Review - On Invitation Only
Cardiovascular disease prevention G. Van Camp Cardiology Department, CHVZ, UZ Brussel, Brussel, Belgium Cardiovascular diseases remain the first killer in the Western countries. Equivalent contributions of prevention initiatives, pharmaceutical developments and technological improvements have led to an important success in the reduction of mortality related to cardiovascular diseases in some of the countries of the Western world. However, increase in life expectance, incomplete adherence to guidelines, difficulties in convincing governments and the population to support and adhere to prevention measures make that the burden of cardiovascular diseases is still extremely high. This review gives a restricted summary of the most important prevention guidelines supported by the European Society of Cardiology. It also illustrates the still very incomplete adherence to these guidelines in the different European countries as published in the EUROASPIRE surveys. Keywords: Cardiology, Prevention, Cardiovascular diseases
Introduction Atherosclerotic cardiovascular disease (CVD) remains the major cause of premature death in Europe. More than 80% of all CVD mortality occurs in developing countries. Not only mortality but also disability caused by CVD remains extremely high and thereby CVD is still the leading somatic cause of loss of productivity: disability-adjusted life years (DALYs) are expected to rise from 85 million DALYs in 1990 to about 150 million DALYs in 2020.1 The World Health Organization (WHO) has underlined the importance of lifestyle, such as tobacco use, unhealthy diet habits, physical inactivity and psychological stress in the explosion of cardiovascular disease in the Western world and the WHO states that threequarters of all CVD mortality may be avoided by adequate coordinated prevention actions.2 The European Society of Cardiology has published his latest prevention guidelines in 2012.3 It remains the actual cornerstone for the most important actions in the prevention of CVD. This review will try to summarize the most important messages from these guidelines and put these into perspective of daily practice. For this purpose the EUROASPIRE survey data will be used, and since the latest published data are those from EUROASPIRE III these results will be discussed.4,5 Unfortunately, preliminary results from EUROASPIRE IV shows very comparable results than the preceding and published survey.
Correspondence to: Guy Van Camp, Cardiology Department, CHVZ, UZ Brussel, Laarbeeklaan 101, 1090 Brussel, Belgium. Email: guy.vancamp @uzbrussel.be
ß Acta Clinica Belgica 2014 DOI 10.1179/2295333714Y.0000000069
The article will be divided into the following sections: 1. 2. 3. 4.
How to measure the risk for CVD? How to apply CVD prevention? How important is the gap between the guidelines and daily practice? A view in the future: how to do it better?
How to Measure Cardiovascular Risk? In Europe risk estimation is based on the SCORE system. The SCORE system estimates the 10-year risk of a first fatal atherosclerotic event (heart attack, stroke, aneurysm of the aorta, or other). In 2007 risk was given as a 10-year risk of cardiovascular death and not of cardiovascular events, fatal and non-fatal together. This is in contrast with other risk scoring systems as the Framingham score. Information from FINRISK shows that fatal risk can be multiplied by a factor 3 to obtain total cardiovascular risk: a 5% SCORE risk of cardiovascular death equates to a 10– 25% risk using the Framingham risk score for total cardiovascular risk.6 The ratio behind risk scoring systems is that the risk of having cardiovascular disease is not determined by one risk factor but by the global risk profile of the individual patient. The estimation of the cardiovascular risk should help the practitioners to make logical management decisions, avoiding over and under treatment. Certain individuals such as patients having presented already a cardiovascular event are at high cardiovascular risk without need for any other risk calculation. However, for most people certainly men .40 years and women .50 years of age or post-menopausal, risk factor screening is
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recommended including the lipid profile.3 In younger persons a low absolute risk may result in a very high relative risk what resulted in the introduction of the relative risk charts (cardiovascular risk age). Women cannot be excluded from risk calculations for cardiovascular disease as the risk is deferred by approximately 10 years but not avoided. The different SCORE charts can be found on http://www. escardio.org/guidelines-surveys/escguidelines/Pages/cvdprevention.aspx. Age, gender, smoking habits, blood pressure and total cholesterol level will determine the SCORE risk using the appropriate SCORE tables depending if the patient is living in a high risk or low risk country. Fine-tuning of cardiovascular risk estimation can be performed when additional patient characteristics are known: central obesity and sedentary lifestyle, socially deprived environment, presence of psychological risk factors, diabetes (SCORE should only be used in diabetes type I patients without target organ damage), low HDL cholesterol and increased triglycerides, fibrinogen, apolipoprotein B, lipoprotein(a), perhaps increased CRP, preclinical evidence of atherosclerosis (plaque on carotid US examination), moderate or severe kidney disease and a family history of premature CVD. Very high risks for cardiovascular disease death are: 1.
2.
3. 4.
documented CVD by invasive or non-invasive testing, previous myocardial infarction, ACS, coronary revascularization or other revascularization procedures, ischaemic stroke, peripheral arterial disease diabetes mellitus (type 1 or 2) with §1 CV risk factors and/or target organ damage (as microalbuminuria 30–300 mg/24 hours) severe chronic kidney disease (GFR,30 ml/minute/1.73 m2) a calculated SCORE §10%.
High risk patients are subjects with: 1. 2. 3. 4.
markedly elevated single risk factors such as familial dyslipidaemias and severe hypertension diabetes mellitus (type 1 or type 2) but without CV risk factors or target organ damage moderate chronic kidney disease (GFR 30–59 ml/ minute/1.73 m2). a calculated SCORE of §5% and ,10% for 10year risk of fatal CVD.
