77 Dialogues in Cardiovascular Medicine - Vol 14 . No. 2 . 2009 Editorial R. Ferrari, D. J. Hearse 79 Lead Article Should cardiovascular disease prevention be undertaken by doctors or policymakers and politicians? - D. A. Wood, K. Kotseva 83 Expert Answers to Three Key Questions Should coronary artery disease prevention be undertaken by doctors or by allied professionals? - G. G. De Backer 101 Should cardiovascular disease prevention be undertaken by national cardiac societies? - G. Kamensky, J. Murin 106 Should cardiovascular disease prevention be undertaken by politicians? D. Greco, G. Laurendi 112 Fascinoma Cardiologica Trails of Discovery: Aldosterone antagonists: a model of translational medicine N. Fitzgerald, J. D. Fitzgerald 119 Summaries of Ten Seminal Papers - K. Kotseva 127 Cardiovascular Disease Prevention The strategy of prevention: lessons from cardiovascular disease – G. Rose Sick individuals and sick populations – G. Rose An updated coronary risk profile. A statement for health professionals – K. Anderson and others Management of raised blood pressure in New Zealand: a discussion document – R. Jackson and others Prevention of coronary heart disease in clinical practice. Recommendations of the Task Force of the European Society of Cardiology, European Atherosclerosis Society and European Society of Hypertension – K. Pyörälä and others Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project – R. M. Conroy and others Exercise-based rehabilitation for patients with coronary heart disease: systematic review and meta-analysis of randomized controlled trials – R. S. Taylor and others Meta-analysis: secondary prevention programs for patients with coronary artery disease – A. M. Clark and others Multiple risk factor interventions for primary prevention of coronary heart disease – S. Ebrahim and others Prevention of cardiovascular disease. Guidelines for assess- ment and management of cardiovascular risk – WHO Bibliography of One Hundred Key Papers 139
Transcript
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Dialogues in Cardiovascular Medicine - Vol 14 . No. 2 . 2009
Editorial R. Ferrari, D. J. Hearse 79
Lead Article Should cardiovascular disease prevention be undertaken by doctors or policymakers and politicians? - D. A. Wood, K. Kotseva 83
Expert Answers to Three Key Questions Should coronary artery disease prevention be undertaken by doctors or by allied professionals? - G. G. De Backer 101Should cardiovascular disease prevention be undertaken bynational cardiac societies? - G. Kamensky, J. Murin 106Should cardiovascular disease prevention be undertaken by politicians? D. Greco, G. Laurendi 112
Fascinoma Cardiologica Trails of Discovery: Aldosterone antagonists: a model of translational medicineN. Fitzgerald, J. D. Fitzgerald 119
Summaries of Ten Seminal Papers - K. Kotseva 127
Cardiovascular Disease Prevention
The strategy of prevention: lessons from cardiovascular disease – G. Rose
Sick individuals and sick populations – G. Rose
An updated coronary risk profile. A statement for health professionals – K. Anderson and others
Management of raised blood pressure in New Zealand: a discussion document – R. Jackson and others
Prevention of coronary heart disease in clinical practice.Recommendations of the Task Force of the European Societyof Cardiology, European Atherosclerosis Society andEuropean Society of Hypertension – K. Pyörälä and others
Estimation of ten-year risk of fatal cardiovascular disease inEurope: the SCORE project – R. M. Conroy and others
Exercise-based rehabilitation for patients with coronary heartdisease: systematic review and meta-analysis of randomizedcontrolled trials – R. S. Taylor and others
Meta-analysis: secondary prevention programs for patients withcoronary artery disease – A. M. Clark and others
Multiple risk factor interventions for primary prevention ofcoronary heart disease – S. Ebrahim and others
Prevention of cardiovascular disease. Guidelines for assess-ment and management of cardiovascular risk – WHO
Bibliography of One Hundred Key Papers 139
78
Avkiran M, PhD Cardiovascular Research The Rayne InstituteSt Thomas’ HospitalLondon, UK
Bassand JP, MDDept of CardiologyUniversity Hospital Jean MinjozBesançon, France
Bertrand ME, MDHôpital CardiologiqueLille, France
Bolli R, MDDivision of CardiologyUniversity of LouisvilleLouisville, KY, USA
Camm JA, MDDept of Cardiac and Vascular SciencesSt George’s University of LondonLondon, UK
Coats A, MDFaculty of MedicineUniversity of SydneySydney, Australia
Cobbe SM, MDDept of Medical CardiologyGlasgow Royal InfirmaryGlasgow, UK
Cohn JN, MDRasmussen Center for Cardiovascular Disease PreventionMinneapolis, MN, USA
Cokkinos DV, MD1st Cardiology DeptOnassis Cardiac Surgery CenterAthens, Greece
Cowie M, MD, PhDDept of Clinical CardiologyNational Heart & Lung InstituteLondon, UK
Danchin N, MDDept of CardiologyHôpital Européen Georges PompidouParis, France
Dargie HJ, MDCardiac ResearchWestern InfirmaryGlasgow, UK
Di Pasquale G, MDDpt of CardiologyMaggiore HospitalBologna, Italy
Dzau VJ, MDDuke University Medical Center & Health System DUMCDurham, NC, USA
Consulting Editors
Editors in ChiefFerrari R, MD, PhDDept of Cardiology, Arcispedale S. AnnaUniversity of Ferrara, Ferrara, Italy
Hearse DJ, BSc, PhDThe Cardiothoracic Centre, The Rayne InstituteSt Thomas’ Hospital, London, UK
Fernandez-Aviles F, MDInstitute of Hematology and Oncology, IDIBAPSHospital University Clinic of Barcelona Barcelona, Spain
Fox KM, MDDept of CardiologyRoyal Brompton HospitalLondon, UK
Fox KA, MDDept of Cardiological ResearchUniversity of EdinburghEdinburgh, UK
Fuster V, MD, PhDCardiovascular InstituteMount Sinai Medical CenterNew York, NY, USA
Hasenfuss G, MDDept of CardiologyGeorg-August UniversitätGöttingen, Germany
Hori M, MD, PhDDept of Internal Medicine and TherapeuticsOsaka University Graduate School of MedicineOsaka, Japan
Katz AM, MDUniversity of Connecticut School of MedicineFarmington, CT, USA
Komajda M, MDDept of CadiologyCHU Pitié-SalpêtrièreParis, France
Komuro I, MD, PhDDept of Cardiovascular Sciences & MedicineChiba University Graduate School of MedicineChiba, Japan
Lakatta EG, MDNational Institute on AgingGerontology Research CenterBaltimore, MD, USA
Libby P, MDCardiovascular MedicineBrigham & Women’s HospitalBoston, MA, USA
Lonn E, MDHamilton Health Sciences General SiteHamilton, Ontario, Canada
Lopez-Sendon JL, MDCCU Dept of CardiologyHospital University Gregorio MaranonMadrid, Spain
Maggioni AP, MDANMC Research CenterFirenze, Italy
Marber MS, MD, PhDCardiovascular Research The Rayne Institute St Thomas’ HospitalLondon, UK
Oto A, MDMedical Office, Hacettepe University School of MedicineAnkara, Turkey
Patrono C, MDDept of PharmacologyUniversity La SapienzaRome, Italy
Pepine CJ, MDDept of MedicineUniversity of FloridaGainesville, FL, USA
Rapezzi C, MDInstitute of CardiologyUniversity of BolognaBologna, Italy
Remme WJ, MD, PhDSticares FoundationRotterdam, The Netherlands
Rosen MR, MDDept of Pharmacology &PediatricsColumbia University College of Physicians & SurgeonsNew York, NY, USA
Ruzyllo W, MDNational Institute of CardiologyWarsaw, Poland
Ryden L, MD, PhDDept of CardiologyKarolinska University Hospital SolnaStockholm, Sweden
Schneider MD, MDBaylor College of MedicineHouston, TX, USA
Seabra-Gomes RJ, MDInstituto do CoracaoHospital Santa CruzCarnaxide, Portugal
Sechtem U, MDDept of Internal Medicine & CardiologyRobert Bosch KrankenhausStuttgart, Germany
Simoons ML, MDThoraxcenterErasmus University Medical CenterRotterdam, The Netherlands
Sleight P, MDDept of Cardiovascular MedicineJohn Radcliffe HospitalOxford, UK
Soler-Soler J, MD Dept of CardiologyHospital General Vall d’HebronBarcelona, Spain
Steg PG, MDDept of CardiologyHôpital Bichat–Claude BernardParis, France
Swedberg K, MD, PhDDept of MedicineSahlgrenska University Hospital OstraGöteborg, Sweden
Tavazzi L, MDDivision of CardiologyPoliclinico San Matteo IRCCSPavia, Italy
Tendera M, MD3rd Division of CardiologySilesian School of MedicineKatowice, Poland
Vanhoutte PM, MDDept of PharmacologyUniversity of Hong Kong Faculty of MedicineHong Kong, China
Widimsky P, MD, PhDVinohrady CardiocenterCharles University HospitalPrague, Czech Republic
Wijns WC, MDCardiovascular Center AalstOLV Hospital, Aalst, Belgium
Dialogues in Cardiovascular Medicine - Vol 14 . No. 2 . 2009
Dialogues in Cardiovascular Medicine - Vol 14 . No. 2 . 2009
79
Roberto Ferrari, MD, PhD
David J. Hearse, BSC, PhD, DSc
ver the past century, life expectancy has increased by approximately 8 years.
Although this is a remarkable achievement, it is also a mixed blessing, and
there is a distinct downside to this success, chief among which is the dra-
matic inversion of the population pyramid that is projected to take place
in the not-too-distant future, made all the more acute by the drop in birth rates in
Western societies. This change in demographics is likely to have major consequences.
To start with, the post–baby boom population aging means that there will not be
enough young people to ensure the sustainability of the funding of health care and
pension benefits for the elderly. This will have dire socioeconomic consequences,
which we are already starting to have to come to grips with in the Western world.
Furthermore, lifestyle, too, is undergoing sweeping changes. Major social milestones
are being crossed increasingly later in life, such as getting married, starting a family, and
assuming greater work responsibilities. No longer is it common to lose our parents
or even grandparents while we are young, and when this happens, we are unprepared
to cope with it.
But let’s not be spoilsports, we should give praise where praise is due. Much to our
pride, cardiologists can take credit for the lion’s share of extended life expectancy, with
6 of those 8 years, while all the other specialists taken together account for only 2 years:
oncologists, for example, can lay claim to only 2.4 months!
Yet although we as cardiologists may justifiably bask in our success, we should take care
not to drop our guard. Cardiovascular disease (CVD) is expected to continue being
the number one killer in the Western world for the next 20 years: we still have plenty
of work ahead of us.
Our potential scope of action is enormous. We have already proven that we can treat
and prevent CVD. Prevention is obviously better than treatment. However, whereas
Editorial
CARDIOVASCULAR DISEASE PREVENTION: UNITED WE CONQUER
O
•••
treatment rests entirely in the hands of the cardiologist, prevention, quite rightly, does
not and should not. And this leads us directly to the question posed in this issue of
Dialogues in Cardiovascular Medicine: who among doctors, cardiac societies, or politi-
cians, should be spearheading the prevention of CVD?
But what exactly is CVD prevention about? In CVD, the archenemy is atherosclerosis
and its clinical manifestations such as angina pectoris, myocardial infarction, transient
ischemic attacks, and ischemic stroke. However, since the ultimate cause of atheroscle-
rosis is still cloaked in mystery, all our attention is directed toward addressing modifi-
able risk factors such as smoking, sedentary behavior, nutritional imbalance, impaired
glucose tolerance and diabetes, hypertension, dyslipidemia, overweight and abdominal
adiposity, heart rate, socioeconomic status, etc.
Clearly, all of this is too much and too important to be left in the hands of the cardiol-
ogist or of the general practitioner alone. Firstly, because they simply do not have the
time, an, secondly, because they do not have the know-how to deal with such a complex
issue on their own.
It is all very well and easy to tell patients to “change their lifestyle” and draw up a list
of do’s and don’ts, of pleasures forbidden and burdens imposed. Taken to the extreme,
the issue becomes a philosophical one, in the sense that if we are really in earnest
about preventing CVD, the majority (if not all) aspects of Western civilization will have
to be altered dramatically.
Of course, this is a pipe dream. Probably the most we can hope for is that the combined
efforts of politicians, policymakers, health authorities, insurance companies, scientific
societies, doctors, and allied professionals may be able to increase awareness among
populations and help countries in transition avoid making the same mistakes as the
more industrialized countries did in the past.
Changing the lifestyle of a population for the better is no easy task—ironically, getting
it to deteriorate is easily done enough: the negative influence of subliminal messages
from consumer society (TV, movies, Internet) is pervasive to the extent that even in
Italy, children now prefer burgers and chips to the traditional plate of spaghetti with
tomato and basil, which of course is the healthier option! Changing the lifestyle of
a population means challenging important vested economic interests—such as the
tobacco industry, to name but one. The introduction of legislation banning smoking in
public places in Italy has been effective in reducing tobacco consumption, and good
results in terms of reduction of CVD mortality are already noticeable. Amazingly, the ban
went down quite well in Italy, raising the hope that decisions of this type may increas-
ingly be understood by the population as being made for their own good and that of
Dialogues in Cardiovascular Medicine - Vol 14 . No. 2 . 2009
Editorial - Ferrari and Hearse
80
•••
their loved ones. Similar legislation is now needed on many other fronts: reduction of
salt (and sugar) in bread and processed foods, use of more fibers, less fat, etc. This
means of course that the food industry will have to completely change its outlook.
The isolated cardiologist can only suggest some or all of these measures to his/her
patients, with more or less immediate short-term success. As for the long term, how-
ever, National Cardiological Societies are far more effective in getting governments to
actively promote the prevention of CVD. Thus, one of the major goals of the European
Society of Cardiology (ESC) is to influence European politicians, and this is exactly
what has been achieved over the past 5 years with the call to action by the European
Summit on CVD Prevention to develop a heart-friendly environment in Europe. The
Summit hopes to ensure the implementation of the 12 July 2007 resolution of the
European Parliament on tackling CVD, as well as that of the European Heart Health
Charter, officially launched in June 2007 in Brussels, and which has gained the support
so far of 14 European health promotion organizations.
By now it should be clear that in the battle to prevent CVD no-one is superfluous, all
are needed: we must abide by the motto of Churchill’s famed Commandos: “United we
conquer.”
And what can Dialogues in Cardiovascular Medicine and its two editors in chief con-
tribute? Food for thought with this “Cardiovascular Disease Prevention” issue, which
raises relevant questions and provides a few leads.
Dialogues in Cardiovascular Medicine - Vol 14 . No. 2 . 2009
Editorial - Ferrari and Hearse
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83
Dialogues in Cardiovascular Medicine - Vol 14 . No. 2 . 2009
Should cardiovascular disease prevention be undertaken by doctors or policymakers and politicians?David A. Wood, MSc, FRCPE, FFPHM, FESC; Kornelia Kotseva, MD, PhD, FESC
Cardiovascular Medicine - National Heart and Lung Institute (NHLI) - Imperial College London - London - UK
The World Health Organization (WHO) report onPrevention of Cardiovascular Disease (CVD) describesthree strategies for prevention: a population strategy,a high-risk strategy, and a secondary prevention strat-egy. The population strategy is paramount because itaddresses the whole population the economic, social,and cultural determinants of CVD, whereas the high-risk and secondary prevention strategies only addressa minority of the population, namely, high-risk andsick individuals. The 61st World Health Assembly ofthe WHO on May 24th, 2008, stated its implementa-tion strategy for prevention and control of noncommu-nicable diseases, of which CVD is the most common.The foundation for this action plan is the global strat-egy for the prevention and control of noncommunicablediseases reaffirmed by the Health Assembly in 2000,the WHO Framework Convention on Tobacco Controlin 2003, and the Global Strategy on Diet, PhysicalActivity, and Health in 2004. The plan is intended tosupport coordinated, comprehensive, and integratedimplementation of strategies and evidence-based in-terventions across individual diseases and risk factors,especially at the national level. A societal approach—health in all policies—by policymakers and politiciansis paramount to preventing CVD.
The World Health Organization report on Preven-tion of Cardiovascular Disease (CVD) describesthree strategies for prevention: a populationstrategy, a high-risk strategy, and a secondary
prevention strategy.1,2 The three strategies comple-ment each other. However, the population strategy isparamount. The fundamental difference between thesethree strategies is that the population strategy address-es the whole population, whereas the high-risk andsecondary prevention strategies only address a minor-ity of the population, namely, high-risk and sick indi-viduals. So the population strategy for prevention ofCVD—not just coronary artery disease, but stroke andother atherosclerotic diseases—addresses all the caus-es in the whole population. The more successful thisall-encompassing strategy is, the more it will favorablyimpact on the need for the other two clinical strategiesby reducing the proportion of high-risk individuals inthe population, and the number of new cases of symp-tomatic atherosclerotic disease. The high-risk strategy
Keywords: cardiovascular disease; prevention; strategy; risk estimation;clinical practiceAddress for correspondence: Prof David A. Wood, CardiovascularMedicine, National Heart and Lung Institute (NHLI), Imperial CollegeLondon, Charing Cross Campus, Fulham Palace Road, London W6 8RF,UK (e-mail: [email protected])Dialogues Cardiovasc Med. 2009;14:83-98
EUROASPIRE EUROpean Action on Secondary and Primary prevention by Intervention to Reduce Events
PREVESE PREVEnción Secundaria del infarto de miocardio en España
SCORE Systematic Coronary Risk Estimation
TASPIC-CRO Treatment And Secondary Prevention ofIschemic Coronary Events in Croatia
identifies those asymptomatic individuals who are ap-parently well, but at high multifactorial risk of develop-ing CVD, with the object of reducing their total CVDrisk through lifestyle, risk factor, and therapeutic man-agement. However, its overall impact on the burdenof disease is limited because it only targets high-riskindividuals, who are a minority of the population. Thesecondary prevention strategy addresses those who’vesurvived the development of symptomatic atheroscle-rotic disease—acute coronary syndromes, angina,stroke, transient cerebral ischemia, peripheral arterialdisease—with the object of reducing the risk of recur-rent cardiovascular events and improving quality oflife and life expectancy. However, it also targets only aminority of sick individuals and is necessarily limitedto survivors. For some, the first manifestation of CVDis sudden collapse and death from acute myocardialischemia inducing fatal ventricular arrhythmias or mas-sive cerebral infarction or ruptured aortic aneurysm. Inaddition, among those who survive the initial ischemicinsult, consequent tissue damage may be so great thatsecondary prevention offers little gain. Prognosis islargely determined by the scale of myocardial or cere-bral damage.
So a population strategy tackling the major social,economic, and cultural determinants of CVD at a so-cietal level is paramount, and without such a strategythese diseases will remain a major cause of ill healthand premature death, regardless of the evidence thathigh-risk and secondary prevention strategies directedat individuals do reduce cardiovascular morbidity andmortality.
POPULATION STRATEGY
The 61st World Health Assembly of the WHO announcedon May 24th, 2008, its implementation strategy for pre-vention and control of noncommunicable diseases—CVD, cancer, chronic obstructive pulmonary disease,and diabetes—of which CVD is the most common.The report noted the rapid rise of noncommunicablediseases, which represents one of the major healthchallenges to global development, threatening econom-ic and social development and the lives and health ofmillions of people. Using current trends, it estimatesthat by 2020 these diseases will account for 73% ofdeaths, and 60% of the disease burden worldwide. Low-and middle-income countries will suffer the greatestimpact of noncommunicable diseases, and the rapidincrease is seen disproportionately in poor and disad-vantaged populations and is contributing to wideninghealth gaps within and between countries. However,
the major causes of these diseases are tobacco use,unhealthy diet, and physical inactivity, which in turnimpact adversely on body weight and its distribution,blood pressure, lipids, and diabetes. The major causesof CVD are preventable.
The foundation for this action plan is the global strat-egy for the prevention and control of noncommunica-ble diseases reaffirmed by the Health Assembly in2000.3 It also builds on the WHO Framework Conven-tion on Tobacco Control adopted by the Health As-sembly in 2003,4 and the Global Strategy on Diet,Physical Activity, and Health, endorsed by the HealthAssembly in 20045 and the strategies to reduce publichealth problems caused by harmful use of alcohol.The plan is intended to support coordinated, compre-hensive, and integrated implementation of strategiesand evidence-based interventions across individualdiseases and risk factors, especially at the nationallevel. The plan has six objectives:
1. To raise the priority accorded to noncommunicabledisease, and to integrate prevention and control ofsuch diseases into policies across all government de-partments. Raising the priority is justified by the factthat noncommunicable diseases are closely linked toglobal social and economic development, and nationalpolicies in sectors other than health—treasury, envi-ronment, agriculture, education, etc—have a majorbearing on the risk factors for noncommunicable dis-eases. So health in all policies is an important princi-ple. In addition, inequalities in access to protection,exposure to risk, and access of care are the cause ofmajor inequalities in the occurrence and outcomes ofnoncommunicable diseases.
2. To establish and strengthen national policies andplans for the prevention and control of noncommunica-ble diseases. Countries need to establish or strengthenexisting policies and plans for prevention and controlof noncommunicable diseases as an integral part oftheir national health policy. The three components are:(i) development of a national multisectoral frameworkfor prevention and control; (ii) integration of preven-tion and control of noncommunicable diseases into anational health development plan; and (iii) reorientat-ing and strengthening health systems to enable themto respond more effectively and equitably to the healthcare needs of people with chronic diseases.
3. To promote interventions to reduce the main sharedmodifiable risk factors for noncommunicable diseases:tobacco use, unhealthy diets, physical inactivity, and
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CVD prevention: by doctors or policymakers and politicians? - Wood and Kotseva
harmful use of alcohol. As the underlying determinantsof noncommunicable diseases often lie outside thehealth sector, strategies need the involvement of pub-lic and private actors in multiple sectors: agriculture,finance, trade, transport, urban planning, education,and sport.
4. To promote research for prevention and control ofnoncommunicable diseases. Priority areas include analytical, health system, operational, economic, andbehavioral research required for program implemen-tation and evaluation
5. To promote partnerships for the prevention and con-trol of noncommunicable diseases. Strong internation-al and national partnerships are required to provideeffective public health responses to the threat posedby noncommunicable diseases. Collaborative workshould be fostered among United Nations agencies,other international institutions, academia, researchcenters, nongovernmental organizations, consumergroups, and the business community.
6. To monitor noncommunicable diseases and theirdeterminants and evaluate progress at the national,regional, and global levels. Monitoring noncommuni-cable diseases and their determinants provides thefoundation for advocacy, policy development, and glob-al action. Monitoring should include time trends inprevalence of risk factors and mortality rates in popu-lations, and also evaluating the effectiveness and im-pact of interventions and progress made.
This international WHO strategy for prevention of non-communicable diseases is complemented by the Eu-ropean Society of Cardiology (ESC) initiative, workingin partnership with the European Heart Network andWHO Regional Office for Europe, to engage the Euro-pean Union (EU) in a coordinated approach to pre-vention of CVD across Europe. A conference of thesethree partners was facilitated by the Irish Ministry ofHealth in February 2004 in Cork.6 This informed theconclusions of the EU Council on Employment, SocialPolicy, Health, and Consumer Affairs in June 2004,7
and an EU Heart Health Conference in 2005, whichresulted in the Luxembourg Declaration.8 This decla-ration defined the characteristics that are associatedwith cardiovascular health as:• Avoidance of tobacco. • Adequate physical activity (at least 30 minutes perday). • Healthy food choices. • Avoiding overweight.
• Blood pressure below 140/90 mm Hg in patientswithout diabetes or target-organ damage or multiplerisk factors. • Total blood cholesterol below 5 mmol/L (approx200 mg/dL).
To achieve these healthy characteristics for the popu-lation as a whole requires a population strategy be-cause it addresses the societal determinants of CVDin populations through national policies aimed ateliminating tobacco consumption, providing and pro-moting healthy food choices, and the opportunities tobe physically active. A combination of a healthy dietand regular physical activity will keep a healthy weightand shape. It will also favorably impact on the preva-lence of physiological and biochemical risk factors, eg,lipids, in the population. This all-encompassing strat-egy shifts the whole distribution of risk factors in thepopulation toward more favorable levels without theneed to medically examine individuals.
CLINICAL STRATEGIES: PRIMARY AND SECONDARY PREVENTION
In contrast, the high-risk primary prevention strategyidentifies those individuals among the apparentlyhealthy population with a high multifactorial risk ofdeveloping CVD, and the secondary prevention strategyaddresses individuals who have developed sympto-matic CVD. The primary prevention strategy requiressome form of screening of the adult population toidentify those at high CVD risk. The secondary preven-tion strategy does not require screening because pa-tients present with symptomatic disease and are med-ically diagnosed. However, these two strategies sharea common aim that is to reduce total cardiovascularrisk through lifestyle interventions, management ofother risk factors, and use of cardioprotective drugtherapies. The distinction between primary and sec-ondary prevention is to some extent artificial sincerisk is a continuum in the population, and many asymp-tomatic high-risk people have evidence of asympto-matic atherosclerosis.
