Prevention of cardiovascular disease events in those with established disease (secondary prevention)

INTRODUCTION — 

Patients with established atherosclerotic cardiovascular disease (ASCVD) have a high risk of subsequent ASCVD events, including myocardial infarction (MI), stroke, and death. For all patients with ASCVD, therapeutic lifestyle changes of proven benefit, which include increased physical activity, dietary modification/weight loss, and smoking cessation, improve outcomes, some beginning within a matter of weeks. Adjunctive drug therapies of proven benefit include statins and aspirin, whose benefits are at least additive. Additional measures include treatment of dyslipidemia and hypertension and management of diabetes mellitus.

This topic is an overview of our approach to the prevention of ASCVD events in those with established ASCVD. These include individuals who have had a cardiovascular event, such as MI, stroke, or transient ischemic attack, and those with symptomatic presentations of ASCVD, such as angina or limb claudication.

In addition, some patients have unequivocable imaging evidence of ASCVD, such as a computed tomography (CT) coronary angiogram, a calcium score test, or other CT imaging or magnetic resonance imaging that documents obstructive (≥50 percent) atherosclerosis in the coronary, cerebrovascular, or peripheral arterial beds. We include these individuals in our definition of established ASCVD.

Our approach in those without ASCVD is presented separately. (See "Overview of primary prevention of cardiovascular disease in adults".)

DYSLIPIDEMIA — 

Management of dyslipidemia, particularly reduction of low-density lipoprotein (LDL) cholesterol, is essential in individuals with atherosclerotic cardiovascular disease. We treat virtually all these patients with evidence-based doses of a high-potency statin and add nonstatin agents, such as ezetimibe or proprotein convertase subtilisin/kexin type 9 inhibitors, for LDL management when indicated. Management and treatment goals are discussed elsewhere. (See "Management of low-density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease", section on 'Initial drug therapy to reduce LDL-C'.)

HYPERTENSION — 

Our recommendations for the establishment of goal blood pressure and the use of weight loss and salt restriction together with adjunctive drug therapies are discussed separately. (See "Goal blood pressure in adults with hypertension" and "Hypertension in adults: Initial drug therapy".)

We recommend therapeutic lifestyle changes of proven benefit for all apparently healthy individuals. In addition, this recommendation should be especially emphasized to patients with blood pressures of 120/80 mmHg or greater [1,2]. Therapeutic lifestyle changes of proven benefit include weight loss, increased physical activity, dietary sodium restriction, and reduction or avoidance of alcohol. Institution of therapeutic lifestyle changes of proven benefit poses little or no risks, and all are likely to be beneficial for all patients regardless of blood pressure. (See "Diet in the treatment and prevention of hypertension" and "Overweight, obesity, and weight reduction in hypertension" and 'Lifestyle modifications' below.)

DIABETES MELLITUS — 

The benefits of glycemic control on microvascular as well as macrovascular disease in patients with type 1 and type 2 diabetes are discussed separately. (See "Glycemic management and vascular complications in type 1 diabetes mellitus", section on 'Macrovascular disease' and "Glycemic management and vascular complications in type 2 diabetes mellitus".)

Apart from their role in glycemic control, some antidiabetic agents provide additional cardiovascular benefits in patients with diabetes and atherosclerotic cardiovascular disease; these include selected sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonist agents. (See "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects'.)

LIFESTYLE MODIFICATIONS — 

Lifestyle modifications such as smoking cessation, increase in physical activity, and improvement in diet have important beneficial effects on cardiovascular disease (CVD) morbidity and mortality that begin relatively shortly after their institution [3,4].

Diet — In observational studies, individuals who self-select for healthy diets experience significantly lower CVD event rates. Dietary interventions, in particular a Mediterranean diet, improve outcomes in patients with established CVD [5]. (See "Healthy diet in adults".)

We agree with the following dietary recommendations of the 2019 American College of Cardiology/American Heart Association (ACC/AHA) guideline on primary prevention of CVD [6]:

●We encourage adherence to diets that emphasize high intakes of vegetables, fruits, nuts, whole grains, lean vegetable or animal protein, and fish.

●Diets should minimize the intake of trans fats, red meat and processed red meats, refined carbohydrates, and sweetened beverages. (See 'Dyslipidemia' above.)

