General recommendations

• Use JBS3 risk calculator to estimate both 10-year risk and lifetime risk of CVD in all individuals except for those with existing CVD or certain high risk diseases: that is, diabetes age >40 years, patients with chronic kidney disease (CKD) stages 3–5, or familial hypercholesterolaemia (FH).

• Total cholesterol (TC) and high density lipoprotein (HDL) cholesterol from a non-fasting blood sample should be used for the lipid profile estimate of CVD risk in the JBS3 calculator.

• Non-HDL cholesterol, measured from a non-fasting blood sample as total cholesterol (TC) minus HDL cholesterol, should be used in preference to low density lipoprotein (LDL) cholesterol as the treatment goal for lipid lowering therapy.

• Intensive risk factor modification with diet, lifestyle intervention, and pharmacological therapy in patients with existing CVD, without the need for estimation of CVD risk.

• Intensive risk factor modification with diet, lifestyle intervention, and pharmacological therapy, in individuals at particularly high risk of developing CVD: that is, diabetes age >40 years, patients with CKD stages 3–5, or FH without the need for estimation of CVD risk.

• Diet, lifestyle intervention, and pharmacological therapy in people at high short term risk. Thresholds for treatment with statins based on 10-year CVD risk will be informed by National Institute for Health and Care Excellence (NICE) guidelines.

• Diet, lifestyle intervention, and for some people pharmacological therapy in those with increased modifiable lifetime risk, as informed by JBS3 calculator metrics.

Risk model refinement recommendations

• Use of non-invasive imaging tools to detect subclinical atherosclerosis is not recommended for CVD risk assessment in the primary prevention setting. Utility for selected groups of individuals requires further study.

• Currently available novel biomarkers do not replace or enhance established methods for CVD risk assessment in the primary prevention setting, but studies are ongoing.

• Common genetic variants associated with blood lipids and coronary events currently perform less well than phenotype based methods for risk assessment and, except for screening for FH, are not recommended for CVD risk assessment in the primary prevention setting.

Lifestyle recommendations

Childhood and adult obesity recommendations

• Multidisciplinary approaches to obesity management in children and young people are required with a ‘lifetime risk’ message. These may include interventions during the early postpartum period as well as regular monitoring of childhood weight and family counselling.

• With appropriate training, all healthcare professions should be able to Ask and Assess adiposity and Advise appropriate adult patients on evidence based ways to target weight change.

Lipid recommendations

• Non-fasting blood samples should be taken to measure TC and HDL cholesterol (HDL-c). The JBS3 risk calculator enables entry of these two measures and it is expected that non-HDL-c (TC minus HDL-c=non-HDL-c) will replace LDL-c in clinical practice as well as in clinical trials.

• All high risk people should receive professional lifestyle support to reduce TC and LDL-c, raise HDL-c, and lower triglycerides to reduce their CVD risk.

• Cholesterol lowering drug therapy is recommended in:

  • Patients with established CVD

  • Individuals at high risk of CVD: diabetes age >40 years, patients with CKD stages 3–5, or FH

  • Individuals with high 10-year CVD risk (threshold to be defined by NICE guidance)

  • Individuals with high lifetime CVD risk estimated from heart age and other JBS3 calculator metrics, in whom lifestyle changes alone are considered insufficient by the physician and person concerned

• Statins are recommended as they are highly effective at reducing CVD events with evidence of benefit to LDL-c levels <2 mmol/L which, justifies intensive non-HDL-c lowering.

• Statins are safe, with trial evidence showing no effects on non-cardiovascular mortality or cancer. There is a small increase in risk of developing diabetes but the benefits of cholesterol lowering greatly exceed any risk associated with diabetes. If statin intolerance develops a stepwise strategy involving switching agents and re-dosing is recommended.

• Despite low HDL-c values contributing to CVD risk, drug therapy to raise HDL-c has not been shown to reduce CVD risk and is not currently indicated.

Blood pressure recommendations

• Hypertension should be suspected when office blood pressure (BP) is persistently elevated: that is, ≥140/90 mm Hg.

• Ambulatory BP monitoring (ABPM) is recommended to confirm the diagnosis of hypertension (daytime mean ABPM ≥135/85 mm Hg).

• All high risk people should receive professional lifestyle support to reduce their BP which may avoid the need for, or complement the use of, drug therapy for hypertension and reduce CVD risk.

• People with an office BP >160/100 mm Hg, a 24 h daytime ABPM average or home ABPM average of >150/95 mm Hg (stage 2 hypertension) should be offered pharmacological therapy to reduce BP.

• People with an office BP >140/90 mm Hg, but <160/100 mm Hg, a 24 h daytime ABPM average or home ABPM average of >135/85 mm Hg (stage 1 hypertension) and established CVD, hypertensive target organ damage, diabetes, CKD, or a high lifetime risk assessed by JBS3 calculator, should be offered pharmacological therapy to reduce BP.

• People with stage 1 hypertension without established CVD, hypertensive target organ damage, diabetes, CKD, or a significant increase in lifetime risk assessed by JBS3 calculator, should receive advice on lifestyle interventions and be scheduled for annual BP and lifetime risk assessment to inform future need for therapy.

• Pharmacological treatment for patients with hypertension should follow the current NICE guidance (CG127) treatment algorithm:

  • Patients <55 years of age should be offered an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) as preferred initial therapy

  • Patients aged ≥55 years should be offered a calcium channel blocker (CCB) as preferred initial therapy

• Combinations of drug treatment are usually required to optimise BP control for the majority of patients.

• Thiazide-like diuretics are an alternative to CCBs and are preferred for patients intolerant of CCBs, or with heart failure or at high risk of heart failure.

• β-blockers are not preferred, unless there are specific indications for use: that is, in patients with symptomatic angina or chronic heart failure.