Primary prevention
Primary prevention of CVD in individuals has tradition-ally focused on single risk factors such as “hyperten-sion” rather than multiple risk factors—or the totalrisk approach—and as a consequence the much larg-er benefits of total CVD risk reduction have not beenachieved. Although there is a continuous relationshipbetween blood pressure and the risk of developing
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CVD, the higher the blood pressure the higher the risk,the term “hypertension” dichotomizes this distributioninto those with a blood pressure consistently greaterthan a specified level, eg, 140/90 mm Hg, and thosewith a blood pressure less than this level, which isdeemed “normal.” The level of blood pressure defining“hypertension” is not based on the epidemiology ofblood pressure and cardiovascular risk, but is ratherdeduced from randomized controlled trials which haveshown evidence of benefit through reducing bloodpressure in those with levels above say 140/90 mm Hg.The consequence of this approach is that someonewith a blood pressure of 142/92 mm Hg is consideredto be “hypertensive” and therefore receives blood pres-sure–lowering therapy, but another person of the sameage and sex with a blood pressure of 138/88 mm Hg is
considered to be “normotensive,” and therefore requir-ing no treatment. Yet the risk of developing CVD isvery similar for these two levels of blood pressure. Moreimportantly, the total risk of developing CVD is not justa function of a single risk factor such as blood pres-sure, but of all the cardiovascular risk factors takentogether. This is called total cardiovascular risk. Thisterm is used to describe the probability of a persondeveloping an atherosclerotic cardiovascular event,based on an assessment of all their risk factors, overa defined period of time.
The importance of estimating total CVD risk before adecision to intervene medically is made is illustratedin Figure 1 and Table I. The figure illustrates that in amiddle-aged man who is a nonsmoker with a bloodpressure 120 mm Hg the absolute risk of developingfatal CVD progressively increases as the total choles-terol to high-density lipoprotein (HDL) cholesterol ratiorises. However, at every level of this lipid ratio, theabsolute risk for a man of the same age who smokescigarettes and has raised blood pressure is substantial-ly higher. In fact, the absolute CVD risk of a ratio of 3.0is actually higher in such a man than a ratio of 7.0 in anonsmoking man with lower blood pressure. Althoughwomen are usually, age for age, at lower absolute riskof CVD than men, this advantage is lost at any levelof the lipid ratio if the woman is a smoker with raisedblood pressure. Another way of illustrating the sameprinciple is Table I. Which person should receive lipid-lowering therapy? In the single risk factor paradigmthe person with the highest cholesterol is the one mostlikely to be treated. But in the total risk paradigm it isthe person at highest CVD risk, namely, the patient withthe lowest cholesterol of 5.0 mmol/L, but with a totalrisk of 21%, who should receive lipid-lowering therapy.
The concept of total CVD risk assessment and manage-ment was first advanced by Jackson in 1993 in the con-text of treating “hypertension.”9 This was followed by the Joint European Societies recommendations in1994,10 which applied this principle to the managementof all risk factors, including diabetes. The Europeancoronary heart disease (CHD) risk chart developed byGraham was based on an original concept pioneeredby Anderson11 and used age, sex, smoking status, bloodcholesterol, and systolic blood pressure to estimatethe 10-year risk of a first fatal or nonfatal CHD event.There were separate charts for those with and withoutdiabetes. A CHD risk of 20% was defined as sufficientlyhigh to justify a more intensive lifestyle interventionand the use of drug therapies to lower blood pressureand cholesterol, and treatment targets for these risk
Dialogues in Cardiovascular Medicine - Vol 14 . No. 2 . 2009
CVD prevention: by doctors or policymakers and politicians? - Wood and Kotseva
30
25
20
15
10
5
0
TC/HDL ratio
Men, smokingSBP=160 mm HgMen, nonsmokingSBP=120 mm HgWomen, smokingSBP=160 mm HgWomen, nonsmokingSBP=120 mm Hg
10-Y
ear
risk
of
tota
l C
VD
(%
)
3 4 5 6 7
Figure 1. The relationship of total cholesterol/HDL cholesterolratio to 10-year fatal CVD events. Men and women aged 60 years with and without risk factors, based on arisk function derived from the SCORE project.
Sex Age Chol BP Smoker Risk(Years) (mmol/L) (mm Hg) (%)
F 60 8 120 No 2
F 60 7 140 Yes 5
M 60 6 160 No 8
M 60 5 180 Yes 21
Table I. Impact of combinations of risk factors on risk.
87
factors were set in the 1998 Joint European Societiesguidelines.12 However, these charts had several limi-tations. First, they were derived from American datafrom the Framingham community study and the appli-cability of this prospective cohort study of white mid-dle-aged men and women to all European populationswas uncertain. Second, the size of the cohort, just over5000 individuals, was fairly small for an epidemiologi-cal study. Third, the definitions of nonfatal CHD eventsdiffered from those used in many other epidemiologi-cal studies making it difficult to validate the chart.Finally, estimating the risk of other manifestations ofatherosclerosis such as stroke or aneurysm of the ab-dominal aorta was not possible.
The third edition of the Joint European Societies Guide-lines published in 200313 used a new system for car-diovascular risk estimation called SCORE (SystematicCoronary Risk Estimation), based on data from 12European prospective cohort studies: 205 178 subjectswith 2.7 million years of follow-up and 7934 cardio-vascular deaths.14 Two charts were produced: one forhigh-risk regions, and the other for low-risk regions(Figure 2, and Figure 3 page 88).13 SCORE estimatesthe 10-year risk of a first fatal atherosclerotic event,whether heart attack, stroke, aneurysm of the aorta, orother fatal manifestation of atherosclerotic disease.All ICD (International Classification of Diseases) codesthat could reasonably be assumed to be atheroscle-rotic are included.
CVD mortality was used rather than total CVD (fatal +nonfatal) events because the definition and ascertain-ment of nonfatal events was not the same in the dif-ferent cohort studies that make up SCORE. However,the use of mortality has the advantage that recalibra-tion of the charts is possible in relation to changingtime trends in CVD mortality. Any risk model will over-predict in countries in which mortality has fallen andunderpredict in those in which it has risen. Recalibra-tion of SCORE to allow for these secular changes inthe population of a given country can be undertakenif good quality up-to-date mortality and risk factorprevalence data are available. The SCORE CVD mor-tality charts have been recalibrated for a number ofEuropean countries: Germany, Greece, Poland, Spain,Sweden, Cyprus, Bosnia and Herzegovina, and Russia.In the 2003 Joint European Societies guidelines, a 10-year risk of CVD of 5% or more for fatal events wasdefined as high risk, and people at this level of riskshould receive a professional lifestyle intervention and,if appropriate, drug therapies to reduce total CVD risk.The choice of a 5% level was arbitrary as risk is a con-tinuum in the population and there are no random-ized controlled trial data that define the level of riskat which it is appropriate to intervene. However, thereis evidence of benefit from trials of single risk factorreduction, which show benefit for individuals at levelsof total risk below 5%. So a 5% CVD risk threshold forintervention is conservative. However, there are othermore important factors to take into account when de-
Dialogues in Cardiovascular Medicine - Vol 14 . No. 2 . 2009
CVD prevention: by doctors or policymakers and politicians? - Wood and Kotseva
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Figure 2. 2003 SCOREChart for high-risk regions.10-Year risk of fatal cardiovas-cular disease (CVD) in popula-tions at high CVD risk based onthe following risk factors: age,gender, smoking, systolic bloodpressure, total cholesterol.
ciding on a risk threshold for treatment at a nationallevel, including the prevalence of high-risk individualsto be targeted and the practicalities and costs to thehealth care system of providing appropriate manage-ment. In the 2007 Joint European Societies guideline,the threshold of a 5% risk of cardiovascular death over10 years was reaffirmed, but these patients were de-scribed as being at “increased risk,” in order to empha-size the continuum of risk in the population, ratherthan an arbitrary threshold for automatic interventionwith drugs.15 The treatment of an individual should beguided by their level of total CVD risk, but the physi-cian also needs to take account of many other factorsbefore committing a patient to life-long therapies.
Younger people, say below the age of 40 years, pose adifferent challenge in the context of total CVD risk. Thecharts show that at younger ages it is almost impos-sible to achieve the 5% CVD risk threshold, howeverhigh their risk factors are. But they will be at very highrisk relative to people of the same age and sex, despitetheir low absolute risk. In the 2003 Guidelines, the rec-ommendation was to extrapolate risk to age 60 yearsto illustrate the high-risk track of an individual if pre-ventive action was not taken. It was not intended thatyoung people should necessarily be treated as if theywere 60 years old, as this could lead to excessive drugtreatment in these age groups. The purpose of the extrapolation was to alert both the patient and theirphysician to the need for lifestyle change, and to sig-
nal the need for a lower threshold for intervention asthey get older. In the most recent Joint European So-cieties guidelines published in 2007, a relative riskchart (Figure 4)15 has been created so that youngerpersons at low absolute risk can be shown their riskrelative to their peers.
At the other end of the spectrum, the vast majority ofolder people, especially men, will have an estimatedrisk of CV death over 10 years that exceeds the 5%threshold for intervention, based on age (and gender)alone, even when other CV risk factor levels are rela-tively low. So as for younger people, clinical judgmentis required in deciding who is most likely to benefitfrom lifestyle and therapeutic interventions by takingaccount of lifestyle, comorbidity, the levels of individ-ual risk factors, and target-organ damage. A CVD risk
Dialogues in Cardiovascular Medicine - Vol 14 . No. 2 . 2009
CVD prevention: by doctors or policymakers and politicians? - Wood and Kotseva
Figure 3. 2003 SCOREChart for low-risk regions.10-Year risk of fatal cardiovas-cular disease (CVD) in popula-tions at low CVD risk based onthe following risk factors: age,gender, smoking, systolic bloodpressure, total cholesterol.
of 5% or higher in the older population is not an au-tomatic indication for drug therapies. Separate chartsare available for both total cholesterol alone, and thetotal cholesterol:HDL cholesterol ratio (Figures 2, 3,5, and 6).13,15 Ideally, the risk chart based on the lipidratio is preferred because HDL cholesterol makes anindependent contribution to CVD risk, especially for
women and those in the middle years of life. Howev-er, measurement of HDL cholesterol is not routine inmany parts of Europe and so total cholesterol can beused instead. The electronic, interactive version ofSCORE, called HeartScore, is available from the ESC(http://www.heartscore.org/Pages/welcome. aspx). Byusing the SCORE risk charts it is possible to identify
Dialogues in Cardiovascular Medicine - Vol 14 . No. 2 . 2009
CVD prevention: by doctors or policymakers and politicians? - Wood and Kotseva
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15% and over10% to 14%5% to 9%3% to 4%2%1%<1%
SCORE
Figure 6. 2007 SCOREChart for low-risk regions. 10-Year risk of fatal cardiovas-cular disease (CVD) in popula-tions at low CVD risk based onthe following risk factors: age,gender, smoking, systolic bloodpressure, total cholesterol(TC)/high-density lipoprotein(HDL)cholesterol ratio.
from the apparently healthy population those individ-uals who are at high risk of dying from CVD, ie, a 5%or higher risk of fatal CVD over 10 years. The advan-tages of using the SCORE CVD risk charts are summa-rized in Table II.
There is no separate SCORE chart for people with dia-betes because in the 2007 Joint European Societiesguidelines they are now automatically classified as highCVD risk and treated accordingly. There are two reasonsfor classifying people with diabetes as high risk. Firstly,individuals diagnosed with diabetes tend to alreadyhave a clustering of other risk factors—obesity andcentral obesity, elevated blood pressure, low HDL cho-lesterol, raised triglycerides—which puts them at highmultifactorial risk of developing CVD. Secondly, peo-ple with diabetes presenting with symptomatic CVDhave a higher case fatality compared with people with-out diabetes. Overall, the impact of diabetes on CVDrisk in SCORE appears to be greater than that for dia-betes in the Framingham study, with relative risks ofapproximately 3 in men and 5 in women.
Although the principle of total CVD risk assessment isnow widely accepted as the most appropriate way ofidentifying those asymptomatic individuals requiringlifestyle and therapeutic intervention, the evidence formultifactorial intervention is less compelling. In a sys-tematic review of 10 trials with disease outcome data,there was no significant effect on total or coronarymortality, but a small and potentially important 10% re-duction in CHD mortality may have been missed.16 Thisapparent lack of effect on coronary mortality reflects a modest reduction in smoking and small changes inblood pressure and lipids, the latter due to limited drugtreatment, in these trials. In contrast, numerous singlerisk factor trials using drug therapies to lower bloodpressure and lipids have shown comparable reductionsin CVD risk that would be predicted from the epidemi-ological relationships. Therefore, if multifactorial in-terventions achieve the same treatment effects as thosein unifactorial trials, this will achieve a substantialcumulative reduction in total CVD risk. The challengeis to achieve such risk reductions through a combina-tion of lifestyle and, where appropriate, drug therapies.
Secondary prevention
All patients with atherosclerotic CVD—coronary arterydisease, cerebral artery disease, peripheral arterialdisease—are eligible for secondary prevention. How-ever, the focus of secondary prevention has been onpatients with coronary disease, and particularly those
who’ve had a myocardial infarction or been revascular-ized. Exercise-based cardiac rehabilitation of coronarypatients reduces both cardiac and total mortality.17 Thismeta-analysis showed no difference in mortality effectbetween exercise-only cardiac rehabilitation and com-prehensive cardiac rehabilitation. Importantly, the ef-fect of cardiac rehabilitation on total mortality was independent of CHD diagnosis, type of cardiac rehabil-itation, dose of exercise intervention, or duration offollow-up. The contribution of secondary preventionprograms with or without exercise was evaluated in aseparate meta-analysis. The effects on mortality andmyocardial infarction were similar for programs thatincluded both exercise and risk factor education, orrisk factor education without exercise, or for exercisealone.18 In a systematic review of trials of secondaryprevention, multidisciplinary disease managementprograms led to a reduction in admissions to hospitaland recurrent myocardial infarction.19 However, thisdistinction between cardiac rehabilitation and second-ary prevention is artificial and these meta-analysesdemonstrate, from different perspectives, the benefitsof a comprehensive approach to reducing total cardio-vascular risk. This comprehensive approach throughsmoking cessation, diet, and physical activity, and sup-plemented with control of blood pressure, lipids andglucose, and the use of cardioprotective drug therapies,should be available to all patients with atheroscleroticCVD, whatever arterial territory is affected.
CLINICAL PRIORITIES, TOTAL CVD RISK ESTIMATION, AND OBJECTIVES
Priorities
The following priorities are recommended for CVD pre-vention in clinical practice in the 2007 Joint EuropeanSocieties guidelines15 based on the principle that in-dividuals at the highest levels of CVD risk gain mostfrom risk factor management.• Patients with established atherosclerotic CVD,whether of the coronary, peripheral, cerebral vesselsor of the aorta, even if asymptomatic.• Asymptomatic individuals who are at high total riskof developing symptomatic CVD because of:– Multiple risk factors resulting in a markedly raisedtotal CVD risk.– Markedly raised levels of single risk factors: choles-terol �8 mmol/L (309 mg/dL), low-density lipoprotein(LDL) cholesterol �6 mmol/L (232 mg/dL), bloodpressure �180/110 mm Hg. – Type 2 diabetes and type 1 diabetes with microalbu-minuria.
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• Close relatives of persons with early-onset atheroscle-rotic CVD (typically before age 60), or at particularlyhigh CVD risk.
As a general guide, a middle-aged person with a 10-year risk of CVD death of 5% or more, is regarded asbeing at sufficiently high risk to justify professionallifestyle intervention and, where appropriate, drug ther-apies to reduce that risk. As the total risk increases,so does the likelihood of requiring medication to low-er blood pressure, modify blood lipids, and controlglucose levels. In addition, aspirin or other antiplatelettherapies may be required.
Total CVD risk estimation
Patients who have a clinical event such as an acutecoronary syndrome or stroke have already declaredthemselves to be at high risk of a further cardiovascularevent and automatically qualify for intensive lifestyleand risk factor management. They do not require CVDrisk estimation using the SCORE charts. In addition,patients who are diagnosed with diabetes are nowclassified as high CVD risk and therefore total CVD riskestimation is also not required. The SCORE charts areintended for estimating CVD risk in the asymptomaticpopulation with no history of CVD or diabetes.
How to use the SCORE risk estimation charts• The low-risk charts are recommended for use inBelgium, France, Greece, Italy, Luxembourg, Spain,Switzerland, and Portugal, and also in countries thathave recently experienced a substantial decline in CVDmortality rates. The high-risk charts are recommendedin all other countries of Europe. Several countries haverecalibrated the SCORE chart to allow for time trends
in mortality and risk factor distributions and thesecountry-specific charts will be more accurate for theirrespective populations. • To estimate a person’s 10-year risk of CVD death, findthe table for their gender, smoking status, and age.Within the table, find the cell nearest to the person’sblood pressure and total cholesterol, or total choles-terol:HDL cholesterol ratio. Risk estimates will needto be adjusted upwards as the person approaches thenext age category.• Low-risk persons should be offered advice to main-tain their low-risk status. While no threshold is univer-sally applicable, the intensity of advice should increasewith increasing risk. In general, those with a risk ofCVD death of 5% or more qualify for intensive advice,and may benefit from drug treatment. At risk levelsover 10%, drug treatment is more frequently required.In persons older than 60, these thresholds should beinterpreted more leniently, because their age-specificrisk is normally around these levels, even when otherCV risk factor levels are “normal.” Therefore, uncriticalinitiation of drug treatments in the elderly should bediscouraged.• Relative risks may be unexpectedly high in young per-sons, even if absolute risk levels are low. The relativerisk chart may be helpful in identifying and counselingsuch persons.• The charts may be used to give some indication ofthe effects of reducing risk factors, although with thecaveat that there will be a time lag before risk is re-duced to these lower levels. For example, those whostop smoking in general halve their risk, but this oc-curs over several years
Qualifiers• The charts can assist in CVD risk assessment andmanagement, but must be interpreted in the light ofthe clinician’s knowledge and experience, especiallywith regard to local conditions.• Risk will be overestimated in countries with a fallingCVD mortality, and underestimated in countries inwhich mortality is increasing.• At any given age, risk estimates are lower for womenthan men. This may be misleading, since, eventually,at least as many women as men die of CVD. The chartsillustrate that risk is merely deferred in women, with a60-year-old woman resembling a 50-year-old man interms of total CVD risk.
Risk will also be higher than indicated in the charts in:• Sedentary subjects and those with central obesity;these characteristics determine many of the other as-pects of risk listed below.
Dialogues in Cardiovascular Medicine - Vol 14 . No. 2 . 2009
CVD prevention: by doctors or policymakers and politicians? - Wood and Kotseva
Advantages of SCORE risk chart
• Intuitive, easy to use tool
• Takes account of the multifactorial nature of CVD
• Allows flexibility in management—if an ideal risk factor level cannot be achieved, total risk can still be reduced by reducing other risk factors
• Allows a more objective assessment of risk over time
• Establishes a common language of risk for clinicians
• Shows how risk increases with age
• The new relative risk chart helps to illustrate how a young person with a low absolute risk may be at a substantially high and reducible relative risk
Table II. Advantages of using the Systematic Coronary RiskEstimation (SCORE) risk chart.
• Socially deprived subjects. • Subjects with a strong family history of premature CVD.• Subjects with diabetes. • Subjects with low HDL cholesterol, increased triglyc-erides, fibrinogen, apolipoprotein B and lipoprotein(a)levels, and perhaps increased high-sensitivity C-reac-tive protein (CRP) and homocysteine levels. • Asymptomatic subjects with preclinical evidence ofatherosclerosis, for example, on ultrasonography.
A relative risk chart (Figure 4) has been developed toinform younger patients of their risk relative to someone of the same age and sex with no risk factors forCVD. So a younger person whose total risk is low canbe up to 12 times more likely to develop CVD than aperson of a similar age and sex who does not smokeand has low blood pressure and lipid levels. Clinicaljudgment is then required to decide, beyond lifestyle,if there is a need to start drug therapies.
Objectives of CVD prevention
In the most recent Joint European Societies guidelines,a new emphasis is given to assist those at low risk ofCVD to maintain this state lifelong.
The desirable characteristics of low total risk include: • No smoking.• Healthy food choices.• Physical activity; 30 minutes of moderate exercise a day. • Body mass index of <25 kg/m2 to avoid central obesity.• Blood pressure of <140/90 mm Hg.• Total cholesterol <5 mmol/L (190 mg/dL).• LDL-cholesterol <3 mmol/L (115 mg/dL).• Glucose < 6.0 mmol/L (110 mg/dL).
In those with established atherosclerotic CVD or dia-betes or at high multifactorial risk of developing CVD,the objective is to lower their total risk in order to re-duce cardiovascular mortality and morbidity. In addi-tion to a healthy lifestyle, more rigorous control ofother risk factors is recommended:• Rigorous blood pressure and lipid control is desirablein the highest-risk subjects and particularly those withestablished atherosclerotic CVD or diabetes:– Blood pressure <130/80 mm Hg if feasible. – Total cholesterol <4.5 mmol/L (175 mg/dL), with anoption of <4 mmol/L (155 mg/dL) if feasible. – LDL-cholesterol of <2.5 mmol/L (100 mg/dL), withan option of <2.0 mmol/L (77 mg/dL) if feasible.– Glucose < 6.0 mmol/L (110 mg/dL).
• Prescribing cardioprotective drug therapies—anti-platelet therapies, β-blockers, angiotensin-convertingenzyme (ACE) inhibitors/angiotensin receptor blockers(ARBs), statins, anticoagulants—in particular groups,especially those with established atherosclerotic CVD.
IMPLEMENTATION OF CVD PREVENTIONIN CLINICAL PRACTICE
Although the Joint European Societies guidelines onprevention of CVD in clinical practice published in1994, 1998, 2003, and 2007 have made recommenda-tions for a healthier lifestyle and set goals for bloodpressure, lipid and glucose management, and the useof cardioprotective drugs, there is a gap between thesestandards of care for all priority groups of patients andthe reality of clinical practice.
Surveys of clinical practice such as EUROASPIRE I, II,and III (EUROpean Action on Secondary and Primaryprevention by Intervention to Reduce Events), whichhave monitored the trends of preventive cardiologypractice in Europe over the last decade, have shownthat integration of CVD prevention into daily clinicalpractice is inadequate.20-22 The first EUROASPIRE survey was carried out in 1995/96 in nine Europeancountries: Czech Republic, Finland, France, Germany,Hungary, Italy, the Netherlands, Slovenia, and Spain.20
The second EUROASPIRE survey was undertaken in1999/2000 in 15 European countries including thosecountries which participated in the first survey, and Bel-gium, Greece, Ireland, Poland, Sweden, and the UK.21
One of the objectives of the second survey was to seeif the practice of preventive cardiology in coronary patients had improved in those countries and centersthat took part in EUROASPIRE II.22 This comparisonof results from the two surveys should be a cause forconsiderable concern to all cardiologists, physicians,and others responsible for the care of coronary patientsin hospital and the community. The adverse lifestyletrends, particularly the increase in smoking in youngerfemale patients, and the substantial increase in obe-sity and central obesity in every country, makes a com-pelling case for more effective lifestyle programs.
About one fifth of coronary patients still continued tosmoke cigarettes, with a significant increase in smokingamong women patients, despite increasing availabilityof new and effective treatments to help patients stopsmoking. The physician’s advice to stop smoking is themost important first step in the smoking cessationprocess, but this advice should be reiterated and rein-
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forced by all health professionals. Body weight contin-ued to increase dramatically: 4 out of 5 patients in thesecond survey had a body mass index (BMI) �25 kg/m2
and one third were obese (BMI �30 kg/m2)—an in-crease from one quarter in the first to one third of allpatients in the second survey. Waistlines also increased,with more than half of all patients being centrally obese(waist circumference �102 cm men and �88 cm women)in the second survey. Weight reduction interventionsinclude dietary modification, increased physical activ-ity, and some drug treatments such as inhibitors ofintestinal fat absorptions and drugs acting on the cen-tral nervous system to suppress appetite. These ad-verse trends in body weight and distribution reflect thesame trends in the general population, and contributeto a worsening of other risk factors such as rising bloodpressure, dyslipidemia, and diabetes.
Blood pressure management showed no improvementover the two surveys. More than half of all patientsstill had blood pressures above the recommended tar-get (<140/90 mm Hg), which increases their risk of re-current coronary disease, stroke, kidney disease, andheart failure. Therapeutic control in patients using bloodpressure–lowering medication remains unchangedacross the two surveys, which leaves more than halfof all patients not reaching the blood pressure goal inthe second survey. This failure to improve managementof blood pressure more effectively was despite largeincreases in prescriptions for all classes of antihyper-tensive medications.
In contrast to blood pressure, the management of bloodlipids improved dramatically across the two surveys,largely because of the increasing use of statins. Theproportion achieving the total cholesterol target of<5.0 mmol/L increased from 14% to 41%, nearly three-fold. Therapeutic control of total cholesterol in thoseusing lipid-lowering medication improved more thantwofold. However, this still leaves nearly half of patientswho did not achieve the total cholesterol target. Thenew Joint European Societies Guidelines (2007) haveset lower cholesterol targets of <4.0 mmol/L for totalcholesterol and <2.0 mmol/L for LDL cholesterol wherefeasible, and these will be an even tougher challenge.
Comparison between the two EUROASPIRE surveysshows that the prevalence of diabetes continued to in-crease, from 18% in the first to 22% in the second sur-vey, reflecting the rise in obesity and central obesity.It is of particular concern that the prevalence of unde-tected diabetes increased nearly fourfold, from 4% inthe first to 15% in the second survey. Therapeutic con-
trol of self-reported diabetes remained poor, with onlyone fourth of patients with a history of diabetes havinga fasting glucose <6.1 mmol/L in the second survey.
