The European Society of Cardiology
Guidelines and management of global risk: the European perspective
Department of Primary Care and General Practice, School of Medicine, University of Birmingham, Edgbaston, Birmingham, UK
* Correspondence: Prof. F.D.R. Hobbs, Division of Primary Care, Public and Occupational Health, Department of Primary Care and General Practice, Primary Care Clinical Sciences Building, School of Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Fax: +44-121-414-6571
f.d.r.hobbs{at}bham.ac.uk
Abstract
The anticipated rise in the prevalence of coronary heart disease (CHD) over forthcoming years throughout the world, including Europe, will place a significant burden on the healthcare system. Consequently, a major challenge that faces the medical profession is to improve the introduction of effective preventive strategies into routine clinical practice in order to blunt the scale of this epidemic. Current levels of risk factor management in patients with established cardiovascular disease are poor, and the implementation of primary preventive strategies to reduce the risk of cardiovascular morbidity and mortality in high-risk patients is even worse. The principal objective of clinical guidelines, such as those for the prevention of CHD issued by the Joint European Societies, is to improve the quality of patient care and health outcomes. However, the development of good guidelines by professional organizations does not guarantee their use in clinical practice. Surveys indicate that the most successful guidelines, in terms of implementation in general practice, are based on robust scientific evidence, are explicit in their recommendations, are uncontroversial, and demand minimal disruption to existing working procedures and workloads.
Key Words: Coronary heart disease • Europe • Guidelines • Primary prevention • Risk factors • Secondary prevention
Introduction
The current principal guidelines for the prevention of coronary heart disease (CHD) in Europe were updated in 2003 after the major recommendations in 1998 by the Second Joint Task Force of the European Society of Cardiology (ESC), the European Atherosclerosis Society (EAS) and the European Society of Hypertension (ESH).1,2 The need to update the recommendations from those originally put forward by the first Joint ESC/EAS/ESH Task Force in 19943 was prompted by new scientific evidence, especially in relation to the undeniable benefits of lipid-lowering therapy. Although the priority of these guidelines is to encourage physicians to focus on preventing events in patients with established CHD or other major atherosclerotic disease by targeting modifiable risk factors (i.e. secondary prevention), they also emphasize the importance of preventive measures in healthy individuals with a high global risk of CHD (i.e. primary prevention). These two patient populations will derive the greatest benefit from intervention.
In general, the approach to cardiovascular disease prevention that is recommended to European physicians is similar to that recommended to physicians in the United States, particularly after the Third Task Force update in 2003. However, certain differences do exist between the two regions with regard to the patient populations that are targeted for screening and intervention, the cholesterol thresholds for drug therapy intervention, and the goal lipid levels that should be achieved.
Global burden of disease study
Results of the Global Burden of Disease Study4,5 suggest that the rewards associated with successful implementation of the Second Joint ESC/EAS/ESH recommendations, in terms of public health, should be tremendous. This healthcare projection study analyzed data from 47 countries for the years 1950–1990 to predict the major worldwide causes of mortality and disability in 2020. The model was based on future health status as a function of projected changes in key socioeconomic parameters that are known to influence health status (income per person, average number of years of education and smoking intensity) and time (as a surrogate for technological change).
The Global Burden of Disease Study identified ischaemic heart disease and cerebrovascular disease as the first and second most common causes of death, respectively, worldwide in 1990.4 In terms of death and disability, lower respiratory tract infections were found to be the leading cause, accounting for 8.2% of the global burden of disability-adjusted life years (DALYs).5 Ischaemic heart disease was the fifth most common cause of death and disability and cerebrovascular disease the sixth, representing 3.4% of DALYs and 2.8% of DALYs, respectively (Table 1).
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By the year 2020, substantial changes are anticipated in worldwide patterns of mortality and disability compared with 1990. Ischaemic heart disease and cerebrovascular disease are expected to remain the leading two causes of death. Moreover, it is estimated that the highest percentage (5.9%) of DALYs in 2020 will be attributable to ischaemic heart disease, and 4.4% will be attributable to cerebrovascular disease (Table 1).