Moderate risk can be recognized when SCORE §1 and ,5% at 10 years and low risk is defined as SCORE ,1%. Finally, supplementary tools can be used to optimize the estimation of cardiovascular disease risk. High-sensitive C-reactive protein (hs-CRP) integrates multiple metabolic and inflammatory factors, playing a role or being present, in the development of unstable atherosclerotic plaques.7 However, the
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dependence of this parameter on other classical risk factors, the lack of precision, specificity and causality, the lack of specific therapeutic strategies and the higher cost of this test compared to the classical ones as blood glucose and lipids makes the use of hsCRP unattractive and the same holds true for fibrinogen.8 Homocysteine and lipoprotein-associated phospholipase 2 are respectively independent risk factors for CVD on the one hand and plaque rupture and atherothrombotic events on the other. Their magnitude of effect on risk estimation is however modest and together with the high cost, these parameters remain second-line markers of CVD risk estimation. In asymptomatic patients at moderate risk, imaging methods can play a role in CVD risk estimation. Stress-testing for coronary artery disease (exercise ECG, stress echocardiography or radionuclide scintigraphy), carotid artery scanning by ultrasound (intima-media thickness .0.9 mm is abnormal and/ or screening for plaques), measurement of the anklebrachial index (ABI,1 is a reliable marker of PAD), and calcium score determined by EBCT (very high negative predictive value if50 in stable asymptomatic patients) have the potential of detecting asymptomatic atherosclerotic disease but cost-effectiveness is still not proven.3 In atherosclerosis, which is an inflammatory systemic disease, immune mechanisms interact with metabolic risk factors initiating and leading to activated lesions in the arterial tree.9 Influenza, chronic kidney disease, obstructive sleep apnoea, erectile dysfunction, autoimmune diseases (psoriasis, rheumatoid arthritis, lupus erythematosus), periodontitis, coronary artery disease after radiation exposure of the chest, vascular disease after transplantation are all situations with a clinical presentation determined by inflammatory processes associated with an increased cardiovascular event rate. The optimal prevention attitude to adopt is unclear and not proven by randomized studies but management of all risk factors appears advisable illustrated by the following examples. Influenza vaccination in the population leads to a very cost-effective reduction of clinical events and annual vaccination is recommended for patients with established CVD.10 A combination of simvastatine 20 mg and ezetimibe 10 mg daily resulted in a significant reduction of major cardiovascular events in patients with advanced chronic kidney disease.11 The treatment of obstructive sleep apnoea in patients with chronic coronary artery disease may result in decreased cardiac events and deaths.12 Weekly administration of 10–20 mg methotrexate in patients with rheumatoid arthritis and psoriasis results in reductions in rates of vascular events and deaths.13
Van Camp
How to Apply CVD Prevention? Prevention of CVD start with the recommendation of healthy lifestyle Changing smoking behaviour is the cornerstone of this essential step in cardiovascular prevention. Smoking is responsible for 50% of all avoidable deaths in smokers, half of these are due to CVD.14 Using the SCORE-tables, smoking will double the 10 years mortality risk for CVD and this effect is even stronger in smokers ,50 years age. The risk associated with smoking shows a dose-response relationship.15 Any form of tobacco use is deleterious and passive smoking increases also the risk of CVD, a strong argument to minimize exposure to environmental tobacco smoke. The immediate and long term benefit of smoking cessation is well documented. A nice example is that smoking cessation after a myocardial infarction results in the most optimal secondary prevention strategy resulting in a mortality benefit of 0.64 [95% confidence interval (CI) 0.58–0.71] compared to continued smoking.16 To achieve the objective of smoking cessation an intensive program must be proposed by the health care providers including professional assistance for optimizing patients motivation and often pharmacological aids. Nicotine replacement therapy, varenicline or bupropion should be prescribed to those smokers who are motivated to stop.17–19 A healthy diet has a central place in the prevention of cardiovascular disease. Most evidence underscoring the impact of healthy dietary habits on cardiovascular risk comes from observational studies.20 The most important characteristics of a healthy diet are: saturated fatty acids ,10% of total energy intake, through replacement by polyunsaturated fatty acids; as little as possible trans-unsaturated fatty acids (,1% of total energy intake); ,5 g of salt/day; 30– 45 g of fibre/day; 200 g fruit/day; 200 g of vegetables/ day; fish at least twice a week; consumption of alcoholic beverages limited to 2 glasses/day (20 g/day alcohol) for men and one glass/day (10 g/day) for women.3 The energy intake should be tailored to the amount of energy needed to obtain a healthy weight (BMI,25 kg/m2. No nutrition supplements are need. Regular physical activity and aerobic exercise training are related to a reduced risk of CVD and non-fatal coronary events and this is true for healthy subjects as for patients with coronary risk factors and cardiac patients.21,22 Therefore guidelines suggest 2.5–5 hours/week of physical activity or aerobic exercise training of at least moderate intensity or 1– 2.5 hours/week of intense exercise for a healthy adult. Patients with a history of coronary artery disease or heart failure should perform moderate-to-vigorous intensity aerobic exercise training §3/week during 30 minutes sessions.3
Cardiovascular disease prevention
Multimodal behavioural intervention focusing on health education, physical exercise but also psychological risk factors should be part of cardiovascular prevention. Attention should be paid to depression and anxiety, and treatment should be offered by psychotherapy and antidepressant/anxiolytic medication when symptoms are severe. Stress-management programs have shown to improve well-being and have a beneficial effect on cardiovascular risk factors and CVD outcomes.23 Weight reduction in overweight (BMI 25–29.9 kg/ m2) and obese (BMI.30 kg/m2) patients is an important aspect of cardiovascular prevention as this is associated with a favourable effect on cardiovascular risk factors such as blood pressure, dyslipidaemia and insulin resistance.3 Increasing BMI is associated with risk of CVD but perhaps that regional distribution of adipose tissue is even more important in determining cardiovascular risk. Therefore the WHO defines §94 cm of waist circumference for men and §80 cm for women as the threshold at which no further weight should be gained and §102 cm for men and §88 cm for women as thresholds at which weight reduction should be advised.24 If diet and behaviour measurements are unsuccessful, medical therapy with orlistat and/or bariatric surgery are often the only options in patients with a BMI§40 kg/m2 or a BMI§35 kg/m2 in the presence of high-risk co-morbid conditions.25,26 Elevated blood pressure is a major risk factor for CVD, renal failure and atrial fibrillation.27 Grade 1, 2 and 3 hypertension are defined as a systolic blood pressure level of 140–159, 160–179 and §180 mm Hg and/or a diastolic blood pressure of 90–99, 100– 109 and §110 mmHg respectively. Methodological aspects, interest of ambulatory blood pressure measurements and blood pressure thresholds with different types of blood pressure measurement are summarized in the new ESH/ESC guidelines for the management of arterial hypertension.28 Following these guidelines a number of tests should be performed routinely making a risk estimation in these patients feasible and reliable.28 The decision to start pharmacological treatment will depend on the blood pressure level and the estimation of the total cardiovascular risk of the individual patient. After a proper history, physical examination and laboratory testing the physician should be able to identify the presence of established cardiovascular or renal disease, the presence of subclinical CVD and/or the co-existence of other cardiovascular risk factors. Prompt initiation of drug treatment is recommended in patients with grade 2 and 3 hypertension with any level of cardiovascular risk but is also recommended in all hypertensive patients with a high cardiovascular risk because of organ damage,