The use of cardioprotective drug therapies has beenshown to reduce cardiovascular and total mortalityand the risk of recurrent coronary events in patientswith CHD: aspirin or other platelet-modifying drugs,β-blockers, in people with myocardial infarction; ACEinhibitors in people with left ventricular dysfunction;and anticoagulants in post–myocardial infarction pa-tients with increased risk of thromboembolism. InEUROASPIRE, prescriptions for cardioprotective medi-cations increased across the two surveys for antiplatelettherapies (81% to 84%), β-blockers (54% to 66%), ACEinhibitors (29% to 43%), and statins (18% to 58%).However, despite the impressive increase in prescrip-tions for all these drug classes, the majority of coronarypatients in Europe had still not achieved the bloodpressure and total cholesterol targets as defined inthe 1998 Joint European Societies guidelines on pre-vention of CHD.
The comparison between these two EUROASPIREsurveys demonstrates a substantial gap between thestandards set in the CVD prevention guidelines andclinical practice. These surveys, uniquely spanning 5years of European clinical practice, show that lifestyletrends in patients with CHD are a growing cause forconcern. Other surveys have also reported inadequaterisk factor management and underuse of prophylacticdrug therapies in patients with CHD in Spain (PREVEn-ción Secundaria del infarto de miocardio en España[PREVESE] I and II, in 1994 and 1998),23,24 France(PREVENIR, 1998 and 1999; Usik 1998 and 2000),25
and Croatia (TASPIC-CRO [Treatment And SecondaryPrevention of Ischemic Coronary Events in Croatia],in 1998 and 2003).26 The EUROASPIRE III survey in 22countries was undertaken in 2006/2007 in 22 coun-tries, including 14 of those countries that participatedin EUROASPIRE II, and the principal results on coro-nary patients in hospital and high-risk patients in pri-mary care have been presented on the ESC Web site(www.escardio.org/euroaspire).
What is abundantly clear from these European surveysis that drug therapies are simply not sufficient and theyhave to be combined with a professional lifestyle in-tervention. Patients need professional support to makelifestyle changes and also manage their risk factorsmore effectively. Simply giving a drug prescription isnot enough. Patients need to understand the nature oftheir disease and how to manage it through achieving
a healthy lifestyle as well as adhering to cardioprotec-tive drug therapies over the long term. Most important-ly of all, the adverse lifestyle trends in coronary patientsreflect the same unfortunate trends in the general pop-ulations of these countries, which makes a compellingcase for a societal strategy for CVD prevention. Theyillustrate how difficult it is for individual patients tochange their behavior, despite the development of life-threatening disease, given that their unhealthy life-styles are shared by an ever-increasing proportion ofthe adult population. To help patients to quit smok-ing, adopt a healthy diet, and increase physical activi-ty requires sustained professional support. Yet only athird of patients with coronary disease access cardiacrehabilitation programs in Europe.27 All patients withcoronary disease as well as those at high risk of devel-oping CVD should be able to access preventive cardiol-ogy programs.
At present, the health care systems in Europe are predominantly focused on acute salvage of ischemictissues through medical interventions, devices, andpharmacological treatments; and not on addressing theunderlying causes of the disease to prevent furthermorbidity and mortality. However, patients require pro-fessional support to make lifestyle changes and to havetheir other risk factors monitored and managed accord-ing to the standards defined in the guidelines. TheESC EUROACTION demonstration project in preventivecardiology took up this challenge by providing a nurse-coordinated multidisciplinary preventive cardiologyprogram for both patients in hospital with coronarydisease and for asymptomatic high-risk individuals inprimary care, together with their families.28,29 The ob-ject of this project was to demonstrate whether sucha professional program could help more patients andtheir families achieve the lifestyle, risk factor, and ther-apeutic goals set out in the prevention guidelines. ThisEUROACTION program was set up in 8 countries and24 hospital and general practice centers and evaluatedin a matched pair cluster randomized controlled trial.
In the hospitals, cardiologists and nurses recruited eligible patients and their families. After a multidisci-plinary assessment of lifestyle, risk factors, and drugtreatment by a nurse, dietitian, and physiotherapist,couples attended at least eight sessions—one everyweek—in which they were assessed by each memberof the team (nurse, dietitian, and physiotherapist) and,as required, by their cardiologist. The patients and theirpartners then attended a group workshop and a super-vised exercise class. The cardiologists initiated anduptitrated the cardioprotective drugs and the nurses
monitored risk factors and adherence to drug treat-ments at each session. At 16 weeks, patients and theirpartners were reassessed by the whole team and a report was sent to their family doctors. In the generalpractice centers, family doctors and nurses recruitedpatients and their families. The program started withthe same nurse assessment of lifestyle, risk factors,and drug treatment as for the hospital patients, butwas open-ended. At each visit—one every week—cou-ples were assessed by the nurse—who led the groupworkshops—and by the family doctors responsiblefor drug treatment. The patients and their partners didnot have supervised exercise classes. Patients in thehospital and general-practice centers were assessedfor family lifestyle, risk factors, medications, health be-liefs, anxiety, and depression, illness perception, andmood. Patients were provided with a personal recordcard for lifestyle and risk factor targets, and their fam-ilies with family support packs (see www.escardio.org/euroaction)
The EUROACTION program incorporated several im-portant principles. It was intentionally set up in busygeneral hospitals and general practices, outside spe-cialist cardiac rehabilitation centers, to provide a ser-vice for all coronary and high-risk patients in routineclinical practice. Integration of the diagnosis and man-agement of patients with continued preventive care inthe same medical facility is likely to result in increasedand sustained participation. In the EUROASPIRE sur-vey, only a third of coronary patients attended cardiacrehabilitation,27 whereas two thirds joined the EURO-ACTION program. Recruitment was even better in pri-mary care, with 9 out of 10 patients joining the program.EUROACTION was inclusive because it addressed all the high-priority patient groups as defined in theguidelines.15 We made no distinction between symp-tomatic coronary disease (secondary prevention) andthose at high risk (primary prevention). All these pa-tients are at high risk of CVD and need professionalsupport to achieve the same lifestyle and risk factortargets. EUROACTION was a family-centered programand actively involved patients’ partners and other fami-ly members. A family intervention is appropriate be-cause married couples show concordance for lifestyle,and concordance for change.30,31
The EUROACTION preventive cardiology program re-duced the risk of CVD compared with usual care mainlythrough lifestyle changes by families, who togethermade healthier food choices and became more physi-cally active (Figures 7 and 8).29 This change led tosome weight loss and, for high-risk patients, a signifi-
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cant reduction in central obesity. Blood pressure con-trol was significantly improved in both coronary andhigh-risk patients, and for patients with coronary dis-ease this was achieved without the use of additionalantihypertensive drugs. Control of blood cholesterolconcentrations in coronary patients was improved inboth the intervention and usual-care groups; and forhigh-risk patients changes over 1 year showed a signif-icant improvement in the proportion achieving the to-tal and LDL-cholesterol targets because of increaseduse of statins. Cardioprotective drugs—aspirin, β-block-ers, ACE inhibitors, and statins—were commonly pre-scribed for coronary patients in both the interventionand usual care groups. However, the use of all cardio-
protective drugs was substantially lower in primarycare, but in intervention there was a significantly in-creased use of ACE inhibitors and statins comparedwith usual care. Although these results are encourag-ing there is scope for further improvement. The smok-ing cessation intervention based on advice reducedrelapse in patients with CHD, but had no effect on theprevalence of smoking in high-risk patients. Even thoughthe protocol recommended the use of smoking cessa-tion therapies, these were not used because of cost.Although the same protocol for risk-factor managementwas used in hospital and general practice, use of bloodpressure and lipid-lowering drugs was much more con-servative in general practice. As a consequence, most
of the high-risk patients did not achievelipid targets. Diabetes care could have beenfurther improved if the intervention nurseshad taken personal responsibility for dia-betes management.
In summary, the EUROACTION demonstra-tion project in preventive cardiology showedthat standards of preventive care in gener-al hospitals and general practices acrossEurope can be improved. This nurse-coor-dinated, multidisciplinary, family-based,ambulatory program achieved healthierlifestyle changes and improvements in otherrisk factors for patients with CHD and thoseat high risk of CVD, and also their partners,compared with usual care. EUROACTION
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Intervention
Usual care
P=0.009
55
40
72
35
78
39
83
67
79
67
16
811
6
P=0.004 P=0.62 P=0.04
Saturated fat<10% of
total energy
Fruits andvegetables>400 g/day
Fish>20 g/day
Only fish>3 times/week
Hospital90
80
70
60
50
40
30
20
10
0
90
80
70
60
50
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30
20
10
0
P=0.005 P=0.07 P=0.13
Fruits andvegetables>400 g/day
Fish>20 g/day
Only fish>3 times/week
Primary care
Figure 7. EUROACTION: Proportions of patients achieving the European targets for healthy diet at 1 year.
is a model of preventive cardiology, which has beensuccessfully implemented and assessed, and can beused in routine clinical practice. To achieve the effectsof EURO-ACTION, we need to go beyond specializedcardiac rehabilitation services and provide local pre-ventive cardiology programs, appropriately adapted tothe medical, cultural, and economic setting of a country.
CONCLUSIONS
However good our clinical prevention programs are,ultimately it is very difficult for patients to quit smok-ing, eat healthily, and be physically active for the restof their lives if the society in which they live is not con-ducive to a healthy lifestyle. A preventive clinical strat-egy will reduce disability and save the lives of someindividuals, but its impact on the overall burden of dis-ease is necessarily limited. This is because most deathsin a population come from those at lower levels of CVDrisk, simply because they are more numerous com-pared with high-risk individuals who, paradoxically,have fewer events in absolute terms—the Rose Para-dox (Figure 9).32,33 So a societal approach—health inall policies—by policymakers and politicians is theparamount strategy for the prevention of CVD.
REFERENCES
1. World Health Organization.
Prevention of Recurrent Heart Attacks and Strokes in low and mid-dle income populations. Evidence-based recommendations for policymakers and health professionals.
Geneva, Switzerland: World Health Organization; 2003.
2. World Health Organization.
Prevention of Cardiovascular Disease. Guidelines for assessmentand management of cardiovascular risk.
Geneva, Switzerland: World Health Organization; 2006.
3. Report by the Director General.
Global strategy for the prevention and control of noncommunicablediseases.
Geneva, Switzerland: World Health Organization; 2000 (DocumentA53/14).
4. WHO Framework Convention on Tobacco Control.
Geneva, Switzerland: World Health Organization; 2003.
5. World Health Assembly Resolution WHA57.17.
Global strategy on diet, physical activity and health.
Geneva, Switzerland: World Health Organization; 2004.
Dialogues in Cardiovascular Medicine - Vol 14 . No. 2 . 2009
CVD prevention: by doctors or policymakers and politicians? - Wood and Kotseva
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
CV
D d
ea
ths
(all
co
ho
rts)
Predicted risk (men aged 50-59 years)
80
60
40
20
0
Figure 9. Illustration of the Rose Paradox. The expected number of cardiovascular (CVD) deaths at increasing levels of predicted risk (expressed in % over 10 years). Illustration of the fact thatmost events occur in low-risk individuals simply because they are more numerous compared to high-risk individuals who, paradoxically, develop fewerevents in absolute terms.
Management of raised blood pressure in New Zealand: a discussiondocument.
BMJ. 1993;307:107-110.
10. Pyörälä K, De Backer G, Graham I, Poole-Wilson PA,Wood D.
Prevention of coronary heart disease in clinical practice.Recommendations of the Task Force of the European Society ofCardiology, European Atherosclerotic Society and European Societyof Hypertension.
Eur Heart J. 1994;15:1300-1331.
11. Anderson K, Wilson PW, Odell PM, Kannel WB.
An updated coronary risk profile. A statement for health professionals.
Circulation. 1991;83:356-362.
12. Wood D, De Backer G, Faergeman D, Graham I,Mancia G, Pyörälä K.
Prevention of coronary heart disease in clinical practice. Recom-mendations of the Second Joint Task Force of European and otherSocieties on coronary prevention.
Eur Heart J. 1998;19:1434-1503.
13. De Backer G, Ambrosioni E, Bort-Johnsen K, et al.
European guidelines on cardiovascular disease prevention in clinicalpractice. Third Joint Task Force of European and other Societieson Cardiovascular Disease Prevention in Clinical Practice.
Estimation of ten-year risk of fatal cardiovascular disease inEurope: the SCORE project.
Eur Heart J. 2003;24:987-1003.
15. Graham I, Atar D, Borch-Johnsen K, et al.
European Guidelines on Cardiovascular Disease Prevention inClinical Practice: Fourth Joint Task Force of the European Societyof Cardiology and Other Societies on Cardiovascular DiseasePrevention in Clinical Prevention in Clinical Practice (Constitutedby representatives of nine societies and by invited experts).
Exercise-based rehabilitation for patients with coronary heart disease: systematic review and meta-analysis of randomised controlled trials.
Am J Med. 2004;116:682-692.
18. Clark A M, Hartling L, Vandermeer B, McAlister FA.
Meta-analysis: secondary prevention programs for patients withcoronary artery disease.
Ann Intern Med. 2005;143:659-672.
19. McAlsiter F A, Lawson F M E, Teo K K, Armstrong PW.
Randomised trials of secondary prevention programmes in coronaryheart disease: systematic review.
BMJ. 2001;323:957-962.
20. EUROASPIRE Study Group. EUROASPIRE.
A European Society of Cardiology survey of secondary preventionof coronary heart disease: principal results.
Eur Heart J. 1997;18:1569-1582.
21. EUROASPIRE Study Group.
Lifestyle and risk factor management and use of drug therapies in coronary patients from 15 countries. Principal results from EUROASPIRE II. Euro Heart Survey Programme.
Eur Heart J. 2001; 22: 554-72.
22. EUROASPIRE Study Group.
Clinical reality of coronary prevention guidelines: a comparison of EUROASPIRE I and II in nine countries.
Lancet. 2001;357:995-1001.
23. De Velasco JA, Cosin J, Lopez-Sendon JL, et al.
La prevencion secundaria del infarto de miocardio en Espana.Estudio PREVESE [Secondary prevention of myocardial infarctionin Spain. The PREVESE study].
Rev Esp Cardiol. 1997;50:406-415.
24. De Velasco JA, Cosin J, Lopez-Sendon JL, De Teresa E,De Oya M, Sellers G.
Nuevos datos sobre la prevencion secundaria del infarto de miocardioen Espana. Resultados del estudio PREVESE II [New data on secondary prevention of myocardial infarction in Spain. Results ofthe PREVESE II study].
Rev Esp Cardiol. 2002;55:801-809.
Dialogues in Cardiovascular Medicine - Vol 14 . No. 2 . 2009
CVD prevention: by doctors or policymakers and politicians? - Wood and Kotseva
98
25. Danchin N, Hanania G, Grenier O, et al.
Évolution du traitement de sortie après hospitalisation pour syndromecoronaire aigu en France entre 1995 et 2000: données des étudesUsik 1995, PREVENIR 1 et 2 et Usic 2000 [Trends in dischargeprescriptions for patients hospitalized for acute coronary syndromes inFrance from 1995 to 2000. Data from the Usik 1995, PREVENIR 1,2 and Usic 2000 surveys].
Ann Cardiol Angeiol. 2003;52:1-6.
26. Reiner Z, Mihatov S, Milicic D, Bergovec M, Planinc D;TASPIC-CRO Study Group Investigators.
Treatment and secondary prevention of ischemic coronary events inCroatia (TASPIC-CRO study).
Eur J Cardiovasc Prev Rehabil. 2006;13:646-654.
27. Kotseva K, Wood D, De Bacquer D, et al; EUROASPIRE II Study Group.
Cardiac rehabilitation for coronary patients: lifestyle, risk factor andtherapeutic management. Results from the EUROASPIRE II survey.
Eur Heart J. 2004;6(suppl J):J17-J26.
28. Wood DA, Kotseva K, Jennings C, et al; EuroActionStudy Group.
EUROACTION: a European Society of Cardiology demonstrationproject in preventive cardiology.
Eur Heart J. 2004;6(suppl J):J3-J15.
29. Wood DA, Kotseva K, Connolly S, et al; EUROACTIONStudy Group.
Nurse-coordinated multidisciplinary, family-based cardiovasculardisease prevention programme (EUROACTION) for patients withcoronary heart disease and asymptomatic individuals at high risk ofcardiovascular disease: a paired cluster randomised controlled trial.
Lancet. 2008;371:1999-2012.
30. Wood DA, Roberts TL, Campbell M.
Women married to men with myocardial infarction are at increasedrisk of coronary heart disease.
J Cardiovasc Risk. 1997;4:7-11.
31. Pyke SD, Wood DA, Kinmonth AL, Thomson SG.
Change in coronary risk and coronary risk factor levels in couplesfollowing lifestyle intervention. The British Family Heart Study.
Arch Fam Med. 1997;6:354-60.
32. Rose G.
The strategy of prevention: lessons from cardiovascular disease.
BMJ (Clin Res Ed). 1981;282:1847-1851.
33. Rose G.
Sick individuals and sick populations.
Int J Epidemiol. 1985;14:32-38.
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Should cardiovascular disease prevention be undertaken by politicians?
D. Greco, G. Laurendi
Should cardiovascular disease prevention be undertaken by national cardiac societies?
G. Kamensky, J. Murin
Expert Answers to Three Key Questions
Should coronary artery disease prevention be undertaken by doctors or by allied professionals?
G. G. De Backer
1
Cardiovascular Disease Prevention
2
3
CAD PREVENTION: WHAT’S IN A WORD?
rom the lead article in thisissue of Dialogues in Cardio-vascular Medicine, it is clearthat a comprehensive coro-
nary artery disease (CAD) preventionprogram should include differentstrategies : a population strategy, ahigh-risk strategy, and a secondaryprevention strategy. Of these, thepopulation strategy is paramount.The importance of this cannot beoveremphasized. Policymakers andhealth economists may be temptedto oppose these strategies. This iswrong; on the contrary, all theseapproaches complement each otherto the extent that the harmoniousdevelopment of all strategies canachieve more than the sum of eachseparately: the different approachesare interactive and mutually sup-portive. However one should alsoaccept that nowadays, in most coun-tries, the health budgets have risento levels that require resetting pri-orities. The limited resources forpreventive medicine should be used
as efficiently as possible. It is there-fore logical that questions are askedas to what are the most efficientapproaches, with the greatest re-turn, and at the lowest cost.
PARAMOUNT ROLE OFPOPULATION STRATEGY
A population strategy requires amultidisciplinary and integrated approach involving policymakers responsible for such diverse fields as education, transport, agriculture,economy, urbanization, finances,and public health. The experiencefrom the North Karelia project inFinland1 is a good example of howan epidemic of CAD was reversedthanks to successful implementa-tion of a population-based preven-tive program.
CAD prevention can also be subdi-vided into primordial, primary, andsecondary prevention. Primordialprevention aims at preventing theoccurrence of risk factors in the com-munity; this can only be achievedthrough reducing lifelong exposureto environmental and lifestyle-re-lated risk factors.
In developing countries, the chal-lenge is to avoid the occurrence ofan epidemic rise in CAD, such astook place in the fifties and sixtiesin Western Europe. This can onlybe achieved by a public health ap-proach in which both medical doc-tors and other health professionalshave a role to play, as a team, and
“Prevention of coronary arterydisease (CAD) is too important tobe left with medical doctors” is aprovocative, but timely statement.It has been repeatedly demonstrat-ed that the standard of preventivecardiology needs to be improvedthroughout Europe. This necessitatesa comprehensive CAD preventionstrategy, particularly with regardto high-risk patients and second-ary prevention. Who should be incharge—medical doctors or otherprofessionals—of which aspects ofthese programs is not important: itis essential that it is done by a teamof well-trained professionals usinga patient-centered approach. Betterorganization of primary care set-tings and sections on preventivecardiology within hospitals, andincentives from health authoritiesand health insurance systems willcontribute to a more successful im-plementation of evidence-basedguidelines on prevention of CADin clinical practice.
F
Keywords: coronary artery disease; preven-tion; guidelines; implementation; health systemsAddress for correspondence:Prof Guy G. De Backer, UniversityHospital, De Pintelaan 185, B 9000 Gent,Belgium (e-mail: [email protected])Dialogues Cardiovasc Med. 2009;14:101-105
Should coronary artery disease prevention beundertaken by doctors or by allied professionals?Guy G. De Backer, MD, PhD, FESC
Department of Public Health - Ghent University - Department of Cardiology - University Hospital Ghent - BELGIUM
Dialogues in Cardiovascular Medicine - Vol 14 . No. 2 . 2009
SELECTED ABBREVIATIONSAND ACRONYMS
CAD coronary artery disease
CVD cardiovascular disease
EUROASPIRE IIIEUROpean Action on
Secondary Prevention through Intervention to Reduce Events–III
within the broader context of collab-oration with policymakers. This in-volves the promotion of healthy life-styles and avoiding the mistakes thatwere made in industrialized coun-tries during the previous century.
This does not mean that the high-risk strategy should not be pursued;it only means that prevention ofCAD is more than the care for high-risk individuals and patients; it callsfor a broader action by health pro-fessionals, policymakers, politicians,and all of society. These aspects arecovered elsewhere in this issue ofDialogues.
COMPLEMENTARY ROLEOF HIGH-RISK AND
SECONDARY PREVENTIONSTRATEGIES
In this paper, we examine the high-risk and secondary preventionstrategies, keeping in mind that theyshould be considered as a “rescueoperation” offering little toward
the fundamental solution to theproblem posed by the current CADepidemic. Nevertheless, since theunderlying condition responsible forthe development of clinical CAD—atherosclerosis of the arterial vessel
wall—is present in a large majorityof adults in most European coun-tries, the high-risk approach is cer-tainly needed.
Figure 1 shows findings from a re-cent population study carried out ina rural community in Belgium in-volving a large cohort of asympto-matic apparently healthy subjectsaged 35 to 55 years.2 It gives theprevalence of intima/media thick-ening or plaques as observed in thecarotid and femoral arteries by ageand gender. In men aged 45 to 55years, the prevalence of abnormali-ties was as high as 81%.
Thus, in most communities in Eu-rope, the high-risk strategy of CADprevention is a prime requirement.
However, one should bear in mindthe fact that this strategy is appliedwhen the disease process is alreadyadvanced, and consequently that itcan only aim to delay clinical eventsfor as long as possible rather thanachieve complete avoidance.
Nevertheless, this in itself is alreadya major achievement. At the pres-ent time, 38% and 42% of all prema-ture deaths in men and women, respectively, in Europe are due tocardiovascular diseases (CVD).3 InBelgium, CVD is the third majorcause of long-term work incapacity.4
Therefore, the high-risk strategy isanticipated to prevent a substantialnumber of early deaths and achievean increase in life expectancy in thecurrent Belgian CAD population.
Secondary prevention of recurrentCAD events in patients with estab-lished CAD speaks for itself partic-ularly in patients who have devel-oped the disease at an early age.This, however could well lead to anincrease in total CVD mortality sincein the very old, when death becomesunavoidable, CVD is by far the com-monest cause of death. So if one canpostpone the first CAD event or de-lay recurrent events in patients withestablished disease one shouldn’tbe surprised that at the end morepeople die from CAD, but havinglived longer in good health.
The Lead Article by David A. Woodand Kornelia Kotseva in this issueof Dialogues clearly shows, basedon findings from the EUROASPIREstudies (EUROpean Action on Sec-ondary Prevention through Inter-vention to Reduce Events) and oth-er surveys, that guidelines on CVDprevention are poorly implementedin daily practice, and that the gapbetween what is recommended byevidence-based guidelines and whatis achieved in daily practice remainsunacceptably large.
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CAD prevention: role of doctors and allied professionals - De Backer
Figure 1. Prevalence of atherosclerosis in carotid and femoral arteries in the Asklepiosstudy.
Table I summarizes the findings fromthe hospital arm of EUROASPIRE III,with, on the left, the recommenda-tions from the guidelines of theThird Joint Task Force published in20035 and, on the right, the resultsfrom EUROASPIRE III illustratingthe situation in 2006-2007.6 Ideally,one should come up with 100% im-plementation for each parameter.The results tell a very different sto-ry, ranging from a low of 12% (waistcircumference <80 cm in women) tothe “highest” percentage of achieve-ment observed (55%, LDL choles-terol <2.5 mmol/L).
There is thus considerable poten-tial in CAD patients throughoutEurope for raising the standard ofpreventive cardiology through in-creased lifestyle interventions, con-trol of risk factors, and optimal useof prophylactic drug therapies.
Table II gives a summary of whatcould help make CAD preventioneasier in practice. Clinicians, andparticularly general practitioners(GPs), are overwhelmed with guide-lines; they generally feel that theguidelines are too complex andtherefore difficult to apply in daily
practice. Recent Joint European TaskForces have made every effort todraft simple, straightforward, clear,and credible guidelines. Given thediversity that still exists amongguidelines from different expert com-mittees, one should aim at a betterharmonization with more focus onareas of consensus rather than on“state-of-the-art” science.