• For pregnant women or women planning pregnancy, the recommendations of the NICE guideline CG107 Hypertension in pregnancy should be followed.

Established CVD recommendations

• For all patients with established CVD, an intensive approach to risk factor modification is recommended, including lifestyle intervention and the use of pharmacological therapy for secondary prevention based on NICE, Scottish Intercollegiate Guidelines Network (SIGN), and European Society of Cardiology (ESC) guidance.

• Statins should be prescribed with a ‘lower is better’ approach to achieve values of at least <2.5 mmol/L for non-HDL-c (equivalent to <1.8 mmol/L for LDL-c).

Post-myocardial infarction recommendations

Stroke recommendations

Peripheral arterial disease recommendations

• Patients with PAD should have intensive risk factor modification including intensive statin therapy and BP managed in line with NICE guidelines.

• Patients with PAD should be screened for diabetes and CKD.

• Patients with PAD should be encouraged to exercise, and supervised exercise programmes should be available for appropriate patients.

• Patients with PAD should be started on an antiplatelet agent with clopidogrel being the agent of first choice.

Diabetes mellitus recommendations

Chronic kidney disease recommendations

• In CKD, the JBS3 risk calculator can be used to highlight the increased CVD risk and to guide appropriate risk factor modification.

Chronic inflammatory disease recommendations

• There is clear evidence of heightened CVD risk in patients with rheumatoid arthritis (RA), as summarised in a recent European League Against Rheumatism (EULAR) consensus document.

• The JBS3 risk calculator now incorporates the appropriate multiplier for CVD risk, based on the presence of RA.

• Intensive management of traditional CVD risk factors should be undertaken in patients with RA, taking into account their CVD risk score.

• Optimisation of inflammation suppression with disease modifying antirheumatic drugs may also help reduce CVD risk.

• CVD risk may be lowered by use of the minimum effective glucocorticoid dose for the shortest possible time.

• Where anti-inflammatory drugs are indicated for symptoms in patients with an average gastroduodenal damage risk, the use of a conventional non-steroidal anti-inflammatory drug (NSAID) with a gastroprotective agent is preferable to use of a cyclooxygenase-2 (COX-2) selective inhibitor.

• Clinical judgement may be used to determine whether a risk multiplier should be applied to patients with other autoimmune conditions.

Chronic obstructive sleep apnoea/hypopnoea recommendations

• Lifestyle advice to support weight loss should be offered to all patients with a diagnosis of obstructive sleep apnoea/hypopnoea syndrome (OSAHS) who are obese or overweight.

• Patients with significant daytime sleepiness and confirmed OSAHS should be offered continuous positive airway pressure (CPAP) treatment.

• CVD risk factors should be assessed using the JBS3 risk calculator and managed according to JBS3 recommendations.

Implementation recommendations

• All patients with established CVD should have access to evidence based prevention/rehabilitation programmes addressing lifestyle, risk factor management, and adherence to drug therapies.

• A national screening programme for ascertainment of FH cases should be supported, including cascade screening and specialist referral.

• The JBS3 approach linked to NHS Health Checks should be used to promote better uptake of lifestyle improvements (and where required drug therapy) in primary care. This should include development of a CVD prevention strategy for individuals who, despite low short term risk, are found to have a high lifetime risk of developing CVD and its complications.

1.2.1 Established CVD

Patients with existing CVD, with or without previous clinical events, have the highest level of risk and benefit from intensive lowering of their risk factors, without the need for estimation of risk levels. CVD affects several vascular beds and may have a variety of clinical presentations. There is increasing evidence that the principles of treatment should be similar, regardless of clinical presentation, with risk factor lowering resulting in reduction of CVD events in different territories. For example, statin use in patients who have sustained a stroke results in substantial lowering of future MI rates. JBS3 therefore includes recommendations for the management of patients with PAD and cerebrovascular disease, in addition to clinical cardiac presentations. Individuals and patients without clinical CVD may also be at high risk because of their risk factor profiles or comorbidities. JBS3 defines categories of patients, for example, diabetes, whose short term (10-year) and lifetime risk levels are sufficiently high to mandate pharmacological risk factor lowering without prior risk assessment.

1.2.2 Risk assessment for CVD prevention in the population

Population studies and randomised clinical trials have shown that a given degree of cholesterol lowering produces the same relative reduction in CVD risk regardless of the absolute risk of the group being targeted, so that those at high absolute risk experience the greatest absolute benefit.11 This occurs regardless of the precise combination of risk factors that determines the overall risk level in an individual. For example, statins appear to be as effective in those with high BP or diabetes as in individuals with elevated cholesterol concentrations. The advantage of this ‘risk based’ approach is that it directs preventative treatments to those who stand to gain the most individually. In current UK guidance, pharmacological treatments are recommended to lower cholesterol values (and where appropriate BP) in those whose 10-year absolute CVD risk exceeds a threshold of 20%. This strategy of identification and targeting of individuals at high 10-year risk was developed, however, at a time when effective drugs such as statins were under patent protection (and therefore expensive) and had uncertain long term safety and efficacy. While it has been fit for purpose for over a decade, several developments have prompted a re-evaluation. In the last 5 years, the cost of potent statins has fallen sharply and this has been accompanied by accumulating evidence of their long term safety and benefit. There is also increasing appreciation that the widely used risk equations can accurately assign a group risk (ie, observed group event rates are close to event rates predicted by the risk model), but are less good at distinguishing which individuals will or will not experience a CVD event in the future. The apparent paradox of accurate risk stratification but poor disease discrimination is explained by the fact that a high proportion of events occur among the ‘intermediate risk majority’. Exposure to risk factors is almost universal and factors such as BP and cholesterol have an approximately normal distribution and a log linear association with CVD risk. Thus, individuals with average risk factor levels contribute a substantial proportion of all CVD events. Setting a high threshold for intervention thus misses many people who might benefit and reduces the population impact. Reducing the burden of CVD by broadening the eligibility for pharmacological intervention therefore seems appropriate.

