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 Cardiology/American Heart Association/American Association for Thoracic Surgery/Preventive Cardiovascular Nurses Association/Society for Cardiovascular Angiography and Interventions/Society of Thoracic Surgeons focused update of prior guidelines for the diagnosis and management of patients with chronic coronary syndrome states that chelation therapy may be considered for reducing cardiovascular events [62]. Cholesteryl-ester transfer protein inhibitors Inhibition of the cholesteryl-ester transfer protein (CETP) leads to large increases in high-density lipoprotein (HDL) and modest reductions in low-density lipoprotein (LDL). Of four large trials, three were terminated early, two for lack of benefit and one due to clear evidence of harm [63]. 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 than the addition of placebo during four years of treatment. One intriguing subgroup finding in the trial of dalcetrapib suggested there may be ADCY9 genotype-dependent effects of this CETP inhibitor on biomarkers as well as clinical cardiovascular outcomes. These observations, at least in part, formed the basis for the ongoing dal-GenE randomized trial [64]. The REVEAL trial compared anacetrapib with placebo in 30,449 patients with chronic atherosclerotic disease. After 4.1 years, anacetrapib-treated patients presented a lower incidence of the primary outcomes (major coronary event, a composite of coronary death, MI, or coronary revascularization) [10.8 versus 11.8 percent]). This benefit was considered statistically significant but not enough to continue research and development of the product [63]. 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 [65]. Allopurinol Among patients with gout, observational studies suggest that urate-lowering therapy with allopurinol is associated with lower CVD and mortality [66,67]. However, a https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very 14/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD 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 cardiovascular disease [68]. 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. Revascularization The role of revascularization in patients with established CVD is discussed elsewhere. (See "Chronic coronary syndrome: Indications for revascularization", section on 'Indications'.) 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 options; 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. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very 15/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD 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 th th sophisticated, and more detailed. These articles are written at the 10 to 12 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 topic (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 (CHD) have higher risks of subsequent cardiovascular events, including myocardial infarction (MI), stroke, and death from cardiovascular disease (CVD). (See 'Identifying patients at high risk' above.) Lifestyle modifications Therapeutic lifestyle changes of proven benefit include avoidance or cessation of smoking, increasing levels of daily physical activity, and 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 CVD, as well as individuals with a 10- year risk >20 percent, with evidence-based doses of a high-intensity statin regardless of the baseline LDL cholesterol. Specific recommendations are provided separately. (See https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very 16/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD "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 atherosclerotic CVD 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 (CAD) on antiplatelet therapy, we do not substitute or add a full-dose oral anticoagulant therapy to aspirin. For some stable atherosclerotic CVD 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.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. SCORE2 working group and ESC Cardiovascular risk collaboration. SCORE2 risk prediction algorithms: new models to estimate 10-year risk of cardiovascular disease in Europe. Eur Heart J 2021; 42:2439. 2. 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Effect of Lifestyle-Focused Text Messaging on Risk Factor Modification in Patients With Coronary Heart Disease: A Randomized Clinical Trial. JAMA 2015; 314:1255. 34. Steg PG, Bhatt DL, Simon T, et al. Ticagrelor in Patients with Stable Coronary Disease and Diabetes. N Engl J Med 2019; 381:1309. 35. Bhatt DL, Steg PG, Mehta SR, et al. Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI): a phase 3, placebo-controlled, randomised trial. Lancet 2019; 394:1169. 36. Hennekens CH, Demets D. The need for large-scale randomized evidence without undue emphasis on small trials, meta-analyses, or subgroup analyses. JAMA 2009; 302:2361. 37. Hennekens CH, DeMets D. Statistical association and causation: contributions of different types of evidence. JAMA 2011; 305:1134. 38. Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. 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Fihn SD, Blankenship JC, Alexander KP, et al. 2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2014; 64:1929. 63. HPS3/TIMI55 REVEAL Collaborative Group, Bowman L, Hopewell JC, et al. Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease. N Engl J Med 2017; 377:1217. 64. Tardif JC, Dub MP, Pfeffer MA, et al. Study design of Dal-GenE, a pharmacogenetic trial targeting reduction of cardiovascular events with dalcetrapib. Am Heart J 2020; 222:157. 65. Ridker PM, Everett BM, Pradhan A, et al. Low-Dose Methotrexate for the Prevention of Atherosclerotic Events. 