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diabetes, cardiovascular or chronic kidney disease. In elderly patients drug treatment is recommended when systolic blood pressure is .160 mmHg. With a lower level of evidence blood pressure should be treated in elderly patients with systolic blood pressures between 140 and 159 mmHg provided that antihypertensive treatment is well tolerated and in patients with grade 1 hypertension at low to moderate risk if blood pressures remain high after a period of time with lifestyle measures. Following the most recent guidelines on the management of arterial hypertension the target value of the systolic blood pressure should be ,140 mmHg, also in the diabetic patients. Only in the elderly patients reduction up to 140–150 mmHg is recommended. The target for the diastolic blood pressure should be ,90 mmHg except for diabetic patients (,85 mmHg). Life style interventions are often insufficient to normalize blood pressure but are important measurements to achieve optimal blood pressure control. The current guidelines state once again that diuretics, beta-blockers, calcium antagonists, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are all suitable for the initiation and maintenance of antihypertensive treatment. Aliskiren, a renin inhibitor and the centrally acting agents have a favourable effect on the blood pressure but side-effects and contra-indication must be taken into account. Most of the hypertensive patients will need more than one drug to normalize blood pressure and combination of more than one class has the advantage of being more potent than increasing the dose of one of the classes. This more effective result together with less side-effects of some combinations favours the use of combination treatment strategies in most of the hypertensive patients. The only combination that should be avoided is the combination between two different blockers of the RAS.28 Renal denervation and baroreceptor stimulation have actually only a low level of evidence recommendation in the treatment of resistant hypertension. Prevention in diabetic patients is of utmost importance to reduce the risk of microvascular and cardiovascular complications. The target HbA1c level to prevent CVD in diabetic patients is ,7%. Statins should be prescribed to all diabetic patients and as already mentioned blood pressure should be ,140/ 85 mmHg. Lipid lowering is another major target in the prevention of CVD. Increased plasma cholesterol and LDL cholesterol are main risk factors for CVD and the same hold true for hypertriglyceridaemia and low HDL cholesterol. Statines are the cornerstone of the treatment of hyperlipidaemia and have proven to have a beneficial effect on CVD. The targets in the treatment of hyperlipidaemia should be: total plasma
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cholesterol ,190 mg/dl and LDL cholesterol ,115 mg/dl in patients with low or moderate risk; LDL ,100 mg/dl in patients at high risk and ,70 mg/dl (or §50% reduction) in patients at very high risk. As for the treatment of hypertension combination treatment may be needed to obtain the targets. The combination of a statin with a bile acid sequestrant or with ezetimibe can be used. Lowering the doses of statins by using a combination therapy sometimes avoids side-effects of the statins. Fibrates (but not gemfibrozil) and particularly fenofibrate, can be added to statins to obtain the target values. This combination lowers further the triglycerides and the residual LDL cholesterol and results in higher HDL cholesterol levels. Antiplatelet therapy cannot be recommended in primary prevention due to the increased risk of major bleeding. However antiplatelet therapy is crucial in secondary prevention. In acute coronary syndromes dual antiplatelet therapy with ticagrelor or prasugrel (clopidogrel as second choice) added to aspirine is recommended for 12 months (unless contraindicated due to excessive bleeding risk) and aspirine should be given in the chronic phase in monotherapy. In patients with non-cardioembolic transient ischaemic attack or ischaemic stroke, secondary prevention with dipyridamole plus aspirine or clopidogrel is recommended. The prevention of stroke in patients with atrial fibrillation is not within the scope of this overview.
How Important Is the Gap between the Guidelines and Daily Practice EUROASPIRE I, II, III and a glimpse at IV survey show us how big the gap between guidelines and daily practice in Europe really is.4,5 A large number of patients having presented already a cardiovascular event do not reach the targets of the guidelines six months after the event and a large variation exists between European countries. Almost 1/3 of the patients with a coronary heart disease were smokers the month before the acute event and only about 50% stopped smoking 6 months after the event (stop smoking results in a 46% relative risk reduction in coronary mortality). Only 2/5 patients perform more physical activity compared to the time before the CV event and only 50% of the patient were told to participate in a revalidation program and of those who were included only 75% participated in at least 50% of the sessions. Less than 20% of the patients had a BMI,25 kg/m2. Eighty per cent of the patients were hypertensive and only 40% reached the target of ,140/90 mmHg. Fifty per cent of the patients had a total cholesterol .175 mg/dl and of those on lipid lowering therapy only 50% reached a value ,175 mg/ dl 6 months after the event. Thirty-three per cent of
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the patients had diabetes mellitus and 2/3 had a HbA1c §6.5% 6 months after the acute event. Six months after the coronary event, 90% of the patients received antiplatelet therapy, 80% were under betablockers, .2/3 received an ACE-I or ARB and 20% received no statins.
A View in the Future: How to do It Better in the Future? The integration of the guidelines into clinical practice remains poor. When treatments are prescribed, often the target values are not reached. Although a lot of reasons can be found to explain this gap (time constraints, the cost of prescribing medications, bad compliance of patients, not enough teaching and training of physicians and patients…) the major question for the future will be: how to do better in the future? The responsibilities of governments, professionals in medical care and patients are equally important and efforts must be made, more than in the past, to integrate our knowledge based on a maximum of evidence into clinical practice. Although a first glimpse on the results of EUROASPIRE IV are not very optimistic, future new initiatives in cardiovascular prevention will be of utmost importance if we want to reduce cardiovascular disease in a cost-effective way.
