7/6/23, 12:50 PM Overview of primary prevention of cardiovascular disease - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Overview of primary prevention of cardiovascular disease : Charles H Hennekens, MD, DrPH : David Seres, MD, Freek Verheugt, MD, FACC, FESC : 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: Aug 25, 2022. INTRODUCTION In the United States and most resource-abundant countries, cardiovascular disease (CVD), which includes coronary heart disease (CHD), stroke, heart failure and peripheral artery disease, are leading causes of morbidity and mortality in adults [1,2]. Further, CVD is becoming the leading cause of death worldwide. An overview of the primary prevention of CVD is presented here, including a discussion of the additive benefits of risk factor reductions through therapeutic lifestyle changes (TLCs) and adjunctive drug therapies of proven benefit. Secondary prevention of CVD, emerging risk factors, and determining individual risk of a patient without known CVD are discussed separately. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk" and "Overview of established risk factors for cardiovascular disease" and "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach".) RATIONALE The following have been identified as major risk factors for cardiovascular disease (CVD). These factors can be modified with therapeutic lifestyle changes (TLCs) or treatment [3]: Smoking Overweight and obesity Unhealthy diet https://www.uptodate.com/contents/overview-of-primary-prevention-of-cardiovascular-disease/print 1/18 7/6/23, 12:50 PM Overview of primary prevention of cardiovascular disease - UpToDate Physical inactivity Dyslipidemia Hypertension Diabetes mellitus (considered in some guidelines as a coronary heart disease [CHD] risk equivalent) Globally, up to 90 percent of the stroke burden may be attributable to modifiable risk factors, which can be substantially reduced by effective implementation of TLCs and adjunctive drug therapies of proven benefit. Additionally, in the descriptive INTERHEART study of patients from 52 countries, nine potentially modifiable factors accounted for over 90 percent of the population-attributable risk of a first myocardial infarction (MI) [4,5]. These included cigarette smoking, dyslipidemia, hypertension, diabetes, abdominal obesity, and psychosocial factors. Additional factors associated with lowered risks included regular physical activity, daily consumption of fruits and vegetables, and daily consumption of small amounts of alcohol. (See "Cardiovascular benefits and risks of moderate alcohol consumption", section on 'Patients without known CVD'.) In descriptive data from a nationally representative survey, five modifiable risk factors for CVD (elevated cholesterol, diabetes, hypertension, obesity, and smoking) accounted for one-half of CVD deaths in United States adults aged 45 to 79 from 2009 to 2010 [6]. The preventable fraction of CVD mortality based on these risk factors was 54 percent for men and 50 percent for women. The deleterious consequences of multiple risk factors are, at least, additive. In the Framingham Heart Study of over 5000 adults, those with five risk factors had a 10-year risk of a first CHD event of 25 to 30 percent, which is comparable to the absolute risk of a recurrent event for many patients who have survived a prior MI or occlusive stroke ( figure 1) [7]. The majority of risk factors for a first CVD and stroke are modifiable by TLCs and adjunctive drug therapies of proven benefit [8]. In the United States, CVD mortality has been declining over the past several decades; however, due in part to increasing overweight and obesity as well as decreasing regular physical activity, the rates of decline have slowed since 2011 and are no longer evident [9]. It had been estimated that nearly half of the recent decline was due to earlier diagnosis and more aggressive treatment of modifiable risk factors, especially of lipids and blood pressure with adjunctive drug therapies, including statins, aspirin, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, and beta adrenergic blockers [10]. The remaining half of the decline in CVD mortality is attributable to primary prevention, in particular TLCs. https://www.uptodate.com/contents/overview-of-primary-prevention-of-cardiovascular-disease/print 2/18 7/6/23, 12:50 PM Overview of primary prevention of cardiovascular disease - UpToDate The benefits of maintaining a healthy lifestyle in the primary prevention of CVD were apparent in observational data from the Nurses Health Study, a large, prospective cohort of over 121,701 female nurses in the United States followed for over 20 years. Women who maintained a desirable body weight, ate a healthy diet, exercised regularly, and did not smoke cigarettes experienced an 84 percent reduction in risk of clinical CVD events [11]. Further, in the Women's Health Study of 39,872 female health professionals in the United States, those