Prevention of cardiovascular disease: recent achievements and remaining challenges

Introduction

After an alarming rise in the mortality from atherothrombotic cardiovascular disease (CVD) in the 1950s in most industrialised countries, the CVD epidemic levelled off and an impressive decline started. That decline has occurred in most European countries, commencing earlier in some compared to others [1]. The majority of the reduction in CVD mortality rates is attributable to preventive efforts more than to changes in care [2]. However, the epidemic is still very dynamic in different parts of the world and changes may again occur in the wrong direction; it was recently reported that the rate of decline in CVD mortality has decelerated in the USA [3] and was absent in young adults in Norway [4].

It could also well be that prevention of CVD in the present generation of adults is to a certain extent only a postponement of events or a reduction of the case fatality rate rather than a complete prevention. Prevention of premature CVD mortality and of disability adjusted life years (DALYs) is great but could be associated with an increase in the prevalence of CVD in the elderly and in the very old, with an epidemic of end-stage CVD such as chronic heart failure, renal insufficiency and vascular dementia with all its consequences in terms of more need for care than for cure and of increasing healthcare costs.

Therefore, more should be invested in the earliest possible prevention of CVD from childhood onwards, in the prevention of the development of an increased total CVD risk. This can be achieved by aiming for a non-smoking generation of adolescents who keep physically active throughout life and preventing the development of overweight and obesity.

Lifestyle, behaviour, socio-economic issues

Societal changes may affect the CVD epidemic in different ways. Globalisation, migration, socio-economic changes and unemployment may have influences. Differences in CVD health among countries, regions and neighbourhoods have increased over the years; these inequalities can be explained by components of human behaviour such as diet, exercise, smoking and job-related features but also by overcrowding, unemployment and other indicators of deprivation. Life expectancy increases continuously with income. In the USA at the age of 40 years, the gap in life expectancy between individuals in the top and bottom 1% of the income distribution is 15 years for men and 10 years for women. Most of the variation in life expectancy across areas was related to differences in health behaviour, including smoking, obesity, and exercise [5].

Smoking of tobacco

Tobacco smoking remains the single most important preventable cause of premature mortality and of DALYs, and quitting smoking is the most cost-effective strategy to prevent CVD. Improvements have been made regarding the smoking of tobacco, in some countries more than in others, with large differences according to socio-economic class. Governmental restrictions and regulations have been successful; high taxes on tobacco products are the most effective policy measure to reduce smoking in the young. However, this needs to be complemented by continuous health education campaigns particularly targeted at the young and other subgroups of society. Restrictions on advertising, promotion and sponsorship by the industry are needed.

Smokers who want to quit should receive professional assistance if required. Brief interventions with advice to stop smoking together with pharmacological support and follow-up visits are effective and safe but insufficiently applied, even in smokers with established coronary heart disease [6]. If a smoker is willing to stop, a quitting plan should be prepared including a quit date, information to friends and family asking for support, removal of all tobacco and of objects associated with smoking behaviour from the immediate surroundings, and finally arrangement of follow-up visits, ideally within the month and every month thereafter for four months. At the follow-up visit the person should be congratulated if he/she had stopped smoking. In case of relapse, a more intensive approach should be considered, such as referral to a smoking cessation specialist or centre.

If advice, encouragement and motivation are likely to be insufficient, drug therapies should be considered early on, including nicotine replacement therapy (NRT), bupropion or varenicline. Smoking cessation pharmacotherapy may double or triple quit rates, and combining pharmacotherapy with counselling improves quit rates further.

The success rate of stopping smoking with varenicline is higher than with bupropion; varenicline doubles the chances of stopping smoking compared to placebo [7]. Varenicline reduces craving for cigarettes and withdrawal symptoms; it should be started one to two weeks before the quit date. Hypersensitivity is the only contraindication. Nausea is the most common side effect, especially at the start of therapy and if taken together with food. Titration of the dose may be necessary in some cases.

Electronic cigarettes, or e-cigarettes, can deliver high concentrations of nicotine as a vapour and have been recommended as a measure to help cessation of smoking of regular cigarettes. Results of studies on the cardiovascular effect of e-cigarettes are inconsistent but an increased risk has been documented in some [8].

Avoidance of passive smoking is another strong recommendation for the prevention of CVD.