References 1 SIGN (Scottish Intercollegiate Guidelines Network). Risk Estimation and the Prevention of Cardiovascular Disease. A National Clinical Guideline. 2007. Report No. 97. Available from: http://www.sign.ac.uk/pdf/sign97.pdf. 2 World Health Organization. Joint WHO/FAO Expert Consultation on Diet, Nutrition and the Prevention of Chronic Diseases, Report No. 91, 2002. 3 Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren M, et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by presentatives of nine societies and by invited experts). Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2012;33:1635–701. 4 Kotseva K, Wood D, De Backer G, De Bacquer D, Pyorala K, Keil U. Cardiovascular prevention guidelines in daily practice: a comparison of EUROASPIRE I, II, and III surveys in eight European countries. Lancet. 2009;373:929–40. 5 Kotseva K, Wood D, De Backer G, De Bacquer D, Pyorala K, Keil U. EUROASPIRE III: a survey on the lifestyle, risk factors and use of cardioprotective drug therapies in coronary patients from 22 European countries. Eur J Cardiovasc Prev Rehabil. 2009;16:121–37. 6 Vartiainen E, Jousilahti P, Alfthan G, Sundvall J, Pietinen P, Puska P. Cardiovascular risk factor changes in Finland, 1972– 1997. Int J Epidemiol. 2000;29:49–56. 7 Kaptoge S, Di Angelantonio E, Lowe G, Pepys MB, Thompson SG, Collins R, et al. C-reactive protein concentration and risk of coronary heart disease,stroke, and mortality: an individual participant meta-analysis. Lancet. 2010;375:132–40. 8 Kaptoge S, White IR, Thompson SG, Wood AM, Lewington S, Lowe GD, et al. Associations of plasma fibrinogen levels with established cardiovascular disease risk factors, inflammatory markers, and other characteristics: individual participant metaanalysis of 154,211 adults in 31 prospective studies: the fibrinogen studies collaboration. Am J Epidemiol. 2007;166: 867–79.
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9 Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352:1685–95. 10 Nichol KL, Nordin J, Mullooly J, Lask R, Fillbrandt K, Iwane M. Influenza vaccination and reduction in hospitalizations for cardiac disease and stroke among the elderly. N Engl J Med. 2003;348:1322–32. 11 Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebocontrolled trial. Lancet. 2011;377:2181–92. 12 Milleron O, Pilliere R, Foucher A, de Roquefeuil F, Aegerter P, Jondeau G, et al. Benefits of obstructive sleep apnoea treatment in coronary artery disease: a long-term follow-up study. Eur Heart J. 2004;25:728–34. 13 Prodanovich S, Ma F, Taylor JR, Pezon C, Fasihi T, Kirsner RS. Methotrexate reduces incidence of vascular diseases in veterans with psoriasis or rheumatoid arthritis. J Am Acad Dermatol. 2005;52:262–7. 14 Prescott E, Hippe M, Schnohr P, Hein HO, Vestbo J. Smoking and risk of myocardial infarction in women and men: longitudinal population study. BMJ. 1998;316:1043–7. 15 Prescott E, Scharling H, Osler M, Schnohr P. Importance of light smoking and inhalation habits on risk of myocardial infarction and all cause mortality. A 22 year follow up of 12 149 men and women in The Copenhagen City Heart Study. J Epidemiol Community Health. 2002;56:702–6. 16 Critchley J, Capewell S. Smoking cessation for the secondary prevention of coronary heart disease. Cochrane Database Syst Rev. 2004;1:CD003041. 17 Stead LF, Perera R, Bullen C, Mant D, Lancaster T. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev. 2008;1:CD000146. 18 Hughes JR, Stead LF, Lancaster T. Antidepressants for smoking cessation. Cochrane Database Syst Rev. 2007;1: CD000031. 19 Rigotti NA, Pipe AL, Benowitz NL, Arteaga C, Garza D, Tonstad S. Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular disease: a randomized trial. Circulation. 2010;121:221–9. 20 Sofi F, Abbate R, Gensini GF, Casini A. Accruing evidence on benefits of adherence to the Mediterranean diet on health: an updated systematic review and meta-analysis. Am J Clin Nutr. 2010;92:1189–96. 21 Nocon M, Hiemann T, Muller-Riemenschneider F, Thalau F, Roll S, Willich SN. Association of physical activity with allcause and cardiovascular mortality: a systematic review and meta-analysis. Eur J Cardiovasc Prev Rehabil. 2008;15:239–46. 22 US Department of Health and Human Services. Physical Activity Guidelines Advisory Committee Report, 2008. Available from: http://www.health.gov/PAguidelines/Report/ pdf/CommitteeReport.pdf. 23 Gulliksson M, Burell G, Vessby B, Lundin L, Toss H, Svardsudd K. Randomized controlled trial of cognitive behavioral therapy vs standard treatment to prevent recurrent cardiovascular events in patients with coronary heart disease: Secondary Prevention in Uppsala Primary Health Care project (SUPRIM). Arch Intern Med. 2011;171:134–40. 24 World Health Organization. Obesity: Preventing and Managing the Global Epidemic. Report of a WHO Consultation. World Health Organization Technical Report Series, Report No. 894, 1998. 25 Drew BS, Dixon AF, Dixon JB. Obesity management: update on orlistat. Vasc Health Risk Manag. 2007;3:817–21. 26 Poirier P, Cornier MA, Mazzone T, Stiles S, Cummings S, Klein S, et al. Bariatric surgery and cardiovascular risk factors: a scientific statement from the American Heart Association. Circulation. 2011;123:1683–701. 27 MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J, et al. Blood pressure, stroke, and coronary heart disease. Part 1, Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet. 1990;335:765–74. 28 Mancia G, Fagard R, Narkiewicz K, Redo´n J, Zanchetti A, Bo¨hm M, et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension. The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2013;34:2159–219.