practicing healthy lifestyle behaviors had a 55 percent lower risk of subsequent stroke [12]. MAJOR COMPONENTS Healthy diet Individuals who self-select for a healthy diet have significantly lower risks of cardiovascular disease (CVD), including both coronary heart disease (CHD) and stroke. Components of a healthy diet include intakes of: Fruits and vegetables Fiber, including cereals Foods with a low glycemic index and low glycemic load Monounsaturated fat rather than trans fatty acids or saturated fats Omega-3 fatty acids (from fish or plant sources) (see 'Omega-3 fatty acids' below and "Dietary fat", section on 'Polyunsaturated fatty acids' and "Healthy diet in adults", section on 'Protein-rich foods') Observational studies have consistently shown that individuals consuming diets high in vegetables and fruits, such as the Mediterranean diet, have a reduced risk of CVD [13]. Individuals who consume more vegetables and fruits also tend to eat less meat and saturated fat. It is plausible, but unproven, that the apparent benefit may be due to specific compounds in vegetables and fruits, but the results of large-scale randomized trials have not generally supported this possibility. (See "Healthy diet in adults", section on 'Mediterranean diet'.) A healthy diet and increased physical activity are therapeutic lifestyle changes (TLCs) to reduce risks of CVD that are supported by a large totality of evidence. Nonetheless, the United States may lead the world in overweight and obesity [14], and only 21 percent reach the daily minimum requirement for physical activity [15-17]. The US Preventive Services Task Force (USPSTF) recommends that adults with CVD risk factors receive behavioral counseling interventions to promote a healthy diet and increased physical activity [18]. CVD risk factors are defined as hypertension or elevated blood pressure, dyslipidemia, mixed or multiple risk factors, especially those with metabolic syndrome or an estimated 10-year CVD risk of 7.5 percent or greater. https://www.uptodate.com/contents/overview-of-primary-prevention-of-cardiovascular-disease/print 3/18 7/6/23, 12:50 PM Overview of primary prevention of cardiovascular disease - UpToDate Antioxidants as a component of a healthy diet show beneficial effects in basic research and observational studies, but randomized trials to detect the most plausible small to moderate benefits have generally shown no net benefit. Thus, the totality of evidence on supplements does not support their routine use for CVD prevention [19]. (See "Vitamin intake and disease prevention", section on 'Antioxidants'.) The role of folic acid supplementation in patients at risk for CVD is discussed separately. (See "Vitamin intake and disease prevention", section on 'Cardiovascular disease'.) Smoking avoidance and cessation Cigarette smoking remains both the leading avoidable cause of premature death worldwide as well as a major avoidable cause of morbidity. The totality of evidence indicates that the amount of cigarettes currently smoked increases morbidity and mortality from CVD, and benefits of cessation begin to appear after only a few months and reach that of the nonsmoker in several years, even among older adults [20]. Thus, for CVD, it is never too late to quit, whereas for cancer it is never too early. The risks of cancer are chiefly related to duration, and even 10 years after quitting the cancer risks remain about midway between those of the continuing and nonsmoker (See "Overview of smoking cessation management in adults" and "Cardiovascular risk of smoking and benefits of smoking cessation" and "Secondhand smoke exposure: Effects in adults".) All smokers should be counseled on a regular basis to quit. A number of approaches, including behavioral therapy, nicotine replacement therapy, varenicline, and other pharmacologic therapies, are available [21]. (See "Overview of smoking cessation management in adults".) Hypertension control Hypertension is a well-established risk factor for CVD, including morbidity and mortality from stroke, coronary heart disease (CHD), heart failure, and sudden death. (See "Cardiovascular risks of hypertension".) Definition Hypertension is defined in the 2017 American Heart Association/American College of Cardiology (AHA/ACC) guidelines as a systolic pressure 130 mmHg or a diastolic pressure 80 mmHg [22]. Goal blood pressure Goal blood pressure may depend in part upon comorbidities (eg, diabetes, chronic kidney disease) and estimated cardiovascular risk; these issues are presented separately. (See "Goal blood pressure in adults with hypertension".) Nonpharmacologic measures All patients with or without hypertension or elevated blood pressure should adhere to a healthy diet and increased physical activity. In addition, those with hypertension or elevated blood pressure should pay particular attention to nonpharmacologic TLCs which include weight reduction, salt restriction, and avoidance of