Primary and Secondary Prevention of Heart Disease
February 1, 2017
February 28, 2019
Kiran Panesar, BPharmS (Hons),
MRPharmS, RPh, CPh
Freelance Medical Writer
Nordic Medical Centre
Addis Ababa, Ethiopia
FACULTY DISCLOSURE STATEMENTS:
Dr. Panesar has no actual or potential conflicts of interest in relation to this activity.
Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.
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Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge
This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.
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Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' conditions and possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.
To highlight the steps pharmacists can take to prevent heart disease in patients with risk factors for heart disease and to prevent progression in patients with existing heart disease.
After completing this activity, the participant should be able to:
- Discuss primary prevention strategies that may be used in counseling patients at high risk for developing heart disease.
- Incorporate guidelines for the prevention of heart disease into his or her daily practice.
- Counsel patients about lifestyle changes that serve as secondary prevention strategies for reducing the progression of heart disease.
- Instruct patients on the proper use of evidence-based pharmacologic treatment proven to reduce heart disease progression.
ABSTRACT: Cardiovascular disease is the greatest cause of deaths worldwide and is linked to a number of risk factors. Many of the risk factors associated with cardiovascular disease are modifiable, and pharmacists can contribute to the prevention of cardiovascular disease through the control of these risk factors. The strategies used to prevent cardiovascular disease may be divided into those for primary prevention and those for secondary prevention. Primary prevention measures include smoking cessation, control of blood pressure, cholesterol, and blood glucose, and the possible use of daily aspirin. Secondary prevention builds upon primary prevention and includes the use of beta-blockers, lipid-lowering therapy, ACE inhibitors, antiarrhythmics, and calcium channel blockers.
Cardiovascular disease (CVD) is the leading cause of mortality worldwide, resulting in 17.3 million deaths per year.1 A recent report has shown that this number is projected to exceed 23.6 million by 2030.1 The most preventable form of CVD, coronary heart disease (CHD), results in 502,000 deaths annually in the United States.2 CHD may be defined as the “narrowing or blockage of the coronary arteries by atheroma, leading to angina, coronary thrombosis or heart attack, heart failure and/or sudden death.”3 An American Heart Association (AHA) policy statement concluded that costs will rise to more than $1 trillion annually in the U.S. by the year 2030, suggesting the great need for preventive measures.2
As the pharmacist’s role broadens beyond the traditional product-oriented functions of dispensing and distributing medications, pharmacists will be increasingly well suited to provide patients with risk-management information and to improve patient compliance with prescribed medication.4 Because of the relatively easy accessibility and perceived affordability of pharmaceutical services, pharmacists are the first point of contact for healthcare services in many cases.
It has been demonstrated that interventions by community-based pharmacists have led to a reduction in risk behaviors and risk factors for CHD.5 For example, interventions for the management of hyperlipidemia, hypertension, and secondary-prevention medications, as well as smoking-cessation programs, have been shown to improve patient outcomes.5
Risk Factors for Heart Disease
In order to determine the various measures that can be taken to prevent heart disease, it is important to first consider the risk factors for heart disease. Heart disease is multifactorial, and large studies such as the Framingham Heart Study and the Seven Countries Study have identified major risk factors.6,7 Interestingly, the presence of one of these risk factors significantly affects the presence of the others. Whereas some risk factors are modifiable and can be altered, others (e.g., the patient’s age) are nonmodifiable. Furthermore, additional risk factors were recently identified that are yet to be established as contributors to CHD. See TABLE 1 for some of these factors.8,9
The risk factors identified by the Framingham Heart Study may be used to calculate a Framingham Risk Score, which assesses the 10-year risk of CHD in patients with risk factors. For the tables used to calculate risk factors, see www.nhlbi.nih.gov/guidelines/cholesterol/risk_tbl.htm. TABLE 2 lists the prevalence of the risk factors considered in the Framingham Score.9
Strategies that are used to prevent heart disease may be divided into those for primary prevention and those for secondary prevention. In primary prevention, measures are taken to reduce risk in patients who are at high risk but do not suffer from CVD; in secondary prevention, the strategies reduce the progression of established disease. TABLE 3 lists the primary and secondary prevention strategies.
Cigarette smoking has been identified as a major risk factor for heart disease.10 Smoking is associated with a number of factors that lead to the formation of atherosclerotic plaques, such as increased catecholamine levels, decreased HDL, increased platelet aggregation and fibrinogen levels, and impaired arterial vasodilation.11 Smoking cessation should be encouraged as part of both primary and secondary prevention of heart disease.