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Cardiovascular disease prevention G. Van Camp Cardiology Department, CHVZ, UZ Brussel, Brussel, Belgium Cardiovascular diseases remain the first killer in the Western countries. Equivalent contributions of prevention initiatives, pharmaceutical developments and technological improvements have led to an important success in the reduction of mortality related to cardiovascular diseases in some of the countries of the Western world. However, increase in life expectance, incomplete adherence to guidelines, difficulties in convincing governments and the population to support and adhere to prevention measures make that the burden of cardiovascular diseases is still extremely high. This review gives a restricted summary of the most important prevention guidelines supported by the European Society of Cardiology. It also illustrates the still very incomplete adherence to these guidelines in the different European countries as published in the EUROASPIRE surveys. Keywords: Cardiology, Prevention, Cardiovascular diseases
Introduction Atherosclerotic cardiovascular disease (CVD) remains the major cause of premature death in Europe. More than 80% of all CVD mortality occurs in developing countries. Not only mortality but also disability caused by CVD remains extremely high and thereby CVD is still the leading somatic cause of loss of productivity: disability-adjusted life years (DALYs) are expected to rise from 85 million DALYs in 1990 to about 150 million DALYs in 2020.1 The World Health Organization (WHO) has underlined the importance of lifestyle, such as tobacco use, unhealthy diet habits, physical inactivity and psychological stress in the explosion of cardiovascular disease in the Western world and the WHO states that threequarters of all CVD mortality may be avoided by adequate coordinated prevention actions.2 The European Society of Cardiology has published his latest prevention guidelines in 2012.3 It remains the actual cornerstone for the most important actions in the prevention of CVD. This review will try to summarize the most important messages from these guidelines and put these into perspective of daily practice. For this purpose the EUROASPIRE survey data will be used, and since the latest published data are those from EUROASPIRE III these results will be discussed.4,5 Unfortunately, preliminary results from EUROASPIRE IV shows very comparable results than the preceding and published survey.
Correspondence to: Guy Van Camp, Cardiology Department, CHVZ, UZ Brussel, Laarbeeklaan 101, 1090 Brussel, Belgium. Email: guy.vancamp @uzbrussel.be
ß Acta Clinica Belgica 2014 DOI 10.1179/2295333714Y.0000000069
The article will be divided into the following sections: 1. 2. 3. 4.
How to measure the risk for CVD? How to apply CVD prevention? How important is the gap between the guidelines and daily practice? A view in the future: how to do it better?
How to Measure Cardiovascular Risk? In Europe risk estimation is based on the SCORE system. The SCORE system estimates the 10-year risk of a first fatal atherosclerotic event (heart attack, stroke, aneurysm of the aorta, or other). In 2007 risk was given as a 10-year risk of cardiovascular death and not of cardiovascular events, fatal and non-fatal together. This is in contrast with other risk scoring systems as the Framingham score. Information from FINRISK shows that fatal risk can be multiplied by a factor 3 to obtain total cardiovascular risk: a 5% SCORE risk of cardiovascular death equates to a 10– 25% risk using the Framingham risk score for total cardiovascular risk.6 The ratio behind risk scoring systems is that the risk of having cardiovascular disease is not determined by one risk factor but by the global risk profile of the individual patient. The estimation of the cardiovascular risk should help the practitioners to make logical management decisions, avoiding over and under treatment. Certain individuals such as patients having presented already a cardiovascular event are at high cardiovascular risk without need for any other risk calculation. However, for most people certainly men .40 years and women .50 years of age or post-menopausal, risk factor screening is
Acta Clinica Belgica
2014
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69
NO.
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recommended including the lipid profile.3 In younger persons a low absolute risk may result in a very high relative risk what resulted in the introduction of the relative risk charts (cardiovascular risk age). Women cannot be excluded from risk calculations for cardiovascular disease as the risk is deferred by approximately 10 years but not avoided. The different SCORE charts can be found on http://www. escardio.org/guidelines-surveys/escguidelines/Pages/cvdprevention.aspx. Age, gender, smoking habits, blood pressure and total cholesterol level will determine the SCORE risk using the appropriate SCORE tables depending if the patient is living in a high risk or low risk country. Fine-tuning of cardiovascular risk estimation can be performed when additional patient characteristics are known: central obesity and sedentary lifestyle, socially deprived environment, presence of psychological risk factors, diabetes (SCORE should only be used in diabetes type I patients without target organ damage), low HDL cholesterol and increased triglycerides, fibrinogen, apolipoprotein B, lipoprotein(a), perhaps increased CRP, preclinical evidence of atherosclerosis (plaque on carotid US examination), moderate or severe kidney disease and a family history of premature CVD. Very high risks for cardiovascular disease death are: 1.
2.
3. 4.
documented CVD by invasive or non-invasive testing, previous myocardial infarction, ACS, coronary revascularization or other revascularization procedures, ischaemic stroke, peripheral arterial disease diabetes mellitus (type 1 or 2) with §1 CV risk factors and/or target organ damage (as microalbuminuria 30–300 mg/24 hours) severe chronic kidney disease (GFR,30 ml/minute/1.73 m2) a calculated SCORE §10%.
High risk patients are subjects with: 1. 2. 3. 4.
markedly elevated single risk factors such as familial dyslipidaemias and severe hypertension diabetes mellitus (type 1 or type 2) but without CV risk factors or target organ damage moderate chronic kidney disease (GFR 30–59 ml/ minute/1.73 m2). a calculated SCORE of §5% and ,10% for 10year risk of fatal CVD.