Thus, by the year 2020, healthcare projections suggest that ischaemic heart disease will be the most important global cause of death and disability. This has implications not only for individual patients but also for healthcare systems in terms of cost and burden of disease. Widespread effective implementation of primary and secondary CHD preventive practices based on clearly defined guidelines should help to reduce the associated premature disability and mortality, and lessen the impact on public health.
Secondary prevention
As discussed above, secondary prevention is the main priority of the Third Joint ESC/EAS/ESH recommendations on CHD prevention (Fig. 1). In Europe, secondary preventive measures are targeted at patients with established cardiovascular disease, specifically those with prior myocardial infarction (MI), previous stroke, angina pectoris or peripheral arterial disease (PAD). Since CHD risk is approximately doubled in men with diabetes mellitus, and more than doubled in women with the disease, when compared with non-diabetic patients with equivalent risk factors, diabetes mellitus is now considered to carry an equivalent coronary risk to the above conditions and is, therefore, not a compelling indication for the introduction of secondary preventive measures. This now mirrors with the situation in the United States: in the third Adult Treatment Panel guidelines of the National Cholesterol Education Program (NCEP), diabetes is considered to be a CHD risk equivalent, i.e. patients with diabetes are considered to be at an equal risk of suffering a coronary event as those with established CHD.6
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A second difference between the European and United States guidelines is in their simplicity, as the former have attempted to be relatively uncomplicated in order to encourage their uptake and implementation by primary care physicians. For example, the European guidelines do not specify any fixed blood cholesterol thresholds above which lipid-lowering therapy is indicated, simply target levels. These targets, which are the same for both primary and secondary prevention, are a total cholesterol below 190 mg dl–1 (5.0 mmol l–1) and a low-density lipoprotein (LDL)-cholesterol below 115 mg dl–1 (3.0 mmol l–1). Concentrations of high-density lipoprotein (HDL)-cholesterol and triglycerides are not currently used as goals of therapy. The targets for systolic blood pressure (SBP) and diastolic blood pressure (DBP) are
140 and 90 mmHg, respectively. Primary prevention
Healthy, high-risk individuals are the most important candidates for primary prevention. This is because many patients with significant atherosclerotic disease are only recognized after they have sustained a major cardiovascular event, such as sudden cardiac death, acute myocardial infarction, angina pectoris or unstable angina. Thus, the aim of primary prevention is to identify early those individuals who are at risk of developing CHD or other atherosclerotic disease (e.g. smokers, or those with elevated blood pressure or adverse lipid profiles) and to instigate the necessary interventions to minimize their risk of cardiovascular morbidity and mortality.
Coronary risk is multi-factorial in aetiology. Furthermore, it is multiplicative, such that the risk associated with the presence of two or more risk factors is greater than the sum of their individual risks. As a result, physicians should base clinical judgements regarding drug therapy on the absolute risk of CHD, which takes into account all the major risk factors, rather than relying on the level of any one factor in isolation.
The Third Joint ESC/EAS/ESH guidelines incorporate a Coronary Risk Chart as a tool to facilitate absolute risk assessment and to identify patients at highest risk using age, gender, smoking status, SBP level and total cholesterol concentration (Fig. 2). However, physicians must also bear in mind that the risk is further elevated in patients with familial hyperlipidaemia, diabetes mellitus, a family history of premature cardiovascular disease, low HDL-cholesterol (39 mg dl–1 [1.0 mmol l–1] in men; 43 mg dl–1 [1.1 mmol l–1] in women), raised triglyceride levels (
180 mg dl–1 [2.0 mmol l–1]), and as the patient approaches the next age band. An absolute cardiovascular death risk of 
5% over 10 years, or one that will exceed 5% if projected to age 60 years, and that is sustained despite corrective lifestyle measures, justifies the selective use of proven drug therapies for the control of blood pressure and blood lipid levels (Fig. 3). According to these criteria, as many as 20% of men (and 1.6% of women) in Europe between the ages of 25 and 74 years are estimated as eligible for primary prevention. The majority of the at-risk population are elderly, with 68% of men and 6.4% of women in the 65–74-year age bracket being candidates for primary prevention (D. Wood, personal communication). Such a high proportion of patients at significant risk of a first cardiovascular event highlights the considerable potential of primary prevention in further reducing morbidity and mortality associated with CHD.