Smoking cessation has been shown to reduce the risk of death by 50% in patients at risk for heart disease.12 The risk of CHD begins to decline a few months after a person stops smoking, and after about 2 to 3 years, the risk decreases to about the risk level of someone who has never smoked. It is important that the patient stop smoking completely to achieve benefit, as there is no evidence that simply smoking fewer cigarettes per day reduces the risk of CVD.13
Patients who have had a myocardial infarction (MI) and continue to smoke have a 22% to 47% increased risk of mortality.14 A study that followed patients for 15 years after a first MI found that the mortality rate in those who continued to smoke after the MI was 82%, compared with 37% in those who stopped smoking.15
It is estimated that about 70% of adults in the U.S. want to stop smoking, and millions of them have tried to do so.16 This willingness presents a patient-counseling opportunity for pharmacists, who are in a pivotal position to help patients determine which smoking-cessation method is best for them. Additionally, pharmacists can discuss the benefits of smoking cessation with patients who may be at risk for heart disease and refer interested patients to an appropriate smoking-cessation professional. When dispensing OTC nicotine-replacement products such as patches, gums, and lozenges or prescription smoking-cessation products such as bupropion, pharmacists can ensure that the patient knows how to use them correctly. In addition, pharmacists can discuss withdrawal symptoms with patients. These symptoms may include depressed mood, sleep disturbances, difficulty concentrating, irritability, restlessness, increased appetite, increased weight, constipation, light-headedness, mouth ulcers, and urges to smoke.17
Blood Pressure Reduction
A large number of prospective, observational studies have associated blood pressure (BP) levels with the incidences of stroke and CHD.18 Indeed, elevated BP, whether systolic (SBP), diastolic (DBP), or pulse pressure (PP), is a risk factor for the development of CHD and stroke.19 The Framingham Heart Study has shown that, with increasing age, there is a gradual shift from DBP to SBP and then to PP as a predictor of CHD risk. DBP is the strongest predictor in patients younger than 50 years; in patients aged 50 to 59 years, all three BP indexes are comparable predictors. In patients aged 60 years and older, PP and SBP are stronger predictors of heart disease.20
Hypertension increases shear stress and therefore may lead to plaque rupture. Furthermore, high BP can cause endothelial damage and may enhance the migration of lipoproteins into the vessel wall. According to the AHA 2002 guidelines, the BP goal is <140/90 mmHg; if renal insufficiency or heart failure is present, the goal is <130/85 mmHg; if diabetes is present, the goal is <130/80 mmHg.21
During counseling sessions, pharmacists can identify patients with borderline or high BP and attempt to identify contributing factors such as obesity, excessive alcohol intake (>3 units/day), excessive salt intake, and lack of exercise.22 For patients with BP ≥130/80 mmHg, pharmacists can initiate lifestyle advice, including the following points23-25:
- In overweight patients, reduce calorie intake and increase physical activity, since weight loss is associated with a modest reduction in BP.
- Reduce alcohol consumption. Consumption of >21 units of alcohol per week may be associated with increased BP, but this effect can be reversed by reducing intake to no more than the recommended limit.
- Reduce salt intake from 10 g to 5 g daily. This can lower BP by up to 4/3 mmHg.
- Increase consumption of fruits and vegetables and low-fat dairy products.
If lifestyle modifications are not effective in 6 to 12 months and BP remains ≥140/90 mmHg (patients with renal insufficiency or heart failure: SBP ≥130 mmHg or DBP 85 mmHg), it may be necessary to initiate drug therapy.21 Possibilities include thiazide diuretics, beta-blockers, calcium channel blockers, ACE inhibitors, angiotensin receptor blockers (ARBs), and direct vasodilators. Alpha-blockers should generally be avoided since they have adverse effects on cardiovascular morbidity and mortality rates. Central alpha antagonists have more adverse effects than benefits, so they should be avoided also.21
Some patients may require two or more antihypertensives to achieve the BP goal. TABLE 4 summarizes indications and adverse effects for each of the drug classes and provides patient counseling points.26,27
The Framingham Heart Study and the Multiple Risk Factor Intervention Trial demonstrated that cholesterol levels are linked to increased heart disease.28,29 According to the AHA, the primary goal of lipid management should be LDL <160 mg/dL if one or more risk factors are present; LDL <130 mg/dL if two or more risk factors are present and the 10-year CHD risk is <20%; or LDL <100 mg/dL if two or more risk factors are present and the 10-year CHD risk is ≥20% or the patient has diabetes.21
In addition to identifying patients with, or at risk for, high LDL, pharmacists can recommend therapeutic lifestyle measures to patients with high LDL. Dietary modifications should be made to lower the LDL: limiting calories from saturated fat to <7% and cholesterol to <200 mg per day. If further reduction of LDL is required, additional dietary measures, weight reduction, and physical activity are recommended. Patients should be encouraged to reduce their consumption of saturated fat; increase their consumption of unsaturated fat, whole grains, fruits, vegetables, and fish; and limit alcohol in order to prevent heart disease.30 Moderate alcohol raises HDL by stimulating the production of apolipoprotein A-I and A-II.