One approach would be to reduce the 10-year absolute CVD risk threshold from the current 20% level. This apparently straightforward solution has been adopted by the latest AHA/ACC guidance which advocates a lowering of the 10-year absolute CVD risk threshold for statin treatment to 7.5% for both men and women.12 Despite a rigorous evidence gathering process, these recommendations have been highly controversial and they have substantial implications for healthcare providers. For example, it has been estimated that the new guidance could result in 33 million adults in the USA being eligible for statins for primary prevention and would apply to approximately 920 million people worldwide were this approach to be adopted internationally. In the UK, the current threshold of 20% already makes around half of all men of >50 years, without clinical CVD, eligible for statins. Adoption of the new US recommended threshold of 7.5% in the UK would result in the great majority of men and a substantial proportion of women >50 years being eligible for preventative use of statins.

1.2.3 Age based approach

One consequence of such a major reduction in threshold for pharmacological intervention is that, beyond a certain age, such a large proportion of the population would be included that estimation of risk levels becomes redundant. A potential alternative approach would be to use an age threshold, for example, 50 years for men, 55 years for women, as the basis for prescription of drugs, without formal estimate of absolute CVD risk. This might involve a statin alone or prescription of multicomponent treatment, for example, a ‘polypill’, aimed at reduction of several CVD risk factors. Both risk stratification with a lower treatment threshold, and an age based selection approach, would greatly expand the indication for drug prescription in the elderly, some of whom may not have modifiable risk factors. The cost effectiveness, acceptability, and implementation challenges of these approaches have yet to be evaluated fully. Importantly, the preferences of people who might be the recipients of drug therapy need to be determined.

1.2.4 Lifetime risk for CVD

Age and gender, which are not modifiable, are such powerful determinants of absolute CVD risk over the relatively short 10-year period, that individuals only cross the pre-set threshold of risk (currently 20%) that mandates drug treatment at an older age, despite having important modifiable CVD risk factors from much earlier in life. In the USA, it has been estimated that up to half of the adult population (predominantly young individuals and women) have a low 10-year CVD risk (<10%), but nevertheless have a high risk of a future event (>39%) over their lifetime.13 With the current approach to risk stratification, such individuals do not get effective risk factor reduction until late in the evolution of their disease, potentially missing the opportunity to influence favourably CVD evolution. Recent risk factor guidelines have attempted to overcome this important problem by ‘extrapolating risk from elderly patients back to younger patients’ but these projections are not easy to understand and are subject to many assumptions.14 There is considerable scope for improvement in the communication of CVD risk to patients and the public.

Most surveys suggest that the majority of the public underestimate their lifetime risk of developing and dying of CVD, considering cancer to be a greater threat despite robust evidence to the contrary.

1.2.5 JBS3 lifetime risk approach

A key change in the new JBS3 Guidelines is the adoption of a ‘lifetime risk’ approach to assess and communicate CVD risk, in addition to 10-year absolute risk estimates. This change is based upon several lines of evidence. Although most CVD events occur after the age of 50 years, the atherosclerotic process begins many years earlier, often from the first decade of life. Studies have confirmed a steady increase in the presence of atherosclerosis with age in individuals dying from non-cardiac causes.15 Exposure to CVD risk factors occurs from early life and this has been shown to promote the progression of this long preclinical phase of arterial disease. In large observational trials, levels of classical CVD risk factors in adolescents (including LDL-c, BMI, smoking, and BP) have been associated with increased carotid intima–medial thickness measurements in adulthood, a marker of emerging arterial disease. The epidemic of obesity and the resulting increase in type 2 diabetes in the young is likely to accelerate disease progression and is predicted to have a substantial adverse impact on the prevalence of CVD in the population over the next 20 years.16

The emergence of CVD appears to be related to long term and cumulative exposure to causal and modifiable risk factors. The Framingham Heart study examined the relationship between CVD risk profiles at the age of 50 years in men and women and the risk of subsequent CVD events, and showed a large difference in outcomes dependent on risk profiles at this age.17 This emphasised the importance of the interaction between risk factors and the arterial wall in early life, suggesting that prevention efforts need to begin earlier. The importance of this risk factor exposure for future CVD was confirmed in a meta-analysis of studies which included more than a quarter of a million men and women, and showed a strong influence of CVD risk factors on lifetime risk of CVD.18 This suggests that there is an opportunity to modify the evolution of disease by earlier intervention.

All studies on the impact of CVD risk factors in the young and the potential benefits of early treatments have been observational and use surrogate measures of CVD. Prospective randomised trials to evaluate the impact of risk factor lowering from a young age on CVD event rates in later life would need to be very long and are not feasible. Indirect evidence from genetic studies, however, and more direct evidence from intervention trials support the concept that a longer period of cholesterol lowering (and other risk factor lowering) could leverage larger reductions in later CVD risk. The Atherosclerosis Risk In Communities (ARIC) study reported that a rare genetic variant in the population resulted in lower PCSK9 values (now an important target for drug treatment), with 28% lowering of lifetime LDL-c concentrations.19 This was associated with an 88% reduction in future CVD events.

More recent work has confirmed that genetic variants which are associated with lower LDL-c values over life are associated with substantially better outcomes than those which can be achieved by equivalent LDL-c lowering with statins in later life.20 FH is perhaps the best example of a monogenic disorder which elevates a causal risk factor, LDL-c, and which results in rapid early manifestations of atherosclerosis and premature CVD morbidity and mortality. In this context, the concept of statin treatment from a young age to reduce lifetime risk is already universally accepted. The benefits of early statin use have been shown on progression of carotid intima–media thickness (cIMT), even in prepubertal children.