The European Society of Cardiology (ESC) guidelines on CVD prevention (both primary and secondary) make a recommendation for a Mediterranean or similar diet to reduce CVD risk [7]. Further, they suggest replacing saturated with unsaturated fats, reducing salt intake, choosing a plant-based food pattern high in fiber, and eating fish, preferably fatty, at least once a week. (See "Healthy diet in adults", section on 'Mediterranean diet' and "Overview of primary prevention of cardiovascular disease in adults", section on 'Healthy diet'.)

For patients with known CVD or those at high risk who consume fish or are willing to do so, we recommend that they consume at least one to two servings per week of oily fish, which is consistent with the AHA recommendations [8]. Consumption of fish as part of a healthy diet is discussed in detail elsewhere. (See "Healthy diet in adults", section on 'Protein-rich foods'.)

Weight reduction — In large-scale prospective studies [9], individuals who are overweight or obese have increased risks for CVD across a large range of levels. In the United States as well as other resource-rich countries, overweight and obesity may be overtaking smoking as the leading avoidable cause of premature death [10]. Weight reduction is difficult to achieve and maintain; among the 90 percent of subjects who are successful initially, approximately 90 percent of those eventually regain the lost weight. However, a clear benefit of weight reduction on cardiovascular outcomes has not been clearly demonstrated. (See "Overweight and obesity in adults: Health consequences" and "Obesity: Association with cardiovascular disease".)

Overweight and obesity also are major contributors to metabolic syndrome a constellation of hypertension, dyslipidemia, and insulin resistance leading to diabetes. In the United States, metabolic syndrome, which confers high risk of a first CVD event, occurs in approximately 40 percent of individuals over age 40. In addition, overweight and obesity in the absence of metabolic syndrome also confer significantly increased risks of CVD [11-16].

All patients with CVD should have a measurement of waist circumference and a calculation of body mass index (BMI; calculated as weight in kilograms divided by height in meters squared). Weight reduction is optimally achieved with multiple strategies, including diet, increased physical activity, and possible pharmacologic therapy. (See "Obesity in adults: Overview of management".)

The 2018 US Preventive Services Task Force (USPSTF) recommendation statement on weight loss to prevent obesity-related morbidity and mortality in adults recommends that clinicians offer or refer adults with a BMI of 30 or higher to intensive, multicomponent behavioral interventions [17].

Physical activity — Regular physical activity has numerous cardiovascular benefits, including weight loss, improvements in lipid profile, and reductions in blood pressure, as well as prevention and management of type 2 diabetes. All these beneficial effects lead to improvements in CVD morbidity and mortality. These issues are discussed in detail elsewhere. (See "Exercise and fitness in the prevention of atherosclerotic cardiovascular disease" and "Cardiac rehabilitation: Indications, efficacy, and safety in patients with coronary artery disease".)

Prior to initiation of an activity program, most high-risk patients should undergo risk assessment with a physical activity history and/or an exercise test [18]. (See 'Cardiac rehabilitation programs' below.)

We agree that the following recommendation for physical activity made in the 2019 ACC/AHA guideline on primary prevention of CVD is applicable to secondary prevention: Adults should engage in at least 150 minutes per week of accumulated moderate-intensity physical activity or 75 minutes per week of vigorous-intensity physical activity [6].

Smoking cessation — Smoking cessation is associated with significant reductions in cardiovascular outcomes. The elevated CVD risk associated with smoking begins to decline within months of smoking cessation and declines to that of individuals who have never smoked within three to five years. These benefits have been shown in secondary and primary prevention. (See "Cardiovascular risk of smoking and benefits of smoking cessation".)

●In a meta-analysis of observational studies that included 12,603 participants who smoked and had a prior myocardial infarction (MI), coronary artery bypass graft surgery, angioplasty, or known coronary heart disease (CHD) [19], quitting smoking was associated with a reduced mortality risk compared with continuing to smoke (relative risk [RR] 0.64, 95% CI 0.58-0.71).

●In a cohort study of 2619 patients, longer durations of smoking cessation after an incident MI were associated with progressively decreasing risks of recurrent coronary events (RR 1.62 [0 to <6 months], 1.60 [6 to <18 months], 1.48 [18 to <36 months], and 1.02 [≥36 months]) [20].

The various major effective modalities to attain and sustain smoking cessation are discussed separately. (See "Overview of smoking cessation management in adults".)

