 mL/min/m²). Additionally, colchicine is metabolized by CYP3A4 and is a substrate for P-glycoprotein, which necessitates careful evaluation for drug-drug interactions.¹⁰

Studies show a significant association between recent respiratory infection and acute MI.¹ Meta-analyses and systematic reviews showed that influenza vaccination was associated with a lower risk of acute MI, cardiovascular death, MACE, and all-cause death in patients with CAD or HF.^1-5,7 However, 1 study found no significant reduction in MI among those who received the influenza vaccine compared with control.⁷ In patients with previous stroke, there was a nonsignificant trend for reduction of recurrent stroke risk.³ No reduction was seen in all-cause death or cardiopulmonary hospitalization in high-risk patients with CCD who received high-dose trivalent influenza vaccine versus standard-dose quadrivalent influenza vaccine, although more vaccine-related adverse reactions occurred in the high-dose trivalent influenza vaccine group.⁶

Although outcome data about the benefit of the COVID-19 vaccination in patients with CCD are unavailable at the time of writing this guideline, the targeted population for whom this guideline is intended is among the highest risk for developing COVID-19–related complications and death.⁸ Therefore, the writing committee supports COVID-19 vaccination for patients with CCD and that the benefits of the COVID-19 vaccination outweigh the potential adverse events related to the vaccine itself.^8-10 For reference, US Centers for Disease Control and Prevention (CDC) guidance may be accessed at https://www.cdc.gov/coronavirus/2019-ncov/communication/guidance.html.¹⁵

Limited data are available that evaluate pneumococcal polysaccharide vaccination in patients with CCD and its effect on cardiovascular outcomes and all-cause death. A population-based cohort study of 6,171 patients (18% with ischemic heart disease) who were hospitalized for pneumonia within 90 days and received previous pneumococcal polysaccharide vaccination found a 58% reduction in ACS events (12 versus 16 events per 100 patient-years [adjusted hazard ratio, 0.42 (95% CI, 0.27-0.66)]).¹¹ A systematic review and meta-analysis of observational studies with >163,000 participants found that the PPSV23, PCV13, or both was associated with a 22% decrease in all-cause death in patients with CCD or those with very high cardiovascular risk, although the study design of some included studies led to a decreased level of design confidence.¹² A retrospective observational study using the 2012-2015 US National Inpatient Sample database evaluated the combined use of pneumococcal polysaccharide vaccine (PPV) and influenza vaccine and found lower mortality rate (2.21% versus 1.03%; P=0.001) and lower cardiac arrest (0.61% versus 0.51%; P<0.001). The relative risk was 0.46 (95% CI, 0.43–0.49) in the adjusted analysis for this combined vaccination group. This group also had significantly reduced risk of mortality among those admitted with MI (relative risk, 0.46), TIAs (relative risk, 0.58), and stroke (relative risk, 0.42) compared with the nonvaccinated group.¹³

Beta blockers have been considered the first antianginal to use in patients with symptomatic CCD, although the evidence basis for this prioritization is not strong. Early randomized, placebo-controlled studies found that beta blockers increased the percentage of patients free of exertional angina, reduced anginal attacks and reduced nitroglycerin consumption.^1,2 A meta-analysis of 72 studies comparing beta blockers with CCBs found fewer episodes of angina per week with beta blockers and lower rates of drug discontinuation.³ No difference was observed in the rate of death or MI between the 2 drug classes. A more recent meta-analysis including only larger studies comparing beta blockers with calcium channel blockers found no difference in the primary endpoint of exercise duration.⁴ In randomized, placebo-controlled trials, CCBs effectively relieve angina, decrease nitroglycerin consumption, and increase exercise duration.^14,15 Long-acting nitrates decrease angina and improve exercise duration.¹⁶ Non-dihydropyridine CCBs (verapamil and diltiazem) can further depress LV function and should not be used in patients with CCD and significant LV dysfunction.¹⁷

In patients with CCD and angina refractory to 1 agent, a combination with another antianginal agent improves symptom control.⁵ Non-dihydropyridine CCBs should be used with caution in patients on beta blockers because of the potential for synergistic induction or exacerbation of bradycardia and LV dysfunction. The addition of a long-acting nitrate to a beta blocker or a CCB improves exercise tolerance, reduces angina frequency and short-acting nitrate use.⁵

Two randomized, placebo-controlled studies showed that the addition of ranolazine on the background of standard anti-anginal therapy improved anginal outcomes.^7,8 In the CARISA (Combination Assessment of Ranolazine in Stable Angina) trial, 823 patients with CCD were randomized to placebo or 1 of 2 doses of ranolazine.⁷ After 12 weeks of therapy, ranolazine improved exercise capacity and more effectively relieved angina compared with placebo. In the ERICA (Efficacy of Ranolazine in Chronic Angina) trial, 565 patients with CCD and persistent symptoms despite a maximally tolerated dose of amlodipine were randomized to ranolazine or placebo.⁸ After 6 weeks, patients randomized to ranolazine had significantly fewer anginal episodes and less nitroglycerin consumption.

Short-acting nitrates help to relieve acute episodes of angina.⁹ One can decrease symptoms by administering a short-acting nitrate prior to activity that typically triggers symptoms. In randomized studies, nitroglycerin spray in comparison with a sublingual formulation is more effective and efficient at relieving angina, but with less headache.¹⁰

The role of ivabradine in patients with CCD has not been studied as extensively as other antianginal therapies. One study comparing ivabradine with atenolol and another comparing it with amlodipine in a double-blind, randomized manner both found similar improvements in exercise time and angina relief with ivabradine.^18,19 Another study found that the addition of ivabradine to atenolol in patients with CCD resulted in improved exercise capacity compared with placebo.¹⁸ However, a more recent study randomized 19,102 patients with CCD, no evidence of HF, and a resting heart rate of at least 70 beats per minute to ivabradine or placebo in addition to GDMT, including standard anti-anginal treatment.¹¹ At approximately 28-month follow-up, the rate of the primary endpoint of cardiovascular death or MI was similar between both groups. In patients with activity-limiting angina, although ivabradine led to improvement in angina class in 24% compared with 18.8% receiving placebo (P=0.01), the primary endpoint of death or MI was significantly higher in the patients randomized to ivabradine (7.6% versus 6.5%; P=0.02), suggesting possible harm when ivabradine is used in this setting.

MUST-EECP (Multicenter Study of Enhanced External Counterpulsation) did not study refractory angina.¹ This therapy has evolved for use in patients with no other options, but the evidence base supporting this shift is inadequate, consisting of observational studies and small RCTs. Enhanced external counterpulsation was a Class 2b recommendation in the 2012 ACC/AHA stable ischemic heart disease guideline, and this was reaffirmed in the 2014 focused update.^2,8 No interval data are available that warrant a change in this recommendation. Enhanced external counterpulsation has limited availability and appears to be used primarily in patients who remain symptomatic and without other therapeutic options.