Smoking is a further example of lifetime cumulative damage related to exposure. Smoking from age 35–44 years results in approximately one decade loss in life expectancy. Stopping smoking from this age ‘recovers’ approximately 90% of this lost decade but the survival benefit decreases progressively the later smoking cessation is achieved.21 Reduction in exposure to risk factors by CVD prevention efforts in younger individuals is thus an important opportunity for lifetime CVD risk reduction.

CVD risk over lifetime can be estimated and takes into account both risk from CVD and competing diseases such as cancer. As with 10-year absolute risk levels, lifetime risk estimates represent an average derived from large cohorts, and thus, caution must be applied for their use with individual patients. Nevertheless, lifetime risk is a novel way of communicating risk to individuals in a clinical setting.

The JBS3 risk calculator with its range of measures and communication tools, aims to empower patients and the public to make appropriate decisions about their lifestyle and drug treatments based on a better understanding of their personal CVD risks. It addresses three key questions:

• Why should I start CVD risk reduction?

• When should I start?

• What should I do?

The details of the new calculator are provided in the Risk Calculator section, together with the novel metrics for communication and illustrative clinical cases. ‘Heart age’ is calculated by estimating the age of someone of the same gender and ethnicity, and with the same annual risk of an event, but with all other risk factors at their ‘optimal’ levels. Heart age is thus a measure of both relative and absolute risk and is easily understood. An ‘old’ heart age provides motivation to individuals to consider what they might do to bring their heart age back to their real chronological age, thus taking responsibility for their own future health. The age by which an individual might expect, with their current risk profile, to sustain their first CVD event is also presented and represents ‘event-free’ survival. The impact of risk factor reduction, both alone and in combination, on these key measures can be estimated. Several graphic presentations have been developed to facilitate communication with patients of different levels of sophistication. All, however, demonstrate a number of key messages. Firstly, the impact of traditional risk factors such as BP, smoking, and cholesterol on lifetime CVD outcome is strongly reinforced. Even a single major risk factor from early life is associated with substantially increased lifetime risk for CVD. It is clear that even a relatively low risk factor burden over a long period has an important impact on future CVD outcomes. Furthermore, the lifetime benefits of even small reductions in risk factors, when introduced at an early age, are shown. The calculator also demonstrates, for the individual's ‘risk profile’, how delay in initiating risk factor reduction (eg, smoking cessation) greatly reduces the lifetime benefits. It also shows that, for most interventions, it is never too late to obtain some benefit. For the individual, it is possible to calculate the age at which the initiation of risk factor modification provides the greatest lifetime benefit and, for the healthcare provider and/or doctor, the balance of clinical versus cost effectiveness of treatments at different ages can be estimated. This type of mathematical modelling addresses the important issue of when best to start drug treatment from both a clinical and economic perspective.

The concept of projecting CVD risk over lifetime has been incorporated in previous national CVD guidelines (eg, New Zealand) and those for other diseases, for example, respiratory disease using lung age.22 ,23 While this approach may still be novel for the medical community, it has been applied by the insurance industry for many years to determine appropriate levels of insurance premiums. They have long understood that the excess morbidity and mortality associated with most CVD risk factors increases with duration of exposure, and that the benefits of interventions depend on the age of initiation of treatment. Lifetime risk measurement is an adjunct to the estimation of 10-year absolute risk levels. It is not intended primarily as a guide to decisions about drug initiation, but rather as a way of allowing an individual to understand the lifetime consequences associated with their current lifestyle/risk factors, and the substantial opportunity to reduce/delay future CVD events by early appropriate lifestyle changes and drug treatments.

Using the JBS3 risk calculator in practice readily demonstrates a number of key points:

• With current behaviour, individuals have accumulated much of their CVD risk before treatment has started.

• Risk factors combine to determine CVD risk, supporting the global risk factor approach rather than concentrating on a single risk factor.

• ‘Event free life years’ can be gained by multiple early interventions and that the benefit of each can be easily demonstrated for an individual's risk factor profile.

• Delay in instituting appropriate risk factor lowering can greatly reduce the ‘lifetime gains’, so that an optimal age for intervention can be estimated for an individual.

• There are striking health benefits from achieving ‘optimal CVD risk factors’ from early in life.

The JBS3 algorithm for CVD risk assessment and management is shown in figure 1. Patients with established CVD or conditions which markedly elevate their CVD risk do not need risk assessment. They should receive evidence based interventions, as outlined by specialist guidelines and JBS3. In the remainder, 10-year CVD risk should be estimated using the JBS3 calculator. If an individual's risk is above the threshold, CVD risk reduction should be prescribed by lifestyle and pharmacological therapy. The appropriate treatment threshold for 10-year risk is currently under review by NICE. In those whose 10-year CVD risk is below the threshold, the new metrics in the JBS3 calculator, such as heart age, should be used to communicate to the patient/individual the opportunities from lifestyle change and, in some cases, pharmacological therapy.

The JBS3 risk calculator complements the NHS Health Check programme in England. This offers CVD risk factor measurement from the age of 40 years. A 10-year risk estimate from this age is of limited value as the great majority of CVD events occur after 50 years of age. We anticipate that the NHS Health Check programme, together with the lifetime risk metrics in JBS3, will provide an exciting opportunity to communicate better the concepts of CVD risk and the benefits of interventions, including lifestyle and in some cases medications. This approach is novel and the impact on public understanding and behaviour as well as its acceptability will need formal testing. It is important to emphasise that, for the majority, the strong message will be the potential gains from an early and sustained change to a healthier lifestyle rather than prescription of drugs. Adoption of JBS3 recommendations will result in significant changes in the approach to CVD prevention. The cost effectiveness and implications for implementation in different age groups will require evaluation. Ensuring equitable access to effective and safe pharmacological agents for those who would benefit is important, but a greater focus on adoption of healthier lifestyles by the wider population for long term CVD risk reduction is a major challenge. Understanding of the lifetime ‘investment’ opportunities is a key step in encouraging individuals to ‘take control’ of their CVD health agenda and that of their families. Strategies will need to be developed not only by medical experts, but by policymakers, health economists, patients, and the public.