Passive smoking has been clearly linked with a higher risk of CVD [21]. Banning smoking in public places quickly reduced the incidence of acute MI in many observational studies [22].

Alcohol — Whereas heavy alcohol consumption and binge drinking are associated with an increased risk of CHD, the cardiovascular effects of low to moderate alcohol intake are less clear [23-27]. The effect of alcohol consumption on CVD is discussed separately. (See "Cardiovascular benefits and risks of moderate alcohol consumption", section on 'Effect of alcohol on cardiovascular risk'.)

Cardiac rehabilitation programs — We recommend referral to a comprehensive, outpatient cardiovascular rehabilitation program for all eligible patients with a recent acute coronary syndrome or revascularization procedure [18]. Other patients, such as those with these diagnoses in the past year, those with chronic angina, or those with peripheral artery disease, may be candidates for referral. These programs are usually designed to provide the patient with assistance in lifestyle modification. (See "Cardiac rehabilitation: Indications, efficacy, and safety in patients with coronary artery disease", section on 'Comprehensive risk factor intervention'.)

Not all patients are able to attend a cardiac rehabilitation program, and many programs limit the number of sessions. Another way to deliver assistance to patients in the adoption of a healthy lifestyle may be for the patient to receive mobile phone text messages periodically. The TEXT ME study randomly assigned 710 patients with CHD to a text message-based prevention program that delivered semi-personalized text messages four times per week with advice, motivation, and information to improve diet, increase physical activity, and encourage smoking cessation (if applicable) [28]. At six months, the intervention group had statistically significant improvements in low-density lipoprotein cholesterol (79 versus 84 mg/dL), systolic blood pressure (128.2 versus 135.8 mmHg, BMI 29.0 versus 30.3), physical activity (936 versus 642.7 metabolic equivalent minutes/week), and percent of patients who smoked (26.0 versus 42.9).

ADJUNCTIVE THERAPIES — 

All patients with established CVD and many other high-risk patients should receive aspirin and statin therapy. Other medications that may be of benefit in some patients include beta blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), aldosterone blockers, platelet P2Y₁₂ receptor blockers, colchicine, and oral anticoagulants. Administration of influenza vaccine also appears to be beneficial in patients with CVD.

Antiplatelet therapy — For patients with established CVD, we encourage long-term aspirin therapy. Long-term antiplatelet therapy with aspirin reduces the risk of subsequent myocardial infarction (MI), stroke, and cardiovascular death among patients with a wide range of manifestations of occlusive CVD. In patients who are unable to take aspirin and in those with a history of gastrointestinal bleeding, clopidogrel is a reasonable alternative.

●Patients who have percutaneous coronary intervention – For patients who have undergone percutaneous coronary intervention (PCI) with stenting or those who have had an acute coronary syndrome (ACS), a P2Y₁₂ receptor blocker is added to aspirin for some period of time. Agent selection and duration of therapy in these patients are discussed separately. (See "Percutaneous coronary intervention with intracoronary stents: Overview", section on 'Antithrombotic therapy' and "Acute ST-elevation myocardial infarction: Initial antiplatelet therapy" and "Acute non-ST-elevation acute coronary syndromes: Initial antiplatelet therapy".)

●Patients at high ischemic risk – Individuals with stable coronary artery disease (CAD) and diabetes who are at very high ischemic risk may benefit from dual antiplatelet therapy (DAPT), especially if their baseline risk of bleeding is low. DAPT typically consists of aspirin with either ticagrelor or clopidogrel. Because reductions in recurrent coronary events may be offset by increases in the risk of major bleeding, clinicians should individualize risk assessment and discuss both the benefits of preventing recurrent CVD events and the risks of bleeding with DAPT [29,30].

•In the Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study (THEMIS) of 19,220 adults with chronic coronary syndrome and type 2 diabetes mellitus, patients randomized to ticagrelor 60 mg twice daily and low-dose aspirin experienced lower rates of ischemic CVD events (cardiovascular death, MI, or stroke) at 40 months, compared with those randomized to low-dose aspirin alone (7.7 versus 8.5 percent; hazard ratio [HR] 0.90; 95% CI 0.81-0.99). However, those randomized to ticagrelor plus aspirin also had increased rates of major bleeding (2.2 versus 1.0 percent; HR 2.32; 95% CI 1.82-2.94) and intracranial hemorrhage (0.7 versus 0.5 percent; HR 1.71; 95% CI 1.18-2.48) [31]. Based on these data, the US Food and Drug Administration approved DAPT for those with chronic coronary syndrome (with or without diabetes).