If 12 weeks of therapeutic lifestyle changes do not reduce the LDL to an acceptable level, then drug therapy is recommended. Drug therapy may include statins, bile acid–binding resins, niacin, or fibrates.9
Statins are the treatment of choice and should be initiated as first-line therapy. Statins should be avoided in pregnancy, hepatic disease, or a history of myositis.9 Although the addition of statins reduces the risk of nonfatal events, the benefits of high-dose statins must be weighed against the risk of myopathy.9 Patients with triglyceridemia may be managed with fibrates, nicotinic acid, and omega-3 fatty acids, and those with a low HDL may be prescribed fibrates and nicotinic acid. In mixed dyslipidemias, a statin may be combined with nicotinic acid or a fibrate.9
It has been demonstrated that low adherence to statin therapy leads to a residual risk of heart disease.31 One study has shown that pharmacist-led interventions may be successful in improving adherence to lipid-lowering medications.32
Obesity has been identified as a major modifiable risk factor for heart disease.33 The risk of heart disease is two to three times greater in overweight women than in lean women.34 The aim of managing obesity should be to achieve a BMI of 18.5 to 24.9 kg/m2.21 Pharmacists should advise obese patients to reduce body weight through diet and increased physical activity. Thirty minutes of walking daily has been shown to reduce the risk of MI by as much as 50%.35,36 Since frequent fluctuations in weight are also associated with an increased risk of CHD, weight-loss programs must not only encourage weight loss, but help maintain it. In counseling patients, pharmacists should remember that 1) more frequent exercise provides more benefit and the aim should be to exercise daily, and 2) the more strenuous the exercise (e.g., jogging), the greater the benefit.9
Blood Glucose Control
Heart disease is more common in people with diabetes, follows a more aggressive course, and has a worse prognosis.37 In fact, type 2 diabetes is associated with a greater than twofold increased risk for heart disease.37 In managing blood glucose, the goal should be to achieve a normal fasting plasma glucose <110 mg/dL and near-normal glycosylated hemoglobin (HbA1c) <7%.21
Pharmacists can help patients initiate appropriate hypoglycemic therapy to achieve near-normal fasting plasma glucose or near-normal HbA1c. The first step of management should be lifestyle measures, including diet and exercise. If this does not control blood glucose levels, then oral hypoglycemic drugs, including sulfonylureas and/or metformin with ancillary use of acarbose and thiazolidinediones (TZDs), may need to be initiated. Insulin is reserved for patients who do not achieve adequate blood glucose control even with oral hypoglycemics.21
Oral hypoglycemic agents include biguanides, sulfonylureas, meglitinide derivatives, alpha-glucosidase inhibitors, TZDs, glucagonlike peptide-1 (GLP-1) agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, selective sodium-glucose cotransporter 2 (SGLT-2) inhibitors, insulins, amylinomimetics, bile acid sequestrants, and dopamine agonists.
Metformin is the only biguanide currently available in the U.S.; it is typically used as a first-line agent unless there are contraindications. Metformin should be taken immediately after a meal because it can induce gastrointestinal (GI) side effects such as abdominal bloating, cramps, nausea, vomiting, and diarrhea.38 Metformin increases uptake of glucose into peripheral cells, reduces hepatic glucose production, and aids weight loss.
Sulfonylureas such as gliclazide and glimepiride are commonly used as second-line agents, or as first-line agents in patients who cannot tolerate metformin. Sulfonylureas are usually taken with a meal. They can cause weight gain and hypoglycemia and they interact with oral anticoagulants.38
TZDs such as pioglitazone and rosiglitazone are an alternative second-line or third-line therapy and usually are taken with a meal. They are associated with an increased risk of fractures, and in some patients they may lead to heart failure. Pioglitazone is also associated with an increased risk of bladder cancer.38
GLP-1 agonists such as exenatide and liraglutide are administered via injection. They have a lower risk of hypoglycemia than do sulfonylureas. A common adverse effect of GLP-1 agonists is nausea, which is usually temporary and disappears approximately 2 weeks after treatment initiation.38 Injection-site reactions have also been reported by users of GLP-1 agonists.