1.2.6 Summary

• Patients with established CVD are at high risk of future events and should be treated with lifestyle interventions and drugs, according to current guidelines and JBS3 recommendations, without the need for CVD risk estimation.

• Individuals with a 10-year absolute CVD risk, currently being reviewed by NICE, should be treated with lifestyle and drug therapy.

• There is justification, from recent safety and efficacy evidence, to widen eligibility for preventative drugs such as statins.

• Absolute risk estimation is heavily dependent on age and gender, so that young people and especially women may not be eligible for treatment, despite having high levels of modifiable CVD risk factors.

• JBS3 has developed a new calculator which addresses this issue and estimates both 10-year CVD risk and CVD risk measures over lifetime.

• New metrics, such as heart age and CVD event-free survival, are displayed to assist communication of CVD risk and motivation for lifestyle change.

• The JBS3 risk calculator will complement the NHS Health Check programme in England. Formal testing of its impact on understanding, behaviour, and outcomes is needed.

1.3.1 Background

A recent review identified at least 70 different CVD risk scoring systems.24 Each system requires a specification of three main components:

• What events are being predicted, for example, CHD, CVD, death?

• What factors are used to make predictions?

• What measure of risk is used?

This section describes the various choices that have been made about the final component, the measures which have been incorporated in the JBS3 risk calculator, and the assumed effects of interventions (appendix 1 contains the technical details).

1.3.2 Approach

1.3.3 Lifetime risk profile

A lifetime risk perspective looks at the development of CVD risk throughout an individual's life, using a variety of summary measures. These include:

• Cumulative risk of CVD: the accumulating risk of a CVD event occurring before each age, retaining in the denominator those individuals who die from other causes and hence who are not available to suffer an event. Risk of a CVD event up to any specified age can be read off from this.

• Survival without CVD: this is a survival curve in which people are withdrawn as ‘failures’ if they suffer either a CVD event or death from another cause. It therefore displays the chance of being alive and without having suffered a CVD event.

• Mean (median) age at first CVD event: the median is simply read off from the preceding survival curve—the mean is the area under the survival curve, added to the current age.

Ulrich et al33 carried out a discrete-time competing risks analysis in 5-year bands, using Framingham for the 5-year CVD risks and Office of National Statistics mortality data for non-CVD risks. This explored a range of measures for communicating the impact of interventions on the long term cause of CVD risk. These have been adapted for use in the JBS3 risk calculator. The Framingham data have been used to create lifetime risk assessments, with allowance for competing risks, for an age range between 50 and 95 years.17 However, these models do not appear to be available for general use. The QRISK Lifetime risks model uses a competing risks analysis, producing both summary CVD risk up to age 95 years, and a curve showing the cumulative risk of a CVD event.34

1.3.4 Intervention assumptions

The table provides an ‘epidemiological’ HR for CVD events, which is the ratio of the daily risks of two different people who differ in this risk factor. However, when assessing the effect of intervening on an individual, it is necessary to decide the HR when an intervention changes the risk factor —that is, the ratio of the daily risks before and after the intervention in the same person. This may be less than the epidemiological HR, but also could be greater.

Direct evidence of the effect of changing behaviour or intervening to change physiological measures comes from clinical trials; it is also possible to make indirect inferences from observing cohort studies. However, evidence is limited and some assumptions are inevitable.

1.3.5 Ongoing and unresolved issues

It is crucial to acknowledge that any numerical summary that is derived from a risk calculator is not the risk of an individual. Many assumptions are used in the calculation, and limited information on each individual is included so that further evidence, such as genetic information, would almost certainly change the assessed risk. It is perhaps best to think of the quoted risk as being constructed on the basis of available evidence from populations and limited information on the individual: it does not exist as an objective state of the world, and hence, it is unreasonable to seek great precision.

Nevertheless, it is reasonable to seek some discrimination, in that different people do get assigned a range of risks, and calibration, so that, for example, when a risk of 70% is quoted for an event, then it will happen in around 70% of cases. Validation details for QRISK Lifetime have been published.34

There are inherent assumptions when population based estimates for risk factor modification effects on CVD outcomes are extrapolated for use in an individual. Nevertheless, these estimates provide the individual with a reasonable guide to the potential benefits of risk modification and emphasise the importance of early intervention of multiple risk factors.

1.3.6 Using the JBS3 risk calculator

The online risk calculator can be accessed at http://www.jbs3risk.com. The profile page highlights that the calculator should not be used for patients with known CVD, where treatment and healthcare professional advice should be followed according to established recommendations. In patients with certain high risk condition such as high BP, diabetes, and CKD, the risk calculator must be used with caution as specific drug treatment and other recommendations may already be indicated in these conditions, as indicated in the relevant JBS3 sections. However, the risk calculator may be of additional help in highlighting the high risk and the benefits of intervention. Note also, that when TC exceeds 7.5 mmol/L the calculator will highlight the possibility of FH, where further assessment is indicated.

The Townsend Quintile score allows the user to input information on social deprivation, where this is available, and can be guided by the visual display. This has some small influence on the risk calculation, but defaults to an average score which should be used when social status is unknown or unclear.