Moderate risk can be recognized when SCORE §1 and ,5% at 10 years and low risk is defined as SCORE ,1%. Finally, supplementary tools can be used to optimize the estimation of cardiovascular disease risk. High-sensitive C-reactive protein (hs-CRP) integrates multiple metabolic and inflammatory factors, playing a role or being present, in the development of unstable atherosclerotic plaques.7 However, the
408
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dependence of this parameter on other classical risk factors, the lack of precision, specificity and causality, the lack of specific therapeutic strategies and the higher cost of this test compared to the classical ones as blood glucose and lipids makes the use of hsCRP unattractive and the same holds true for fibrinogen.8 Homocysteine and lipoprotein-associated phospholipase 2 are respectively independent risk factors for CVD on the one hand and plaque rupture and atherothrombotic events on the other. Their magnitude of effect on risk estimation is however modest and together with the high cost, these parameters remain second-line markers of CVD risk estimation. In asymptomatic patients at moderate risk, imaging methods can play a role in CVD risk estimation. Stress-testing for coronary artery disease (exercise ECG, stress echocardiography or radionuclide scintigraphy), carotid artery scanning by ultrasound (intima-media thickness .0.9 mm is abnormal and/ or screening for plaques), measurement of the anklebrachial index (ABI,1 is a reliable marker of PAD), and calcium score determined by EBCT (very high negative predictive value if50 in stable asymptomatic patients) have the potential of detecting asymptomatic atherosclerotic disease but cost-effectiveness is still not proven.3 In atherosclerosis, which is an inflammatory systemic disease, immune mechanisms interact with metabolic risk factors initiating and leading to activated lesions in the arterial tree.9 Influenza, chronic kidney disease, obstructive sleep apnoea, erectile dysfunction, autoimmune diseases (psoriasis, rheumatoid arthritis, lupus erythematosus), periodontitis, coronary artery disease after radiation exposure of the chest, vascular disease after transplantation are all situations with a clinical presentation determined by inflammatory processes associated with an increased cardiovascular event rate. The optimal prevention attitude to adopt is unclear and not proven by randomized studies but management of all risk factors appears advisable illustrated by the following examples. Influenza vaccination in the population leads to a very cost-effective reduction of clinical events and annual vaccination is recommended for patients with established CVD.10 A combination of simvastatine 20 mg and ezetimibe 10 mg daily resulted in a significant reduction of major cardiovascular events in patients with advanced chronic kidney disease.11 The treatment of obstructive sleep apnoea in patients with chronic coronary artery disease may result in decreased cardiac events and deaths.12 Weekly administration of 10–20 mg methotrexate in patients with rheumatoid arthritis and psoriasis results in reductions in rates of vascular events and deaths.13
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How to Apply CVD Prevention? Prevention of CVD start with the recommendation of healthy lifestyle Changing smoking behaviour is the cornerstone of this essential step in cardiovascular prevention. Smoking is responsible for 50% of all avoidable deaths in smokers, half of these are due to CVD.14 Using the SCORE-tables, smoking will double the 10 years mortality risk for CVD and this effect is even stronger in smokers ,50 years age. The risk associated with smoking shows a dose-response relationship.15 Any form of tobacco use is deleterious and passive smoking increases also the risk of CVD, a strong argument to minimize exposure to environmental tobacco smoke. The immediate and long term benefit of smoking cessation is well documented. A nice example is that smoking cessation after a myocardial infarction results in the most optimal secondary prevention strategy resulting in a mortality benefit of 0.64 [95% confidence interval (CI) 0.58–0.71] compared to continued smoking.16 To achieve the objective of smoking cessation an intensive program must be proposed by the health care providers including professional assistance for optimizing patients motivation and often pharmacological aids. Nicotine replacement therapy, varenicline or bupropion should be prescribed to those smokers who are motivated to stop.17–19 A healthy diet has a central place in the prevention of cardiovascular disease. Most evidence underscoring the impact of healthy dietary habits on cardiovascular risk comes from observational studies.20 The most important characteristics of a healthy diet are: saturated fatty acids ,10% of total energy intake, through replacement by polyunsaturated fatty acids; as little as possible trans-unsaturated fatty acids (,1% of total energy intake); ,5 g of salt/day; 30– 45 g of fibre/day; 200 g fruit/day; 200 g of vegetables/ day; fish at least twice a week; consumption of alcoholic beverages limited to 2 glasses/day (20 g/day alcohol) for men and one glass/day (10 g/day) for women.3 The energy intake should be tailored to the amount of energy needed to obtain a healthy weight (BMI,25 kg/m2. No nutrition supplements are need. Regular physical activity and aerobic exercise training are related to a reduced risk of CVD and non-fatal coronary events and this is true for healthy subjects as for patients with coronary risk factors and cardiac patients.21,22 Therefore guidelines suggest 2.5–5 hours/week of physical activity or aerobic exercise training of at least moderate intensity or 1– 2.5 hours/week of intense exercise for a healthy adult. Patients with a history of coronary artery disease or heart failure should perform moderate-to-vigorous intensity aerobic exercise training §3/week during 30 minutes sessions.3
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Multimodal behavioural intervention focusing on health education, physical exercise but also psychological risk factors should be part of cardiovascular prevention. Attention should be paid to depression and anxiety, and treatment should be offered by psychotherapy and antidepressant/anxiolytic medication when symptoms are severe. Stress-management programs have shown to improve well-being and have a beneficial effect on cardiovascular risk factors and CVD outcomes.23 Weight reduction in overweight (BMI 25–29.9 kg/ m2) and obese (BMI.30 kg/m2) patients is an important aspect of cardiovascular prevention as this is associated with a favourable effect on cardiovascular risk factors such as blood pressure, dyslipidaemia and insulin resistance.3 Increasing BMI is associated with risk of CVD but perhaps that regional distribution of adipose tissue is even more important in determining cardiovascular risk. Therefore the WHO defines §94 cm of waist circumference for men and §80 cm for women as the threshold at which no further weight should be gained and §102 cm for men and §88 cm for women as thresholds at which weight reduction should be advised.24 If diet and behaviour measurements are unsuccessful, medical therapy with orlistat and/or bariatric surgery are often the only options in patients with a BMI§40 kg/m2 or a BMI§35 kg/m2 in the presence of high-risk co-morbid conditions.25,26 Elevated blood pressure is a major risk factor for CVD, renal failure and atrial fibrillation.27 Grade 1, 2 and 3 hypertension are defined as a systolic blood pressure level of 140–159, 160–179 and §180 mm Hg and/or a diastolic blood pressure of 90–99, 100– 109 and §110 mmHg respectively. Methodological aspects, interest of ambulatory blood pressure measurements and blood pressure thresholds with different types of blood pressure measurement are summarized in the new ESH/ESC guidelines for the management of arterial hypertension.28 Following these guidelines a number of tests should be performed routinely making a risk estimation in these patients feasible and reliable.28 The decision to start pharmacological treatment will depend on the blood pressure level and the estimation of the total cardiovascular risk of the individual patient. After a proper history, physical examination and laboratory testing the physician should be able to identify the presence of established cardiovascular or renal disease, the presence of subclinical CVD and/or the co-existence of other cardiovascular risk factors. Prompt initiation of drug treatment is recommended in patients with grade 2 and 3 hypertension with any level of cardiovascular risk but is also recommended in all hypertensive patients with a high cardiovascular risk because of organ damage,