Guidelines should therefore be sum-marized in short, self-explanatory,
simple figures and tables; this wasdone with the latest Joint Task Forceguidelines7; pocket versions becameimmediately available as well as oth-er aids to help practitioners in theirdaily practice. Clinicians may alsobe helped by management toolssuch as the Heart Score model thathas now become available on CD-ROM.8
Furthermore, the European guide-lines should not be considered assomething carved in stone to be im-posed on clinicians. On the contrary,it is strongly recommended that lo-cal Task Forces interact with nation-al societies to adopt/adapt theseguidelines, taking into considera-tion local, socioeconomic, and cul-tural issues. Europe is extremelydiversified in terms of cultures andlanguages, which makes implemen-tation a real challenge.
Some have criticized the guidelinesinasmuch as clinicians may not feelcommitted because they are notpart of the creation of the guide-lines. This has not been the case in Europe within the 4th Joint TaskForce, where GPs, specialists, andother health professionals were wellrepresented. This should be repeat-ed at national level within nationalJoint Alliances, letting all healthprofessionals be involved in draft-ing the prevention program.
GPs and other health professionalsshould have sufficient time to spendon preventive medicine. As time ismoney, insurance systems shouldbudget for reimbursement of pre-ventive actions. Government policiesshould more actively promote CADprevention. More attention shouldgo into adherence to lifestylechanges and long-term drug thera-pies, including educational pro-grams addressed at patients andtheir families as well as at healthprofessionals.
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CAD prevention: role of doctors and allied professionals - De Backer
Guideline EUROASPIRE III
Smoking cessation/smokers 48%
Regular physical activity 34%
BMI <25 kg/m2 18%
Waist circumference <94 cm (men) 25%
<80 cm (women) 12%
BP <140/90 mm Hg 50%
Total cholesterol <4.5 mmol/L 49%
LDL cholesterol <2.5 mmol/L 55%
Fasting blood glucose <7.0 mmol/L (diabetics) 27%
HbA1c <6.5% (diabetics) 35%
Table I. Implementation of guidelines in clinical practice in the EUROASPIRE III.
Abbreviations: BP, Blood pressure; EUROASPIRE III, EUROpean Action on Secondary Preventionthrough Intervention to Reduce Events–III; BMI, body mass index; HbA1c, glycated hemoglobin A1c;LDL, low-density lipoprotein.
• Simple, clear, credible, and harmonized guidelines
• Guidelines adapted/adopted, translated and disseminated at the national level
• Sufficient time
• Positive and helpful government policies (defined prevention strategy with resources, incen-tives including remuneration for prevention as well as treatment)
• Educational policies that facili-tate patient adherence to advice
• Health systems driven by prevention rather than by care
Table II. What could make the practice of CAD prevention easier?
WHAT IS THE ROLE OF DOCTORS VERSUS
OTHER HEALTH PROFESSIONALS?
Who is best qualified to implementCAD prevention in daily practice?Probably no single professionalgroup is capable of ensuring CADprevention on its own. Doctors aretrained to diagnose and treat CAD.When they are asked about theirrole in health care, they tend to em-phasize the care of the individualpatient precisely because this iswhat they have been always taughtto do. Teaching in most medicaluniversities focuses on the approachto the individual patient with onlypoor coverage of preventive- or com-munity-oriented public health strate-gies. This is unfortunate, becausedoctors can play a major role inCAD prevention by providing adviceto persons at high risk and patientswith established CAD. The consul-tation with the doctor provides andideal opportunity to discuss riskfactor management, changes in life-style, and compliance with drugtherapies. The medical consultationcan also be considered as the mostappropriate setting to adapt thelevel of prevention to the patient’stotal cardiovascular risk. It is unfor-tunate that many medical consulta-tions are still exclusively dominatedby concern with short-term imme-diate issues, at the expense of thefuture. Lack of time and money is aproblem, but the question can beasked whether reallocating sometime from treatment to preventionwould not be worthwhile.
GPs are also in best position to involve the patient’s family, whichis of great importance in securingadherence to lifestyle changes andcompliance. If GPs are to take upthe challenge of CAD preventioneffectively, they will need appropri-ate training in the following aspects:
• Patient-centered methods in theconsultation process.• Motivation for change: how tosupport and strengthen the patients’decision to implement healthyhabits.• Evaluation of multifactorial riskand use of risk charts.• Communication on the outcomesand risks of interventions• Definition of treatment goals andimplementation of follow-up.
Identical requirements apply tocardiologists or other specialists in-volved in high-risk or secondaryprevention programs. The alterna-tive is to share these above-de-scribed tasks with trained nursesor other health professionals. Con-trolled studies have shown thatnurse-managed programs are ableto improve lifestyle, risk factor con-trol, appropriate use of cardiopro-tective drugs, and quality of life.9
Nurses are trained in how to man-age patients treatments, but maylack specific knowledge about diet,exercise, and behavior changes, al-though specialized nurses may beable to fill that gap.
Dietitians may be of great help inachieving dietary goals, but theyoften have very little training in ex-ercise prescription or behavioralchange. Exercise physiologists areknowledgeable about physical ac-tivity requirements, but less so ofthe psychological aspects involved.Psychologists, for their part oftenlack physiological knowledge.
How can all this be improved? Uni-versity courses are now increasinglybeing tailored to fill this gap by pro-viding the scientific bases to devel-op behavioral models for achievinglifestyle changes through interven-tions on diet, exercise and smoking,as well as weight, blood pressure,and lipid and blood glucose abnor-malities.
However, it is unlikely that in thenear future any one professionalwill be able to provide the compre-hensive, multifactorial, and multi-disciplinary package that is neededin the high-risk strategy of CAD pre-vention. Most high-risk subjectsand patients with established CADcontinue to rely on GPs and cardiol-ogists for implementing primary andsecondary prevention, and variousstudies have clearly demonstratedthe gap between evidence-basedguidelines and what is achieved indaily practice. All indications showthat this is best addressed by aim-ing at structural changes for CADprevention programs to be carriedout by a teams of health profession-als with the doctor—very often theGP—as coordinator. These teamsshould provide easily understand-able information, empathic motion-al support, allow patients to askquestions, and develop strategiesto assess adherence.
Large differences exist between Eu-ropean countries in terms of avail-ability of GPs, specialists, nurses,and other health professionals. Insome countries, this may influencethe decision as to what role doctorsor other professionals have in CADprevention.
WHAT ROLE DOES THE PATIENT HAVE?
In addition to doctors and otherhealth professionals, there is a thirdplayer who should not be left outof this discussion, namely, the pa-tient or the high-risk subject. AllCAD prevention strategies shouldbe based on a patient-centered ap-proach. Doctors and other healthprofessionals should always be care-ful to appraise and take into accountthe patient’s concerns, beliefs, andvalues, and respect the patient’schoices even if they differ from thehealth professional’s personal views.
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The responsibility of the health pro-fessional is to offer a correct andbalanced account of the scientificand technical issues related to CADprevention so that the high-risk sub-ject and the patient can be as wellinformed as possible.
Adherence to lifestyle managementand lifelong drug therapies can onlybe achieved if patients make thistheir own decision. Lifestyle man-agement and drug treatment goalsshould be set in collaboration withthe patients, taking into accounttheir values and priorities. Oneshould also realize that behavioralchange is part of the self-manage-ment of health in general. Self-man-agement is defined as a person’sability to manage symptoms, treat-ment, and lifestyle in order to adaptto chronic conditions such as es-tablished CAD. Self-managementcan be learned and optimized bypatient-centered self-managementinterventions based on the theoryof self-efficacy promotion10; but atthe end of the day, the decision totake action rests with the patient.
ORGANIZATIONAL ASPECTS
There is more to consider in CADprevention beyond the patient anddoctors or other health profession-als, and that is the organizationalcontext in which primary or second-ary prevention of CAD is developed.
One of the most frequently heardcomplaints of doctors when it comesto CAD prevention is that they lacktime. This has much to do with theorganizational structure of primarycare settings and of specific sec-tions for preventive cardiology inhospitals. CAD prevention can beimproved when quality assuranceis introduced into daily practice onthe basis of registration and plannedfollow up. Setting up a patient reg-
ister is of great importance to guar-antee attendance of follow up vis-its. All this is more easily achievedin settings where doctors are assist-ed by other health professionals.Follow up by nurses has been shownto be as effective or even more ef-fective than by doctors. This appliesboth to primary care and preventivecardiology in all hospitals wherecardiac patients are taken care of.
REFERENCES
1. Puska P, Tuomilehto J, Nissinen A,Vartainen E, eds.
The North Karelia Project: 20 years resultsand experiences.
National Public Health Institute,Helsinki, Finland. 1995.
2. Rietzschel E, De Buyzere ML,Bekaert S, et al; AsklepiosInvestigators.
Rationale, design, methods and baselinecharacteristics of the Asklepios study.
Eur J Cardiovasc Prev Rehabil.2007;14:179-191.
3. European Cardiovascular DiseaseStatistics 2008.
European Heart Network, 2008. Logstrup S, ed.
4. www.riziv.fgov.be.Accessed 23 March 2009.
5. De Backer G, Ambrosioni E,Borch-Johnsen K, et al.
European guidelines on cardiovascular disease prevention in clinical practice.Third Joint Task force of European andother Societies on Cardiovascular diseaseprevention in clinical practice.
6. EUROASPIRE III, presented at theESC Annual Congress 2007 Vienna,Austria. 2007.
7. Graham I, Atar D, Borch-Johnsen K,Boysen G, Burell G, Cifkova R, et al.
European Guidelines on cardiovascular disease prevention in clinical practice: full text.Fourth Joint Task Force of theEuropean Society of cardiology and othersocieties on cardiovascular disease preven-tion in clinical practice.
Secondary prevention in coronary heart dis-ease: a randomized trial of nurse led clinicsin primary care.
Heart. 1998;80:447-452.
10. Sol BG, van der Bijl JJ, Visseren FL.
Vascular risk management through nurse-led self-management programs.
J Vasc Nurs. 2005;23:20-24.
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ardiovascular disease (CVD)causes more than half thedeaths in Europe (52%) andin the European Union
(EU) (42%).1-3 Coronary artery dis-ease (CAD) is the leading cause ofmortality in men over 45 years, andin women over 65 years throughoutEurope, and 51% of patients hadpremature CAD at the time of theirfirst clinical manifestation of CAD.4,5
In addition, while CVD mortality, in-cidence, and fatalities are falling inmost Western European countries,they are either not falling as fast,or are even rising, in Central andEastern European countries. Thereason is simple: in spite of thewell-known fact that most CAD iseminently preventable,6 the mostimportant risk factors are frequentlynot only not under control, but theyare even increasing particularly incountries with relatively less-devel-oped economies.7-9
FIRST WAS THE INITIATIVEOF THE EUROPEAN
SOCIETY OF CARDIOLOGY
Michael Tendera, during his presi-dency of the European Society ofCardiology (ESC), in 2004 in hisConcise Guide in Influencing HealthPolicy in Europe correctly empha-sized that “Cardiologists alone cannot handle the problem of cardio-vascular disease. Therefore, thereis a strong need to further developexternal relations on the political
level, with industry, other profes-sional organizations and the press.”In the same year a most importantconference the Cork Conference,held on 24-26 February, 2004, inCork, Ireland, was organized by theEU Commission, the ESC, the Eu-ropean Heart Network, and EUmembers states. This conferenceprepared an important document,Promoting Heart Health—A Euro-pean Consensus.10 This documentemphasized not only the great bur-den of cardiovascular diseases onthe EU population, which can beconsiderably prevented, but it alsomentioned the importance of max-imal collaboration at every statelevel, where the National CardiacSocieties (NCSs) should play an im-portant and leading role. This ideawas supported by the LuxembourgDeclaration, which was preparedduring the Heart Health Conferencein Luxembourg on 29 June, 2005(http://www.noellmobilesystems.com/en/luxembourg-declaration.132.html).
THE EUROHEART PROJECT
Many discussions of, and argumentsby, the ESC finally helped to per-suade the EU to support a cardio-vascular prevention project in Eu-rope. The resultant EuroHeart is a3-year project co-funded by the Eu-ropean Commission Public HealthProgram 2003-2008. To strengthen
Cardiovascular disease, mainlythrough coronary artery disease(CAD), is the number one killer inmen and women in Europe eventhough most deaths and disabilitiesfrom CAD could be avoided byadopting healthy lifestyles. Becausemost CAD risk factors usually haveno warning signs, continuous andintensive education on a healthylifestyle at a population level is ofenormous importance. The EuropeanSociety of Cardiology (ESC), to-gether with its National CardiacSocieties and the support of theEuropean Union and other profes-sional organizations, initiated thepan-European EuroHeart preven-tion project, with the aim of reduc-ing the burden of CAD in Europe.The first year of the project clearlyestablished the undisputable roleof National Cardiac Societies inCAD prevention.
Should cardiovascular disease prevention be undertaken by national cardiac societies?Gabriel Kamensky*, MD, PhD; Jan Murin†, MD, PhD*Associate Professor of Internal Medicine and Cardiology - 5th Internal Clinic - Department of Noninvasive Cardiovascular Diagnostics †Professor of Internal Medicine and Cardiology - 1st Internal ClinicComenius University Hospital Bratislava - Bratislava - SLOVAKIA
C
Keywords: cardiovascular disease; coro-nary artery disease; mortality; epidemiology;EuroHeart project; European Heart HealthCharter; cardiac societiesAddress for correspondence:Prof Gabriel Kamensky, 5th Internal Clinic,Dpt of Noninvasive CardiovascularDiagnostics, Comenius University HospitalBratislava, Ruzinovska 26, 826 06Bratislava, Slovakia(e-mail: [email protected])Dialogues Cardiovasc Med. 2009;14:106-111
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cross-sector cooperation, it hasbeen developed by the ESC alongwith the European Heart Network,and brings together 33 partners in 22European countries (among which18 heart foundations and 11 NCSs)as it also includes associated part-ners who will act as experts in oneor more work packages. The projectstarted in April 2007 and will finishin March 2010.
The general objectives are to ad-dress the significant burden of CVDin Europe and to determine specificareas of policies and public healthinterventions that can contribute topreventing avoidable deaths anddisability. The strategic objectivesof EuroHeart Project are to:• Strengthen cross-sector coopera-tion through the launch of a Euro-pean Heart Health Charter throughmobilizing support for cardiovascu-lar health promotion and CVD pre-vention. The aim of the Charter isto substantially reduce the burdenof CVD in the European Union andthe World Health Organization(WHO) European Region and to re-duce inequalities/inequities in thedisease burden within and betweencountries.• Obtain comprehensive and com-parable information on policies andmeasures impacting on cardiovas-cular health promotion and CVDprevention through the mapping andanalyzing of national plans, policies,and measures across Europe.• Improve the awareness, diagnosis,and treatment of CVD in womenthrough investigating issues con-cerning CVD in women.
• Promote best practice in preven-tion and treatment of cardiovascularconditions through the implemen-tation and adaptation to nationalsituations of European guidelineson CVD prevention in those coun-tries where there is a gap. • Improve prevention practices atprimary care level by developinglocal-language versions of the Web-based interactive CVD risk assess-
ment tool, HeartScore, by facilitat-ing the translation, adaptation, andimplementation of the Europeanguidelines on CVD prevention. Theadaptation/translation of the guide-lines to the national situations willallow networking and developmentof national alliances among sisterorganizations (eg, equivalent to theJoint Prevention Committee at Eu-ropean level).
WHAT ARE THE EXPECTED RESULTS?
• Events to launch the EuropeanHeart Health Charter at Europeanand national levels (already fulfilled).• Comprehensive comparable infor-mation on policies and actions im-
pacting on cardiovascular healthpromotion and CVD prevention in16 countries in Europe.• A model for national action planson cardiovascular health promotionand CVD prevention.• Compilation of information onresearch surveys, women in clinicaltrials, events in women, and aware-ness raising campaigns on womenand CVD.
• Local language versions of Heart-Score.• Capacity-building among healthprofessionals through the imple-mentation and adaptation to na-tional situations of the Europeanguidelines on CVD prevention.
Nowadays, it is very clear that suchan extensive project as EuroHeart,to be successful, has to be led notonly by experts in the field, but alsoby experts from recognized author-ities as the NCS surely representsin most European countries. Asshown in Table I, eleven NSCs areinvolved in the EuroHeart Projectand many other societies are par-ticipating through their founda-tions (Table II, page 108).
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SELECTED ABBREVIATIONSAND ACRONYMS
CAD coronary artery disease
CVD cardiovascular disease
NCS national cardiac society
Country Name of partner Contact name
Cyprus Cyprus Society of Cardiology Pambis Nicolaides
Czech Republic Czech Society of Cardiology Michael Aschermann
Estonia Estonian Society of Cardiology Margus Viigima
Finland Finnish Cardiac Society Juha Hartikainen
Greece Hellenic Society of Cadiology Harisios Boudoulas
Luxembourg Societé Luxembourgeoise Jean Beisselde Cardiologie
Poland Polish Cardiac Society Adam Torbicki
Portugal Sociedade Portuguesa Daniel Ferreirade Cardiologia
Slovakia Slovak Society of Cardiology Gabriel Kamensky
Slovenia Slovenian Society of Cardiology Zlatko Fras
Turkey Turkish Society of Cardiology Ahmet Ünver
UK British Cardiovascular Society Nicholas Brooks
Table I. Overview of National Cardiac Societies’ participation in the EuroHeart project.
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THE EUROPEAN HEARTHEALTH CHARTER
AT EUROPEAN AND NATIONAL LEVELS
The European Heart Health Charterwas officially launched on 12 June2007 in Brussels among Europeanofficials and many representativesof the NCS and Heart Foundations(Figure 1). Four months later, theESC reported on how it felt aboutwitnessing an unprecedented sup-
port from its member societies. Inthe final count, 24 countries havelaunched their own national versionof the Heart Health Charter, withthe involvement and commitmentof national officials and partner organizations, hence promoting alliances and creating a favorableenvironment for heart health pro-motion. The Charter was translatedby NCS or Heart Foundations into24 European languages, all avail-able on the Web site dedicated to
the Charter (http://www.heartchar-ter.eu/read-charter/default.aspx).
A common feeling shared by all wasthe enthusiasm generated by theCharter and its launch at nationallevel. Most launches were blessedwith the presence of at least theHealth Minister, which shows thatexchange and communication ispossible with the highest healthauthorities.
Cyprus was luckier, with the addi-tional presence of fellow citizenMarkos Kyprianou, European Com-missioner for Health at that time,who, by his attendance, reiteratedhis interest in heart health promo-tion across Europe. Pambis Nico-laides, President of the CyprusCardiac Society, noted that,
The presence of politicians was im-
portant, because they realized that
health campaigns organized by doc-
tors and the Foundation were not
enough, and that effective policies
measures and intervention changes in
the legislation, educational programs,
and agriculture policies were needed
in order to promote a healthier envi-
ronment and a healthier Europe.
Although most launches acrossEurope borrowed some elements ofthe European launch in Brussels,each country adapted it to the localcontext.
For instance, the launch of theCharter in Austria received a partic-ular European focus as it took placeat the opening of the ESC Congress2007 in Vienna and involved theHealth Minister Klodsky.
Iceland in particular aimed at a verydefinite target. In mid-August, theIcelandic Cardiac Society and itspresident Karl Andersen, along withthe Health Minister and the Ice-landic Heart Association, were de-termined to “eradicate preventable
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Partner name Partner country
European Society of Cardiology France
European Heart Network Belgium
Belgian Heart League Belgium
Cyprus Society of Cardiology Cyprus
Danish Heart Foundation Denmark
Estonian Heart Association Estonia
Estonian Society of Cardiology Estonia
Finnish Heart Association Finland
Finnish Cardiac Society Finland
French Federation of Cardiology France
German Heart Foundation Germany
Hellenic Heart Foundation Greece
Hellenic Cardiological Society Greece
Hungarian Heart Foundation Hungary
Icelandic Heart Foundation Iceland
Irish Heart Foundation Ireland
Italian Heart Foundation Italy
ALT Italian Association Against Thrombosis Italy
Istituto Auxologico Italiano Italy
Société Luxembourgeoise de Cardiologie Luxembourg
Netherlands Heart Foundation Netherlands
Norwegian Heart and Lung Patient Organisation Norway
Polskie Towarzystwo Kardiologiczne Poland
Sociedade Portuguesa de Cardiologia Portugal
Slovak Heart to Heart League Slovakia
Slovak Society of Cardiology Slovakia
Slovenian Heart Foundation Slovenia
Slovenian Society of Cardiology Slovenia
Spanish Heart Foundation Spain
Turkish Society of Cardiology Turkey
National Heart Forum UK
University of Oxford UK
British Cardiovascular Society UK
Table II. Complete list of partners in the EuroHeart project.
heart disease in this country, and(…) are dead serious about it!” For Karl Andersen,
the launch of the European Heart
Health Charter in Brussels managed
to reach the ears of governments and
health policy makers all over Europe.
In Iceland, the health authorities lis-
tened.
In Romania, the alliance createdaround the Romanian Cardiac So-ciety, the College of Physicians, andthe Romanian Societies of Diabetes,Nephrology and Obesity, along withthe Health Minister and the StateSecretary of the Ministry of Educa-tion, Research and Youth, are de-termined
for the first time in the long history
of Romanian medical specialties, (…)
to reduce the cardiovascular burden
in Romanian population using Pre-
vention strategies,
says Dan Gaita. In Cyprus, thelaunch also took place in theHouse of Parliament.
Other countries rightly took theopportunity of World Heart Day on30 September 2007 to organizeevents. This was the case in partic-ular for Slovenia, Slovakia, andEstonia. In Slovakia the alliancewas created around the Slovak So-
ciety of Cardiology, the Slovak HeartFoundation, the Slovak Heart toHeart League, the WHO office inSlovakia, the Office for public healthalong with the Health Minister(Figure 2). The European HeartHealth Charter official signing wasthe beginning of the nationwideeducational campaign on the topicof cardiovascular prevention calledMOST (mesiac o srdcovych témach =Month Of Heart Topics) and simul-taneously a part of the final prepara-tion of the National CardiovascularProgram.11 In Bosnia and Herze-govina, an event similar to that in
Brussels was arranged, when theFoundation of Health of Bosnia andHerzegovina and Heart of the Re-public of Srpska, invited local chil-dren to participate in a balloon re-lease. Some countries, like Belgium,Greece, or Poland have had diffi-culty in fixing a convenient date, dueto the relatively unstable politicalsituation or general elections, butthe commitment and conviction oflocal stakeholders is still very strong.The launch in Belgium finally tookplace on 23 October in Brussels, inthe presence of the Belgian Commu-nity Health Ministers. In Lithuania,where the Health Program has setthe target to reduce mortality ratesfrom both coronary heart disease(CHD) and strokes for the popula-tion under 65 years of age by 15%through the limitation of major riskfactors for CHD in the whole popu-lation, the launch, attended by thePresident of the Lithuanian Societyof Cardiology, the Health Minister,and the Director of Kaunas Univer-sity Hospital, is
expected to address the inadequate
control of risk factors of community
and health care authorities. It was
also the occasion to plant an oak tree
beside the Library of Kaunas Univer-
sity of Medicine.
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Press and media are constant fac-tors in and partners of all nationallaunches, with good coverage de-sirable in local newspapers and ontelevision. Indeed, the word “his-toric” comes back on many occa-sions at the launches’ events. AsNick Boon, president of the BritishCardiovascular Society puts it:
This is truly an historic moment in
the battle against CVD. For the first
time all EU Governments will work
together to implement a range of
uniform measures, including tobac-
co control and marketing campaigns
to improve unhealthy diets and help
people to do more exercise.
According to Lars Rydén (Co-Chairof the European Heart Health Char-ter Steering Committee, Co-Chair ofthe ESC Committee for EuropeanUnion Relations) the wide accept-ance of the European Heart HealthCharter in Europe represents a greatstep forward. The ESC together withits NCS have been able to work to-gether very successfully with theEuropean heart Network, WHO, andthe European Commission. The nec-essary support from Member Statesto adopt Council Recommendationshas been built and the Committeecan be even more demanding andambitious in its relationship withEuropean Institutions.
The ESC has been able to createplatforms where organizations fromvarious groups can keep their indi-vidual identities while at the sametime working toward an exactlyshared goal. The fact that the jointEuropean prevention guidelineshave been signed by all these differ-ent professional organizations hascertainly helped establish legitimacyin maintaining alliances and pro-moting good clinical practice.
SHOULD CVD PREVENTIONBE UNDERTAKEN
BY NATIONAL CARDIAC SOCIETIES?
Coming back to the main issueraised by this article “whether CVDprevention should be undertakenby national cardiac societies,” theanswer is quite obvious.
NCSs represent an extraordinarilyhuge potential of experts and spe-cialists in cardiovascular medicinenowadays. Their role can be per-ceived in the following areas: • An NCS usually represents thehighest national level of authorityin the field of CVD prevention. • Most of them have in their struc-ture a Working Group on CVD Pre-vention, which is particularly focusedon the topic of CVD prevention.• As the relevant scientific authori-ties, NCSs continuously elaborateor translate the latest PreventionESC Guidelines, which are ultimate-ly published not only in each NCS’sofficial journal, but also on its Website, which has a link to the ESCWeb site. • NCSs prepare all the latest rele-vant scientific statements, whichare to be implemented to the Na-tional Heart Health Plans or to na-tional legislation, with a view toreaching the highest possible na-tionwide implementation in real life. • NCSs actively organize scientificmeetings with the aim of improv-ing education and implementationof the latest Guidelines using Heart-Score, not only by specialists, butmainly by general practioners.12-14
• Some NCSs founded their ownHeart Foundations which, in con-trast to an NCS as a professionalorganization for cardiologists, canact more actively toward patients’
education, media cooperation, etc.• NCSs, in cooperation with theirfoundations, should produce edu-cational materials on healthy life-style, in their native languages.Educational materials are in printand/or on a Web site.• Nationwide projects (shorter orlonger duration) oriented to popula-tion education including risk factormeasurements, should be continu-ously introduced and implementedby NCSs and their Heart Founda-tions in cooperation with other pro-fessional organizations. • NCSs and their Heart Foundationsshould prepare and implement na-tionwide registers of high-risk pa-tients with the aim of obtainingreasonable information on the levelof risk factor control, so as to elimi-nate the usually great regional socio-economic differences in cardiovas-cular mortality and morbidity.15-17
REFERENCES
1. Sans S, Kesteloot H, Kromhout D.
The burden of cardiovascular diseases mor-tality in Europe. Task Force of the EuropeanSociety of Cardiology on CardiovascularMortality and Morbidity Statistics in Europe.