Once the profile page is completed, it is then possible to advance to display estimated CVD risk in various formats, as detailed below. Display of these various formats can be changed from the top menu display. The ‘intervention’ section on the right hand side of all screens (other than the profile page) allows the user to input various interventions to see the effect on CVD risk estimates. More displays are available, revealed using the ‘more’ button on the menu bar.

The following examples demonstrate these various displays and show a number of clinical scenarios to highlight the potential value of the JBS3 risk calculator.

Example 1: young female with adverse risk factors

This example demonstrates the potential effect of early risk factor modification on CVD risk, and the clinical benefits of early versus delayed/no intervention. It also demonstrates the variety of visual displays designed to assist clinical discussion and to facilitate a person's understanding of the importance for them, as an individual, of early lifestyle modification and risk factor reduction.

In addition, it demonstrates some of the disadvantages of using current 10-year absolute risk in young females. Finally, this example demonstrates how the risk calculator can predict optimal time for intervention to achieve the greatest clinical gain and how it might be used to inform the balance of clinical gains versus economic consequences when pharmacological therapy is required in addition to other lifestyle interventions.

Profile of subject 1 (figure 2)

• A 35-year-old female smoker

• Systolic BP of 160 mm Hg

• TC of 7.0 mmol/L, HDL-c of 1.4 mmol/L (non-HDL-c 5.6 mmol/L)

• Family history of premature CVD

The risk calculator estimates this person's heart age to be 47 years (figure 3)—predicting an average survival to the age of 71 years without a CVD event, but a 10-year CVD event risk of 1.9% (figure 4).

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Figure 2

Profile of subject 1.

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Figure 3

Heart age of subject 1 is 47 years.

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Figure 4

Subject 1 has an average survival to the age of 71 years.

The percentage chance of having had a CVD event increases with age as shown in figure 5.

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Figure 5

The percentage chance of having had a cardiovascular disease event by age for subject 1.

Effect of risk factor modification

Intervention in this individual at her current age of 35 years, including stopping smoking and introducing other lifestyle changes and, if necessary, drug therapy to reduce systolic BP to 130 mm Hg and TC to 4.0 mmol/L (non-HDL-c 2.6 mmol/L), has the following effect on her risk profile (figures 6 and 7).

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Figure 6

Effect of risk factor modification on heart age for subject 1.

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Figure 7

Effect of risk factor modification on survival for subject 1.

Heart age is reduced from 47 years to 30 years and the average age to first CVD event is increased from age 71 to age 85, gaining 14 years of expected life without a CVD event through risk factor modification.

These benefits can also be demonstrated graphically comparing the temporal effects of early sustained intervention versus no intervention (figures 8 and 9). Note that as the lines diverge, this indicates the optimal time for risk factor modification to obtain maximum clinical benefit.

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Figure 8

Chance of survival free of heart attack or stroke for subject 1.

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Figure 9

Percentage chance of having had a heart attack or stroke for subject 1.

The clinical benefits of early intervention to modify risk factors are shown in figure 10, demonstrating that, although risk factor modification at any age has some clinical benefit, the number of potential years gained begins to fall off sharply if intervention is delayed beyond the age of 40 years.

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Figure 10

Event-free years gained or lost for the age that intervention starts for subject 1.

The following additional visual displays can also be used to highlight further the value gained for an individual by early intervention, the various displays enhancing the potential impact on different individuals who often resonate more with one particular display. This first display (figure 11) demonstrates outcome with and without intervention as compared to the general population, and shows the substantial impact of intervention at an early age.

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Figure 11

Outcome with and without intervention as compared to the general population for subject 1.

The next display (figure 12) demonstrates the effect of intervention in 100 identical individuals who undertake this level of risk factor modification from age 35–80, with 46 of the 100 individuals being prevented from having a CVD event.

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Figure 12

The effect of intervention in 100 individuals identical to subject 1 who undertake the same level of risk factor modification from age 35–80 years.

This can also be displayed in an alternative format that shows what would happen to 100 people who carry on as usual compared to 100 people who undertake the intervention (figure 13).

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Figure 13

The situation that is expected to occur if 100 people identical to subject 1 carry on as usual.

Or, simply displayed as the difference between the two groups (figure 14).

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Figure 14

The difference between individuals identical to subject 1 who either carry on as usual or receive intervention.

Using the visual displays as above, the risk calculator can demonstrate the difference between early intervention compared to the effect of waiting for the 20% absolute risk threshold to be crossed, which in this individual would occur at age 64 years. Although there are still significant benefits from risk factor modification at age 64 years, these are predicted to be considerably less than those obtained by early intervention at age 35 years under the assumptions stated (figure 15).

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Figure 15

Risk factor modification at age 35 years compared with that at age 64 years for subject 1.

Optimal clinical and economic benefits

As demonstrated, the JBS3 risk calculator is able to display the optimal time for risk factor modification which will provide the maximum clinical benefit over time (figure 10). As the event-free years gained starts to fall off with increasing age, the compound interest in ultimate gain will be reduced.

Where lifestyle modification alone is insufficient to provide the optimal clinical gains in future risk reduction, it is often necessary to introduce pharmacological interventions to optimise risk reduction. Here there is a potential economic consequence which needs to be balanced against clinical gain. The JBS3 risk calculator provides a tool to facilitate this by providing an estimate of event-free years gained per year of intervention (figure 16). Not only does this provide an absolute estimate of the number years gained per year of intervention, which may inform an arbitrary threshold for commencing drug therapy, but it also provides an estimate, within an individual, of the point at which starting therapy provides the maximum benefit per year of intervention.

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Figure 16

Event-free years gained or lost per year of intervention for subject 1.

Note that, for this particular risk profile, the optimal age to start treatment to achieve the maximum gain per year of intervention would be age 50 years. However, it is important to note that commencing treatment at the earlier optimal age for maximum clinical benefit still provides an additional gain for each year of intervention, which will be considerably greater for this individual rather than in others who have a much lower baseline risk profile.