Diet

Regarding the dietary habits of the population, changes have occurred in different areas. For example, the intake of salt and saturated fats has been reduced in most societies. The food industry has reduced the presence of trans fatty acids in different food items; this has been promoted by regulatory initiatives in some communities. However, the potential to prevent CVD through dietary adaptations is still poorly implemented. Adherence to a balanced diet is generally limited; the control of elevated blood pressure, dyslipidaemias and dysglycaemia can largely be improved through changes in lifestyle. Achieving better adherence with dietary recommendations requires the understanding of the determinants of poor compliance. At the population level, structural measures such as product information, and consumer-friendly nutrition labelling may improve health-friendly choices. Energy-dense, nutrient-deficient foods are generally highly accessible and inexpensive; the marketing of such foods could be limited and taxed. On the other hand, fruits and vegetables tend to be more expensive; the subsidising of their costs may be useful.

At the clinical level, general practitioners have an opportunity to provide counselling about diet for the management of coronary risk factors. However, barriers to that were reported related to time limitations, knowledge and perceived efficacy [9]. The extent to which physicians are familiar with a healthy dietary pattern (i.e., DASH, Mediterranean diet) and with translating that information into practical recommendations may be limited. A multidisciplinary approach including nutritionists and dieticians may help but needs improved reimbursement coverage.

At the individual level, new strategies may help to improve patient self-management and to induce sustainable behaviour change. Many apps and devices are available that provide data that can be useful for lifestyle changes and patient self-management. In Table 1 dietary targets of a well-balanced diet to prevent CVD are summarised.

Table 1. Dietary targets to prevent CVD.

Physical activity

The promotion of physical exercise is a crucial and central issue in all strategies of CVD prevention.

At the individual level, physical activity should be advised at different time points; it should become part of regular life from childhood onwards. Children and adolescents should be encouraged to spend 30 to 45 minutes daily in exercise activities either at school or in their leisure time. This should be maintained for as long as possible through young adulthood.

 Healthy adults in all age groups are recommended to choose enjoyable physical activities which fit in with their daily routine on most days of the week. They are recommended to engage in at least 150 minutes a week of moderate aerobic physical activity (30 minutes for 5 days/week) or 75 minutes a week of vigorous aerobic physical activity (15 minutes for 5 days/week) or a combination thereof. At the individual level, exercise prescription should be more personalised. Therefore, a short history of the physical activity level of the individual is needed (how many minutes per day spent on average in activities at moderate or vigorous intensity). On that basis and considering individual choices, advice can be given on the most appropriate types of activity, on how to progress, on which goals to set in order to achieve and maintain the health benefits of an active lifestyle. Barriers towards achieving a more active lifestyle as perceived by the individual should be identified and ways of overcoming them should be explored. For people at work, active travelling should be recommended as well as taking active breaks from prolonged periods of sitting. Based on results from a meta-analysis of 16 studies with more than one million individuals, it was shown that one hour of activity offsets the risk from eight hours of sitting [10]. In people unable to meet the minimum, or in sedentary subjects who just start some activity, even the lowest recommended level should be encouraged. It should be stressed that any increase in activity will be associated with a health benefit, even before a training effect is evident, and that it is fine to work progressively towards any given target.

Management of CVD risk factors

All current guidelines on the prevention of CVD in clinical practice recommend the assessment of total CVD risk because atherosclerotic CVD is usually the product of a number of risk factors. Prevention of CVD in a given person should be adapted to his or her total CVD risk: the higher the risk the more intensive the action should be. The stratification of the community into different levels of total CVD risk was given in recent guidelines [11].

Dyslipidaemias

Randomised controlled trials (RCTs) have clearly demonstrated that reducing the low-density lipoprotein-cholesterol (LDL-C) level with diet and/or lipid-lowering drugs can reduce the risk of CVD events. This evidence is greatest for the use of statins. In other RCTs, more versus less LDL-C reduction was studied in coronary patients, resulting in more CVD prevention with more intensive statin therapies [12]. It was also shown that a gradient exists between the degree of lowering LDL-C and the magnitude of CVD prevention [13].

The treatment goals for LDL-C depend on the total CVD risk of the patient and of the baseline LDL-C level. In patients at very high CVD risk, an LDL-C goal of <1.8 mmol/L (70 mg/dL), or a reduction of at least 50% if the baseline LDL-C level is between 1.8 and 3.5 mmol/L (70 and 135 mg/dL), is recommended.