DPP-4 inhibitors such as sitagliptin have a low risk of hypoglycemia and do not lead to weight gain.38
SGLT-2 inhibitors such as dapagliflozin and canagliflozin prevent reabsorption of glucose and facilitate its excretion in the urine. They are associated with a low risk of hypoglycemia and modest control of BP and weight. SGLT-2 inhibitor use may result in hypotension and dehydration.38
Many antidiabetic agents affect the patient’s weight. The effect of these medications on weight is summarized in TABLE 5.39
Counseling points for insulin are as follows:
- Draw air into the syringe in an amount corresponding to the prescribed amount of insulin. Invert the vial and draw up a little more insulin than prescribed.
- The best sites for self-injection are the front and outer sides of the thigh and the abdomen.
- Clean the injection site with an alcohol wipe, pinch the skin at the injection site in a broad fold, and insert the needle at a 45-degree angle into the SC tissue. Inject the insulin slowly, then press one finger against the injection site while pulling out the needle.
- Rotate the injection site in the chosen area.
- Discard disposable needles and syringes in a sharps container.
- Insulin should be stored at a temperature of 2°C-8°C when not in use. Opened vials may be stored at room temperature for up to 28 days.
- Self-monitor for adverse reactions—in particular, adverse reactions to bovine or porcine insulin.40
All diabetic patients are at risk for hypoglycemic episodes, and a discussion of this should form a part of the counseling session. Patients should be aware of the symptoms of hypoglycemia (sweating, weakness, confusion) and know how to manage such episodes (e.g., by drinking fruit juice). More importantly, patients should be aware that regular eating patterns and blood glucose monitoring will prevent episodes of hypoglycemia.40
The use of aspirin to prevent ischemic events in patients without a history of CHD is controversial. To maximize the risk-benefit ratio, aspirin use should therefore be targeted to patients at high risk for heart disease. Aspirin should be avoided in patients with an increased aspirin tolerance and in those at risk for GI bleeding or hemorrhagic stroke.41,42 A reduction of up to 28% in the risk of cardiac events has been shown in a number of patient populations taking aspirin regularly, including men older than 40 years, postmenopausal women, and younger patients with multiple CVD risk factors.43 The current recommendation is for patients at high risk for heart disease to receive low-dose aspirin therapy (75 mg/day).21
The use of antioxidants for prevention of heart disease has not been established because the results of various trials have been controversial. Although the Cambridge Heart Antioxidant Study (CHAOS) found a reduced rate of heart disease in patients taking large doses of antioxidants, the Heart Outcomes Prevention Evaluation (HOPE) study, Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico GISSI-Prevenzione study, and Heart Protection Study (HPS) found no benefit from vitamin E supplementation.44-47
Secondary prevention relies on early detection of the disease process and the application of interventions to prevent disease progression in symptomatic patients.9 Secondary prevention includes all of the strategies for primary prevention, as well as other measures that are discussed in this section.
