7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk : Charles H Hennekens, MD, DrPH, Jose Lopez-Sendon, MD, PhD : Joann G Elmore, MD, MPH, Christopher P Cannon, MD, Juan Carlos Kaski, DSc, MD, DM (Hons), FRCP, FESC, FACC, FAHA : Sara Swenson, MD, Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Oct 25, 2022. INTRODUCTION Patients with established cardiovascular disease (CVD) have a high risk of subsequent CVD events, including myocardial infarction (MI), stroke, and death. Many individuals without established CVD are also at very high risk, such as those with metabolic syndrome, multiple risk factors, diabetes, or chronic kidney disease. For all these high-risk patients, therapeutic lifestyle changes, which include increased physical activity, dietary modification/weight loss, and smoking cessation are of proven benefit and improve outcomes beginning within a matter of weeks. In addition, adjunctive drug therapies of proven benefit include statins and aspirin, whose benefits are at least additive. This topic is a broad overview of our approach to the prevention of CVD events in those with established CVD or at very high risk. Our approach in those without CVD is presented separately. (See "Overview of primary prevention of cardiovascular disease".) For the purpose of this topic, we are addressing the broad group of patients who have signs or symptoms of established CVD such as angina, transient ischemic attack, or claudication or those who have had a discrete adverse CVD event such as MI or stroke. In addition, this topic is meant to include recommendations for those at high risk but without overt CVD. High risk is defined directly below. (See 'Identifying patients at high risk' below.) https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very- 1/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD IDENTIFYING PATIENTS AT HIGH RISK Among patients without established disease, very high-risk individuals are defined in most guidelines as those whose 10-year risk is >20 percent, and high-risk individuals are defined as those whose 10-year risk is >7.5 to 20 percent according to cardiovascular disease (CVD) risk factor tables or scores [1-3] (see "Cardiovascular disease risk assessment for primary prevention: Risk calculators"). These higher-risk subjects are likely to include most patients with diabetes or 2 chronic kidney disease with estimated glomerular filtration rate <60 mL/min/1.73 m , as well as many with metabolic syndrome (the constellation of overweight and obesity, dyslipidemia, hypertension, and insulin resistance), a precursor of diabetes. (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach" and "Metabolic syndrome (insulin resistance syndrome or syndrome X)", section on 'Epidemiology and risk factors' and "Chronic kidney disease and coronary heart disease", section on 'Chronic kidney disease as an independent risk factor for CHD' and "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Reducing the risk of macrovascular disease'.) In addition, some guidelines define individuals to be at high risk if an imaging study documents atherosclerosis in the arterial circulation. 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 about 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. DYSLIPIDEMIA We treat all patients with atherosclerotic cardiovascular disease (CVD), as well as individuals with a 10-year risk >20 percent, with evidence-based doses of a high-intensity statin regardless of the https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very- 2/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD baseline low-density lipoprotein (LDL) cholesterol. For patients with a 10-year risk between 7.5 and 20 percent, we treat with a moderate-intensity statin. In trials among patients with familial hypercholesterolemia, treated with either 80 mg atorvastatin or 40 mg of rosuvastatin and needing further lipid modification, PCSK9 inhibitors have demonstrated CVD benefits over three years [4]. PCSK9 inhibitor use is discussed in detail elsewhere. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease", section on 'Our approach'.) HYPERTENSION Our recommendations for the establishment of goal blood pressure and the use of drug therapies are discussed separately. (See "Goal blood pressure in adults with hypertension" and "Choice of drug therapy in primary (essential) hypertension".) We recommend lifestyle changes for all apparently healthy individuals. In addition, this recommendation should be especially emphasized to patients with blood pressures of 120/80 mmHg or greater [5-7]. Therapeutic lifestyle changes of proven benefit include weight loss, increased physical activity, dietary sodium restriction, and reduction or avoidance of alcohol. Institution of these therapeutic lifestyle changes pose little or no risks, and all are likely to 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 in detail elsewhere. (See "Glycemic control and vascular complications in type 1 diabetes mellitus", section on 'Macrovascular disease' and "Glycemic control and vascular complications in type 2 diabetes mellitus" and "Glycemic control for acute myocardial infarction in patients with and without diabetes mellitus".) LIFESTYLE MODIFICATIONS Lifestyle modifications such as smoking cessation, increase in physical activity, and improvement in diet have important beneficial effects on CVD morbidity and mortality that begin relatively shortly after their institution [8,9]. https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very- 3/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD 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 [10]. (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 [11]: 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 [12]. 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", 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 [13]. 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 [14], 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 [15]. Weight reduction is difficult to achieve and maintain; among the 90 percent of subjects who are successful initially, about 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 about 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 [16-21]. https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very- 4/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD 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 [22]. 