In patients at high CVD risk, an LDL-C goal of <2.6 mmol/L (100 mg/dL), or a reduction of at least 50% if the baseline LDL-C level is between 2.6 and 5.2 mmol/L (100 and 200 mg/dL), is recommended. In subjects at moderate risk, an LDL-C goal of <3.0 mmol/L (115 mg/dL) should be considered.

Based on the results of the IMPROVE-IT trial, further LDL-C lowering by adding ezetimibe should be considered in CVD patients with an LDL-C ≥70 mg/dL (≥1.8 mmol/L) despite the maximally tolerated dose of statin [14]. A new family of lipid-lowering drugs has now become available. These proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9) reduce LDL-C further in addition to what can be achieved with statins. In the FOURIER trial, the inhibition of PCSK9 with evolocumab on a background of statins lowered LDL-C to a median of 30 mg/dL (0.78 mmol/L), and reduced CVD events [15].

The use of this drug should be considered in patients at very high CV risk in whom LDL-C remains elevated despite being treated with a maximal statin dose in combination with ezetimibe, or in patients with statin intolerance.

Arterial hypertension

Elevated blood pressure (BP) is one of the most powerful modifiable risk factors for CVD. The beneficial effects of BP-lowering therapies to reduce stroke, myocardial infarction, heart failure and death have been shown in numerous RCTs and in different meta-analyses [16]. BP lowering can be achieved through lifestyle changes and drug therapies.

Results from post hoc analyses of trials from the past suggested the existence of a J-shaped association between achieved BP and CVD risk. Results from more recent trials [17,18], where more intense BP lowering was compared with less intense reduction, have re-opened the discussion regarding the most optimal BP goals to achieve in patients with arterial hypertension. In a recent systematic review and network meta-analysis including 42 trials and 144,220 patients, it was found that reducing systolic BP to levels below the BP targets that were recommended previously reduces the risk of CVD and all-cause mortality [19]. All this calls for BP lowering based on the patient’s potential to benefit without harm rather than on reducing the BP to a specific target. Therefore, in patients at very high risk, as is the case in the presence of CVD, BP lowering may require more intensive strategies than those currently recommended in the guidelines. However, this should be decided on a more personalised basis. Lower treatment targets are also associated with a higher medication burden and with an increased risk of side effects.

Recommendations regarding BP targets in patients with arterial hypertension, based on the 2016 ESC guidelines on CVD prevention in clinical practice [11], are given in Table 2.  

Table 2. Blood pressure targets for patients with arterial hypertension.

Dysglycaemia

In people with impaired glucose tolerance, the development of type 2 diabetes mellitus (DM) can be postponed or prevented. In patients with type 2 DM, CVD events can be prevented through good control of CVD risk factors. Intensive management of hyperglycaemia will also reduce the risk of microvascular complications.

Unfortunately, the prevalence of type 2 DM is increasing in most parts of the world, mainly due to unbalanced diets and a lack of physical activity. The diagnosis of DM is also still problematic in a large number of individuals, and even in patients with established CVD [6]. Screening should be considered by assessing HbA1c or fasting blood glucose. When there is still doubt, an oral glucose tolerance test should be offered.

For the majority of non-pregnant adults with either type 1 or type 2 DM, a target of HbA1c of < 7.0% (< 53 mmol/mol) is recommended to reduce CVD risk and the risk of microvascular complications. At diagnosis, or early in the course of type 2 DM, a target of HbA1c of ≤ 6.5% (≤ 48 mmol/mol) should be considered in patients who are not frail and do not have CVD.

Metformin is recommended as first-line therapy if tolerated and not contraindicated following the evaluation of renal function.

In patients with DM and CVD, the use of sodium-glucose co-transporter-2 (SGCT2) inhibitors reduced CVD and total mortality without major adverse effects [20]. These drugs should be considered early in the management of DM in these patients.

Optimal control of the LDL-C level and of the BP is of great importance in all patients with DM (see above).

Conclusions

Prevention of atherothrombotic CVD has been a success story in medicine and public health; however, challenges remain related to residual CVD risk, environmental factors, the ageing of the population and poor adherence to recommendations regarding CVD prevention. Some of these factors relate to human behaviour and to socio-economic features. Tackling these “causes of the causes” is a major challenge at national and international level. More research should also be focused on the (cost-) effectiveness of preventive strategies. The potential for further gains in preventing CVD is important. It is up to society to make the best use of it.