•In a prespecified subgroup analysis of the 11,154 participants with PCI, ticagrelor and aspirin decreased rates of ischemic CVD events, compared with aspirin alone (7.3 versus 8.6 percent; HR 0.85; 95% CI 0.74-0.97). They also had higher rates of major bleeding (2.0 versus 1.1 percent) but comparable rates of intracranial hemorrhage, fatal bleeding, cardiovascular mortality, and all-cause mortality [32].

Other groups of patients who may benefit from longer durations of treatment with DAPT are discussed separately. (See "Long-term antiplatelet therapy after coronary artery stenting in stable patients".)

The role of antiplatelet therapy in patients with CVD is discussed in numerous other topics:

●In atherosclerotic cardiovascular disease (ASCVD) (see "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease")

●In patients who have undergone coronary artery stent placement (see "Long-term antiplatelet therapy after coronary artery stenting in stable patients")

●In the first year following ACS (see "Acute non-ST-elevation acute coronary syndromes: Initial antiplatelet therapy" and "Acute ST-elevation myocardial infarction: Initial antiplatelet therapy")

●In patients who have had a stroke (see "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke")

●In patients with peripheral artery disease

Anticoagulant therapy — In patients who require full-dose anticoagulation for a specific indication, such as atrial fibrillation or venous thromboembolic disease, we typically do not add aspirin, since this increases the risk of bleeding. This issue is discussed separately. (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease", section on 'Anticoagulated patients' and "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy", section on 'Our approach'.)

In patients without a specific indication for anticoagulation, we do not substitute or add full-dose oral anticoagulant therapy to aspirin therapy to lower the risk of subsequent CVD events. For select patients with stable CAD on antiplatelet therapy who are at high risk of cardiovascular events and low risk of bleeding, adding rivaroxaban 2.5 mg orally twice daily may be considered, based on results of the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial. Such patients include those with peripheral artery disease or a history of ischemic stroke, multivessel CAD, incomplete coronary revascularization, diabetes, patients with a body weight >60 kg (132 pounds), prior coronary artery bypass surgery, chronic kidney disease, or multiple prior ischemic events.

A large, randomized trial has evaluated the efficacy of adding low-dose rivaroxaban, an oral direct Xa inhibitor, to aspirin therapy for secondary CVD prevention in individuals at high risk of CVD events. In the COMPASS trial, 27,395 patients with stable CAD or peripheral arterial disease were randomly assigned to rivaroxaban plus aspirin, rivaroxaban alone, or aspirin alone with a mean follow-up of 23 months [33]. The dose of rivaroxaban in the combination arm was 2.5 mg orally twice per day; in the rivaroxaban-only arm, the dose was 5 mg orally twice per day. Compared with those assigned at random aspirin alone, patients assigned to rivaroxaban plus aspirin had a 22 percent significant decreases in cardiovascular mortality (1.7 versus 2.2 percent; HR 0.78, 95% CI 0.64-0.96) and 49 percent decrease in ischemic stroke (0.7 versus 1.4 percent; HR 0.51, 95% CI 0.38-0.68). There was also a possible but nonsignificant 14 percent reduction in MI (1.9 versus 2.2 percent; HR 0.86; 95% CI 0.70-1.05). As expected, those assigned to combination therapy had a 70 percent significant increase in major bleeding events (3.1 versus 1.9 percent; HR 1.70, 95% CI 1.40-2.05), with the gastrointestinal tract being the most common site of major bleeding. The risk of intracranial hemorrhage was comparable between the two groups. Mortality and cardiovascular outcomes were similar in the rivaroxaban-alone and aspirin-alone groups, but there were significantly more major bleeding events in those assigned to rivaroxaban and aspirin. Clinicians should be aware of the balance between prevention of thrombosis and causing serious bleeding.

The optimal antithrombotic strategy in patients with other reasons for anticoagulation, such as atrial fibrillation, is discussed elsewhere. (See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy", section on 'After 12 months' and "Overview of lower extremity peripheral artery disease", section on 'Antithrombotic therapy' and "Management of symptomatic peripheral artery disease: Claudication", section on 'Antithrombotic therapy'.)