It is not the role of JBS3 and the risk calculator to determine a threshold for intervention with drug therapy, but it does provide a tool which may help inform the selection of the appropriate metric threshold, based on both clinical and economic benefit. Whether this would be based on an absolute value of event-free years gained per year of intervention across a population, the maximum gain per year of intervention within an individual, or a combination of the two, would be a public health policy decision, in conjunction with an informed choice of the individual and their responsible clinician.

Example 2: 35-year-old male with significant risk factors

The JBS3 risk calculator emphasises the potential advantages of early intervention to modify CVD risk factors. Although in many cases this may require the additional introduction of pharmacological therapy, it also highlights the potential benefits of early lifestyle modification. For example, for a 35-year-old male, smoking 20 cigarettes per day, with a TC of 6.8 mmol/L, HDL-c of 1.2 mmol/L (non-HDL-c of 5.6 mmol/L), a systolic BP of 158 mm Hg, and a family history of premature CVD, the risk calculator would predict a heart age of 44 years (figure 17) and an expected age of survival without a CVD event of 66 years, but a 10-year risk of only 3.2% (figure 18).

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Figure 17

Heart age of subject 2.

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Figure 18

Expected age of survival without a cardiovascular disease event for subject 2.

By instituting lifestyle changes alone, stopping smoking, weight reduction, exercise and dietary advice, it would be reasonable to expect a modest reduction in TC to 5.9 mmol/L (non-HDL-c 4.7 mmol/L) and systolic BP to 145 mm Hg, without drug therapy. Heart age would then be reduced to 38 years (figure 19) with an average expected gain of 10 years before a CVD event (figures 20 and 21).

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Figure 19

Effect on heart age of instituting lifestyle changes alone for subject 2.

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Figure 20

Effect of lifestyle changes on age of subject 2 at which a heart or stroke occurs.

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Figure 21

Percentage chance of survival free of heart attack or stroke for subject 2.

However, if intervention was delayed until the age of 60 years, the potential gain, although substantial, would be considerably reduced, even if intensive risk factor reduction with additional drug therapy was instituted at this stage, to achieve more optimal risk factor reduction (BP 130 mm Hg, TC 4.0 mmol/L, non-HDL-c 2.8 mmol/L) (figures 22 and 23). The ‘compound interest’ gained from early lifestyle changes outweighs the benefits from late intervention, even with additional drug therapy.

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Figure 22

Effect of delaying intervention until the age of 60 years for subject 2 on survival without a heart attack or stroke.

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Figure 23

Effect of delaying intervention until the age of 60 years for subject 2 on percentage chance of survival free of heart attack or stroke.

Of course, there are still additional advantages to be gained from this intensive, more optimal risk factor modification at the younger age (figures 24 and 25), where additional drug therapy is likely to be required to achieve this level of risk factor modification. Here, the balance of lifestyle modification alone versus additional drug therapy might merit further discussion with the individual and appropriate advice from their healthcare professional.

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Figure 24

Effect of more intensive risk factor modification at a younger age for subject 2.

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Figure 25

Effect of more intensive risk factor modification at a younger age for subject 2 on percentage chance of survival free of heart attack or stroke.

Example 3: 58-year-old male with multiple risk factors

The JBS3 risk calculator also emphasises the importance of intensive risk factor modification in those with substantial 10-year absolute risk. For a 58-year-old male, who smokes between 10 and 20 cigarettes per day, has a systolic BP of 155 mm Hg and a TC of 6.8 mmol/L (non-HDL-c 5.6 mmol/L), from the least affluent social background Townsend quintile, but with no significant pre-existing family history of CVD, the risk calculator would predict a heart age of 73 years and an average expected age of survival without a CVD event to age 72 years, with a 10-year risk of a CVD event of 17% (figure 26).

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Figure 26

Average expected age of survival without a heart attack or stroke for subject 3.

Intensive risk factor modification including stopping smoking, reducing TC to 3.7 mmol/L (non-HDL-c 2.5 mmol/L), and reducing systolic BP to 125 mm Hg has the effect of gaining an average of a further 7 years without CVD event, as shown in figure 27.

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Figure 27

Effect of intensive risk factor modification on average expected survival without a heart attack or stroke for subject 3.

There are both short and longer term gains, as shown by the reduction in percentage risk of a future CVD event over time (figure 28).

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Figure 28

Percentage chance of having had a heart attack or stroke for subject 3.

1.3.7 Conclusion

The JBS3 risk calculator provides an estimate of short term, 10-year CVD risk as well as longer term ‘lifetime’ risk with the potential benefits of risk factor modification. These are designed to facilitate an informed discussion between an individual and their healthcare professional regarding decisions about lifestyle changes and, where indicated, pharmacological therapy. Different visual displays are likely to resonate more with certain individuals so the spectrum of displays provided within the JBS3 risk calculator allows flexibility healthcare professionals on how to give individuals an understanding of CVD risk and the benefits of intervention. As new evidence evolves, the JBS3 risk calculator can be updated to allow a contemporary understanding of CVD risk and its modification.

1.4.1 Refining CVD risk assessment using new technologies

Risk equations, using traditional CVD risk factors, can accurately assign group risk (ie, observed group event rates are close to event rates predicted by the group model), but perform less well in distinguishing which individual will or will not experience a CVD event in the future. This is largely explained by the fact that the majority of the CVD events occur among those at ‘intermediate risk’. Since the publication of the Framingham risk score in 1976, there have been extensive efforts to identify additional factors which might refine risk prediction over and above the traditional risk factors contained in the score. An important aim has been to identify individuals within the intermediate risk category who are destined to suffer a CVD event in the future (and who therefore might merit pharmacological treatment) as well as those likely to have a good outcome without intervention. This approach is consistent with widespread interest in more personalised healthcare and new technologies.