There are two aspects to secondary prevention: lifestyle changes and drug treatment. Lifestyle changes include smoking cessation, increased physical activity, weight loss (if obese/overweight), dietary improvements (reduced total and saturated fat intake; increased fruit, vegetable, and fiber intake), and moderate alcohol consumption. Evidence-based therapy includes antiplatelets and anticoagulants, ACE inhibitors, betablockers, and statins.9
Antiplatelets and Anticoagulants
In addition to the management of hyperlipidemia, hyperglycemia, and high BP, as required, secondary prevention involves the use of an antiplatelet agent. Patients should be started on aspirin 75 to 162 mg per day, and this should be continued indefinitely unless contraindicated. The Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial showed that clopidogrel was as effective as aspirin in the secondary prevention of heart disease and therefore may be used as a suitable alternative to aspirin in patients intolerant to aspirin. It should be noted, however, that clopidogrel is associated with adverse gastric effects similar to those of aspirin. Clopidogrel 75 mg per day should be added to aspirin for 12 months in patients who have experienced an acute coronary syndrome or undergone percutaneous coronary intervention with stent placement. Patients with atrial fibrillation should be managed with warfarin to an international normalized ratio of 2.0 to 3.0.9 In counseling patients, pharmacists should keep in mind that the use of warfarin with aspirin and/or clopidogrel is associated with an increased risk of bleeding.9
ACE Inhibitors and ARBs
One of the major factors affecting the long-term outcome of a patient following a coronary event such as MI is left ventricular (LV) disease. ACE inhibitors prevent the development of LV disease by modifying the process by which the heart repairs itself in response to an MI, thereby reducing mortality. It is recommended that ACE inhibitors be initiated and continued indefinitely in all patients with LV ejection fraction ≥40% and in those with hypertension, diabetes, or chronic kidney disease, unless contraindicated. The most common adverse effect noted with ACE inhibitors is cough. For patients who cannot tolerate ACE inhibitors or have heart failure, ARBs may be used.9
Beta-blockers should be started and used indefinitely in all patients who have had an MI, acute coronary syndrome, or LV dysfunction.9 Beta-blockers have a number of features, including rate control, antiarrhythmic effects, and BP-lowering properties.9
The growing role of the pharmacist allows for a number of interventions for the primary and secondary prevention of heart disease. Key areas of input include identifying patients who have had or are at high risk for coronary disease, ensuring evidence-based prescribing, recommending suitable therapeutic agents, optimizing doses for maximal benefit, counseling patients on therapy, and ensuring that patients are aware of adverse effects and what to do if they occur. These measures should be undertaken together with adoption of a healthful lifestyle and should take into consideration coexisting risk factors.
- Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics—2014 update: a report from the American Heart Association. Circulation. 2014;129:e28-e292.
- Weintraub WS, Daniels SR, Burke LE, et al. Value of primordial and primary prevention for cardiovascular disease: a policy statement from the American Heart Association. Circulation. 2011;124:967-990.
- National Service Framework for Coronary Heart Disease. London, England: Department of Health; 2000.
- O’Loughlin J, Masson P, Déry V, Fagnan D. The role of community pharmacists in health education and disease prevention: a survey of their interests and needs in relation to cardiovascular disease. Prev Med. 1999;28:324-331.
- George PP, Molina JA, Cheah J, et al. The evolving role of the community pharmacist in chronic disease management—a literature review. Ann Acad Med Singapore. 2010;39:861-867.
- Wilson PW, D’Agostino RB, Levy D, et al. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97:1837-1847.
- Feinleib M. Seven countries: a multivariate analysis of death and coronary heart disease. JAMA. 1981;245:511-512.
- Torpy JM, Lynm C, Glass RM. JAMA patient page. Risk factors for heart disease. JAMA. 2003;290:980.
- Mohamad TN. Primary and secondary prevention of coronary artery disease. http://emedicine.medscape.com/article/164214-overview#a2. Accessed January 18, 2017.
- Xu B, Généreux P, Yang Y, et al. Validation and comparison of the long-term prognostic capability of the SYNTAX score-II among 1,528 consecutive patients who underwent left main percutaneous coronary intervention. JACC Cardiovasc Interv. 2014;7:1128-1137.
- Hanna IR, Wenger NK. Secondary prevention of coronary heart disease in elderly patients. Am Fam Physician. 2005;71:2289-2296.
- Wilhelmsen L. Coronary heart disease: epidemiology of smoking and intervention studies of smoking. Am Heart J. 1988;115(1pt2):242-249.
- U.S. Department of Health and Human Services. The Health Benefits of Smoking Cessation: a Report of the Surgeon General. Rockville, MD: CDC; 1990. DHHS Publication No. (CDC) YO-K-116.
- Gibbons RJ, Chatterjee K, Daley J, et al. ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients With Chronic Stable Angina). J Am Coll Cardiol. 1999;33:2092-2197.
- Daly LE, Mulcahy R, Graham IM, Hickey N. Long term effect on mortality of stopping smoking after unstable angina and myocardial infarction. Br Med J (Clin Res Ed). 1983;287:324-326.
- CDC. Smoking cessation. www.cdc.gov/tobacco/data_statistics/fact_ sheets/cessation/quitting/index.htm. Accessed January 18, 2017.
- McRobbie H, McEwen A. Helping smokers to stop: advice for pharmacists in England. www.ncsct.co.uk/usr/pub/helping-smokers-stopguidance-for-pharmacist-in-england.pdf. Accessed January 17, 2017.
- Collins R, MacMahon S. Blood pressure, antihypertensive drug treatment and the risks of stroke and of coronary heart disease. Br Med Bull. 1994;50:272-298.