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The adoption of cardiovascular death risk as a measure of absolute risk was a controversial step and a major departure from all other cardiovascular disease guidelines but was guided by the consequence that different charts could then be generated for low risk (southern) as well as high risk (northern) European populations.
Guideline implementation
EUROASPIRE
Despite the existence of clear, simple, evidence-based guidelines for the primary and secondary prevention of CHD in clinical practice and the size of the at-risk population, the integration of these recommendations into routine clinical care has been somewhat disappointing.7–9
Between 1995 and 1996, shortly after publication of the first Joint ESC/EAS/ESH recommendations for CHD prevention,3 a survey was conducted across Europe to determine the extent to which the Task Force's recommendations on risk factor documentation and management in patients with established CHD were being incorporated into clinical practice.7 This study, known as EUROASPIRE (EUROpean Action on Secondary Prevention through Intervention to Reduce Events), involved review of the medical records of consecutive patients (
70 years of age) who had been hospitalized for coronary artery bypass grafting (CABG), percutaneous transluminal coronary angioplasty (PTCA), acute myocardial infarction or acute myocardial ischaemia without infarction. An interview to audit follow-up risk management was held at least 6 months, and an average of 18 months, after hospital admission.
A total of 4863 medical records were reviewed and 3569 patients were interviewed at least 6 months after hospitalization. The results of the survey exposed serious deficiencies in the control of modifiable risk factors among patients who had already sustained a coronary event. For example, 19% were still smoking, 53% had hypertension (SBP140 mmHg and/or DBP90 mmHg) and 44% had raised total plasma cholesterol (213 mg dl–1 [5.5 mmol l–1]). Thus, EUROASPIRE revealed substantial scope for more rigorous enforcement of the European Task Force recommendations in order to further reduce the incidence of cardiovascular events in the community.
EUROASPIRE I I
A second survey, EUROASPIRE II,9 was conducted in 15 countries in Europe in 1999–2000 to determine whether there had been any improvement in the practice of preventive cardiology in patients with established coronary disease compared with the initial EUROASPIRE study. As in EUROASPIRE, the medical records of consecutive patients (
) admitted to hospital for CABG, PTCA, acute myocardial infarction or myocardial ischaemia were reviewed, and follow-up interviews (
) were conducted at least 6 months after hospitalization for the primary event (median of 1.44 years after discharge).
EUROASPIRE II showed a persisting high prevalence of adverse lifestyle characteristics, other risk factors and under-use of prophylactic drug therapies in patients with established CHD. At the time of interview, 21.1% of patients smoked (range: 14.6% [Slovenia] to 30.1% [Hungary]), 50.5% had elevated blood pressure (SBP140 mmHg and/or DBP 90 mmHg; range: 37.3% [Ireland] to 63.0% [Germany]), and 58% had a serum total cholesterol level 193 mg dl–1 (5.0 mmol l–1); range: 40.4% (Sweden) to 76.6% (Belgium). The results also revealed substantial variations among countries in patients' lifestyles.
Thus, the lifestyle, risk factor and therapeutic goals set by the Second Joint ESC/EAS/ESH Task Force for secondary prevention are not being achieved in a significant proportion of patients throughout Europe. A particularly disappointing aspect of the EUROASPIRE findings was that this shortfall in standards was occurring even when the follow-up care is initiated in tertiary referral centres, which should represent best practice, not average practice. A possible explanation for this behaviour may be that cardiologists perceive their role as being to treat the acute event, and that risk factor management should be the responsibility of the primary care physician. Primary care physicians may interpret this lack of a hospital discharge plan as an indication that the cardiologist does not endorse risk-management strategies. Furthermore, primary care physicians are more likely to continue with therapy prescribed by the consulting cardiologist than to initiate treatment themselves.