Eur Heart J. 1997;18:1231-1248.
2. Ezzati M, Lopez AD, Rodgers A, et al.
Selected major risk factors and global andregional burden of disease.
Lancet. 2002;360:1347-1360.
3. Health statistics.
Atlas on mortality in the European Union.
Data 1994–97. Luxembourg: Office forOfficial Publications of the EuropeanCommunities; 2002.
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4. Menotti A, Lanti M, Kromhout D,et al.
Forty-year coronary mortality trends andchanges in major risk factors in the first 10years of follow-up in the seven countriesstudy.
Eur J Epidemiol. 2007;22:747-754.
5. European Cardiovascular DiseaseStatistics.
British Heart Foundation and EuropeanHeart Network, 2008.
6. Yusuf S, Hawken S, Ôunpuu S, etal; INTERHEART Study Investigators.
Effect of potentially modifiable risk factorsassociated with myocardial infarction in 52countries (the INTERHEART study): case-control study.
Lancet. 2004;364:937-952.
7. EUROASPIRE II Study Group.
Lifestyle and risk factor management anduse of drug therapies in coronary patientsfrom 15 countries. Principal results fromEUROASPIRE II Euro Heart SurveyProgramme.
Eur Heart J. 2001;22:554-572.
8. Boersma E, Keil U, De Bacquer D,et al; EUROASPIRE I and II StudyGroups.
Blood pressure is insufficiently controlled inEuropean patients with established coronaryheart disease.
J Hypertens. 2003;21:1831-1840.
9. De Bacquer D, De Backer G,Ostör E, Simon J, Pyörälä K; EU-ROASPIRE I Study Group.
Predictive value of classical risk factors andtheir control in coronary patients: a follow-up of the EUROASPIRE I Cohort.
North-south gradients in Britain for strokeand CHD: are they explained by the samefactors?
Stroke. 2003;34:2604-2609.
17. Muller-Nordhorn J, Rossnagel K,Mey W, et al.
Regional variation and time trends in mor-tality from ischaemic heart disease: East andWest Germany 10 years after reunification.
J Epidemiol Community Health.2004;58:481-485.
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THE BURDEN OF CARDIOVASCULAR DISEASE
ardiovascular disease (CVD)is without doubt the mostsevere and frequent healthdisorder in industrialized
countries. In the Western world, aswell as in developing countries, theburden of CVD has been rising dra-matically, year after year. In Italy, 1 out of 2 deaths is due to CVD, andout of a total population of 57 mil-lion, at least 1.5 million suffer froma serious form of coronary artery dis-ease (CAD) at any time. The situa-tion is similar in the rest of Europe.
While mortality rates in Italy aregradually falling thanks to earlierdiagnosis and treatment, the inci-dence of coronary events is increas-ing due to the rapidly aging popula-tion. Figure 1 shows the incidenceand 28-day mortality of myocardialinfarction and stroke in Italy, in the35-to-74–year age-range.1,2
The remarkable success achieved byearly diagnosis and treatment hasconsiderably reduced mortality. Butalthough CAD no longer representsan immediate threat to life, a ma-jority of CAD survivors continue tosuffer from chronic disease. This hasa considerable negative impact ontheir quality of life and imposes aheavy burden in terms of healthcare–related costs and loss of pro-ductivity on society. In other words,the huge gains achieved in reduc-
tion of mortality and morbiditycome at the expense of a steady risein the demand for health care andsocial resources by CAD sufferers.All prospective disease preventionpublic health models concur in theirpredictions that in the near futurethe weight of chronic diseases willconsume the greatest part of avail-able health resources, thus deeplyundermining the present universalhealth care system that providesfree care for all in Italy.
Since the 1970s, there have beenrepeated calls in Italy to address theCAD epidemic by implementingrecommendations to improve thepopulation’s lifestyle by increasingthe awareness of the risks causedby deleterious behaviors and by en-couraging initiatives by physiciansfor the evaluation and intensive careof patients at high risk.3 Neverthe-less, over the last 30 years, in spiteof the steadily increasing incidenceof CAD, the overall record of publichealth authorities in terms of pre-vention has been poor.4
CAD PREVENTION
The main determinants of CAD arewell known: smoking, alcohol, un-healthy diet, sedentariness, hyper-tension, and high levels of choles-terol, together make up more than80% of the factors incriminated. Overthe last 30 years, countless studieshave confirmed the strength of thisevidence. In parallel, intervention
The incidence of cardiovasculardisease (CVD) has been increasingsteadily over the past several yearsand is currently one of the biggestpublic health concerns in Italy.One of the chief objectives in CVDprevention is primary prevention of coronary artery disease (CAD).Longitudinal epidemiological stud-ies have confirmed the benefit oflifetime maintenance of the popu-lation at low levels of risks. CVDprevention cannot and should not bethe responsibility of doctors alone,but should involve politicians/policymakers, as well as the media,local institutions, schools, foodproducers, etc. These players shouldavoid futile prohibitions, and worktogether to “make health choiceseasy.” Primary prevention is an in-vestment for the future. The Italianoperational model is based on athree-pronged policy including in-dividual prevention, communityprevention, and surveillance.
Should cardiovascular disease prevention be undertaken by politicians? Donato Greco*, MD; Giovanna Laurendi†, MD*Chief of the Prevention Department of the Italian Ministry of Health †Prevention Department of the Italian Ministry of Health - Rome - ITALY
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Keywords: prevention; cardiovascular disease; health policy; risks factor; publichealthAddress for correspondence:Giovanna Laurendi, MD, DirezioneGenerale della Preventione Sanitaria, Via Giorgio Ribotta 5, 00144 Rome, Italy(e-mail: [email protected])Dialogues Cardiovasc Med. 2009;14:112-118
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studies have overwhelming demon-strated how modifying these riskfactors significantly reduces the in-cidence of CAD, with greater effec-tiveness than pharmacological andsurgical treatments.5,6 This is ex-emplified by the effect of the recentban on smoking in public places toeliminate passive smoking in Italy,the outcome of which was to reducehospital admissions for myocardialinfarction by 10% by the first yearof implementation.7
PRIMARY PREVENTIONFOR CAD IS POSSIBLE, EFFECTIVE, AND VITAL
Longitudinal epidemiological stud-ies have shown the benefit of life-time maintenance of the populationat low levels of risks (ie, blood pres-sure lower than 120/80 mm Hg, cho-lesterol <200 mg/dL, body mass in-dex (BMI) <25, no smoking, absence
of diabetes). Such a benefit is diffi-cult to prove, as the population’sprevalence of CAD at low risk is low(4% in Italy) and observational epi-demiological studies of many years’duration are required to show abenefit, such as ARIC (the Athero-sclerosis Risk In Communities trial),MRFIT (the Multiple Risk FactorIntervention Trial), the Chicago GasCompany Study, or the Italian CuoreProject).
The Chicago Gas Company Studyin particular showed that people atlow risk survive longer, with betterquality of life, and lower health carecosts in their latter years of life thanpeople at high risk.8-10
Effective prevention implies settingup a health policy with the supportof health care professionals andcitizen associations, at national, re-gional, and district levels). Although
we need to know more about thecontribution of other risk factorssuch as genetics, environmental pol-lution, etc, what we already knowis sufficient to achieve significantsuccess in prevention.
SOCIAL INEQUALITY
An important aspect to take into ac-count is the consequences of socialinequality: the incidence of risk fac-tors (smoking, alcohol, unhealthydiet, and physical inactivity) differsaccording to social status. There isextensive evidence that lower sociallevels (in terms of education, in-come, geographic localization) ex-perience a higher a prevalence ofsmoking, alcoholism, physical inac-tivity, and poor dietary habits. Theprevalence is even greater in themore vulnerable segments of thepopulation such as children, women,and the elderly.
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Should CVD prevention be undertaken by politicians? - Greco and Laurendi
Figure 1. Italian Cuore (Heart) Project: National Registry of Acute Coronary and Cerebrovascular Events.
CAD prevention therefore has a roleof primary social and political im-portance: Equal rights to health orto a universal health care systemare illusory, as long as this problemof severe social inequality with re-gard to the prevalence of major riskfactors of CAD is not adequatelyaddressed.
WHO SHOULD BE IN CHARGE?
While it is the purview of the healthcare system to address the afore-mentioned CVD and CAD risk factorsand their consequences, other in-stances should be involved with re-spect to defining policies in termsof the tobacco, alcohol, and foodindustry, and promoting regularphysical activity. The medical pro-fession has a role in advocacy, incounseling, in encouragement. Butregulating the aforementioned hugetobacco, alcohol, and food marketsis not in their hands. The main roleof health professionals is to restoredamage to health caused by others,and even the best efforts by doctorsin support of risk prevention poli-cies often has no demonstrable im-pact on the incidence of diseasesdetermined by those factors.
Thus, successful prevention of CVDand CAD cannot and must not bemerely the prerogative of physicians,and it is an illusion to believe thatthe medical profession alone caneffectively combat the ill effects ofthe tobacco, alcohol, and food in-dustry. Politicians are needed toset standards in terms of economy,education, advertising, agriculturalproduction, etc. What is required is a true inter-institutional synergy:health is no longer the exclusiveconcern of health professionals,but a shared and collective respon-sibility encompassing the majorplayers of society. Therefore it iscrucial that the awareness of their
important role in preserving publichealth is adequately shared by allsectors involved.
The above considerations are con-sistent with the “Health in all poli-cies” framework as formulated bythe World Health Organization(WHO) and the European Union(EU). Each social sector has to takeresponsibility for its role in healthand adhere to the “inter-institution-al pact” proposed by the publichealth authorities so as to imple-ment improvements in education,the economy, in working conditions,etc. Alliances should be establishedwith schools, food producers, tradeinterests, local institutions, the me-dia, the industry, in order to carryout concrete actions. In doing this,one should avoiding illusory prohi-bitions and seek to find commongrounds among all stakeholders soas to “make health choices easy.”
Only through mobilization of all ofthese players can CVD and CADprevention aim to achieve success.
AN ECONOMIC CONCEPT
The slogan “prevention is econom-ically advantageous” still reignssupreme in the medical world. Al-though this concept may be appeal-ing at first glance with respect toprevention models, which argue thattoday’s disease prevention–relatedcosts will translate into savings as-sociated with each illness prevent-ed, its actual economic outcomeoften remains doubtful. Physicianstoday in Italy solicit funds from theDirector General of the Health Ad-ministration for prevention mea-sures such as information campaigns,screenings, laboratory tests. Thesedemands are based on old estab-lished methods involving the NNT(number needed to treat), cost-ben-efits ratios, etc. Thus, to give an ex-ample, it is claimed that it is worth-
while to measure the blood pressureof a thousand individuals becauseby doing so, it is possible to detect20 people with permanent hyper-tension, even though they are un-aware of this. So we treat 20 peoplesuffering from permanent hyperten-sion for the rest of their lives, hop-ing that in following years, the inci-dence of CAD will drop from 10 to 5.
Even in this oversimplified example,the model remains logical, becausewe reduce expenses, allow peopleto live their last years of life in abetter way, and reduce the incidenceof stroke, which is a burden for thepatients and their families.
But what is the point of view ofthose who must make the necessarydecisions and allocate funds? Thesad truth is that the Director Gen-eral of the Health Administrationis acutely aware of the cost of pre-vention, but, during his/her usuallyshort term in office, will not see anyeconomically convincing returnson this investment.
The paradox about primary preven-tion is that doctors ask persons notto smoke, not to drink alcohol, toexercise more, etc, while at the sametime up to 75% of the cost of ciga-rettes goes to taxes for the State.Alcoholic beverages are also a valu-able source of taxes for the State.The Italian automobile industry, apillar of our economy, is stronglysupported by the State, at the ex-pense of alternatives that would re-sult in less sedentariness. And sowe arrive at the absurdity that thedoctors dealing with prevention areactually paid on public funds stem-ming from taxes paid by those veryindustries that promote unhealthybehaviors.
Primary prevention results in a netloss in economic terms, as it involvesextensive spending for public aware-
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ness campaigns and generates nomoney-bringing activities. In con-trast, secondary prevention involvesa whole range of periodic tests andlong-term prophylactic treatments,in other words, it generates a mar-ket that feeds a specific economywith many beneficiaries.
Within the 10 coming years therewill certainly be fewer cases of CAD.This will lead to an increase in work-ing productivity and a reduction inhealth care expenditure. Whetherthis will balance out the increase inpreventive costs and the costs forregular periodic health controls re-mains unclear.
We are beginning to realize that itis not periodical checks that lowercholesterol: cholesterol is reducedby physical activity and a healthydiet. Thus we can encourage peopleto reduce their salt intake, improvetheir diet, and walk more, in orderto keep their blood pressure downand their cholesterol under control.
The implication is that primary pre-vention requires a lot of time andprofessional skill. The current finan-cial context, which is decidedlygloomy, explains the reluctance ofsociety for funding primary preven-tion. Politicians, like the DirectorGeneral of the Health Administra-tion, only see the costs, not the ben-efits. Can we expect that a HealthCouncillor, and the Director General,who, in Italy, is in office for only ashort period of 2 years, will put upwith a budget in the red, all in thename of a future benefit which isnot even clearly definable?
WHAT IS THE ROLE OF POLITICIANS?
It is easy to object that politiciansshould not only take into consider-ation short-term objectives or beonly concerned with addressing a
nation’s most immediate needs, butthat they should also plan for a bet-ter tomorrow.
Public schools in Italy result in anet financial loss for the State. Butsince when is investment in educa-tion supposed to provide econom-ic returns? And yet, schools anduniversities also represent a hugemarket that provides work for mil-lions of employees, as well as beingthe key to prevention. Again, whatabout research? Only a small sectorof research is economically benefi-cial over the short term. For themost part it provides no immediatebenefits at all, but only over longperiods of time.
As far as the health sector is con-cerned, the greater part of public in-vestment is used to sustain the uni-versal health care system: more thanthree quarters of this investment is spent on personnel salaries andcosts of hospitalization for 10 mil-lion Italians each year. Each year,surgery is carried out on 4 millionpatients; medical examinations areperformed on tens of millions ofpeople. The entire health system is geared toward responding to the health demands of sick people,which represent the “principal mar-ket” of health care efforts.
Even though the Italian populationtoday is beginning to perceive theneed for prevention and demandthat it be implemented, usually thisis limited to secondary prevention.
What they are saying is, in essence“I want medical examinations andtests to see if I am well or have adisease, or whether I am at risk ofany disease.” In contrast, there isonly a token demand for primaryprevention. This begs the question,should there be a substantial offerfor primary prevention if consumerthemselves do not ask for it?
In other words, notwithstanding thesound economics that must be applied to the health care system,we cannot restrict ourselves to themere goal of balancing the econom-ic budget. We must also take intoaccount the fact that a significantshare of public health investmentshould be considered as insurancefor the future, such as supportingprevention, and be prepared to ac-knowledge that public health budg-eting should aim beyond potentialshort-term economic returns.
Two approaches to prevention exist:(i) helping subjects at high risk toavoid complications, or (ii) identi-fying people at high risk in order tohelp them achieve low-risk status byimplementing a healthy lifestyle.Each of these approaches is effica-cious, provided there is synergy be-tween action at the individual leveland at the community level.
EVIDENCE-BASED PREVENTION
With each passing day, evidence ofthe effectiveness of prevention ac-cumulates. Even though there areinstances of intervention trials thatwere launched with great hopes,but failed to live up to expectations,many more confirmed how relativelysimple measures could have greatpreventive efficacy, both with regardto the behavior of the individual aswell as to social policies.
In assessing the value of primaryprevention measures versus second-ary prevention measures, the scalesunquestionably tip in favor of thefirst, as primary prevention ensuresadded years of good quality of life,while secondary prevention (screen-ing, chemotherapy) adds to thera-peutic efficacy (thereby creating veryimportant markets for diagnosticsand pharmaceuticals: with regard toCVD prevention, statins, for exam-
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ple, are the one most importantitem of cost in public health spend-ing in Italy). The change needed inattitudes toward prevention is sim-ple: these should evolve from con-sidering health as a cost to consid-ering it as investment and insurancefor the future. Furthermore, we be-lieve that CVD prevention shouldnot concern the medical professionalone, but above all should be un-dertaken by the community, in viewof the common good.
IS PREVENTION ONLY AN INDIVIDUAL
RESPONSIBILITY?
It is both useless and counterpro-ductive to envisage prevention asplacing blame on individuals or institutions for lifestyles and behav-iors that put health at risk. Prohibi-tions and punitive policies with regard to individual behaviors, eventhough motivations may be laud-able, fail to achieve any long-last-ingly significant results. The onlyworkable alternative is to reach aconsensus on policies aiming toachieve a progressive awareness of the need for implementation ofhealthy behaviors by the population.
Thus, although it is impossible tosimply outlaw smoking, it is possi-ble to increase cigarette prices. Although we cannot eliminate al-cohol, retail sales can be restrictedby imposing strict age limitations.We do not seek to establish a veg-etarian world, but we do want fruitand vegetables to be easily avail-able. We do not want to give up ourcars, but we would like to be ableto enjoy more pedestrian zones inour cities, and walk without riskingbeing driven over.
Paramount is the education of theindividual, which also entails edu-cation at institutional level. Cam-paigns aimed at individuals only are
doomed to fail, they should be di-rected at institutions, the industry,and all stakeholders as well, andalways seek to establish a consensusby generating freely agreed uponcommitments by all.
WHO SHOULD BE RESPONSIBLE:
THE DOCTOR OR THEPOLITICIAN?
Is all this the responsibility of themedical profession? Is it the doctorwho has to create pacts and al-liances with schools, with industry,with agriculture, etc? Are doctorsthe most appropriate players to planand carry out these tasks?
The GP, and above all the cardio-logist, naturally have far deeperknowledge about CVD preventionissues that any politician, whoseknowledge of health issues will ex-tend only as long as his/her man-date. Thus politicians must rely onhealth professionals as technicalconsultants, who will deliver theirexpertise on the why and wherefore,though it is the politician who allotsthe resources to be used for pre-vention who will have to make deci-sions on the how, where, and when.
However, individuals and commu-nities, by following the advice ofhealth professionals, may also ex-ert a significant influence by adopt-ing healthier lifestyles and askingpoliticians to provide for preventionmeasures to be set up, in particu-lar primary prevention. Politicianswill eventually have to listen totheir constituents’ demands if theywant to keep their votes. Thus, eventhough health professionals have a vital role with regard to primaryprevention (take, for example, anti-smoking counseling), politiciansare responsible for making strategicchoices based on realistic goals andable to achieve realistic results.
WHAT IS BEING DONE IN ITALY?
CVD in Italy is one of the biggestpublic health concerns and one ofthe main causes of morbidity andmortality in our country. All healthand social indicators (mortality,hospital discharges, invalidity pen-sions, pharmaceutical costs) concurto reflect the huge human, social,and economic burden associatedwith CVD.
In addition, CVD is compoundedby the fact that it constitutes oneof the most important risk factorsfor diseases linked to aging, cogni-tive capacity, and disability. In acountry such as Italy where life ex-pectancy is continuously rising, itis therefore of utmost importanceto set up CVD preventive measures,in order to achieve better healthconditions and preserve the popu-lation’s quality of life.
In view of the overwhelmingly con-clusive evidence that correctingcardiovascular risk factors markedlyreduces the risk of CVD, the ItalianMinistry of Health has made CVDprevention a top priority and hasbeen gradually putting in place acomprehensive strategy, with thefollowing landmarks: • In 2003-2005, the National HealthPlan promoted action aimed at re-ducing CVD and cerebrovasculardisease mortality and implementingan integrated system of care andassistance to patients suffering fromthese diseases. • In 2004, Law No. 138 implement-ed “urgent procedures to confrontsituations dangerous to publichealth” under the purview of theMinistry of Health’s National Centerfor the Prevention and Control ofDiseases (CCM, Centro nazionaleper la prevenzione e il controllo dellemalattie), which drew inspirationfrom the experience of the interna-
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tional community in dealing withchronic diseases. To address car-diovascular risk, the CCM createdthe CUORE (Heart) project, whichaims at better prevention througha Cardiovascular Risk Charter to en-courage community physicians toact to reduce risk factors and rein-force epidemiological surveillance.• On 23 March 2005, a Memoran-dum laid out an agreement betweenState, Regions, and AutonomousProvinces to include CVD preventionin the 2005-2007 National Preven-tion Plan, and earmarked financialresources for its implementation.Each region has already made pre-vention plans for the reduction ofcardiovascular risk, while operationsfor secondary prevention are in theplanning stages. The National Cen-ter for the Prevention and Controlof Diseases (CCM) has set downguidelines relating to the “spreadingof the Cardiovascular Risk Charter”and how to avoid relapses in sub-jects having already suffered car-diovascular disorders.
The operational model provides forthe development of three planningareas: individual prevention, com-munity prevention, and surveillance(Figure 2).
Individual prevention predominant-ly involves the sphere of primarycare. In compliance with the termsof the Cardiovascular Risk Charter,primary care physicians and alliedprofessionals evaluate their patients’cardiovascular risk and suggestchanges in lifestyle to reduce thisrisk and, where necessary, prescribedrugs to control blood pressure,and blood glucose and lipid levels.
At the population (community) lev-el, effective public health initiativeshave been implemented to reducecardiovascular risk. These includesocietal measures such as the recentlaw protecting nonsmokers by ban-ning cigarette smoking in publicplaces, increasing the price of ciga-rettes, and banning cigarette ad-vertising, and other measures to
encourage physical activity, such asbanning automobile traffic in his-toric centers of cities, building bi-cycle lanes and creating pedestrianzones. Educational programs areaimed at the public in the form of campaigns and groups, such asthose found in schools.
Preventive operations involve theentire Italian health care system(SSN, Servizio sanitario nazionale),beginning with the Department forPrevention, hospitals and hospitalspecialists, and health care centers,all the way to primary care physi-cians, health workers, and socialhealth services.
The road ahead is still a long anddifficult one, but Italy is makingsteady headway in bringing aboutmomentous changes in cultural at-titudes and medical practice, andshowing encouraging progress inachieving ambitious national healthobjectives in the field of CVD pre-vention.
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Gene and cell therapy of arrhythmias - Rosen and others
Figure 2. Overview of cardiovascular prevention.
REFERENCES
1. Palmieri L, Barchielli A, Cesana GC,et al.
The Italian Register of CardiovascularDisease: attack rates and case fatality forcerebrovascular events.
Cerebrovasc Dis. 2007;24:530-539.
2. Gruppo di Ricerca del ProgettoRegistro per gli Eventi Coronarici eCerebrovascolari.
Registro nazionale italiano degli eventi coro-narici maggiori: tassi di attacco e letalitànelle diverse aree del paese.
Ital Heart J Suppl. 2005;6:667-673.
3. Giampaoli S, Palmieri L, Donfran-cesco C, et al.
Uso ed Applicazione Della Carta delRischio Cardiovascolare. 2nd ed. Rome,Italy: Pensiero Scientifico Editore; 2007.
4. EUROASPIRE I and II Group; Eu-ropean Action on Secondary Preven-tion by Intervention to Reduce Events.
Clinical reality of coronary preventionguidelines: a comparison of EUROASPIRE Iand II in nine countries. EUROASPIRE Iand II Group. European Action on SecondaryPrevention by Intervention to Reduce Events.
Lancet. 2001;357:995-1001.
5. Palmieri L, Donfrancesco C,Giampaoli S, et al.
Favorable cardiovascular risk profile and10-year coronary heart disease incidence inwomen and men: results from the ProgettoCUORE.
Eur J Cardiovasc Prev Rehabil. 2006;13:562–570.
6. Giampaoli S, Palmieri L, Panico S,et al.
Favorable cardiovascular risk profile (lowrisk) and 10-year stroke incidence inwomen and men: findings on twelve Italianpopulation samples.
Am J Epidemiol. 2006;163:893-902.
7. Cesaroni G, Forastiere F, Agabiti N,et al.
Effect of the Italian smoking ban on popu-lation rates of acute coronary events.
Circulation. 2008;117:1183-1188.
8. Giampaoli S, Vanuzzo D, et al.
“Atlante italiano delle malattie cardiovas-colari, II Edizione 2004”.
Ital Heart J. 2004;5(suppl 3):1-101.
9. Daviglus M, Liu K, Pirzada A, et al.
Cardiovascular risk profile earlier in lifeand medicare costs in the last year of life.
Arch Intern Med. 2005;165:1028-1034.
10. Brissette I. Fisher B. Spicer DA,et al.
Worksite characteristics and environmentaland policy supports for cardiovascular dis-ease prevention in New York state.