https://www.uptodate.com/contents/overview-of-primary-prevention-of-cardiovascular-disease/print 4/18 7/6/23, 12:50 PM Overview of primary prevention of cardiovascular disease - UpToDate excess alcohol intake. (See "Overview of hypertension in adults", section on 'Nonpharmacologic therapy'.) Pharmacologic therapy Antihypertensive drugs are necessary for patients with persistent hypertension despite TLCs. Most patients will require multiple antihypertensive drug therapies to achieve their blood pressure goal. The choice of a specific agent for hypertension is presented separately. (See "Choice of drug therapy in primary (essential) hypertension".) Dyslipidemia Several large-scale randomized trials and their meta-analyses of statins in high-, moderate-, and low-risk primary prevention subjects without clinical evidence of CHD have demonstrated clinical benefits on CVD, including myocardial infarction (MI), stroke, and CVD death as well as total mortality [23]. Deciding who should be screened for dyslipidemia may vary based on different guidelines. This issue is discussed in detail separately. In contrast to blood pressure reduction where multiple therapies are commonly needed, statin therapy may be sufficient for the vast majority of patients requiring lipid modification. (See "Screening for lipid disorders in adults".) All primary prevention subjects, especially those with dyslipidemia, should be counseled to achieve and maintain a desirable body weight, engage in regular physical activity, and eat a healthy diet. Deciding when statin treatment should be initiated and the choice of adjunctive pharmacologic therapy of lipid disorders in primary prevention of CVD are discussed in detail separately. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease".) Physical activity Numerous observational studies have consistently shown that individuals who self-select for increased physical activity have lower morbidity and mortality from CHD ( figure 2). Regular physical activity is recommended in the early school years and throughout life. Common recommendations include moderate-intensity exercise for 150 minutes a week, vigorous- intensity exercise for 75 minutes a week, or an equivalent combination of these activities. Adults with limited exercise capacity due to comorbidities should stay as physically active as their condition allows [15,16]. Even modest amounts of regular physical activity, such as brisk walking for 20 minutes daily, are associated with significant benefits on risk of CHD [17]. Nonetheless, perhaps less than 20 percent of United States adults achieve this level of daily activity [15,16]. Although beneficial for all Americans, the USPSTF recommends that adults with CVD risk factors receive behavioral counseling interventions to promote a healthy diet and physical activity [18]. https://www.uptodate.com/contents/overview-of-primary-prevention-of-cardiovascular-disease/print 5/18 7/6/23, 12:50 PM Overview of primary prevention of cardiovascular disease - UpToDate (See 'Healthy diet' above.) The role of increased physical activity for primary prevention is discussed in detail separately. (See "Exercise and fitness in the prevention of atherosclerotic cardiovascular disease".) Weight loss In the United States and worldwide, overweight and obesity are important modifiable causes of premature deaths [14]. Overweight and obesity increase risk for several major risk factors for CVD, including hypertension, dyslipidemia, and insulin resistance, while weight loss has been shown to improve these parameters [24-26]. Data from large prospective cohort studies have consistently shown that individuals with higher body weights have a linear increase in morbidity and mortality from CHD, after appropriate adjustment for smoking and other confounders. (See "Overweight and obesity in adults: Health consequences".) In addition, in data from a random sample of the United States population from the National Center for Health Statistics, over 40 percent of adults aged 40 and over have metabolic syndrome, which is defined by the presence of three or more of the following: abdominal obesity, hypertriglycerides 150 mg/dL, high-density lipoprotein (HDL) <40 mg/dL in men or <50 mg/dL in women, systolic blood pressure 130 mmHg or diastolic blood pressure 85 mmHg, fasting glucose 100 mg/dL. These individuals have a 10-year risk of a first CHD event of 16 to 18 percent, which is as high as many individuals who have already had an MI or stroke [27]. Such high-risk primary prevention subjects should be considered for pharmacologic or perhaps even surgical therapeutic options [28]. Selection of treatment for overweight subjects is based upon an initial risk assessment. All should be evaluated for their willingness and ability to adopt TLCs as well as other interventions of proven benefit. All individuals who are willing, ready, and able to lose weight should receive information about behavior modification, diet, and increased physical