The role of anticoagulant therapy in secondary prevention in patients with an ACS is discussed elsewhere. (See "Acute coronary syndrome: Oral anticoagulation in medically treated patients".)

Statins and other lipid-lowering agents — The role of statin therapy in patients at high cardiovascular risk is discussed above. (See 'Dyslipidemia' above.)

Beta blockers — In patients with recent acute MI or in those with heart failure (HF) due to systolic dysfunction, oral beta blockers may be a part of their treatment regimen. The evidence supporting these recommendations is presented elsewhere. (See "Acute myocardial infarction: Role of beta blocker therapy" and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.)

In patients with chronic coronary syndrome and angina, beta blockers reduce the severity and frequency of anginal attacks. With the exception of patients with HF, the evidence is limited about whether beta blockers lower the risk of death in patients with chronic coronary syndrome when combined with contemporary secondary prevention strategies. Some of our contributors continue beta blockers indefinitely in patients with chronic coronary syndrome, while others stop them if they are not needed for control of symptomatic ischemia. (See "Beta blockers in the management of chronic coronary syndrome", section on 'Efficacy of beta blockers in stable angina' and "Beta blockers in the management of chronic coronary syndrome", section on 'Survival'.)

ACE inhibitors or ARBs — Many patients with established CVD will benefit from ACE inhibitor or ARB therapy. The most common indications are attainment of goal blood pressure, the treatment of acute MI, or the presence of HF, left ventricular ejection fraction below 40 percent, diabetes, or proteinuric kidney disease. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Recommendations for use" and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

Other high-risk individuals include those with diabetes or chronic kidney disease. In these high-risk patients, ACE inhibitors and ARBs have been hypothesized to have cardioprotective effects independent of blood pressure lowering, but the available evidence suggests that the attained blood pressure is of primary importance. ACE inhibitors or ARBs may also be a first-line drug of choice to control blood pressure in diabetic and metabolic syndrome patients with or without prior MI. (See "Renin-angiotensin system inhibition in the treatment of hypertension", section on 'Specific indications for use'.)

Polypill — Polypills combine fixed doses of medications such as aspirin, ace-inhibitor and statin into one pill and have been proposed as a method to increase medication adherence. Their use in primary prevention of CVD is discussed elsewhere. (See "Overview of primary prevention of cardiovascular disease in adults", section on 'Single-pill combination medications'.)

In the Secondary Prevention of Cardiovascular Disease in the Elderly (SECURE) trial of nearly 2500 patients from seven European countries with recent MI, treatment with a polypill containing aspirin (100 mg), ramipril (2.5, 5, or 10 mg), and atorvastatin (20 or 40 mg) was shown to lower risk of major adverse cardiovascular events compared with usual care [34]. Eligible patients were either older than 75 or at least 65 years of age with at least one additional risk factor (diabetes mellitus, mild or moderate kidney disease, previous MI [defined as infarction occurring before the index event], previous coronary revascularization). The mean age of participants was 76 years and 70 percent were male. Time from MI to randomization was a median of 8 days (interquartile range 3 to 37).

After 36 months of follow-up, the following outcomes were observed:

●Those assigned to the polypill had significantly lower rates of cardiovascular events (cardiovascular death, nonfatal type 1 MI, nonfatal ischemic stroke, or urgent revascularization): 9.5 versus 12.7 percent; HR 0.76, 95% CI 0.60-0.96 compared with the usual care group.

●There were no differences in blood pressure and low-density lipoprotein (LDL) cholesterol levels during follow-up between the two treatment groups.

●Medication adherence as reported by the patients was higher in the polypill versus usual-care group.

●Adverse event rates were similar between treatment groups.

The lack of difference in follow-up blood pressure or LDL cholesterol suggest that the ramipril and statin components of the polypill may have had pleiotropic effects, beyond the lowering of these risk factors, that resulted in lower rates of secondary CVD [35]. (See "Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease".)

Mineralocorticoid receptor antagonist — The use of a mineralocorticoid receptor antagonist (eg, spironolactone or eplerenone) is recommended for certain patients with heart failure and reduced ejection fraction. This is described in detail elsewhere. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Mineralocorticoid receptor antagonist'.)