Prev Chron Dis. 2008;5:A37.
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119
he theme common to the previ-ous Trails of Discovery essays1,2
has been to identify specificscientists whose research was
fundamental to the introduction ofnovel cardiovascular drugs into clini-cal practice. A subsidiary theme hasbeen to examine the contribution ofacademic and industrial research col-laboration to such advances, suggest-ing perhaps that the current vogue of“translational medicine” has a longerhistory than is currently recognized.This essay summarizes the events lead-ing to the discovery and developmentof aldosterone antagonists and theirevolution over the subsequent 50 yearsof research.
DISCOVERY ANDSYNTHESIS
OF ALDOSTERONE
The existence of aldosterone, previous-ly termed electrocortin, had been de-bated since the mid-1930s followingthe identification of cortisol, corti-costerone, and desoxycorticosterone(DOCA). After extraction of thesesteroids from adrenal glands there wasa residual amorphous material that hadsome biological activity, first identifiedby Kuizinga and Cartland in the late
1930s.3 Over the next 15 years therewas intense both basic and appliedresearch on a range of anti-inflamma-tory steroids and sex hormones. Apotentially confounding issue was thefact that cortisol possessed effects bothon carbohydrate metabolism and elec-trolyte secretion, leading to a widelyheld opinion that cortisol was thephysiologically important mineralocor-ticoid hormone.4 The first isolation of electrocortin (subsequently termedaldosterone) relied on two importanttechnical developments: (i) the use of
partition chromatography pioneeredby Martin and Synge; and (ii) the de-velopment of a specific radiolabeledbioassay (Na24/K42).5
The imaginative application of thesenew techniques by the Taits (Figures 1& 2), working at the Central MiddlesexHospital in London, led to the purifica-tion of a very small quantity of aldo-sterone.6,7 They carried out pilot studiesand identified some chemical group-ings. In 1952, they began a collabora-tion with Professor Tadeus Reichsteinin the Department of Chemistry, Basel.Reichstein had been awarded the NobelPrize in Physiology or Medicine in 1950for his previous work on adrenal corti-costeroids (Figure 3, page 120). Hehad identified the glucocorticoids cor-tisone and cortisol, as well as the min-
T
Trails of DiscoveryAldosterone antagonists: a model of translational medicine
Nicola Fitzgerald; J. Desmond Fitzgerald, BSc, FRCP, FFPMMateria Medica - Mere, Nr Knutsford - UK
Figure 1. Zoologist, biologist, andendocrinologist Sylvia A. S. Tait (1917-2003).
Born in Russia, identified aldosterone at theCourtauld Institute of Biochemistry at the
Middlesex Hospital Medical School, in London, in collaboration with her future husband,
eralocorticoid activity of deoxycorti-costerone. Furthermore, he identifiedcompounds with dual activities, ie,corticosterone and 17-hydroxydeoxy-corticosterone. The Taits collaboratedwith Reichstein from 1952 to 1958.
There is a fascinating account in greatdetail of the correspondence betweenthe British and Swiss collaboratorsduring this period, which describesmany of the ups and downs encoun-tered before finally identifying thestructure of aldosterone.5 The first crys-tallization of aldosterone was achievedon July 11th, 1953, in collaborationwith the medicinal chemists of CibaAG, Basel, ie, Wettstein, Neher, and vonEuw. At that time there was a largemedicinal chemistry steroid group ledby Wettstein. Ciba had been working onsteroid research since the mid-1930sand an excellent account of their stud-ies over the next 30 years has beenpublished.8 The discovery of the anti-inflammatory actions of cortisone inrheumatoid arthritis by Hench stimu-lated much chemical research onsteroids, not only at Ciba, but notablyat Merck, Organon, and Schering. As aconsequence of the intensive compet-itive patent situation in this field, a
rather unique patent pool consortiumwas set up with the aid of the US Re-search Corporation. The initial isolationof adequate quantities of aldosteronewas made possible by Neher at Cibawho extracted material from 1500 kgof pig adrenals, yielding finally 60-70mg of amorphous pure aldosterone,which Reichstein crystallized in August1953.9,10 This was followed in 1955 bythe first synthesis of aldosterone bythe Ciba chemists.11,12 In their jointpublication of 1953, the authors con-cluded:
…we therefore consider that we have found
a new important hormone of the adrenal cor-
tex. We will report later about experiments
leading to the chemical identification and
synthesis of this compound as well as other
more detailed biological experiments. We
reserve the right to suggest a new name for
the compound at that time.9,10
DISCOVERY OFSPIRONOLACTONE
In the early 1950s, Green, the Directorof the Biology Division at Searle, ini-tiated a research program seekingnovel antihypertensive agents. Thehypertension model used was theDOCA salt rat in which a 20-mg pelletof DOCA induced an early DOCA-de-pendent rise in blood pressure and alater (21 days onwards) phase inde-
pendent of the presence of DOCA. Thissecondary phase was referred to as themetacorticoid hypertension.13,14
Green left Searle in the mid-50s totake up an academic post and the an-tihypertensive program was taken overby Frank Sturtevant, who has describedbriefly how the first aldosterone an-tagonists were found.15 He writes:
…in the 1950s, biologists at Searle were
allowed to devote 50% of their time to re-
search of their own choosing. Thus when
top management decided that there was no
more interest in the pharmacologic screen-
ing of the spironolactone series synthesized
by Jack A. Cella and Bob C. Tweit, for reasons
of their own, we independently chose to
transfer our activities from this interesting
series of compounds to our respective
basic research programs.
Sturtevant was working on experimen-tal mineralocorticoid and renal hyper-tension while in the nearby labs CharlieKagawa was examining the effects ofthe suspended spironolactone seriesin blocking the activities of the sodi-um-retaining actions of DOCA and al-dosterone. Over a chance meeting atlunchtime, Kagawa, Sturtevant, andvan Arman discussed their explorato-ry findings with the spironolactonesand suggested that the compound(SC-5233) be taken into clinical trials.
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Figure 3. Tadeus Reichstein (1897-1996),shared the Nobel Prize in Physiology or
Medicine in 1950 with E. C. Kendall and P. S. Hench for their work on adrenal cortexhormones and isolation of cortisone and of
1. April 1955 2 705712 Cardioregulatory agents specifically for treating cardiac arrhythmias or hypotension
2. April 1958 2 875 195 The capacity to decrease serum concen-tration of cholesterol without estrogenic side effects
3. December 1959 Unique capacity to block (DOCA) actionson urinary sodium and potassium
Subsequently abandoned The compounds are antihypertensive agents
4. December 1961 3 013 012 They are diuretic agents
Example CPD7 is spironolactone To block the effects of DOCA
Table I. Cyclopentanophenantrene patent claims (Searle 1956-61).
Thus the first aldosterone antagonist(SC-5233) was discovered serendipi-tously using compounds synthesizedfor very different reasons (Table I).
The first aldosterone antagonist to bestudied clinically was the spironolac-tone SC-5233, the pharmacology, speci-ficity, and preclinical toxicology ofwhich are described by Kagawa et alin their 1959 paper.16 It would seemthat the senior management in Searleaccepted the proposal to take the firstantagonist, SC-5233, into clinical trials.The serendipitous nature of this deci-sion is emphasized if one reviews thehistory of the series of spironolactonepatents that were published between1953 and 1963 by the Head of Chem-istry, Cella. A range of biological prop-erties were listed in different patents(Table I). The claim for clinical utilityin these differing patents suggeststhat the original chemistry programwas one in search of a disease target,which presumably led research man-agement to abandon the chemistrysynthetic program in 1957, but recon-sidered this decision some years later.Notably, the first patent to describethe antialdosterone actions of spirono-lactone as a novel diuretic was pub-lished in 1963, several years after Liddlepublished the clinical effects of fivespironolactone analogs in trials be-tween 1957 and 1960.
The initial clinical studies were per-formed by Liddle’s group at VanderbiltUniversity, Nashville (Figure 4). In aseminal paper, published in Science in1957,17 Liddle showed that SC-5233(which he somewhat confusinglytermed spirolactone) increased theurinary excretion of sodium in a pa-tient with congestive heart failure, aswell as the sodium-retaining actionsof DOCA in patients with Addison’sdisease. Liddle had been studying thepathogenesis of edematous states withBartter’s group at the National Insti-tutes of Health (NIH) and had pub-lished a bioassay in the dog to mea-
sure the content of aldosterone in theurine of patients with congestive heartfailure and ascites secondary to he-patic cirrhosis.18
In the same volume of Science, theSearle researchers showed that bothSC-5233 and a more potent analog(SC-8109: the 19-NOR analog) reversedthe sodium-retaining actions of DOCAand aldosterone in adrenalectomizedrats. It was this model devised by
Kagawa that enabled the screening ofcompounds for aldosterone antago-nist properties. In the paper, Kagawaet al showed that the two compoundscaused a dose-dependent inhibitionthat was reversible.16
Three years later, Liddle’s group pub-lished the clinical effects of five analogsof SC-5233 in edematous patients.19
They concluded that:…a number of steroid 17-spirolactones have
proved to be effective diuretic agents in
man... by antagonizing the renal tubular ac-
tions of aldosterone.
One of the four spirolactone analogswas SC-9420, which was subsequentlymarketed as spironolactone.
Somewhat surprisingly, neither thepublications from the Searle nor fromLiddle’s Vanderbilt research groupsacknowledge each other at the end oftheir publications. Liddle just thanksDr Gantt for supplying the compound,but made no mention of financialsupport.
While Liddle viewed spironolactonesas novel diuretics to be used as sup-plementary therapy with diureticsworking by a different mode of action,19
Sturtevant showed that the spirolac-tones SC-5233 and SC-8109 reducedmetacorticoid-induced hypertensionin rats. He concluded that:
…the mineralocorticoid and antihyperten-
sive properties of SC-5233 are not directlyrelated.20
SPIRONOLACTONE:CLINICAL ASPECTS
It would seem that the introductionof SC-9420 (spironolactone) was basedon a series of comparative trials withother analogs from the same chemi-cal series (Figure 5, page 122). Thus,investigators in Canada21 and theUK22 both worked with SC-8109, whileanother UK group23 worked with theearlier compound SC-5233. Presumablyit was the combination of potency andoral activity that led to the final selec-tion of spironolactone, whose oral activity was 46 times more potent thanSC-5233 and 5 times more potent thanSC-8109.
The objective in developing spirono-lactone (aldactone) for clinical use wasas a novel diuretic agent that had acomplementary mode of action to thatof the well-established popular thiazidediuretics. The advantage was thatwhen coadministered with a thiazide,it caused an additional Na/water loss,but also reversed the hypokalemic ef-
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Figure 4. Grant Liddle (1921-1989). Born into a Mormon family, studied medicineat the University of California, San Francisco
(UCSF), became first research fellow in theMetabolic Research Unit at UCSF. In 1956
became chief of the Endocrine Service atVanderbilt University Medical Center, where he made important contributions to clinical
endocrinology (pharmacology of steroidhormones, tests of pituitary-adrenal glandfunction, pathophysiology and treatment of
fects of chronic thiazide therapy. Thefirst published symposium on the clin-ical use of aldosterone antagonists, in1960, which was sponsored by Searle,comprises 17 papers presented byleading American clinical scientists in the field of cardiorenal research.Presentations were made on the ef-fects of spironolactones on: primaryaldosteronism, congestive heart fail-ure, nephrosis, hepatic failure, and hy-pertension. The eminent editor, Pro-fessor Bartter, described the purposeof the meeting as “pooling of clinicalresults” because of limitations bothof drug supply and patient material.24
By 1960, it became clear that spirono-lactone was a novel diuretic with ad-ditional antihypertensive effects.25
While Searle was pursuing the exploita-tion of the spironolactones, the Cibascientists were also synthesizing manyanalogs of aldosterone, but for use as an agonist with potential utility inAddison’s disease and postoperativeshock. In 1958, Desaulles, working atthe Ciba Laboratories, provisionallyidentified an endogenously producedantagonist of aldosterone, which hetermed sodium excretion factor.26
Unfortunately, other investigators couldnot confirm these findings. It is note-worthy that no attempt was made bythe aldosterone research group toidentify aldosterone antagonists. Thisis somewhat surprising in that FranzGross was carrying out experimentalcanine studies to examine the actionof electrocortin in adrenalectomizeddogs, a preparation his group had beenusing for the previous 10 years. It isperhaps ironical that Professor Liddle,who had been so deeply involved inaldosterone research, published anappreciation of Gross’s work in 1978,27
in which he recollected that in a paperin 1958 entitled “Renin und Hyper-tensin, physiologische und pathololo-gische Wirkstoffe?” he proposed thehypothesis that the renin-angiotensinsystem stimulated aldosterone secre-tion, and was in turn suppressed by
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SC-5233 is 3-(3-keto-17β-hydroxy-4-androsten-17α-yl)-propionic acid-γ-lactone
SC-8109 is 3-(3-keto-17β-hydroxy-19-nor-4-androsten-17α-yl)-propionic acid-γ-lactone
SC-9420 is 3-(3-keto-7α-acetylthio-17β-hydroxy-4-androsten-17α-yl)-propionic acid-γ-lactone (Aldactone, spironolactone)
CH3
C O
O
C C O
C O
O
C C O
C O
O
S CO
C C O
Figure 5. The relative potencies of three spironolactones in a single system (reversal ofurinary Na/K ratio in adrenalectomized rats receiving desoxycorticosterone acetate) are as follows:
the sodium-retaining action of aldo-sterone (Figure 6).28 Thus, given theconsiderable biological expertise pres-ent at Ciba, it remains a mystery as towhy no attempt was made to find analdosterone antagonist.
Spironolactone was marketed in theearly 1960s for the indications listed inTable II. Initially, the therapeutic em-phasis was on its diuretic activity, and,subsequently, as second-line therapyin essential hypertension.29 The rec-ommended daily dose for treating hy-pertension was 100 to 300 mg daily.The optimal hypotensive effect is ob-served after about 2 weeks’ dosing. In the context of serendipity, pharma-cokinetic studies subsequently foundthat spironolactone is metabolized inthe liver to three metabolites, two ofwhich have equal antialdosterone ac-tivity to the parent compound, eachhaving a terminal plasma half-life of 13to 15 hours compared with the parentcompound, which has a half-life of 2hours. Thus, spironolactone is basicallya prodrug.30
While spironolactone has useful clini-cal effects, it has significant tolerabil-ity problems due to painful gyneco-mastia and menstrual disturbances inpremenopausal women. These sideeffects are attributed to its androgenicand progesteronergic properties. Forthese reasons, spironolactone was notused in trials of the effects of antihy-pertensive therapy on morbidity andmortality in the 1980s.
Given the affinity of spironolactoneand its metabolites, not only for themineralocorticoid receptor, but alsofor the reproductive hormonal recep-tors, there was clearly a need to iden-tify a compound with significantlygreater receptor selectivity and conse-quently improved patient tolerability.Thus, new chemical analogs were iden-tified in a revived program at CibaGeigy in the late 1970s, stimulated bythe then Research Director Dr Heini
Keberle and led by Dr Kalvoda, whoapplied novel molecular modelingtechniques to the problem (personalcommunication). Advances in the mo-lecular biology of steroid receptorspermitted chemical analogs to be test-ed for selective receptor binding prop-erties. Several hundred steroid analogswere tested for their competitive affini-ties for mineralocorticoid, androgen,and progesterone receptors. The intro-duction of 9α, 11α epoxy groups into
the spironolactone molecule resultedin the discovery of more potent andhighly selective aldosterone antago-nists, of which epoxymerenone (CGP-30083) proved to be the optimal com-pound. This compound, now calledeplerenone, was patented between1983/84 (US patent number 4559,332)and subsequently taken into clinicaltrials.31
Due to an assessment of the costs ofpreclinical and clinical developmentin relation to the probable financialreturn, the compound was not devel-oped by Ciba Geigy but licensed to,ironically, the Searle company. As aresult of these delays the compound,which was shown to be effective forthe treatment of hypertension andcongestive heart failure (1994-2002),was finally registered in the UnitedStates approximately 18 years after itschemical synthesis. Extensive clinical
trials have confirmed that the improvedspecificity of eplerenone is reflectedin the absence of gynecomastia andmenstrual disturbances.32
DISCUSSION
The evolution of our understanding ofthe role of aldosterone in the patho-physiology of cardiovascular diseaseover the past 50 years is an excellentexample of the pivotal role of transla-tional medicine in finding improvedmedicines. The academic/industrialcollaboration between the Taits, Reich-stein, and the Ciba steroid chemistsmade aldosterone available for physio-logical studies. No doubt other groupswould eventually have characterizedand synthesized aldosterone. It wasthe Searle biologists Sturtevant andKagawa who had the imaginative interest to examine the abandonedspironolactone compounds in theirnovel adrenalectomized and DOCArat models.15 The simultaneous col-laboration with the clinical scientistLiddle in Nashville must have been adecisive factor in finally identifyingspironolactone (aldactone) as the pre-ferred compound among five analogsby studying them in human subjects.19
Presumably, the eminent ResearchDirector in Searle, Professor Victor Drill,had a major influence in the decisionto pursue these compounds. This issomething that would be impossiblein today’s strict ethical and regulatoryenvironment, although the Food andDrug Administration (FDA) is now try-ing to encourage companies to carryout early proof-of-concept clinical trials.
For the next 30 years, spironolactonewas regarded as a moderately usefulagent among the enlarging pool ofother cardiovascular agents such asdiuretics, angiotensin-converting en-zyme inhibitors, and β-blockers fortreating both hypertension and conges-tive heart failure. It was the realizationin the 1980s that aldosterone had arange of extrarenal receptors and ac-
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• Primary hyperaldosteronism
– Diagnostic
– Preoperative management
– Maintenance for inoperable
patients
• Edematous syndromes
– Congestive heart failure
– Cirrhosis of the liver
– Nephrotic syndrome
• Essential hypertension
• Selected hypokalemic states
Table II. Therapeutic indications for spirono-lactone.
tions, especially on the heart andblood vessels, that renewed interestin the field of aldosterone antagonists.Mineralocorticoid receptors are pres-ent not only in the kidney, but also thebrain, blood vessels, cardiac tissue, aswell as salivary and sweat glands. It is probable that aldosterone acts as a paracrine hormone as well as a sys-temic one in some of these tissues.Experimental studies in rats show thatsustained exposure to aldosteronecauses ventricular hypertrophy andmyocardial fibrosis independent ofeffects on blood pressure.33 These effects can be prevented either byspironolactone or eplerenone admin-istration. Clinical studies reveal thatelevated plasma aldosterone levels in-crease both vasculopathy and cardiacdysfunction.34
This new paradigm concerning thesystemic pathophysiological role ofaldosterone led to the evaluation ofaldosterone antagonists for their ther-apeutic effects on morbidity and mor-tality in patients with congestive heartfailure. Pitt et al,35 in a groundbreak-ing trial, showed that adding spirono-lactone (25 mg daily) to standardtherapy for congestive heart failurereduced morbidity and mortality by30% in patients with New York HeartAssociation (NYHA) class III/IV. Ananalogous study with eplerenone (25to 50 mg daily) in patients with con-gestive heart failure resulted in a sig-nificant reduction in all-cause and car-diovascular mortality.36 Clearly, thereis much yet to be learned about thetherapeutic potential of specific al-dosterone antagonists, even 50 yearsafter their introduction into clinicalresearch.
We would like to thank Dr Kalvoda, Dr Keberle,and Dr Scholer, as well as Drs Wyler and
Schilling (Roche AG) for invaluable discussionsand advice in the preparation of this paper.
REFERENCES
1. Fitzgerald JD.
The importance of chance and the preparedmind in the discovery of β-blockers.
Dialogues Cardiovasc Med. 2000;5:172-176.
2. Fitzgerald JD.
Penicillin for cholesterol: the bumpy ride ofthe discovery and development of HMG-CoAreductase inhibitors or statins.
Dialogues Cardiovasc Med. 2006;11:307-314.
3. Kuizinga MH, Cartland GF.
Fractionation studies of adrenal corticalextract with notes on the distribution ofbiological activity amongst the crystallineand amorphous fractions.
Endocrinology. 1939;24:526-535.
4. Bush IE.
Species differences in adrenocorticalsecretion.
J Endocrinol. 1953;9:95-101.
5. Tait SAS, Tait JF.
Personal history: the correspondence of S. A. S. Simpson and J. F. Tait with T. Reichstein during their collaborative workon the isolation and elucidation of a struc-ture of electrocortin (later aldosterone).
Steroids. 1998;63:440-453.
6. Tait JF, Simpson SAS, Grundy H.
The effect of adrenal extract on mineralmetabolism.
Lancet. 1952;1:122-129.
7. Grundy HM, Simpson SA, Tait JF.
Isolation of a highly active mineralocorticoidfrom beef adrenal extract.
Nature. 1952;169:795-796.
8. Heusler K, Kalvoda J.
Between basic and applied research: Ciba’sinvolvement in steroids in the 1950s and 60s.
Steroids. 1996;61:492-503.
9. Simpson SA, Tait JF, Wettstein A,et al.
Konstitution des Aldosterons, des neuenMineralocorticoids.
Experientia. 1954;10:132-133.
10. Simpson SA, Tait JF, Wettstein A,Neher R, von Euw J, Reichstein T.
Isolierung eines neuen KristallisiertenHormones aus Nebennieren mit Besondershoher Wirksamkeit auf dem Mineral-stoffwechsel.
Experientia. 1953;9:333-335.
11. Schmidlin J, Anner G, Billeter JR,Wettstein A.
Über Synthesen in der Aldosteron-Reihe.
Experientia. 1955;40:365-368.
12. Neher R, Desaulles P, Vischer E,Wieland P, Wettstein A.
Isolierung, Konstitution und Synthese einesneuen Steroids aus Nebennieren. ÜberSteroide, 155, Mitteilung.
Sustained hypertension following the admin-istration of desoxycorticosterone acetate.
J Exp Med. 1951;93:361.
15. Sturtevant FM.
A lesson to be gained from basic researchprogrammes.
Current Contents. 1992;9.
16. Kagawa CM, Sturtevant FM, vanArman CG.
Pharmacology of a new steroid that blockssalt activity of aldosterone and desoxy-corticosterone.
J Pharmacol Exp Ther. 1959;126:123-130.
17. Liddle GW.
Sodium diuresis induced by steroidal antag-onists of aldosterone.
Science. 1957;126:1016-1018.
18. Liddle GW, Cornfield J, CasperGT, Bartter FC.
The physiological basis for a method ofassaying aldosterone in extracts of humanurine.
J Clin Invest. 1955;34:1410-1416.
124
Dialogues in Cardiovascular Medicine - Vol 14 . No. 2 . 2009
Aldosterone antagonists: a model of translational medicine - Fitzgerald and Fitzgerald
19. Liddle GW.
Aldosterone antagonists.
Arch Intern Med. 1958;102:998-1004.
20. Sturtevant FM.
Antihypertensive effects of an aldosteroneantagonist.
Science. 1958;127:1393-1394.
21. Bolte E, Verdy M, Marc-Aurle J,et al.
Studies on new diuretic compounds: spiro-lactone and chlorothiazide.
CMAJ. 1958;79:881-888.
22. Cranston WI, Juel-Jensen BE.
The effects of spironolactone and chlorthali-done on arterial pressure.
Lancet. 1962;1:161-164.
23. Slater JDH, Nabarro JDN.
Clinical and metabolic effects of aldosteroneantagonism.
Lancet. 1959;2:931-934.
24. Bartter FC.
The Clinical Use of Aldosterone Antagonists.
Springfield, Ill: Charles C Thomas. 1960.
25. Grieble HG, Johnston LC.
Treatment of arterial hypertensive diseasewith diuretics I: effects on blood pressure ofbendroflumethiazide, potassium chlorideand spironolactone.
Arch Intern Med. 1962;110:26-33.
26. Desaulles PA.
Preliminary note on certain pharmacologicalproperties of 3β, 16α-dihydroxy-allopregnan-20-on.
Experientia. 1959;15:301-303.
27. Liddle GW.
An appreciation of Professor Franz Gross on the twentieth anniversary of the publica-tion of his concept of the interrelationshipsbetween aldosterone and renin.
Klin Wochenschr. 1978;56(suppl 1):3-4.
28. Gross F.
Renin und Hypertensin: physiologische oderpathologische Wirkstoffe?
Klin Wochenschr. 1958;36:693-706.
29. Copthee WS, Liddle GW.
Mode of action and clinical usefulness ofaldosterone antagonists.
Ann N Y Acad Sci. 1960;88:815-821.
30. Averdiek WPM, Hermens AJ,Merkus HM.
New insights into the pharmacokinetics ofspironolactone.
Clin Pharmacol Ther. 1985;38:469-474.
31. de Gasparo M, Joss U, RamjouleHP, et al.