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. This is 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 heart 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 [23]. (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 [11]. Smoking cessation Smoking cessation produces statistically significant and clinically important benefits on CVD, beginning within a matter of months and reaching the nonsmoker in 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, among 12,603 smokers who had a prior myocardial infarction (MI), coronary artery bypass graft surgery, angioplasty, or known coronary heart disease (CHD) [24], the relative risk (RR) of mortality for quitters compared with those who continued to smoke was 0.64 (95% CI 0.58-0.71). In a cohort study of 2619 patients who survived to hospital discharge after a first MI [25], among those who quit smoking (patients who quit and restarted were considered active smokers), the RR for recurrent events progressively and significantly decreased with longer https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very- 5/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD duration of cessation (RR 1.62 at 0 to <6 months, 1.60 from 6 to <18 months, 1.48 for 18 to <36 months, and 1.02 for 36 months). 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 [26]. Banning smoking in public places quickly reduced the incidence of acute MI in many observational studies [27]. Alcohol Moderate alcohol consumption is associated with a reduced risk of CHD; however, binge drinking increases the risk for CHD [28-32]. The effect of alcohol consumption on CVD is discussed in greater detail elsewhere. (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 (ACS) or revascularization procedure [23]. 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 heart disease", section on 'Comprehensive risk factor intervention'.) Text messaging 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) [33]. At six months, the intervention group had statistically significant improvements in LDL 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 cardiovascular disease (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 P2Y receptor blockers, colchicine, and 12 https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very- 6/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD oral anticoagulants. Administration of influenza vaccine also appears to be beneficial in patients with CVD. Antiplatelet therapy For patients with established CVD, we recommend 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. For patients who have undergone percutaneous coronary intervention (PCI) with stenting or those who have had an acute coronary syndrome (ACS), a P2Y receptor blocker is added to 12 aspirin for some period of time. The role of antiplatelet therapy in patients with CVD is discussed in numerous other topics: In atherosclerotic CVD (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: Early antiplatelet therapy" and "Acute ST-elevation myocardial infarction: Antiplatelet therapy") In patients who have had a stroke (see "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke") The use of dual antiplatelet therapy has been evaluated in populations other than those with ACS or those who have had PCI. In the THEMIS trial, 19,220 patients with chronic coronary syndrome and type 2 diabetes mellitus were randomly assigned to ticagrelor 60 mg or placebo twice per day. All patients received low-dose aspirin once per day. Patients assigned at random to ticagrelor and aspirin had a 10 percent lower risk of ischemic CVD events (cardiovascular death, MI, or stroke) at 40 months when compared with aspirin alone (7.7 versus 8.5 percent; hazard ratio [HR] 0.90, 95% CI 0.81-0.99) but a highly significant and clinically important large increases 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) [34]. Based on these data, the US Food and Drug Administration (FDA) approved dual antiplatelet therapy for this population with or without diabetes. As is the case for all such patients, the health care provider must weigh the benefits on occlusion against the risks on bleeding for each of their individual patients. In a prespecified subgroup analysis of THEMIS (THEMIS-PCI) in the 11,154 patients with PCI, patients assigned to ticagrelor and aspirin had a 15 percent significant decreased incidence of https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very- 7/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD ischemic CVD events compared with those assigned to aspirin and placebo (7.3 versus 8.6 percent; HR 0.85, 95% CI 0.74-0.97). In this subgroup, those assigned to ticagrelor and aspirin also had an over 80 percent significantly increased risks of major bleeding (2.0 versus 1.1 percent) [35]. Intracranial hemorrhage occurred in 0.6 percent of both groups. In the subgroup of patients with chronic coronary syndrome and type 2 diabetes mellitus with no history of PCI, there was no apparent benefit. This subgroup analysis contributes to the formulation of the hypothesis that patients with stable coronary artery disease (CAD) and diabetes at very high ischemic risk and low bleeding risk may have a net benefit with long-term dual antiplatelet therapy with aspirin and ticagrelor. Health care providers may wish to consider these possibilities in discussions with their patients [36,37]. (See "Long-term antiplatelet therapy after coronary artery stenting in stable patients".) The role of aspirin in patients without established CVD but at high risk is discussed separately. (See "Aspirin in the primary prevention of cardiovascular disease and cancer", section on 'All- cause mortality'.) Anticoagulant therapy For most patients with stable CAD on antiplatelet therapy, rivaroxaban 2.5 mg orally twice per day and aspirin may be considered for some stable atherosclerotic CVD patients at high risk of cardiovascular events and low risk for bleeding, based on the COMPASS trial, which is presented below. 