Colchicine — For patients with chronic CAD receiving other secondary preventive drug therapies (ie, statins and aspirin and/or other antiplatelet agents), we suggest adding colchicine 0.5 (or 0.6) mg per day. In randomized trials in the secondary prevention of CAD, colchicine improved cardiovascular outcomes [36-38]. Although studies have evaluated colchicine doses that range from 0.5 to 1 mg daily, we typically use 0.6 mg daily because it is available in the United States as a generic formulation and less expensive.

The most common side effects (diarrhea, nausea, vomiting, and abdominal pain) are usually mild. Transient, and usually painless, elevations of creatinine kinase have also been reported; this may be related to other drugs such as statins or other lipid-lowering drugs [39]. The dose of colchicine may need to be reduced in patients taking P-glycoprotein (P-gp) inhibitors or strong CYP3A4 inhibitors, including certain beta blockers, calcium channel blockers, or amiodarone.

Colchicine is contraindicated in patients with hepatic or kidney function impairment (estimated glomerular filtration rate <30 mL/min/1.73 m²).

Colchicine reduced the risk of cardiovascular events in the Low-Dose Colchicine 2 (LoDoCo2) trial. This trial randomly assigned 5522 patients, 85 percent men, with chronic CAD to 0.5 mg of colchicine once per day or placebo [36]. Almost all trial participants were taking a lipid-lowering agent and antithrombotic therapy (ie, antiplatelet or anticoagulant). After two and half years, those assigned to colchicine had a decreased risk of the primary composite endpoint (HR 0.69, 95% CI 0.57-0.83), with reductions in MI (3.0 versus 4.2 percent; HR 0.70, 95% CI 0.53-0.93) and ischemia-driven coronary artery revascularization (4.9 versus 6.4 percent; HR 0.75, 95% CI 0.60-0.94). The incidence of death from non-cardiovascular causes appeared higher in the colchicine group; however, this finding did not achieve statistical significance (0.7 versus 0.5 percent; HR 1.51, 95% CI 0.99-2.31). All-cause mortality was similar in both groups (relative risk 1.08, 95% CI 0.71-1.62). Colchicine produced no significant adverse effects except for a somewhat higher rate of myalgia (21.2 versus 18.5 percent). In post hoc subgroup analyses, benefits were similar among those with and without a history of prior ACS or timing of reported ACS [37]. A subsequent meta-analysis had similar findings to those of LoDoCo2 [38].

Prior studies have evaluated the use of colchicine in patients following ACS with similar results [40,41]. These are discussed in detail separately. (See "Overview of the nonacute management of ST-elevation myocardial infarction", section on 'Colchicine'.)

Sodium-glucose cotransporter 2 inhibitors — Certain sodium-glucose cotransporter 2 inhibitors reduce cardiovascular outcomes in patients with heart failure with reduced ejection fraction (with or without diabetes mellitus) and in patients with type 2 diabetes mellitus and existing CVD. This is discussed separately. (See "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Primary components of therapy'.)

Glucagon-like peptide 1 receptor agonists — Selected glucagon-like peptide 1 receptor agonists reduce cardiovascular outcomes in individuals with established ASCVD or at high risk of ASCVD. The cardiovascular effects of these agents in patients with and without diabetes are discussed separately. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Obesity in adults: Drug therapy", section on 'Preferred medications'.)

Marine omega-3 fatty acids — Many patients with established CVD or at high risk of CVD have hypertriglyceridemia. The role of marine omega-3 fatty acid therapy in patients with hypertriglyceridemia is discussed separately. (See "Hypertriglyceridemia in adults: Management", section on 'Marine omega-3 fatty acids'.)

We do not routinely recommend marine omega-3 fatty acids in individuals with CAD without hypertriglyceridemia. For such patients, there is less evidence supporting their use.

COVID-19 and influenza vaccination — We encourage all patients with CVD to receive periodic vaccinations against coronavirus disease 2019 (COVID-19), which continues to mutate and confers high risks of hospitalizations and deaths (table 1). (See "COVID-19: Vaccines".)

As with adults in the general population, we recommend an annual influenza vaccine for patients with CVD [18]. (See "Seasonal influenza vaccination in adults".)

Individuals with established CVD and high-risk primary prevention subjects have increased risks for complications of influenza infection. In a cross-sectional study of 80,000 adults hospitalized with influenza (of whom 20 percent had chronic CVD, 20 percent chronic kidney disease, and 15 percent diabetes), 11.7 percent had an acute cardiovascular event during hospitalization, most commonly acute HF or acute ischemic heart disease [42].