activity. (See "Obesity in adults: Prevalence, screening, and evaluation" and "Obesity in adults: Overview of management", section on 'Morbidity' and "Obesity in adults: Overview of management", section on 'Mortality'.) Management of type 2 diabetes The prevalence of type 2 diabetes has increased to epidemic proportions, largely due to the increase in overweight status and obesity. Mortality from diabetes results mainly from macrovascular complications of CHD, stroke, and peripheral artery disease. In addition, there are several major microvascular complications, especially retinopathy, nephropathy, and neuropathy. To reduce macrovascular complications, multifactorial interventions are crucial, especially weight reduction, increased physical activity, and control of blood pressure, lipids, and glucose https://www.uptodate.com/contents/overview-of-primary-prevention-of-cardiovascular-disease/print 6/18 7/6/23, 12:50 PM Overview of primary prevention of cardiovascular disease - UpToDate [29]. (See "Overview of general medical care in nonpregnant adults with diabetes mellitus" and "Treatment of hypertension in patients with diabetes mellitus".) For microvascular complications, tight glycemic control reduces microvascular complications in both type 1 and type 2 diabetes mellitus. Tight glycemic control may also reduce risks of macrovascular complications in patients with type 1 and type 2 diabetes mellitus [30-32]. The target A1C levels in patients with diabetes should be tailored to the individual by weighing the benefits on morbidity and mortality against the risk of hypoglycemia. Details of glycemic control in patients with diabetes are discussed separately. (See "Glycemic control and vascular complications in type 1 diabetes mellitus" and "Glycemic control and vascular complications in type 2 diabetes mellitus".) Aspirin Any decision to recommend aspirin should be based upon an individual clinical judgment that includes an assessment of the magnitude of both the absolute CVD risk reduction and the absolute increase in major bleeding. Thus, prescription of aspirin should be based on consideration of benefits and risk, not age [33]. Aspirin use for primary prevention of CVD is discussed in more detail separately. (See "Aspirin in the primary prevention of cardiovascular disease and cancer", section on 'Possible benefits'.) Omega-3 fatty acids Omega-3 fatty acids significantly reduce triglycerides in a dose- dependent manner [34], but their independent benefits on clinical CVD are less clear, especially in those already treated with evidence-based doses of statins [35]. The role of this treatment in secondary prevention patients with hypertriglyceridemia is discussed separately. (See "Hypertriglyceridemia in adults: Management", section on 'Marine omega-3 fatty acids'.) For patients without hypertriglyceridemia, the role of this treatment is uncertain, and practice varies. In a randomized trial in primary prevention of 25,871 adults without known cardiovascular disease (VITAL), after a median of 5.3 years, low-dose n-3 polyunsaturated fatty acid (PUFA; 1 g/day) did not reduce the primary endpoint of major cardiovascular events, which included both heart disease and stroke (hazard ratio [HR] 0.92, 95% CI 0.80-1.06) [36]. Among secondary outcomes, there was a reduction in total MI (HR 0.72, 95% CI 0.59-0.90), percutaneous intervention (HR 0.78, 95% CI 0.63-0.95), total CHD (HR 0.83, 95% CI 0.71-0.97), and death from MI (HR 0.50, 95% CI 0.26-0.97). Benefits and risks of small amounts of daily alcohol In numerous case-control and prospective cohort studies, individuals who consume small amounts of alcohol have lower risks of morbidity and mortality from CHD than nondrinkers. The benefit seems related to the small amount of alcohol consumed rather than the type of alcoholic beverage. In some, but not the majority of analytic studies, individuals who consume red wine tend to have lower risks than https://www.uptodate.com/contents/overview-of-primary-prevention-of-cardiovascular-disease/print 7/18 7/6/23, 12:50 PM Overview of primary prevention of cardiovascular disease - UpToDate those who consume other types of alcohol. This inconsistent finding may be due to other components in red wine or confounding by social class. A meta-analysis of nearly 600,000 individuals in 83 prospective studies who consumed alcohol found the lowest risk of all-cause mortality occurred at those whose alcohol intake was about 100 g/week (approximately six drinks/week) [37]. In this analysis, individuals self selection for the consumption of small amounts of daily alcohol intake had a decreased risk of mortality from MI but not from other causes. Thus, any benefit of daily alcohol intake for coronary artery disease must be weighed against the risks, which include hypertension, cerebral hemorrhage, and breast cancer. In addition, there have been significant increases in the United States in mortality from alcoholic cirrhosis [38]. The differences between consuming small and larger amounts of daily alcohol will mean the difference between avoidance and causation of premature death [3]. (See "Overview of the risks and benefits of alcohol consumption" and "Cardiovascular benefits and risks of moderate alcohol consumption".) ADDITIVE BENEFITS OF MULTIPLE RISK FACTOR REDUCTIONS Lifestyle changes In primary prevention, modification of multiple major risk factors will produce reductions in risk of coronary heart disease (CHD) and stroke that are at least additive [39]. A European prospective cohort study of 2339 individuals, including 1507 men and 832 women aged 70 to 90 without cardiovascular disease (CVD) or cancer at baseline, assessed whether self- selection for a Mediterranean diet, being physically active, having small to moderate alcohol intake daily, and/or not smoking reduced all-cause and cause-specific mortality [40]. After a mean follow-up of 10 years, compared with those who adopted zero or one lifestyle change, those who self-selected for all four therapeutic lifestyle changes (TLCs) had a 67 percent lower risk of CVD mortality and a 65 percent lower risk of total deaths. A prospective cohort study of over 20,000 Swedish men aged 45 to 79 without cancer, CVD, or CVD risk factors assessed whether individuals who self-selected for all of the five low-risk factors (healthy diet, moderate alcohol consumption, not smoking, being physically active, and having no abdominal adiposity) had lower risks of myocardial infarction (MI) [41]. During the 11-year follow-up, these men who practiced a healthy lifestyle had an 86 percent lower risk for MI (95% CI 0.04-0.43). Similar results for primary prevention of stroke derived from the analyses of combined data from two large prospective cohorts, the Health Professionals Follow-up Study (43,685 men) and https://www.uptodate.com/contents/overview-of-primary-prevention-of-cardiovascular-disease/print 8/18 7/6/23, 12:50 PM Overview of primary prevention of cardiovascular disease - UpToDate Nurses' Health Study (71,243 women), in which a low-risk lifestyle was defined as not smoking, 2 body mass index (BMI) <25 kg/m , 30 minutes/day of moderate activity, modest alcohol consumption, and scoring in the top 40 percent on a healthy diet score [42]. Compared with participants having none, adults with all five low-risk factors had significantly lower risks of stroke (relative risks 0.31 in men and 0.21 in women). Polypills Polypills to reduce CVD contain various combinations of medications such as statins, antihypertensive medications, and aspirin [43]. From a population health standpoint, a polypill strategy is attractive because it seeks to minimize nonadherence, as it provides the major CV drug classes in one pill. Another potential advantage is decreased costs [44]. As such, they may be useful as a population-based strategy in resource-limited settings. The authors of TIPS-3 estimate that widespread use of the polypill may avert >3 to 5 million CVD events globally [45]. Potential disadvantages include increased adverse effects, individual patient variability concerning the optimal combination of medications, and difficulty in titration with fixed dosing. In addition, while many polypill formulations include aspirin, the role of aspirin in primary prevention is controversial. Finally, it may not be usable if a patient has an allergy to any of the drugs in the combination pill. (See "Aspirin in the primary prevention of cardiovascular disease and cancer", section on 'Possible benefits'.) Polypills are not available commercially in the United States or Europe. A 2017 systematic review of 13 randomized trials concluded that the effects of polypills on mortality or CVD events were inconclusive. However, most of the included trials evaluated changes in risk factors rather than CVD events [46]. In some but not all individual randomized trials, polypills increased adherence and decreased blood pressure and cholesterol but increased adverse events [45,47-51]. A 2021 individual-level meta-analysis examined three large RCTs of 18 162 individuals evaluating the effect of fixed dose polypills comprised of two antihypertensives and a low dose statin (with or without aspirin) on primary CVD prevention. [52] During a median follow-up of 5 years, the primary CVD outcome (a composite of cardiovascular death, myocardial infarction, stroke, or arterial revascularization) occurred in 3 percent of individuals given the polypill compared with 4.9 percent in the control group (hazard ratio [HR] 0.62, 95% CI 0.53 0.73). GI side effects were more common in those taking the additional aspirin, although other bleeding was neither common nor significantly different in those treated with aspirin versus not. The use of polypills has been proposed as a strategy to decrease CVD in underserved communities. In an open-label trial among 303 low-income adults in Alabama without CVD, 96 percent of whom were Black individuals, those randomized to receive a polypill containing https://www.uptodate.com/contents/overview-of-primary-prevention-of-cardiovascular-disease/print 9/18 7/6/23, 12:50 PM Overview of primary prevention of cardiovascular disease - UpToDate atorvastatin (10 mg), amlodipine (2.5 mg), losartan (25 mg), and hydrochlorothiazide (12.5 mg) had a greater decrease in mean blood pressure (9 versus 2 mmHg, -7 mmHg difference, 95% CI 12 to -2), and LDL cholesterol levels (15 versus 4 mg/dL, -11 mg/dL difference, 95% CI -18 to -5) at one year compared with those in the usual care group [50]. Adherence at one year was 86 percent. 