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. We do not recommend substituting or adding full-dose oral anticoagulant therapy to aspirin therapy in an attempt to lower the risk of subsequent CVD events. The use of aspirin plus anticoagulant therapy in patients with a specific indication for anticoagulant, such as atrial fibrillation or venous thromboembolic disease, is discussed separately. (See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy", section on 'Our approach' and "Atrial fibrillation in adults: Use of oral anticoagulants".) In stable patients, rivaroxaban, an oral direct Xa inhibitor, has been tested in secondary CVD prevention using a very low-dose regimen added to aspirin therapy. 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 [38]. 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 https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very- 8/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD 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. Health care providers 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'.) 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'.) https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very- 9/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD 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", section on 'Polypills'.) In the Secondary Prevention of Cardiovascular Disease in the Elderly (SECURE) trial of nearly 2500 patients from 7 European countries with recent myocardial infarction (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 [39]. 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 myocardial infarction (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 events had lower rates of cardiovascular events (cardiovascular death, nonfatal type 1 myocardial infarction, nonfatal ischemic stroke, or urgent revascularization): 9.5 versus 12.7 percent; hazard ratio [HR] 0.76, 95% CI 0.60-0.96) compared with the usual care group. There were no differences in blood pressure and LDL cholesterol levels during follow-up between the two treatment groups. https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very 10/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD 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 [40]. (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 epleronone) 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 who have been provided with recommendations for therapeutic lifestyle changes and prescribed appropriate preventive medications (which may include statins and aspirin), we suggest treatment with colchicine 0.5 (or 0.6) mg per day. In randomized trials in the secondary prevention of CAD, patients assigned to colchicine had improved outcomes. (See "Overview of established risk factors for cardiovascular disease", section on 'Inflammation'.) 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 [41]. The dosage 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 renal or hepatic impairment. Colchicine reduced risks of CAD in the 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 [42]. 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 (RR 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 https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very 11/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD similar among those with and without a history of prior ACS or timing of reported ACS [43]. A subsequent meta-analysis had similar findings to those of LoDoCo2 [44]. Prior studies have evaluated the use of colchicine in patients following ACS with similar results [45,46]. These are discussed in detail separately. (See "Overview of the nonacute management of ST-elevation myocardial infarction".) Sodium-glucose co-transporter 2 inhibitors Certain sodium-glucose co-transporter 2 (SGLT2) 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 in detail elsewhere. (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'.) 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" and "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. The OMEMI trial randomly assigned 1027 patients aged 70 to 82 years with a recent (within two to eight weeks) MI to treatment with 1.8 g marine n-3 polyunsaturated fatty acid or corn oil [47]. Among enrolled patients, the mean triglyceride level was 111 mg/dL, that is, most did not have hypertriglyceridemia (defined as a triglyceride level 150 mg/dL). The rate of the primary composite endpoint (nonfatal MI, unscheduled revascularization, stroke, all-cause death, or heart failure hospitalization) after two years was similar in both treatment groups (21.4 versus 20.0 percent; HR 1.08, 95% CI 0.82-1.42). The small sample size may have limited the ability to detect statistically significant differences in outcomes. COVID-19 and influenza vaccination As with adults in the general population, we recommend annual influenza vaccine for patients with CVD [23]. (See "Seasonal influenza vaccination in adults".) We also encourage all patients with CVD to receive vaccination against COVID-19, due to increased risk of severity of COVID-19 infection ( table 1). (See "COVID-19: Myocardial infarction and other coronary artery disease issues" and "COVID-19: Vaccines".) https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very 12/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD 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 [48]. Influenza vaccines may reduce mortality and CVD outcomes in these patients [49-53]. 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 [54]. 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) [55]. 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 [56-59]. (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 CHD, 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 a recommendation for chelation therapy in patients with CAD. There is only one randomized trial of this issue, the TACT trial. TACT assigned 1708 patients with prior MI at random to 40 infusions of a chelation solution or placebo over one to two years [60]. The primary composite endpoint (total mortality, recurrent MI, stroke, coronary revascularization, or hospitalization for angina) occurred less https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very 13/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD frequently in the chelation group (26 versus 30 percent; HR 0.82, 95% CI 0.69-0.99) during a median follow-up of 4.6 years. This observed possible benefit needs to be interpreted in the context of the potential for unmasking and the use of multiple interim analyses, as well as the high rate of dropouts [61]. Further randomized evidence is necessary in order to make any evidence-based recommendations. Nonetheless, the 2014 American College of