- Castelli WP. Epidemiology of coronary heart disease: the Framingham study. Am J Med. 1984;76:4-12.
- Franklin SS, Larson MG, Khan SA, et al. Does the relation of blood pressure to coronary heart disease risk change with aging? The Framingham Heart Study. Circulation. 2001;103:1245-1249.
- Pearson TA, Blair SN, Daniels SR, et al. AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke: 2002 update: consensus panel guide to comprehensive risk reduction for adult patients without coronary or other atherosclerotic vascular diseases. Circulation. 2002;106:388-391.
- Ramsay L, Williams B, Johnston G, et al. Guidelines for management of hypertension: report of the third working party of the British Hypertension Society. J Hum Hypertens. 1999;13:569-592.
- Elmer PJ, Grimm R Jr, Laing B, et al. Lifestyle intervention: results of the Treatment of Mild Hypertension Study (TOMHS). Prev Med. 1995;24:378-388.
- Manolio TA, Levy D, Garrison RJ, et al. Relation of alcohol intake to left ventricular mass: the Framingham Study. J Am Coll Cardiol. 1991;17:717-721.
- Graudal NA, Galloe AM, Garred P. Effects of sodium restriction on blood pressure, renin, aldosterone, catecholamines, cholesterols, and triglyceride: a meta-analysis. JAMA. 1998;279:1383-1391.
- Riaz K. Hypertensive heart disease. http://emedicine.medscape.com/article/162449-overview#a14. Accessed January 18, 2017.
- Centre for Pharmacy Postgraduate Education. New medicine service—antihypertensives. www.cppe.ac.uk/learningdocuments/pdfs/nms%20 antihypertensives%20jan%2013.pdf. Accessed January 18, 2017.
- Kannel WB, Dawber TR, Kagan A, et al. Factors of risk in the development of coronary heart disease—six year follow-up experience. The Framingham Study. Ann Intern Med. 1961;55:33-50.
- Stamler J, Wentworth D, Neaton JD. Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA. 1986;256:28232828.
- Woodward M, Tunstall-Pedoe H, Batty GD, et al. The prognostic value of adipose tissue fatty acids for incident cardiovascular disease: results from 3944 subjects in the Scottish Heart Health Extended Cohort Study. Eur Heart J. 2011;32:1416-1423.
- Banach M, Stulc T, Dent R, Toth PP. Statin non-adherence and residual cardiovascular risk: there is need for substantial improvement. Int J Cardiol. 2016;225:184-196.
- Deichmann RE, Morledge MD, Ulep R, et al. A metaanalysis of interventions to improve adherence to lipid-lowering medication. Ochsner J. 2016;16:230-237.
- Eckel RH, Krauss RM. American Heart Association call to action: obesity as a major risk factor for coronary heart disease. AHA Nutrition Committee. Circulation. 1998;97:2099-2100.
- Colditz GA, Coakley E. Weight, weight gain, activity, and major illnesses: the Nurses’ Health Study. Int J Sports Med. 1997;18(suppl3):S162-S170.
- Powell KE, Thompson PD, Caspersen CJ, Kendrick JS. Physical activity and the incidence of coronary heart disease. Ann Rev Public Health. 1987;8:253-287.
- American College of Sports Medicine Position Stand. Exercise and physical activity for older adults. Med Sci Sports Exerc. 1998;30:992-1008.
- Conget I, Giménez M. Glucose control and cardiovascular disease: is it important? No. Diabetes Care. 2009;32(suppl 2):S334-S336.
- Sweetman SC, ed. Martindale: The Complete Drug Reference. 27th ed. London, England: Pharmaceutical Press; 2011.
- Fox CS, Golden SH, Anderson C, et al. Update on prevention of cardiovascular disease in adults with type 2 diabetes mellitus in light of recent evidence: a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care. 2015;38:1777-1803.
- Kumanan R, Sudha S, Jayaveera KN. Can a pharmacist improve life of diabetes patient? An overview. Res J Pharm Biol Chem Sci. 2010;1:5-11.
- U.S. Preventive Services Task Force. Aspirin for the primary prevention of cardiovascular events: recommendation and rationale. Ann Intern Med. 2002;136:157-160.
- Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324:71-86.
- Hayden M, Pignone M, Phillips C, Mulrow C. Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2002;136:161-172.
- Stephens NG, Parsons A, Schofield PM, et al. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet. 1996;347:781-786.
- Yusuf S, Dagenais G, Pogue J, et al. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:154-160.
- Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet. 1999;354:447-455.
- Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7-22.