Influenza vaccines may reduce mortality and CVD outcomes in these patients [43-47]. In a 2013 meta-analysis of trials conducted among persons with CVD or at high risk, those receiving an influenza vaccine had fewer cardiovascular events than those in the control group [48]. A randomized clinical trial of 2571 participants at 30 centers across eight countries found that primary outcomes (all-cause death, MI, and stent thrombosis) were less frequent in participants assigned influenza vaccine versus those assigned placebo (5.3 versus 7.2 percent) [49].

Revascularization — The role of revascularization in patients with established CVD is discussed elsewhere. (See "Chronic coronary syndrome: Indications for revascularization", section on 'Indications'.)

THERAPIES WITH UNCERTAIN OR NO BENEFIT — 

The following therapies have not been shown to improve outcomes in patients with CVD:

●Antioxidant vitamins – Antioxidant vitamins, which are nonprescription and sold over the counter, have promising basic research and supportive observational data, but the randomized evidence has not demonstrated clinical benefits on CVD in secondary or primary prevention. The hypothesis that vitamin E, beta-carotene, and/or vitamin C decrease the risks of CVD has been tested in several large-scale randomized trials in secondary and primary prevention. The results have not supported either the potential beneficial mechanisms suggested from basic research or possible benefits hypothesized from observational studies [50-53]. (See "Vitamin intake and disease prevention".)

●Homocysteine and folic acid – Although, in observational studies, subjects with elevated levels of homocysteine have an increased risk of coronary heart disease, and given the fact that vitamin supplementation with folic acid lowers homocysteine levels, data from multiple randomized trials designed to test the hypothesis show no significant benefits of folic acid supplementation on the risks of CVD.

●Postmenopausal hormone therapy – The relationship between postmenopausal hormone therapy and cardiovascular risk is discussed separately. (See "Menopausal hormone therapy and cardiovascular risk".)

●Chelation – The totality of evidence does not support chelation therapy in patients with coronary artery disease (CAD) [54-56]. As an example, in the 2024 Trial to Assess Chelation Therapy 2 (TACT2) of 959 participants with diabetes and prior myocardial infarction (MI), ethylenediaminetetraacetic acid-based chelation reduced blood lead levels but was not superior to placebo in reducing the composite endpoint of death, recurrent MI, stroke, coronary revascularization, or hospitalization for angina (35.6 versus 35.7 percent; hazard ratio [HR] 0.93; 95% CI 0.76-1.16) or any of the individual component endpoints [57]. The role of chelation therapy in the management of elevated blood lead levels is discussed separately. (See "Lead exposure and poisoning in adults: Management", section on 'Chelator administration and monitoring'.)

●Cholesteryl-ester transfer protein inhibitors – Inhibition of the cholesteryl-ester transfer protein (CETP) leads to large increases in high-density lipoprotein and modest reductions in low-density lipoprotein. Of four large trials, three were terminated early, two for lack of benefit and one due to clear evidence of harm [58]. In the fourth trial, the addition of the CETP inhibitor anacetrapib to intensive statin treatment in patients with atherosclerotic vascular disease resulted in a modest but significantly lower incidence of major coronary events, compared with placebo. The role of CETP and its inhibition in CVD risk reduction are discussed separately. (See "HDL cholesterol: Clinical aspects of abnormal values", section on 'CETP and CVD risk' and "HDL cholesterol: Clinical aspects of abnormal values", section on 'CETP inhibition'.)

●Methotrexate – Methotrexate has been postulated to lower the risk of CVD by reducing inflammation. However, in the Cardiovascular Inflammation Reduction Trial (CIRT) of 4786 patients with known MI or multivessel CAD who also had diabetes mellitus or metabolic syndrome, rates of the combined CVD outcome (nonfatal MI, nonfatal stroke, or cardiovascular death) were similar between the low-dose methotrexate (15 to 20 mg weekly) and placebo groups [59].