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: Assessment of cardiovascular risk" and "Society guideline links: Primary prevention of cardiovascular disease".) 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 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 topics (see "Patient education: Atherosclerosis (The Basics)") Beyond the Basics topics (see "Patient education: High cholesterol and lipids (Beyond the Basics)" and "Patient education: Diet and health (Beyond the Basics)" and "Patient education: Quitting smoking (Beyond the Basics)" and "Patient education: Losing weight (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 in adults (Beyond the Basics)" and "Patient education: Type 2 diabetes: Overview (Beyond the Basics)") https://www.uptodate.com/contents/overview-of-primary-prevention-of-cardiovascular-disease/print 10/18 7/6/23, 12:50 PM Overview of primary prevention of cardiovascular disease - UpToDate SUMMARY AND RECOMMENDATIONS Major risk factors The following major risk factors for cardiovascular disease (CVD) are modifiable and should be considered in all adults: poor diet, smoking, hypertension, dyslipidemia, physical inactivity, overweight and obesity, and diabetes mellitus. (See "Healthy diet in adults" and "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Exercise and fitness in the prevention of atherosclerotic cardiovascular disease" and "Obesity in adults: Overview of management" and "Glycemic control and vascular complications in type 1 diabetes mellitus" and "Glycemic control and vascular complications in type 2 diabetes mellitus" and "Overview of smoking cessation management in adults".) Multiple risk factor reduction Reductions of multiple risk factors, through therapeutic lifestyle changes (TLCs) and adjunctive drug therapies of proven benefit, are likely to have at least additive benefits in the primary prevention of CVD. (See 'Additive benefits of multiple risk factor reductions' above.) Role of aspirin The decision to recommend aspirin should be based upon an individual clinical judgment that includes an assessment of the magnitude of both the absolute CVD risk reduction and the absolute increase in major bleeding, not just age. (See "Aspirin in the primary prevention of cardiovascular disease and cancer".) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Lopez AD, Mathers CD, Ezzati M, et al. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 2006; 367:1747. 2. Virani SS, Alonso A, Aparicio HJ, et al. Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association. Circulation 2021; 143:e254. 3. Caldwell M, Martinez L, Foster JG, et al. Prospects for the Primary Prevention of Myocardial Infarction and Stroke. J Cardiovasc Pharmacol Ther 2019; 24:207. 4. Feigin VL, Krishnamurthi RV, Parmar P, et al. Update on the Global Burden of Ischemic and Hemorrhagic Stroke in 1990-2013: The GBD 2013 Study. Neuroepidemiology 2015; 45:161. 5. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004; 364:937. https://www.uptodate.com/contents/overview-of-primary-prevention-of-cardiovascular-disease/print 11/18 7/6/23, 12:50 PM Overview of primary prevention of cardiovascular disease - UpToDate 6. Patel SA, Winkel M, Ali MK, et al. Cardiovascular mortality associated with 5 leading risk factors: national and state preventable fractions estimated from survey data. Ann Intern Med 2015; 163:245. 7. Anderson KM, Odell PM, Wilson PW, Kannel WB. Cardiovascular disease risk profiles. Am Heart J 1991; 121:293. 8. Meschia JF, Bushnell C, Boden-Albala B, et al. 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In: Antioxidants and Cardiovascular Disease, Tardiff JC, Bourassa MG (Eds), Springer, 20 https://www.uptodate.com/contents/overview-of-primary-prevention-of-cardiovascular-disease/print 12/18 7/6/23, 12:50 PM Overview of primary prevention of cardiovascular disease - UpToDate 05. p.305. 20. LaCroix AZ, Lang J, Scherr P, et al. Smoking and mortality among older men and women in three communities. N Engl J Med 1991; 324:1619. 21. Gaballa D, Drowos J, Hennekens CH. Smoking Cessation: The Urgent Need for Increased Utilization of Varenicline. Am J Med 2017; 130:389. 22. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension 2018; 71:e13. 23. Collins R, Reith C, Emberson J, et al. 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