Why is clinical practice lagging behind guideline recommendations?
Dutch national guidelines on cholesterol testing
Robust research examining the reasons underlying the poor adherence to guidelines for the prevention of CHD and, by extrapolation, the measures that should be taken to address the situation, are somewhat limited. However, one such randomized controlled trial has been conducted in the Netherlands10 to evaluate the feasibility and extent of application of the Dutch College of General Practitioners' guidelines on blood cholesterol monitoring in general practice.11
The guidelines were disseminated by post to 32 Dutch primary care physicians in 20 general practices. In addition, 10 of the general practices underwent an intensive 5-month intervention programme designed to promote the uptake of the guidelines. This programme consisted of group education, individual face-to-face instruction at the practice premises on guideline content and application, desktop computerized decision support materials for coronary risk assessment, and personal performance feedback. The remaining 10 general practices (the control group) did not undergo the support programme. The primary outcome parameter was defined as the degree of appropriate cholesterol testing of patients at high risk of CHD, measured by audit of a total of 3950 patient records.
Surprisingly, the results of this Dutch study showed that the intervention programme had no effect on guideline implementation. The likelihood of a patient with a positive risk factor profile having their serum cholesterol level tested and recorded did not improve either in the intervention group (odds ratio at baseline=5.1 [95% confidence interval=3.7–7.4]; odds ratio at follow-up=4.9 [95% confidence interval=3.1–8.4]) or in the control group (odds ratio at baseline=4.2 [95% confidence interval=3.1–5.8]; odds ratio at follow-up=3.8 [95% confidence interval=2.6–5.9]).
Thus, despite an intensive support programme designed to encourage primary care physicians to incorporate the national cholesterol guidelines into routine daily practice, no improvement in prevalence of cholesterol monitoring in high-risk patients was detected. It seems that although the majority of doctors acknowledge the importance of reducing blood cholesterol levels, few actually put appropriate measures into practice in their patients. Several reasons were put forward to account for this lack of enforcement, including lack of time during routine consultations, increase in workload, reimbursement concerns, motivation, doubts on the evidence upon which the guidelines were based, complexity of the guideline algorithm, practice organization and patient compliance. A more proactive approach is clearly needed to change primary care physicians' attitudes towards preventive medicine, complemented by a supportive public health programme.
Barriers to effective uptake of guidelines
Other data, also originating from the Netherlands, have examined more closely the characteristics of clinical guidelines that influence their incorporation into routine general practice.12 Over a period of 3 months, this observational study monitored how well 61 primary care physicians adhered to 47 separate recommendations from 10 clinical guidelines issued by the Dutch College of General Practitioners. The degree of adherence to each recommendation was then related to the presence or absence of 12 pre-defined attributes within that recommendation.
Overall, the recommendations were followed in 61% (7915/12,880) of clinical decisions. Table 2 shows the rate of compliance with the recommendations according to whether or not a particular attribute was present. Adherence to a recommendation among physicians was more likely if it was based on strong scientific evidence and was well defined, but less likely if it was controversial, involved a change in existing routines or demanded an increase in workload.
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Other factors responsible for the current disparity between guideline recommendations and actual clinical performance by physicians in cardiovascular disease prevention include gaps in knowledge and confusion over the recommendations.13 For example, physicians may use CHD algorithms inappropriately or be unsure of the specified target goals for lipid fractions during treatment.14,15
The REACT survey
Further information on attitudes towards guidelines has been obtained from the Reassessing European Attitudes about Cardiovascular Treatment (REACT) survey.13,16 REACT evaluated the acceptance of and/or implementation of CHD guidelines and cholesterol treatment guidelines among 754 primary care physicians in five European countries (France, Germany, Italy, Sweden and the United Kingdom).13 The most common barriers to implementation of the prevention programmes were reported as lack of time (38%), prescribing costs (30%) and poor patient compliance (17%) (Fig. 4).