Three new epoxy-spirolactone derivatives:characterisation in vivo and in vitro.
in New Zealand: a discussion documentR. Jackson and others. BMJ. 1993
9Multiple risk factor interventions for
primary prevention of coronary heart diseaseS. Ebrahim and others. Cochrane Database
of Systematic Reviews. 2006
Prevention of cardiovascular disease. Guidelines for assessment and
management of cardiovascular riskWHO. WHO Library. 2007
10
Exercise-based rehabilitation for patients withcoronary heart disease: systematic review andmeta-analysis of randomized controlled trials
R. S. Taylor and others. Am J Med. 2004
7
5
An updated coronary risk profile. A statement for health professionalsK. Anderson and others. Circulation. 1991
3
Selection of seminal papers by David A. Wood, MSc, FRCPE, FFPHM,FESC; Kornelia Kotseva, MD, PhD, FESC, Cardiovascular MedicineNational Heart and Lung Institute (NHLI) - Imperial College London Charing Cross Campus - Fulham Palace Road, London W6 8RF - UK
Highlights of the years by Ian Mudway, MDLung Biology - Division of Life Sciences
Franklin Williams Building 150 Stamford Street - London SE1 9NN - UK
www.dialogues-cvm.org
Prevention of coronary heart disease in clinical practice. Recommendations of the Task
Force of the European Society of Cardiology, European Atherosclerosis Society
and European Society of HypertensionK. Pyörälä and others. Eur Heart J. 1994
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ose coins the term “the prevention paradox”in this paper based on his Adolf Streichermemorial lecture in 1980; defined as “a mea-sure that brings large benefits to the communi-ty offers little to each participating individual.”
He juxtaposes the “mass” and “high-risk” strategies forcardiovascular prevention. The mass approach is based onthe principle of shifting the whole distribution of a riskfactor in the population, eg, reducing blood pressure byreducing population salt consumption, as compared witha “high-risk” strategy that identifies those individuals withvery high blood pressure and advises them individually toreduce their salt intake and take drug therapies. Althoughthese individuals are at very high risk of cardiovasculardisease (CVD), there are relatively few of them at the topend of the distribution of blood pressure. So however suc-cessful this individualized strategy may be for those beingtargeted, it cannot impact on the larger proportion ofdeaths occurring among the many people with slightlyraised blood pressure. Although their CVD risk is onlymodestly increased, there are many more of them and sotheir relative contribution to the total burden of CVD ismuch greater. So hypertension clinics only offer a limitedanswer to the wider population who will develop CVD.Therefore, Rose argues that a mass strategy is inherentlythe only answer to the problem of a mass disease. In thiscase: reduce the exposure of the whole population to thedeterminants of raised blood pressure rather than targetingonly those individuals who have very high blood pressure.However, from the individual’s perspective the mass strate-gy offers little: some more than others and some not at all,whereas the high-risk strategy will definitely benefit thosespecific individuals to the extent that they comply withthe advice and treatment. This is the medical approach—doctors identifying individuals at high risk and managingthem accordingly. The mass approach is political.
R
The Centers for Disease Control and Prevention report that 5 homosexual men
from Los Angeles have a rare form of pneumoniaassociated with a weakened immune system:
the first recognized cases of AIDS;the Israeli Air Force destroys Iraq’s Osirak
nuclear reactor; and 800 passengers are killedwhen seven coaches of an overcrowded train fall off
the tracks into the River Kosi in Bihar, India
1981
The strategy of prevention: lessons from cardiovascular disease
G. Rose
Br Med J (Clin Res Ed). 1981;282:1847-1851
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n this classic paper, Rose reflects on the etiologyand prevention of disease as a clinician concernedwith sick individuals, and as an epidemiologist con-cerned with sick populations. He was throughout hisprofessional life both a physician and an epidemi-
ologist. Here Rose compares two approaches to preventionof cardiovascular disease: the “high-risk” strategy, whichseeks to identify high-risk individuals and offer them indi-vidual protection; and the “population strategy,” whichseeks to control the determinants of disease incidence inthe whole population.
The high-risk strategy is the traditional medical approachto prevention and has several advantages. The interventionis appropriate to the individual. Individuals will be moti-vated to do something about their increased risk and sowill physicians. It is a cost-effective use of resources, andthe benefit-to-risk ratio is favorable. However, this approachhas a number of disadvantages. It involves screening toidentify those at high risk. It does not address the under-lying causes of the disease in the population, but onlyidentifies those individuals who are susceptible to suchcauses, and, however effective our individual care is, theywill always be replaced by more and more of the same. Thepotential for this approach is limited because predictingthose individuals who are going to develop the disease isvery uncertain, at least in the short term. It is also limitedbecause a large number of people at a small risk may giverise to more cases of disease than the small number whoare at high risk. Finally, it requires an individual to changetheir behavior (eg, to give up smoking), which may runcounter to the behavioral norms for that population, andthus more difficult for the individual to achieve.
The population strategy, in attempting to control the determinants of disease incidence, has several powerful advantages. First, it is radical because it aims to remove theunderlying causes that make the disease common. It alsohas a much larger potential, compared with the high-riskstrategy, to prevent disease in the population as a whole.Finally, it shapes the norms of behavior for the population(eg, a smoking ban in all public places) and so it is much
easier for the smoking individual to quit. However, thisapproach also has its disadvantages of which the mostimportant is that a preventive measure that brings muchbenefit to the population offers little to each participatingindividual—which Rose termed the “prevention paradox.”
Although these two approaches are complementary, thepopulation strategy is paramount. Managing high-risk individuals is a temporary expedient.
I
British telecom announces it is phasing out its emblematic red telephone booths;
Coca-Cola releases “New Coke”: the new drink is a failure and the original formula is back
on the market after only 3 months; and US Route 66, established on November 11,
1926, dubbed “Main Street of America,” is decommissioned
1985
Sick individuals and sick populations
G. Rose
Int J Epidemiol. 1985;14:32-38
he Framingham epidemiological study, whichstarted in 1948, followed up a cohort of healthywhite Americans who were free of cardiovascu-lar disease (CVD), and related their lifestyles,physiology, and biochemistry to subsequent
development of CVD. These pioneering investigators coinedthe term “risk factor” to describe those personal character-istics—smoking habits, blood pressure, cholesterol, dia-betes—that were shown in this prospective cohort studyto be independently related to the risk of developing CVD.
Twenty-nine years later, Truett published a coronary heartdisease (CHD) risk equation for use by clinicians basedon a multivariate analysis of CHD. In addition to age andsex, risk factors included systolic blood pressure, serumcholesterol, cigarette smoking, glucose intolerance, andleft ventricular hypertrophy on the electrocardiogram. CHDrisk tables in the form of a handbook, based on Framinghamequations, were published in 1973, and this was followedby an even simpler version of the equations on a pocket-sized card. Yet, although the Framingham study becamefamous for being the first to define the causes of CVD,which led to risk factor intervention trials to reduce risk, theCHD risk tables did not engage the interest of physicians.Blood pressure was assessed and treated by physicians inisolation as a disease called “hypertension” rather than seenas one component of the total CVD risk of an individual.
This seminal paper by Anderson provided an update onthe equations, which informed the development of theCHD risk chart in the Joint European Societies recommen-dations on prevention of CHD published in 1994, as wellas many other versions of risk estimation around the world.What distinguished Anderson’s updated coronary risk pro-file from previous versions? First, the baseline examinationwas a larger and more recent examination from this study(1968-75) and included members of the original Framinghamcohort who were free of CVD and the second-generationstudy population, the Framingham Offspring Cohort. Sec-ond, the contribution of high-density lipoprotein (HDL)cholesterol, which was measured for the first time in theFramingham study in 1968, was included. The new equations
were used to derive a worksheet for clinicians to estimateCHD risk of patients by assigning a point score to eachrisk factor, eg, cigarette smoking scored 4 points, diabetesin women 6 points, and left ventricular hypertrophy onthe ECG 9 points. By adding up these points you couldrelate this score to the probability (%) of developing CHDover 5 or 10 years. The authors also provided a table tocompare the estimated risk for a given patient’s age andsex to the average 10-year risk for the Framingham popula-tion. Anderson et al suggested that estimating CHD riskcould be useful in projecting patient progress in clinic atwhich preventive cardiology is the goal, such as managingblood pressure and lipids.
Risk scores can provide a framework for intervention. Theydid so for the first time in an official guideline in 1993 whenJackson recommended managing blood pressure in thecontext of absolute CVD risk.
130
Edith Cresson is appointed France’s first female prime minister by President FrançoisMitterrand, but her unpopularity compels her
to leave office after less than one year;Queen Elizabeth II addresses the US Congress,
the first British monarch to do so; and Prince Norodom Sihanouk returns to Phnom
Penh, Cambodia, after 13 years of exile, becomingking two years later. The Guinness Book of World
Records identifies him as the politician having served the world’s greatest
variety of political offices since 1941
1991
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An updated coronary risk profile. A statement for health professionals
K. Anderson, P. W. Wilson, P. M. Odell, W. B. Kannel
Circulation. 1991;83:356-362
T
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ackson and colleagues’ seminal paper on the man-agement of raised blood pressure represented aparadigm shift in thinking about the concept of“hypertension” and its treatment. In the 1950s,the first drugs for lowering blood pressure were
used to treat malignant hypertension, often symptomatic,with very high blood pressure levels, and usually fatal ifleft untreated. Subsequently, randomized controlled trialsshowed that treating less extreme cases of raised bloodpressure reduced the risk of cardiovascular disease (CVD)—initially stroke and then coronary disease and renal disease.As a consequence, the level for initiating antihypertensivedrug treatment was progressively lowered. However, bloodpressure is a risk factor for CVD, not a disease in itself. As theblood pressure rises, so does risk of CVD, and so the defi-nition of high blood pressure is arbitrary. Yet, in the early1990s, guidelines for the management of blood pressurebased all decisions to treat on the blood pressure level alone.
Jackson et al asked the question, when is the risk of CVDsufficiently high, in someone with raised blood pressure, tojustify drug treatment? In other words, they put the manage-ment of blood pressure in the context of total CVD risk. Heillustrated this principal with a simple clinical example. A60-year-old woman with a diastolic pressure of 100 mm Hg,but no other risk factors, has an absolute risk of develop-ing CVD of about 10% over 10 years, but would be eligiblefor antihypertensive drug therapy. In contrast, a man of 70 years with multiple risk factors for CVD, but a diastolicblood pressure of 95 mm Hg, which would give him an ab-solute risk of say 50% over 10 years, may not receive drugtherapy. So he proposed that estimation of absolute riskof developing CVD, based on an assessment of all risk fac-tors, is a prerequisite to a decision about treating bloodpressure with drugs.
Jackson et al recommended that people with an absoluterisk of 20% or more in 10 years, and a sustained blood pres-sure of greater than 150 mm Hg systolic or 90 mm Hg dias-tolic (phase 5), should be considered for treatment to lowerblood pressure. To calculate absolute CVD risk, they useddata from the Framingham epidemiological study and ex-
pressed this as a figure relating different levels of bloodpressure to numbers of risk factors (one, two, three, ormajor) for men and women at different ages from 40 to 70years. He defined risk factors as cigarette smoking, diabetes,a ratio of cholesterol to high-density lipoprotein of >6:1, a body mass index of >30 kg/m2, and a family history ofpremature CVD (in a parent or sibling before the age of 55years). A major risk factor was principally defined as thediagnosis of symptomatic CVD. The authors qualified thisrecommendation on absolute risk by acknowledging thatyounger people in their 20s or 30s with blood pressuresgreater than 150 mm Hg systolic or 90 mm Hg diastolicmay require blood pressure treatment even though theyare at low absolute risk. Similarly, people between theages of 40 and 60 years with blood pressure levels above170 mm Hg systolic or 100 mm Hg diastolic may also bene-fit from blood pressure–lowering even when their absoluterisk of CVD is less than 20%.
This recommendation to view blood pressure managementin the context of absolute CVD risk challenged the tradi-tional view of “hypertension” and its management and wasfollowed by a succession of risk charts starting with the JointEuropean Societies’ CHD Risk Chart in 1994 and then theNew Zealand Cardiovascular Risk Chart the following year.The principle of total CVD risk being the overriding deter-minant of whether or not to treat blood pressure in thecontext of primary prevention is now universally acceptedby all international guidelines on CVD prevention.
J
Poet and playwright, and former dissident VáclavHavel is elected President of the Czech Republic;
Spanish road racing cyclist Miguel Indurain wins his third Tour de France, which he was
to win five times, five years in a row; and the public is allowed inside the State Rooms
of Buckingham Palace for the first time
1993
Management of raised blood pressure in New Zealand: a discussion document
R. Jackson, P. Barham, J. Bills, T. Birch, L. McLennan, S. MacMahon, T. Maling
BMJ. 1993;307:107-111
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n 1992, Kalevi Pyörälä, Professor of Medicine at theUniversity of Kuopio, brought together the EuropeanSociety of Cardiology, European AtherosclerosisSociety, and European Society of Hypertension in aunique partnership to create a common European
agenda for prevention of coronary heart disease (CHD).The recommendations of these three Societies for clinicalpractice were announced at the World Congress of Cardi-ology in Berlin in 1994. Central to this guidance was theconcept of risk: “For a proper assessment of CHD risk inan individual, the presence or absence and the degree ofseverity of each individual risk factor has to be considered.”Up to this point, risk factor guidelines addressed singlerisk factors, eg, management of “hypertension” or “hyper-lipidemia,” resulting in undue emphasis being placed onindividual risk factors rather than total CHD risk. A newCoronary Risk Chart was the centerpiece of these recom-mendations, based on a risk function derived from Fram-ingham. Using this chart, clinicians could estimate theprobability of their patients developing CHD over 10 years,based on age, sex, smoking habit, systolic blood pressure,and total cholesterol. A CHD risk of 20% or higher was asignal for intensive risk factor modification, including theuse of drugs, if appropriate. The chart was published inblack and white to facilitate dissemination throughout Eu-rope, and a full color version was distributed at the WorldCongress. This European risk chart was the first of its kindand was followed by the New Zealand Cardiovascular RiskChart, and other variations on the central theme of target-ing those patients at highest multifactorial risk; the higherthe total risk the more intensive the intervention. Thisunique European partnership between these three majorSocieties broke the silo mentality of treating single riskfactors in isolation. This first Task Force laid the foundationson which three subsequent Task Forces on cardiovasculardisease prevention in 1998, 2003, and 2007 were able toenlarge this European collaboration of professional Soci-eties and produce updated guidelines for evidence-basedpreventive cardiology practice founded on the centralprincipal of total risk assessment and management.
Prevention of coronary heart disease in clinical practice.Recommendations of the Task Force of the European Society of Cardiology, European Atherosclerosis Society and EuropeanSociety of Hypertension
K. Pyörälä, G. De Backer, I. Graham, P. A. Poole-Wilson, D. Wood
Eur Heart J. 1994;15:1300-1331
I
The Zapatista Army of National Liberation begins its war in Chiapas, Mexico;
the Church of England ordains its first female priests; and Nature reports the finding of the first complete
Australopithecus afarensis skull in Ethiopia
1994
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he Joint European Societies’ recommendationson coronary heart disease (CHD) preventionin 1994 broke the mould of single risk factormanagement by advocating total CHD risk estimation as the prerequisite to deciding to
treat blood pressure or lipids. The CHD risk charts werebased on the Anderson Framingham equation, with thecaveat that this epidemiological study may underestimateCHD risk in very-high-risk European populations, such ascountries in Eastern Europe, and underestimate risk in low-risk populations of southern Europe.
A European epidemiological database was needed and thiswas the birth of the SCORE (Systematic COronary RiskEvaluation) project. Graham and colleagues pooled data-sets from 12 European prospective cohort studies—205 178persons (117 098 men and 88 080 women) with 2.7 millionyears of follow-up and 7934 cardiovascular deaths, of which5652 were deaths due to coronary heart disease—com-pared with just […] individuals in the Framingham study.Ten-year risk of fatal cardiovascular disease was calculatedusing a Weibull model in which age was used as a mea-sure of exposure to risk (time) rather than as a risk factor.Equations were calculated for high-risk and low-risk regionsof Europe, and for each of these regions you can eithercalculate cardiovascular disease (CVD) risk using totalcholesterol or the ratio of total cholesterol/high-densitylipoprotein (HDL) cholesterol. The risk threshold for inter-vention was defined as a total CVD risk of 5% or higher forfatal cardiovascular disease over 10 years.
T
The final signal is received from NASA’s Pioneer 10space probe 7.5 billion miles from Earth;
an American businessman is admitted to theVietnam France Hospital in Hanoi with
the first diagnosed case of SARS;and the Human Genome Project is completed,
with 99% of the genome sequenced
2003
Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project
R. M. Conroy, K. Pyörälä, A. P. Fitzgerald, S. Sans, A. Menotti, G. De Backer, D. De Backer, P. Ducimetière, P. Jousilahti, U. Keil, et al; SCORE Project Group
Eur Heart J. 2003;24:987-1003
vidence for cardiac rehabilitation was first sum-marized by Oldridge who reported in 1988 thatpatients receiving exercise therapy had fewercardiac deaths and longer survival comparedwith those with usual medical care. Subsequent
updates of this original meta-analysis, three in total, andfurther trials, found the same result: reductions in totaland coronary mortality ranging from 20% to 32%, but noreduction in the risk of recurrent myocardial infarction orrevascularization.
Taylor and colleagues’ paper updated the systematic reviewof exercise-based cardiac rehabilitation and meta-analysisand addressed previous concerns regarding applicabilityof this evidence to routine clinical practice. Previous meta-analyses had not reported outcomes of secondary preven-tion through risk factor modification and the impact ofmodern cardioprotective drug therapies on the magnitudeof benefit of exercise-based cardiac rehabilitation. A totalof 48 randomized controlled trials were included with a to-tal of 8940 patients with coronary artery disease. Of these,19 trials were exercise only, 30 were comprehensive cardiacrehabilitation (in combination with psychosocial or educa-tional interventions), and 1 trial directly compared exercisewith a comprehensive approach. Overall cardiac rehabilita-tion was associated with a significant reduction in all-causemortality (odds ratio [OR], 0.80; 95% confidence interval(CI), 0.68 to 0.93), and total cardiac mortality (OR, 0.74; 95%CI, 0.61 to 0.96), and trials conducted in the last decade(with increasing use of revascularization and cardioprotec-tive drug therapies) continued to show benefits of cardiacrehabilitation. However, there were no differences in ratesof nonfatal myocardial infarction, coronary artery bypassgrafting (CABG), or percutaneous coronary intervention(PCI) with cardiac rehabilitation.
For risk factor management, the proportion of patients whowere smoking was reduced significantly with cardiac reha-bilitation (OR, 0.64; 95% CI, 0.50 to 0.83). However, otherrisk factor changes were more modest. Systolic blood pres-sure was significantly reduced, but only by 3.2 mm Hg(95% CI, –5.4 to –0.9 mm Hg), and there was no reduction
in diastolic pressure. Total cholesterol was only reduced by–0.37 mmol/L (95% CI, –0.63 to –0.11 mmol/L) with no sig-nificant difference in low-density lipoprotein (LDL) levels.These modest reductions suggest that drug treatments werenot being effectively used in these programs. So, apart fromsmoking, these cardiac rehabilitation programs did notimpact on risk factor management to the extent now possi-ble with a combination of a lifestyle intervention, focusingon both diet and physical activity, and using modern drugtherapies to lower blood pressure and modify blood lipids.Diabetes, which is an important risk factor for coronaryartery disease, was not addressed in this meta-analysis.
Interestingly, Taylor et al tested several a priori hypotheseson the effect of cardiac rehabilitation on total mortalityacross particular subgroups: type of cardiac rehabilitation(exercise only versus comprehensive cardiac rehabilitation);dose of exercise intervention (based on a composite mea-sure of duration of exercise, plus intensity, frequency, andlength of exercise sessions); and program duration. Therewas no difference in outcome, expressed as total mortality,between exercise-only versus comprehensive cardiac reha-bilitation. Nor was there any difference by exercise dose(which is surprising) or duration of the programs. The latterfinding is in contrast to the first review by Oldridge whoreported a greater reduction in all-cause death, with reha-bilitation trials with follow-up lasting more than 36 months.
So, do we only need to offer our coronary patients an exer-cise program of light intensity and short duration? The an-swer is unequivocally no. These results are hypothesis-gen-erating and need to be rigorously evaluated in randomizedcontrolled trials assessing clinical and cost-effectiveness.
E
Arsenal FC remains undefeated for a whole seasonto win the Premiership title; the last Oldsmobilerolls off the assembly line; and Canada wins the
World Ice Hockey Championship in Prague
2004
Exercise-based rehabilitation for patients with coronary heart disease: systematic review and meta-analysis of randomized controlled trials
R. S. Taylor, A. Brown, S. Ebrahim, J. Jolliffe, H. Noorani, K. Rees, B. Skidmore, J. A. Stone, D. R. Thompson, N. Oldridge
Am J Med. 2004;116:682-692
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lark et al, in this meta-analysis, aimed to de-termine the effectiveness of secondary preven-tion programs, with and without exercise, inpatients with coronary artery disease. Sixty-three randomized controlled trials were identi-
fied, including 26 trials that were not included in a system-atic review of cardiac rehabilitation (see Taylor RS et al,Am J Med. 2004;116:682-692), and this meta-analysis isbased on 21 295 patients. The risk ratio for all 40 trials reporting all-cause mortality was 0.85 (95% confidence in-terval [CI], 0.77 to 0.94), and this result differed over time:0.97 (95% CI, 0.82 to 1.14) at 12 months and 0.53 (95% CI,0.35 to 0.81) at 24 months. In those trials reporting follow-up at least 5 years after initiation of the program the ben-efit was clearly sustained with a risk ratio of 0.77 (95% CI0.63 to 0.93). There was no heterogeneity in treatment effectbetween the three types of secondary prevention programsincluded, namely, programs without exercise, programs withexercise, and exercise-only programs. The risk ratio for all-cause mortality in all exercise-based programs (27 trialsand 6940 patients) was 0.83 (95% CI, 0.72 to 0.96) comparedwith a risk ratio of 0.87 (95% CI, 0.76 to 0.99) for the nonex-ercise-based programs (14 trials and 9202 patients). The riskratio for recurrent myocardial infarction was 0.83 (95% CI,0.74 to 0.94) over a median follow-up of 12 months, and thisoutcome did not differ between the three types of programs.These beneficial results should not be viewed as “best casescenario,” as trial participants assigned to control groupsalso received better than usual care, and therefore the im-pact on all-cause mortality and recurrent myocardial infarc-tion is likely to be even greater in everyday clinical practice.
Despite these impressive benefits, other studies consis-tently demonstrate that fewer than 50% of patients withcoronary artery disease access prevention and rehabilitationprograms. In addition, those groups less likely to be re-ferred, to attend, and to complete such programs are oftenthose in greatest need, such as women, the elderly, low-in-come groups, and ethnic minorities. The clinical challengeis to increase access to, and participation in, comprehen-sive prevention and rehabilitation programs for all patientswith atherosclerotic disease.
C
In Bucharest, Romania, Adriana Iliescu gives birth at 66, becoming the oldest woman
in the world to do so;Prince Charles weds Camilla Parker Bowles,
who assumes the titles of Her Royal Highness and Duchess of Cornwall;
and on December 31st, another second is added, 23:59:60, called a leap second,
to end the year 2005: the last time this occurred was on June 30, 1998
2005
Meta-analysis: secondary prevention programs for patients with coronary artery disease
A. M. Clark, L. Hartling, B. Vandermeer, F. A. McAlister
Ann Intern Med. 2005;143:659-672
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vidence from single risk factor interventions suchas lowering blood pressure, or lowering choles-terol, is impressive. So when you intervene on allcardiovascular risk factors at the same time—stopping smoking and reducing blood pressure
and cholesterol—you would expect the combined effect tobe impressive. In this systematic review from the CochraneCollaboration the evidence from randomized controlledtrials of multiple risk factor interventions in primary pre-vention of cardiovascular disease (CVD) is summarized withsurprising results.
Interventions used counseling and/or educational ap-proaches with or without pharmacological interventions inrelation to smoking cessation, reducing blood pressure, andcholesterol. Thirty-nine trials meeting the selection crite-ria were analyzed and 10 of these reported clinical events.The pooled odds ratios for total and coronary heart dis-ease (CHD) mortality were 0.96 (95% confidence interval[CI], 0.89 to 1.04) and 0.96 (95% CI, 0.92 to 1.01), respective-ly. So multiple risk factor interventions have very limited,if any, impact on mortality. However, the authors qualifythis statement by pointing out that a small (about a 10%reduction in coronary mortality), but potentially importantbenefit of treatment may have been missed. Importantly,in the 38 trials reporting risk factor changes, the odds of areduction in risk factor prevalence were 20% (95% CI, 8%to 31%), which is an important health benefit. In contrast,the mean difference in systolic blood pressure between in-tervention and control was only –3.6 mm Hg, and the reduc-tion in cholesterol only –0.07 mmol/L, which, althoughstatistically significant, is very modest. Indeed these dif-ferences may be overestimates of the treatment effect, be-cause they are based on those who stayed in the trials. Moreintensive lifestyle intervention, and the appropriate use ofdrug therapies, would produce larger differences in risk fac-tor control, which would be expected to further reduce CVD.
What this review highlights is the apparent discrepancybetween the unequivocal benefit of single risk factor trials,eg, to lower blood pressure, and those observed in multi-ple risk factor trials.