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Topic 1505 Version 93.0 https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very 22/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD GRAPHICS [1-3] Comorbidities the CDC classifies as risk factors for severe COVID-19* Established, probable, and possible risk factors (comorbidities that have been associated with severe COVID-19 in at least 1 meta-analysis or systematic review, in observational studies, or in case series): Age 65 years Asthma Cancer Cerebrovascular disease Children with certain underlying conditions Chronic kidney disease Chronic lung disease (interstitial lung disease, pulmonary embolism, pulmonary hypertension, bronchiectasis, COPD) Chronic liver disease (cirrhosis, non-alcoholic fatty liver disease, alcoholic liver disease, autoimmune hepatitis) Cystic fibrosis Diabetes mellitus, type 1 and type 2 Disabilities (eg, ADHD, cerebral palsy, congenital malformations, limitations with self-care or activities of daily living, intellectual and developmental disabilities, learning disabilities, spinal cord injuries) Heart conditions (such as heart failure, coronary artery disease, or cardiomyopathies) HIV Mental health disorders (mood disorders including depression, schizophrenia spectrum disorders) Neurologic conditions (dementia) 2 2 th Obesity (BMI 30 kg/m ) and overweight (BMI 25 to 29 kg/m ), or 95 percentile in children Physical inactivity Pregnancy or recent pregnancy Primary immunodeficiencies Smoking (current and former) Sickle cell disease or thalassemia Solid organ or blood stem cell transplantation Substance use disorders Tuberculosis Use of corticosteroids or other immunosuppressive medications Possible risk factors but evidence is mixed (comorbidities have been associated with severe COVID-19 in at least 1 meta-analysis or systematic review, but other studies had reached different conclusions): Alpha 1 antitrypsin deficiency Bronchopulmonary dysplasia Hepatitis B https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very 23/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD Hepatitis C Hypertension CDC: Centers for Disease Control and Prevention; COVID-19: coronavirus disease 2019; COPD: chronic obstructive pulmonary disease; ADHD: attention deficit hyperactivity disorder; HIV: human immunodeficiency virus; BMI: body mass index. Listed comorbidities are associated with severe COVID-19 in all adults independent of age. People of color are also at increased risk of severe disease and death, often at a younger age, due to systemic health and social inequities. Risk of severe disease also rises steadily with age, with more than 93% of deaths occurring among adults 50 years and 74% of deaths occurring in adults 65 years. Underlying medical conditions are also associated with severe illness in children, but evidence implicating specific conditions is limited. Children with the following conditions might be at increased risk for severe illness: medical complexity; genetic, neurologic, or metabolic conditions; congenital heart disease; obesity; diabetes; asthma or other chronic lung disease; sickle cell disease; immunosuppression. References: 1. Centers for Disease Control and Prevention. Underlying medical conditions associated with high risk for severe COVID- 19: Information for healthcare providers. Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical- care/underlyingconditions.html (Accessed on March 1, 2022). 2. Centers for Disease Control and Prevention. Science brief: Evidence used to update the list of underlying medical conditions that increase a person's risk of severe illness from COVID-19. Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/underlying-evidence-table.html (Accessed on March 1, 2022). 3. Centers for Disease Control and Prevention. Risk for COVID-19 infection, hospitalization, and death by age group. Available at: https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by- age.html (Accessed on June 16, 2022). Graphic 127477 Version 15.0 https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very 24/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD Contributor Disclosures Charles H Hennekens, MD, DrPH Patent Holder: Brigham and Women's Hospital [Co-inventor on patents concerning inflammatory markers and cardiovascular disease, C-reactive protein]. Consultant/Advisory Boards: Amgen [Migraine, cardiovascular disease]; UCB [Osteoporosis]. All of the relevant financial relationships listed have been mitigated. Jose Lopez-Sendon, MD, PhD Grant/Research/Clinical Trial Support: Amgen [Hyperlipemia]; Anthos [Atrial fibrillation]; AstraZeneca [Acute coronary syndrome]; Bayer [Heart failure]; Boehringer Ingleheim [Diabetes, heart failure]; Lilly Daichi-Sankio [Acute coronary syndrome]; Merck [Heart failure]; Pfizer [Atrial fibrillation and heart failure]; Sanofi [Diabetes]. Consultant/Advisory Boards: Menarini [Chronic angina]. All of the relevant financial relationships listed have been mitigated. Joann G Elmore, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Christopher P Cannon, MD Grant/Research/Clinical Trial Support: Amgen [Lipids, heart failure]; Applied Therapeutics [DM]; Ascendia [ACS]; Better therapeutics [Diabetes]; Biogen [Alzheimers]; Boehringer-Ingelheim [AF, DM, HF, CKD]; Daiichi Sankyo [AF]; Merck [Lipids, DM]; Novo Nordisk [DM]; Pfizer [DM, lipids]; Rhoshan [ACS]. Consultant/Advisory Boards: Aegerion/Amryt [Lipids]; Alnylam [Lipids]; Amarin [Lipids]; Amgen [Lipids]; BI [AF, DM]; Bristol-Myers Squibb [AF, ACS]; Eli Lilly [DM, ACS]; Janssen [AF, DM, ACS/CAD]; Lexicon [DM, CKD, HF]; Merck [Lipids, DM]; Pfizer [AF, DM, lipids]; Rhoshan [ACS]; Sanofi [Lipids, ACS, DM]. All of the relevant financial relationships listed have been mitigated. Juan Carlos Kaski, DSc, MD, DM (Hons), FRCP, FESC, FACC, FAHA Consultant/Advisory Boards: Glycardial Diagnostic [Biomarkers]. Speaker's Bureau: Menarini [Angina pectoris]; Servier [Angina pectoris]. All of the relevant financial relationships listed have been mitigated. Sara Swenson, MD No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very 25/25