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diabetes, cardiovascular or chronic kidney disease. In elderly patients drug treatment is recommended when systolic blood pressure is .160 mmHg. With a lower level of evidence blood pressure should be treated in elderly patients with systolic blood pressures between 140 and 159 mmHg provided that antihypertensive treatment is well tolerated and in patients with grade 1 hypertension at low to moderate risk if blood pressures remain high after a period of time with lifestyle measures. Following the most recent guidelines on the management of arterial hypertension the target value of the systolic blood pressure should be ,140 mmHg, also in the diabetic patients. Only in the elderly patients reduction up to 140–150 mmHg is recommended. The target for the diastolic blood pressure should be ,90 mmHg except for diabetic patients (,85 mmHg). Life style interventions are often insufficient to normalize blood pressure but are important measurements to achieve optimal blood pressure control. The current guidelines state once again that diuretics, beta-blockers, calcium antagonists, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are all suitable for the initiation and maintenance of antihypertensive treatment. Aliskiren, a renin inhibitor and the centrally acting agents have a favourable effect on the blood pressure but side-effects and contra-indication must be taken into account. Most of the hypertensive patients will need more than one drug to normalize blood pressure and combination of more than one class has the advantage of being more potent than increasing the dose of one of the classes. This more effective result together with less side-effects of some combinations favours the use of combination treatment strategies in most of the hypertensive patients. The only combination that should be avoided is the combination between two different blockers of the RAS.28 Renal denervation and baroreceptor stimulation have actually only a low level of evidence recommendation in the treatment of resistant hypertension. Prevention in diabetic patients is of utmost importance to reduce the risk of microvascular and cardiovascular complications. The target HbA1c level to prevent CVD in diabetic patients is ,7%. Statins should be prescribed to all diabetic patients and as already mentioned blood pressure should be ,140/ 85 mmHg. Lipid lowering is another major target in the prevention of CVD. Increased plasma cholesterol and LDL cholesterol are main risk factors for CVD and the same hold true for hypertriglyceridaemia and low HDL cholesterol. Statines are the cornerstone of the treatment of hyperlipidaemia and have proven to have a beneficial effect on CVD. The targets in the treatment of hyperlipidaemia should be: total plasma
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cholesterol ,190 mg/dl and LDL cholesterol ,115 mg/dl in patients with low or moderate risk; LDL ,100 mg/dl in patients at high risk and ,70 mg/dl (or §50% reduction) in patients at very high risk. As for the treatment of hypertension combination treatment may be needed to obtain the targets. The combination of a statin with a bile acid sequestrant or with ezetimibe can be used. Lowering the doses of statins by using a combination therapy sometimes avoids side-effects of the statins. Fibrates (but not gemfibrozil) and particularly fenofibrate, can be added to statins to obtain the target values. This combination lowers further the triglycerides and the residual LDL cholesterol and results in higher HDL cholesterol levels. Antiplatelet therapy cannot be recommended in primary prevention due to the increased risk of major bleeding. However antiplatelet therapy is crucial in secondary prevention. In acute coronary syndromes dual antiplatelet therapy with ticagrelor or prasugrel (clopidogrel as second choice) added to aspirine is recommended for 12 months (unless contraindicated due to excessive bleeding risk) and aspirine should be given in the chronic phase in monotherapy. In patients with non-cardioembolic transient ischaemic attack or ischaemic stroke, secondary prevention with dipyridamole plus aspirine or clopidogrel is recommended. The prevention of stroke in patients with atrial fibrillation is not within the scope of this overview.
How Important Is the Gap between the Guidelines and Daily Practice EUROASPIRE I, II, III and a glimpse at IV survey show us how big the gap between guidelines and daily practice in Europe really is.4,5 A large number of patients having presented already a cardiovascular event do not reach the targets of the guidelines six months after the event and a large variation exists between European countries. Almost 1/3 of the patients with a coronary heart disease were smokers the month before the acute event and only about 50% stopped smoking 6 months after the event (stop smoking results in a 46% relative risk reduction in coronary mortality). Only 2/5 patients perform more physical activity compared to the time before the CV event and only 50% of the patient were told to participate in a revalidation program and of those who were included only 75% participated in at least 50% of the sessions. Less than 20% of the patients had a BMI,25 kg/m2. Eighty per cent of the patients were hypertensive and only 40% reached the target of ,140/90 mmHg. Fifty per cent of the patients had a total cholesterol .175 mg/dl and of those on lipid lowering therapy only 50% reached a value ,175 mg/ dl 6 months after the event. Thirty-three per cent of
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the patients had diabetes mellitus and 2/3 had a HbA1c §6.5% 6 months after the acute event. Six months after the coronary event, 90% of the patients received antiplatelet therapy, 80% were under betablockers, .2/3 received an ACE-I or ARB and 20% received no statins.
A View in the Future: How to do It Better in the Future? The integration of the guidelines into clinical practice remains poor. When treatments are prescribed, often the target values are not reached. Although a lot of reasons can be found to explain this gap (time constraints, the cost of prescribing medications, bad compliance of patients, not enough teaching and training of physicians and patients…) the major question for the future will be: how to do better in the future? The responsibilities of governments, professionals in medical care and patients are equally important and efforts must be made, more than in the past, to integrate our knowledge based on a maximum of evidence into clinical practice. Although a first glimpse on the results of EUROASPIRE IV are not very optimistic, future new initiatives in cardiovascular prevention will be of utmost importance if we want to reduce cardiovascular disease in a cost-effective way.