Multiple risk factor interventions for primary prevention of coronary heart disease
Grigori Perelman is awarded the Fields Medal for proving the Poincaré conjecture,
one of seven Millennium Prize Problems;Slobodan Milosevic is found dead in his cell
at the UN war crimes tribunal’s detention center; and Basque terrorist organization ETA declares
a permanent cease-fire in their campaign for Basque independence from Spain
2006
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oncommunicable diseases, of which halfare due to cardiovascular disease (CVD), arepredicted to increase substantially over the coming years, and much of this diseaseburden will fall on low- and middle-income
countries. This World Health Organization (WHO) reportdeparted from the traditional view of CVD prevention by thisorganization in moving the focus from single risk factorsto total risk assessment and management. In contrast tothe 2003 WHO/International Society of Hypertension (ISH)statement on management of “hypertension” (the singlerisk factor approach), this document provides guidance topolicymakers and health care workers on how to target in-dividuals at high risk of developing CVD, at all levels ofthe health system and in different resource settings, usingevidence-based and cost-effective preventive approaches.This guide to CVD prevention was based on the total riskapproach to prevention of CVD elaborated in the WorldHealth Report of 2002. The centerpiece is the new WHO/ISHcardiovascular risk prediction charts that were developedfor each of the 14 WHO subregions.
The charts only provide approximate estimates of CVDrisk in people who have not already developed cardiovas-cular disease. These risk estimates represent the averagefor the subregion and do not capture the variation in CVDrisk within subregions or countries. They are a useful toolfor health care workers to identify those at high CVD risk,and to motivate patients, particularly to change behaviorand, when appropriate, to take antihypertensive and lipid-lowering drugs and aspirin. The charts are available forpeople with and without diabetes. In settings where facili-ties for measuring cholesterol are not available, versionsof the prediction charts that do not use cholesterol areavailable. The risk factors included in the charts—age, sex,smoking habit, systolic blood pressure, cholesterol, anddiabetes—do not encompass all factors that contribute tothe development of CVD. Health care worker must thereforetake into account obesity (and especially central obesity),family history of CVD, a sedentary lifestyle, low high-den-sity lipoprotein (HDL) cholesterol, raised triglycerides, dys-glycemia (impaired fasting glucose and glucose intolerance),
and other factors such as ethnicity and socioeconomic sta-tus. The CVD risk thresholds for intervention are stratifiedaccording to resource setting: high-resource, 20%; medium-resource, 30%; and low-resource, 40% risk of developingCVD over 10 years. There are huge differences in the preva-lence of high-risk individuals between WHO regions. Forexample, in European region C, about 40% of men have aCVD risk of 30% or higher, compared with only 4% in Africanregion E.
The objective of this report is to reduce the incidence ofheart attacks, strokes, renal failure associated with hyper-tension and diabetes, as well as the need for amputationof limbs because of ischemia, by reducing total CVD risk.It is an evidence-based framework for CVD prevention thatcan be adapted to suit different political, social, culturaland medial circumstances.
Prevention of cardiovascular disease. Guidelines for assessment and management of cardiovascular risk
World Health Organization
WHO Library: Geneva, Switzerland. 2007
N
Ban Ki-moon becomes the new United NationsSecretary-General; former chess world champion
Garry Kasparov is arrested in Moscow for participating in a banned march; and Gordon
Brown is elected Leader of the UK Labour Partyand Prime Minister of the United Kingdom
Dialogues in Cardiovascular Medicine - Vol 14 . No. 2 . 2009
ACE Inhibitor Myocardial Infarction Collaborative Group. Indications for ACE inhibitors in the early treatment of acute myo-cardial infarction. Systematic overview of individual data from 100 000 patients in randomized trials.
Circulation. 1998;97:2202-2212.
Advisory Board of the International Heart Health Conference. The Victoria Declaration: On Heart Health.
In: Declaration of the Advisory Board of the International Heart Health Conference 1992. Victoria, British Columbia, Canada. 1992.
Advisory Board of the Second International Heart The Catalonia Declaration: investing in heart health. Health Conference. In: Declaration of the Advisory Board of the Second Inter-
national Heart Health Conference 1996. Barcelona, Spain: Catalonia, Spain. 1996.
Allender S, Scharbotough P, Peto V, et al. European Cardiovascular Disease Statistics. 2008 edition. London, UK: British Heart Foundation 2008.
Anand SS, Yusuf S. Oral anticoagulant therapy in patients with coronary artery disease:a meta-analysis.
JAMA. 1999; 282: 2058-67.
Anderson KM, Odell PM, Wilson PW, Kannel WB. Cardiovascular disease risk profiles.
Am Heart J. 1991;121(1 pt 2):293-298.
Anderson KM, Wilson PW, Odell PM, Kannel WB. An updated coronary risk profile. A statement for health professionals.
Circulation. 1991;83:356-362.
Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk people.
BMJ. 2002;324:71-86.
Bartnik M, Ryden L, Ferrari R, et al; Euro Heart The prevalence of abnormal glucose regulation in patients with Survey Investigators. coronary artery disease across Europe. The Euro Heart Survey on
diabetes and the heart.
Eur Heart J. 2004;25:1880-1890.
Bhatt DL, Steg PG, Ohman EM, et al; REACH International prevalence, recognition and treatment of cardiovas-Registry Investigators. cular risk factors in outpatients with atherothrombosis.
JAMA. 2006;295:180-189.
Bibliography of One Hundred Key Papersselected by David A. Wood, MSc, FRCPE, FFPHM, FESC and Kornelia Kotseva, MD, PhD, FESC
Cardiovascular Medicine - National Heart and Lung Institute (NHLI) - Imperial College London London - UK
Cardiovascular Disease Prevention
Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Blood pressure lowering treatment trialists’ collaboration.
Lancet. 2003;362:1527-1535.
British Cardiac Society, British Hypertension Society, Joint British Societies’Guidelines on Prevention of Cardiovascular Diabetes UK, HEART UK, Primary Care Cardiovascular Disease in Clinical Practice. Society, The Stroke Association. Heart. 2005;91(suppl V):V1-V52.
Bucher HC, Hengstler P, Schindler C, Meier G. N-3 polyunsaturated fatty acids in coronary heart disease: a meta-analysis of randomized controlled trials.
Am J Med. 2002;112:298-304.
Cannon CP, Braunwald E, McCabe CH, et al; Pravastatin or Intensive versus moderate lipid lowering with statins after acute Atorvastatin Evaluation and Infection Therapy—Thrombolysis coronary syndromes (PROVE-IT). In Myocardial Infarction 22 Investigators. N Engl J Med. 2004;350:494-504.
Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins.
Lancet. 2005;366:1267-1278.
Conroy RM, Pyorala K, Fitzgerald AP, et al. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project.
Eur Heart J. 2003;24:987-1003.
Danchin N, Hanania G, Grenier O, et al. Evolution du traitement de sortie après hospitalisation pour syndromecoronaire aigu en France entre 1995 et 2000: données des études Usik 1995, Prevenir 1 et 2 et Usic 2000. [Trends in discharge prescriptions for patients hospitalized for acute coronary syndromes in France from 1995 to 2000. Data from the Usik 1995, Prevenir 1,Prevenir 2 and Usic 2000 surveys].
Ann Cardiol Angeiol.2003;52:1-6.
De Backer G, Ambrosioni E, Bort-Johnsen K, et al. European guidelines on cardiovascular disease prevention in clinicalpractice. Third Joint Task Force of European and other Societies on Cardiovascular Disease Prevention in Clinical Practice.
de Lemos JA, Blazing MA, et al; A to Z Investigators. Early intensive vs a delayed conservative simvastatin strategy in people with acute coronary syndromes: phase Z of the A to Z trial.
JAMA. 2004;292:1307-1316.
De Velasco JA, Cosin J, Lopez-Sendon JL, De Teresa E, Nuevos datos sobre la prevencion secundaria del infarto de miocardioDe Oya M, Sellers G. en Espana. Resultados del estudio PREVESE II. [New data on
secondary prevention of myocardial infarction in Spain. Results of the PREVESE II study].
Rev Esp Cardiol. 2002;55:801-809.
De Velasco JA, Cosin J, Lopez-Sendon JL, et al. La prevencion secundaria del infarto de miocardio en Espana. Estudio PREVESE (Secondary prevention of myocardial infarction in Spain. The PREVESE study).
Rev Esp Cardiol. 1997;50:406-415.
Domanski MJ, Exner DV, Borkowf CB, Geller NL, Effect of angiotensin converting enzyme inhibition on sudden cardiacRosenberg Y, Pfeffer MA. death in patients following acute myocardial infarction. A meta-
analysis of randomized clinical trials.
J Am Coll Cardiol. 1999;33:598-604.
140
Dialogues in Cardiovascular Medicine - Vol 14 . No. 2 . 2009
Bibliography of One Hundred Key Papers
Ebrahim S, Beswick A, Burke M, Davey Smith G. Multiple risk factor interventions for primary prevention of coronary heart disease.
EUROASPIRE Study Group. EUROASPIRE. A European Society of Cardiology survey of second-ary prevention of coronary heart disease: principal results.
Eur Heart J. 1997;18;1569-1582.
EUROASPIRE Study Group. Clinical reality of coronary prevention guidelines: a comparison of EUROASPIRE I and II in nine countries.
Lancet. 2001;357:995-1001.
EUROASPIRE Study Group. Lifestyle and risk factor management and use of drug therapies in coronary patients from 15 countries. Principal results from EURO-ASPIRE II. Euro Heart Survey Programme.
Eur Heart. 2001;22:554-572.
EUROPA Investigators. The European Trial on Reduction of Cadiac Events with Perindoprilin Stable Coronary Artery Disease Investigators. Efficacy of perin-dopril in reduction of cardiovascular events among people with stablecoronary artery disease: randomised, double-blind, placebo-con-trolled, multicentre trial (the EUROPA study).
Lancet. 2003;362:782-788.
Expert Panel on Detection, Evaluation, and Treatment of Executive Summary of the Third Report of the National Cholesterol High Blood Cholesterol in Adults. Education Program (NCEP) Expert Panel on Detection, Evaluation,
and Treatment of High Blood Cholesterol in Adults (Adult TreatmentPanel III).
JAMA. 2001;285:2486-2497.
Flack J, Neaton J, Grimm R, et al; Multiple Risk Blood pressure and mortality among men with prior myocardial Intervention Trial Research Group. infarction.
Circulation. 1995;92:2437-2445.
Fonarow G, French W, Parsons L, Sun H, Malmgren J; Use of lipid-lowering medications at discharge in patients with acuteNational Registry of Myocardial Infarction 3 Participants. myocardial infarction: data from the National Registry of
Myocardial Infarction 3.
Circulation. 2001;103:38-44.
Fourth International Heart Health Conference. The Osaka Declaration: Health, Economics and Political Action: Stemming the Tide of Cardiovascular Disease.
In: Declaration of the Fourth International Heart Health Conference 2001. Osaka, Japan.
Fox KAA, Cokkinos DV, Deckers J, Keil U, Maggioni A, The ENACT study: a pan-European survey of acute coronary Steg G; ENACT (European Network for Acute Coronary syndromes. Treatment) Investigators. Eur Heart J. 2000; 21:1440-1449.
Fox KAA, Goodman SG, Klein W, Brieger D, Steg PG, Management of acute coronary syndromes. Variations in practice Dabbous O, Avezum A; GRACE Investigators. and outcome.
Eur Heart J. 2002;23:1177-1189.
Freemantle N, Cleland J, Young P, Mason J, Harrison J. �-Blockade after myocardial infarction: systematic review and meta regression analysis.
BMJ. 1999;318:1730-1737.
141
Dialogues in Cardiovascular Medicine - Vol 14 . No. 2 . 2009
Bibliography of One Hundred Key Papers
Gaede P, Vedel P, Larsen N, Jensen GV, Parving H, Multifactorial intervention and cardiovascular disease in patients with Pedersen O. type 2 diabetes.
N Engl J Med. 2003;348:383-393.
Ghandehary H, Kamal-Bahl S, Wong ND. Prevalence and extent of dyslipidemia and recommended lipid levelsin US adults with and without cardiovascular comorbidities: The National Health and Nutrition Examination Survey 2003-2004.
Am Heart J. 2008;156:112-119.
Graham I, Atar D, Borch-Johnsen K, et al. European Guidelines on Cardiovascular Disease Prevention in Clinical Practice: Fourth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Pre-vention in Clinical Prevention in Clinical Practice (Constituted by representatives of nine societies and by invited experts).
Gustafsson I, Hildebrandt P, Selbaek M, et al. Long-term prognosis of diabetic patients with myocardial infarction: relation to antidiabetic treatment regimen. The TRACE Study Group.
Eur Heart J. 2000;21:1937-1943.
Haskell WL, Alderman EL, Fair JM, et al. Effects of intensive multiple risk factor reduction on coronary ather-osclerosis and clinical cardiac events in men and women with coro-nary artery disease. The Stanford Coronary Risk Intervention Project (SCRIP).
Circulation. 1994;89:975-990.
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.
Heidrich J, Behrens T, Raspe F, Keil U. Knowledge and perception of guidelines and secondary prevention of coronary heart disease among general practitioners and internists. Results from a physician survey in Germany.
Eur J Cardiovasc Prev Rehab. 2005;12:521-529.
Hobbs R, Erhardt L. Acceptance of guideline recommendations and perceived implemen-tation of coronary heart disease prevention among primary care physicians in five European countries: the Reassessing European Attitudes about Cardiovascular Treatment (REACT) survey.
Fam Practice. 2002;19:596-604.
Jackson R. Updated New Zealand cardiovascular disease risk-benefit predictionguide.
BMJ. 2000;320:709-710.
Jackson R, Barham P, Bills J, et al. Management of raised blood pressure in New Zealand: a discussion document.
BMJ. 1993;307:107-110.
Jolliffe JA, Rees K, Taylor RS, et al. Exercise-based rehabilitation for patients with coronary heart disease.
Cochrane Database of Systematic Reviews. 2001.
Khot UN, Khot MB, Bajzer CT, et al. Prevalence of conventional risk factors in patients with coronary heart disease.
JAMA. 2003;290:898-904.
142
Dialogues in Cardiovascular Medicine - Vol 14 . No. 1 . 2009
Bibliography of One Hundred Key Papers
Klein S, Burke LE, Bray GA, et al. Clinical implications of obesity with specific focus on cardiovascular disease: a statement for professionals from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism:endorsed by the American College of Cardiology Foundation.
Circulation. 2004;110:2952-2967.
Kotseva K, Wood D, De Bacquer D, Heidrich J, De Backer G. Cardiac rehabilitation for coronary patients: lifestyle, risk factor and therapeutic management. Results from the EUROASPIRE II Survey.
Eur Heart J Suppl. 2004;27:35-41.
Latini R, Maggioni AP, Flather M, Sleight P, Tognoni G. ACE inhibitor use in people with Myocardial infarction. Summary of evidence from clinical trials.
Circulation. 1995;92:3132-3137.
Law M, Wald N, Morris J. Lowering blood pressure to prevent myocardial infarction and stroke:a new preventive strategy.
Health Technol Assess. 2003;7:1-94.
Leal J, Luengo-Fernández R, Gray A, Petersen S, Rayner M. Economic burden of cardiovascular diseases in the enlarged European Union.
Eur Heart J. 2006;27:1610-1619.
Leeder S. A Race Against Time: The Challenge of Cardiovascular Disease in Developing Economies.
New York, NY: Columbia University/The Center for Global Healthand Economic Development; 2004.
Lopez A, Mathers CD, Ezzati M, Jamison D, Murray C. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data.
Lancet. 2006;367:1747-1757.
Löwel H, König W, Engel S, Hörmann A, Keil U. The impact of diabetes mellitus on survival after myocardial infarc-tion: can it be modified by drug treatment? Results of a population-based myocardial infarction register follow-up study.
Diabetologia. 2000;43:218-226.
Lubsen J, Wagener G, Kirwan BA, de Brouwer S, Effect of long-acting nifedipine on mortality and cardiovascular ACTION (A Coronary disease Trial Investigating Outcome morbidity in patients with symptomatic stable angina and hyperwith Nifedipine GITS) Investigators. tension: the ACTION trial.
J Hypertens. 2005;23:641-648.
Malmberg K, Yusuf S, Gerstein HC, et al; Impact of diabetes on long-term prognosis in patients with unstableOASIS Registry Investigators. angina and non-Q-wave myocardial infarction: results of the OASIS
(Organization to Assess Strategies for Ischemic Syndromes) registry.
Circulation. 2000;102:1014-1019.
Manuel DG, Lim J, Tanuseputro P, et al. Revisiting Rose: strategies for reducing coronary heart disease.
BMJ. 2006;332:659-662.
McGuire DK, Emanuelsson H, Granger CB et al. Influence of diabetes mellitus on clinical outcomes across the spectrumof acute coronary syndromes. Findings from the Gusto-IIb study. Gusto IIb Investigators.
Eur Heart J. 2000;21:1750-1758.
Mendis S, Abegunde D, Yusuf S, et al; WHO-PREMISE (Phase I) Study Group. Bull WHO. 2005;83:820-828.
143
Dialogues in Cardiovascular Medicine - Vol 14 . No. 1 . 2009
Bibliography of One Hundred Key Papers
Mukamal KJ, Nesto RW, Cohen MC, et al. Impact of diabetes on long-term survival after acute myocardial infarction: comparability or risk with prior myocardial infarction.
Diabetes Care. 2001;24:1422-1427.
Muntner P, DeSalvo K, Wildman R, Raggi P, He J, Whelton P. Trends in the prevalence, awareness, treatment and control of car-diovascular risk factors among noninstitutionalized patients with a history of myocardial infarction and stroke.
Am J Epidemiol. 2006;163:913-920.
Murchie P, Campbell, N, Ritchie LW. Secondary prevention clinics for coronary heart disease: four year follow up of a randomised controlled trial in primary care.
BMJ. 2003;326;84-90.
Nissen S, Tuzcu EM, Libby P, et al. CAMELOT Investigators. Effect of antihypertensive agents on car-diovascular events in patients with coronary heart disease and normal blood pressure. The CAMELOT Study: A Randomized Controlled Trial.
JAMA. 2004;292:2217-2226.
Pearson T, Bales VS, Blair L, et al. The Singapore Declaration: forging the will for heart health in the next millennium.
CVD Prevention. 1998;1:182-199.
Pearson T, Laurora I, Chu H, Kafonek S. Lipid Treatment Assessment Project (L-TAP): a multicenter survey toevaluate the percentages of dyslipidemic patients receiving lipid-low-ering therapy and achieving low density lipoprotein cholesterol goals.
Arch Intern Med. 2000;160:459-467.
Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein choles-terol levels and low-dose anticoagulation on obstructive changes insaphenous-vein coronary-artery bypass grafts.
N Engl J Med. 1997;336:153-162.
Pyörälä K, De Backer G, Graham I, Poole-Wilson PA, Prevention of coronary heart disease in clinical practice.Wood D. Recommendations of the Task Force of the European Society of
Cardiology, European Atherosclerotic Society and European Society of Hypertension.
Eur Heart J. 1994;15:1300-1331.
Qureshi AI, Suri MF, Guterman LR, Hopkinset LN. Ineffective secondary prevention in survivors of cardiovascular eventsin the US population: report from the Third National Health and Nutrition Examination Survey.
Arch Intern Med. 2001;161:1621-1628.
Reiner Z, Mihatov S, Milicic D, Bergovec M, Planinc D; Treatment and secondary prevention of ischemic coronary events in TASPIC-CRO Study Group Investigators. Croatia (TASPIC-CRO study).
Eur J Cardiovasc Prev Rehab. 2006;13:646-654.
Rose G. The strategy of prevention: lessons from cardiovascular disease.
Br Med J (Clin Res Ed). 1981;282:1847-1851.
Rose G. Sick individuals and sick populations.
Int J Epidemiol. 1985;14:32-38.
Rose G. The Strategy of Preventive Medicine.
Oxford, UK: Oxford University Press; 1992.
144
Dialogues in Cardiovascular Medicine - Vol 14 . No. 2 . 2009
Bibliography of One Hundred Key Papers
Schwartz GG, Olsson AG, Ezekowitz MD, et al; Effects of atorvastatin on early recurrent ischemic events in acute Myocardial Ischemia Reduction With Aggressive coronary syndromes: the MIRACL study: a randomized controlled Cholesterol Lowering Study Investigators. trial.
JAMA. 2001;285:1711-1718.
Simes J, Furberg CD, Braunwald E. Effects of pravastatin on mortality in people with and without coro-nary heart disease across a broad range of cholesterol levels. The prospective pravastatin pooling project.
Eur Heart J. 2002;23:207-215.
Smith S, Jackson R, Pearson T, et al. Principles for national and regional guidelines on cardiovascular disease prevention: a scientific statement from the World Heart and Stroke Forum.
Circulation. 2004;109:3112-3121.
Sprangers RLH, Stam F, Smid HEC, et al. Multidisciplinary structured lifestyle intervention reduces the esti-mated risk of cardiovascular morbidity and mortality.
Neth Heart J. 2004;12:443-449.
Taylor R, Brown A, Ebrahim S, et al. Exercise-based rehabilitation for patients with coronary heart disease:systematic review and meta-analysis of randomised controlled trials.
Am J Med. 2004;116:682-692.
Van Ganse E, Laforest L, Alemao E, Davies G, Gutkin S, Lipid-modifying therapy and attainment of cholesterol goals in Yin D. Europe: the Return on Expenditure Achieved for Lipid Therapy
(REALITY) study.
Curr Med Res Opin. 2005;21:1389-1399.
Wilson K, Gibson N, Willan A, Cook D. Effect of smoking cessation on mortality after myocardial infarction:meta-analysis of cohort studies.
Arch Intern Med. 2000;160:939-944.
Wood D, De Backer G, Faergeman D, Graham I, Prevention of coronary heart disease in clinical practice. Recommen-Mancia G. Pyörälä K. dations of the Second Joint Task Force of European and other
Societies on coronary prevention.
Eur Heart J. 1998;19:1434-1503.
Wood D, Durrington P, Poulter N, McInnes G, Rees A, British Joint British recommendations on prevention of coronary heartCardiac Society, British Hyperlipidaemia Association, British disease in clinical practice. Hypertension Society, and British Diabetic Association. Heart. 1998;80(suppl 2):S1-S29.
Wood DA, Kotseva K, Connolly S, et al; EUROACTION Nurse-coordinated multidisciplinary, family based cardiovascularStudy Group. desease prevention programme (EUROACTION) for patients with
coronary heart disease and asymptomatic individuals at high risk ofcardiovascular disease: a paired cluster randomised controlled trial.
Lancet. 2008;371:1999-2012.
World Health Organization. Prevention of Coronary Heart Disease. Report of a WHO Expert Committee.
Geneva, Switzerland: World Health Organization; 1992. WHO Technical Report Series 678.
World Health Organization. Global Strategy for the Prevention and Control of Noncommunicable Diseases. Report by the Director General.
Geneva, Switzerland: World Health Organization; 2000 (Document A53/14).
145
Dialogues in Cardiovascular Medicine - Vol 14 . No. 2 . 2009
Bibliography of One Hundred Key Papers
World Health Organization and Wellcome Trust. Secondary Prevention of Non-Communicable Diseases in Low- and Middle-Income Countries Through Community-Based and Health Service Interventions. Report of the Cambridge Meeting.
Switzerland and London, UK: World Health Organization and Wellcome Trust: Geneva; 2001.
World Health Organization. CVD Risk Management Package for Low- and Medium-Resource Settings.
Geneva, Switzerland: World Health Organization; 2002.
World Health Organization. Integrated Management of Cardiovascular Risk: Report of a WHO Meeting, July 2002.
Geneva, Switzerland: WHO Library; 2002.
World Health Organization. The World Health Report 2002: Reducing Risks, Promoting Healthy Life.
Geneva, Switzerland: WHO Library; 2002.
World Health Organization. Reduction of cardiovascular burden through cost-effective integratedManagement of Cardiovascular Risk: Addressing Hypertension, Smoking Cessation, and Diabetes.
Geneva, Switzerland: World Health Organization; Report, 9-12 July 2002.
World Health Organization. WHO Framework Convention on Tobacco Control.
Geneva, Switzerland: World Health Organization, 2003.
World Health Organization. Prevention of Recurrent Heart Attacks and Strokes in Low and Middle Income Populations. Evidence-Based Recommendations for Policy Makers and Health Professionals.
Geneva, Switzerland: World Health Organization; 2003.
World Health Organization. World Health Assembly Resolution WHA57.17. Global Strategy on Diet, Physical Activity and Health.
Geneva, Switzerland: World Health Organization; 2004.
World Health Organization. Cardiovascular Disease Prevention. Translating Evidence into Action.
Geneva, Switzerland: World Health Organization, 2005.
World Health Organization. Preventing Chronic Disease: A Vital Investment.
Geneva, Switzerland: World Health Organization; 2005.
World Health Organization. Prevention of Cardiovascular Disease: Guidelines for Assessment and Management of Total Cardiovascular Risk.
Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myo-cardial infarction in 52 countries (the INTERHEART study): case control study.
Lancet. 2004;364:937-952.
146
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Bibliography of One Hundred Key Papers
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2. Darling RC, Brewster DC, Ottinger LW. Autopsy study of unoperated abdominal aorticaneurysms: the case for early resection.Circulation. 1977;56(suppl II):II161-II164.
3. Schulman JL. Immunology of influenza. In:Kilbourne ED, Alfade RT, eds. The InfluenzaViruses and Influenza. Orlando, Fla: AcademicPress Inc; 1975:373-393.
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Fascinoma Cardiologica articles (A Lexiconof the Heart; Icons of Cardiology; Plants andthe Heart; Trails of Discovery, etc) should notexceed 2000 words (8 standard typedpages), should include 3 to 5 illustra-tions (figures and tables), and cite nomore than 15 references. A maximum of5-10 keywords should be included. No abstract.