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The physicians surveyed in REACT also believed that 92% of their patients knew that elevated blood cholesterol levels increased the risk of CHD. However, this contrasted with the responses from a separate component of the survey, which interviewed 5104 members of the general public from the same five countries.16 Only 51% appreciated the association between cholesterol and cardiovascular disease; awareness of the importance of LDL-cholesterol and HDL-cholesterol levels was even lower, at 23% and 25%, respectively. Important public health initiatives are clearly needed to increase understanding of elevated cholesterol level as a coronary risk factor. Physicians in the REACT survey felt that this would be achieved most effectively through better patient information (49%) and more time spent educating the patient (20%).13
Future European guidelines: what is likely to change?
The Joint ESC/EAS/ESH guidelines for the prevention of CHD are undergoing regular review. Several changes occured in the new recommendations.
Diabetes and cardiovascular risk
Firstly, patients with type 2 diabetes mellitus were identified as a specific target population for prevention. Type 2 diabetes is associated with such a pronounced increase in CHD risk that there is a strong case for treating patients with diabetes as aggressively for cardiovascular risk factors as non-diabetic patients who have already sustained a major event.
Compelling evidence for this has come from a population-based study in Finland, which compared the incidence of myocardial infarction, stroke and cardiovascular mortality over 7 years in patients with type 2 diabetes versus those without diabetes.17 The populations were further segregated into subgroups according to whether or not the individual had suffered a prior myocardial infarction. The 7-year incidence rates of cardiovascular events in the 4 subgroups are shown in Fig. 5. It is clear that the risk of a first event among patients with diabetes is at least as high as the risk of a second event among patients without diabetes. The differences between diabetic and non-diabetic patients without a history of myocardial infarction are even more striking. For example, the 7-year incidence of a first myocardial infarction in non-diabetic patients was just 3.5% compared with 20.2% in diabetic patients, almost a 6-fold increase.
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The public health implications of these data acquire even greater significance when one considers that the burden of type 2 diabetes is set to increase dramatically over coming years in all regions of the world. Recent estimates from the World Health Organization (WHO) predict that, if current trends continue, the worldwide prevalence of diabetes among adults will rise from 135 million in 1995 to 300 million in the year 2025.18
The elderly
The elderly are a second segment of the population likely to be identified in future guidelines as warranting special consideration. As mentioned previously, the majority of individuals with an absolute CHD risk of 20% over 10 years, as determined from the Coronary Risk chart in the Third Joint ESC/EAS/ESH recommendations,1 will be in their 60s or 70s. Data from the Heart Protection Study 19 (see below) also suggest that the elderly will benefit from aggressive lipid-lowering therapy as much as younger individuals. Since the size of the elderly population in Europe is steadily increasing, efforts to prevent cardiovascular disease in these individuals should significantly reduce the economic burden placed on the healthcare system.
The Heart Protection Study
The results of the Heart Protection Study19,20 had prompted a sea change in attitudes towards CHD prevention, which are likely to be reflected in the new European guidelines. The Heart Protection Study investigated the long-term effects of LDL-cholesterol-lowering therapy (simvastatin 40 mg/day for 5 years) versus placebo on mortality and fatal or non-fatal vascular events in patients at high risk of cardiovascular disease. It involved 20,536 participants, 40–80 years of age, with total blood cholesterol 135 mg dl–1 (3.5 mmol l–1) and a history of CHD, occlusive disease of non-coronary arteries, diabetes or treated hypertension. A total of 5806 (28%) of the patients were 70 years of age at entry, 5963 (29%) had type 1 or 2 diabetes and one-third of the diabetics also had known coronary disease. Mean baseline total cholesterol was 228 mg dl–1 (5.9 mmol l–1).
The main finding of the Heart Protection Study was that long-term simvastatin therapy versus placebo significantly decreased all-cause mortality (12.9% versus 14.7%; 
), vascular mortality (7.6% versus 9.1%; 
), nonfatal myocardial infarction or coronary death (8.7% versus 11.8%; ), stroke (4.3% versus 5.7%; ), and revascularization (9.1% versus 11.7%; ).19 Analysis of the data according to prior disease category also showed a highly significant reduction in major vascular events with simvastatin in diabetic patients with no previous CHD (13.8% on simvastatin versus 18.6% on placebo; ). Moreover, patients receiving simvastatin benefited irrespective of their pre-treatment cholesterol concentration, age or gender.