References 1 SIGN (Scottish Intercollegiate Guidelines Network). Risk Estimation and the Prevention of Cardiovascular Disease. A National Clinical Guideline. 2007. Report No. 97. Available from: http://www.sign.ac.uk/pdf/sign97.pdf. 2 World Health Organization. Joint WHO/FAO Expert Consultation on Diet, Nutrition and the Prevention of Chronic Diseases, Report No. 91, 2002. 3 Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren M, et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by presentatives of nine societies and by invited experts). Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2012;33:1635–701. 4 Kotseva K, Wood D, De Backer G, De Bacquer D, Pyorala K, Keil U. Cardiovascular prevention guidelines in daily practice: a comparison of EUROASPIRE I, II, and III surveys in eight European countries. Lancet. 2009;373:929–40. 5 Kotseva K, Wood D, De Backer G, De Bacquer D, Pyorala K, Keil U. EUROASPIRE III: a survey on the lifestyle, risk factors and use of cardioprotective drug therapies in coronary patients from 22 European countries. Eur J Cardiovasc Prev Rehabil. 2009;16:121–37. 6 Vartiainen E, Jousilahti P, Alfthan G, Sundvall J, Pietinen P, Puska P. Cardiovascular risk factor changes in Finland, 1972– 1997. Int J Epidemiol. 2000;29:49–56. 7 Kaptoge S, Di Angelantonio E, Lowe G, Pepys MB, Thompson SG, Collins R, et al. C-reactive protein concentration and risk of coronary heart disease,stroke, and mortality: an individual participant meta-analysis. Lancet. 2010;375:132–40. 8 Kaptoge S, White IR, Thompson SG, Wood AM, Lewington S, Lowe GD, et al. Associations of plasma fibrinogen levels with established cardiovascular disease risk factors, inflammatory markers, and other characteristics: individual participant metaanalysis of 154,211 adults in 31 prospective studies: the fibrinogen studies collaboration. Am J Epidemiol. 2007;166: 867–79.
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9 Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352:1685–95. 10 Nichol KL, Nordin J, Mullooly J, Lask R, Fillbrandt K, Iwane M. Influenza vaccination and reduction in hospitalizations for cardiac disease and stroke among the elderly. N Engl J Med. 2003;348:1322–32. 11 Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebocontrolled trial. Lancet. 2011;377:2181–92. 12 Milleron O, Pilliere R, Foucher A, de Roquefeuil F, Aegerter P, Jondeau G, et al. Benefits of obstructive sleep apnoea treatment in coronary artery disease: a long-term follow-up study. Eur Heart J. 2004;25:728–34. 13 Prodanovich S, Ma F, Taylor JR, Pezon C, Fasihi T, Kirsner RS. Methotrexate reduces incidence of vascular diseases in veterans with psoriasis or rheumatoid arthritis. J Am Acad Dermatol. 2005;52:262–7. 14 Prescott E, Hippe M, Schnohr P, Hein HO, Vestbo J. Smoking and risk of myocardial infarction in women and men: longitudinal population study. BMJ. 1998;316:1043–7. 15 Prescott E, Scharling H, Osler M, Schnohr P. Importance of light smoking and inhalation habits on risk of myocardial infarction and all cause mortality. A 22 year follow up of 12 149 men and women in The Copenhagen City Heart Study. J Epidemiol Community Health. 2002;56:702–6. 16 Critchley J, Capewell S. Smoking cessation for the secondary prevention of coronary heart disease. Cochrane Database Syst Rev. 2004;1:CD003041. 17 Stead LF, Perera R, Bullen C, Mant D, Lancaster T. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev. 2008;1:CD000146. 18 Hughes JR, Stead LF, Lancaster T. Antidepressants for smoking cessation. Cochrane Database Syst Rev. 2007;1: CD000031. 19 Rigotti NA, Pipe AL, Benowitz NL, Arteaga C, Garza D, Tonstad S. Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular disease: a randomized trial. Circulation. 2010;121:221–9. 20 Sofi F, Abbate R, Gensini GF, Casini A. Accruing evidence on benefits of adherence to the Mediterranean diet on health: an updated systematic review and meta-analysis. Am J Clin Nutr. 2010;92:1189–96. 21 Nocon M, Hiemann T, Muller-Riemenschneider F, Thalau F, Roll S, Willich SN. Association of physical activity with allcause and cardiovascular mortality: a systematic review and meta-analysis. Eur J Cardiovasc Prev Rehabil. 2008;15:239–46. 22 US Department of Health and Human Services. Physical Activity Guidelines Advisory Committee Report, 2008. Available from: http://www.health.gov/PAguidelines/Report/ pdf/CommitteeReport.pdf. 23 Gulliksson M, Burell G, Vessby B, Lundin L, Toss H, Svardsudd K. Randomized controlled trial of cognitive behavioral therapy vs standard treatment to prevent recurrent cardiovascular events in patients with coronary heart disease: Secondary Prevention in Uppsala Primary Health Care project (SUPRIM). Arch Intern Med. 2011;171:134–40. 24 World Health Organization. Obesity: Preventing and Managing the Global Epidemic. Report of a WHO Consultation. World Health Organization Technical Report Series, Report No. 894, 1998. 25 Drew BS, Dixon AF, Dixon JB. Obesity management: update on orlistat. Vasc Health Risk Manag. 2007;3:817–21. 26 Poirier P, Cornier MA, Mazzone T, Stiles S, Cummings S, Klein S, et al. Bariatric surgery and cardiovascular risk factors: a scientific statement from the American Heart Association. Circulation. 2011;123:1683–701. 27 MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J, et al. Blood pressure, stroke, and coronary heart disease. Part 1, Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet. 1990;335:765–74. 28 Mancia G, Fagard R, Narkiewicz K, Redo´n J, Zanchetti A, Bo¨hm M, et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension. The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2013;34:2159–219.
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