●Allopurinol – Among patients with gout, observational studies suggest that urate-lowering therapy with allopurinol is associated with lower CVD and mortality [60,61]. However, a larger trial of allopurinol in patients with ischemic heart disease and no history of gout did not show that it was efficacious in reducing rates of CVD [62]. In the ALL-HEART open-label multicenter trial in the United Kingdom, 5937 participants aged ≥60 years were randomly assigned to receive allopurinol or usual care and followed for the composite outcome of MI, stroke, or cardiovascular death. After an average of 5 years, those assigned to allopurinol and those assigned to usual care had similar rates of the composite endpoint (11 versus 11.3 percent; HR 1.04, 95% CI 0.89-1.21). These results do not support the hypothesis that allopurinol be given to individuals with ischemic heart disease for secondary CVD prevention.

SECONDARY PREVENTION IN OLDER ADULTS — 

Age is a major risk factor for all clinical manifestations of CVD. As the relative benefits of both therapeutic lifestyle changes and adjunctive drug therapies appear to be similar across all ages up to approximately 85 years, the absolute benefits are larger in older adults. We offer preventive strategies to older adults with the caveat that randomized trials have enrolled and followed patients into their 80s, but there are far more patients in middle than older ages.

In addition, for many older adults, maintaining a high quality of life may be more important than quantity of life. These issues need to be considered by the health care provider and each of their older adult patients.

Since older adults tend to be on many drug therapies, clinicians should be aware of the greater potential for drug-drug interactions, especially in those with high-risk comorbidities such as chronic kidney disease.

PATIENT EDUCATION — 

Patient education regarding his or her risk factors and their management is central to secondary prevention. Patients with chronic coronary syndrome, also referred to as stable ischemic heart disease, should have an individualized education plan to optimize care and promote wellness that includes education on medication adherence, an explanation of medication management and cardiovascular risk reduction strategies in a manner that respects the patient's level of understanding, a comprehensive review of all therapeutic lifestyle changes of proven benefit, a description of appropriate levels of exercise, introduction to self-monitoring skills, and information on how to recognize worsening cardiovascular symptoms and take appropriate action.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lipid disorders in adults".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Medicines after an ischemic stroke (The Basics)" and "Patient education: Medicines after a heart attack (The Basics)")

●Beyond the Basics topics (see "Patient education: Quitting smoking (Beyond the Basics)" and "Patient education: Exercise (Beyond the Basics)" and "Patient education: High cholesterol and lipids (Beyond the Basics)" and "Patient education: Aspirin in the primary prevention of cardiovascular disease and cancer (Beyond the Basics)" and "Patient education: High blood pressure treatment in adults (Beyond the Basics)" and "Patient education: Type 2 diabetes: Treatment (Beyond the Basics)" and "Patient education: Risks and benefits of alcohol (Beyond the Basics)" and "Patient education: Diet and health (Beyond the Basics)" and "Patient education: Losing weight (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Identifying patients at high risk – Patients with established coronary heart disease have higher risks of subsequent cardiovascular events, including myocardial infarction, stroke, and death from cardiovascular disease.

●Lifestyle modifications – Therapeutic lifestyle changes of proven benefit include avoidance or cessation of smoking, increasing levels of daily physical activity, and a healthy diet. Modifications of multiple major risk factors may produce additive benefits. (See 'Lifestyle modifications' above.)

●Pharmacologic treatment

•Statins – We treat all patients with atherosclerotic cardiovascular disease (ASCVD), as well as individuals with a 10-year risk >20 percent, with evidence-based doses of a high-intensity statin regardless of the baseline low-density lipoprotein cholesterol. Specific recommendations are provided separately. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Management of low-density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

•Aspirin – Patients with established ASCVD are treated with long-term aspirin therapy. Specific recommendations are provided separately. (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)

•Colchicine – For patients with chronic coronary disease who are receiving other secondary preventive drug therapies, we suggest adding colchicine 0.5 (or 0.6) mg per day (Grade 2B). (See 'Colchicine' above.)

•Anticoagulant therapy for some patients – For most patients with stable coronary artery disease on antiplatelet therapy, we do not substitute or add a full-dose oral anticoagulant therapy to aspirin. For some stable ASCVD patients who are at high risk of cardiovascular events and at low risk for bleeding, a regimen of rivaroxaban 2.5 mg orally twice per day and aspirin may be considered. (See 'Anticoagulant therapy' above.)

•Other potential treatments – Other medications that may be of benefit in some patients include beta blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or aldosterone blockers. (See 'Adjunctive therapies' above.)