Thus, in the Heart Protection Study, lowering LDL-cholesterol with simvastatin reduced the incidence of major vascular events by approximately one-quarter among a wide range of high-risk patients irrespective of their initial cholesterol level. In particular, it has extended the populations of patients likely to benefit from statin therapy to include those without a history of CHD, but who have diabetes, cerebrovascular disease or peripheral arterial disease.
Treatment thresholds and targets
Aside from the important data on stroke prevention, perhaps the most provocative finding of the Heart Protection Study was that the risk reduction for major cardiovascular events with simvastatin therapy did not appear to be dependent upon the cholesterol level at presentation. Stratification of participants into subgroups based on their initial LDL-cholesterol concentration revealed highly significant risk reductions among the 6793 patients with an LDL-cholesterol level 116 mg dl–1 (3.0 mmol l–1) at entry (17.6% with simvastatin versus 22.2% with placebo; ), and even among the 3421 patients whose baseline LDL-cholesterol level was <100 mg dl–1 (2.6 mmol l–1); 16.4% with simvastatin versus 21.0% with placebo; 
.19 Similarly, there were significant reductions in the risk of major cardiovascular events in patients with a pre-treatment total cholesterol level below 193 mg dl–1 (5.0 mmol l–1); 17.7% with simvastatin versus 23.1% with placebo; .
These results are likely to influence future lipid targets specified in Joint ESC/EAS/ESH recommendations. The cholesterol targets for primary and secondary prevention in the current guidelines are a total cholesterol level 190 mg dl–1 (5.0 mmol l–1) and an LDL-cholesterol level 115 mg dl–1 (3.0 mmol l–1) (Fig. 1). For continued high-risk individuals, such as those with diabetes, the new European guidelines advocate an LDL target below 2.5 mmol/L or total cholesterol target below 4.5 mmol/L. However, the Heart Protection Study has provided evidence that reducing blood cholesterol below these levels further decreases the risk of cardiovascular events. It is possible, therefore, that the revised guidelines may recommend basing clinical decisions regarding the initiation of statin treatment on an individual's overall medical history rather than on whether their blood cholesterol fractions fall above or below given threshold values. However, evidence for whether targets for LDL-cholesterol reduction should be lowered will have to await the outcomes of trials specifically testing differential low cholesterol targets, such as the Treating to New Targets (TNT) and PRavastatin Or atorVastatin Evaluation and Infection Therapy (PROVE IT) studies.
Conclusion
Morbidity and mortality associated with CHD is predicted to rise to epidemic proportions in Europe over forthcoming years unless effective primary and secondary preventive strategies are incorporated successfully into routine clinical practice. The recommendations of the Third Joint Task Force of European and other Societies on coronary prevention1 provide relatively simple but explicit instructions on identifying at-risk patients, the lifestyle and therapeutic interventions that should be introduced, and the targets that should be achieved. However, surveys evaluating how meticulously these guidelines are followed by primary care physicians reveal substantial under-performance. Initiatives are clearly needed to improve uptake of these guidelines – that is, to make best practice, common practice – in order to improve patient care and outcomes, and lessen the burden on healthcare systems. Guidelines are most likely to be integrated into general practice if they have a strong evidence base, are specific in their instructions, consistent with current clinical attitudes, and require only minor changes in practice management.
The new guidelines reflect the findings of recent studies showing the benefits of intervention in hitherto untreated patient populations, such as the elderly and patients with diabetes. For example, randomized controlled clinical trials of lipid-lowering therapy, such as the Heart Protection Study19 and the Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study,21 have provided evidence for the benefits of cholesterol reduction in patients not previously considered eligible for statin treatment. As a consequence, efforts to improve risk factor status can be expected to involve an increase in prescribing practice. This is not only because of the extended number of patients for whom lipid-lowering therapy will be indicated, but also because of the need for polypharmacy to treat all of the modifiable risk factors to increasingly stringent targets.
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