It should be emphasised that an aetiological role is not a prerequisite for a novel predictive biomarker. The efficacy of a more tailored approach to CVD prevention based on genes, biomarkers, or imaging, is crucially dependant on how well these technologies predict CVD events and how much they add to existing risk equations.

New tools for CVD risk assessment fall into three broad categories: those developed to detect the presence of subclinical atherosclerosis, blood based biochemical markers of CVD risk, and genotype. Their value in clinical practice and implementation will depend not only on predictive accuracy but on their cost, safety, and convenience.

1.4.2 Tools to detect subclinical atherosclerosis

Atherosclerotic lesions develop as early as the first decade of life, advancing with time in many different vascular territories before clinical manifestations occur. These are usually consequent on atherosclerotic plaque rupture, and typically occur beyond the age of 50 years. Several non-invasive imaging methods are now available for detecting subclinical atherosclerosis during this preclinical window.

1.4.3 Blood markers

Atherosclerotic lesions are exposed to the circulating blood, which can be readily sampled by venepuncture. As a consequence a large body of research has documented alterations in lipid subfractions, apolipoproteins, coagulation, and inflammation markers, and other blood constituents in those with or at higher risk of cardiovascular events. The interest in these ‘emerging risk factors’ is twofold: first, in the possibility that one or more might be aetiologically involved in CVD (like LDL-c), and so amenable to therapeutic targeting; and second that information on emerging risk factors might assist CVD risk assessment, which does not necessarily require that the measure is causally involved in the disease.

Of the many hundreds of markers in this category, the most widely studied have been fibrinogen,46 C reactive protein (CRP),47 interleukin 6,48 B-type natriuretic peptide or NT-B-type natriuretic peptide,49 apolipoproteins A1 and B,50 lipoprotein (a),51 and lipoprotein associated PLA2.52

1.4.4 Genotype

Genome-wide association studies (GWAS), which compare the frequencies of many hundreds of thousands of single nucleotide polymorphisms (SNPs) in patients and healthy controls, have identified several susceptibility genes or genetic regions for CHD.61^–63 More are likely to be identified in the future as collaborative efforts to pool genetic data from independent studies progress. As with other common diseases, the effect at each locus is weak (typically a 5–10% increase in risk), the loci are dispersed across multiple chromosomes, each inherited independently, and the effect of each appears to be additive and independent. Few genetic loci for the common forms of stroke have been identified to date, but GWAS are ongoing.

Although these findings are beginning to provide new insights into disease aetiology, the potential for common SNPs of modest effect to improve prediction of CVD is limited.64 The reasons for this are:

1. The risk conferred by any one SNP is small

2. Few in a population carry the very small or very large number of risk alleles sufficient to cause substantial differences in risk; although those who carry a heavy burden of alleles will be at high risk, the number needed to screen to identify such individuals would be very large

3. The frequency distribution of common independently inherited risk alleles for CVD approximates a normal distribution, with most individuals carrying an intermediate number of risk alleles. Because the association with risk is additive, more cases of disease would be expected in the many people with an intermediate number of risk alleles than in the minority with a large number of alleles.

Although the common risk alleles, identified from GWAS, are constrained in their ability to help predict CVD risk, there may be scope for improvements. Genetic tests that capture a wider range of variability in a given gene or region, rather than simply a few SNPs, may help improve genotype based risk prediction in the future.

1.5.1 Introduction

Despite the wealth of information on the risk factors which drive the development of CVD and its clinical consequences, the impact on the behaviour of the public and the overall risk profile has been disappointing. The AHA recently introduced a simple seven-point scoring system for the ‘ideal’ CVD health and in subsequent studies almost no subjects achieved the lowest (best) score.65 Similarly, the Health Survey for England (2012) showed that overall 60% of the adult population met the UK guidelines for aerobic physical activity, yet 55% of men and 47% women, in the lowest income quintile, met the guidelines.66

The JBS3 recommendations emphasise the importance of adoption of a healthy lifestyle for future CVD health in the population. The reductions in CVD risk factors from beneficial lifestyle changes, introduced early and sustained over years, result in substantial gains in later CVD outcomes.

The new metrics incorporated in the JBS3 calculator (in addition to 10-year CVD risk) are designed to facilitate communication of the ‘investment in health’ concept and the value of a healthy lifestyle. Services are available to help deliver appropriate behavioural changes (eg, smoking cessation), but more emphasis on a coordinated approach including weight control, diet, and physical activity is required, with long term adherence. Achieving healthier lifestyles for the public remains a challenge and discussions between healthcare professionals and their patients are not sufficient to deliver change at a population level. A recent cost effectiveness analysis in the USA demonstrated that legislation to mandate lifestyle changes (eg, banning smoking in public places, food composition/pricing) is very effective and the medical profession needs to engage closely with other professional groups, health services management, and politicians.67

1.5.2 Smoking cessation: interventions and specialist services

1.5.3 Diet

1.5.4 Physical activity and exercise

Physical fitness and activity status as part of CVD risk prediction

Physical fitness: There is sufficient evidence for the use of physical fitness levels as a determinant in CVD risk estimation:

• Physical fitness levels above 7 metabolic equivalents (METs) and up to 10.6 METs is associated with the lowest CVD risk

• A one MET increase is equivalent to a 14% reduced risk in premature CVD death.

The MET is a unifying expression of fitness that defines peak levels of activity, as multiples of the energy cost, above that required to maintain a seated position at rest. One MET (or 3.5 mL of oxygen per kilogram of bodyweight per minute) is equal to the amount of oxygen used each minute during seated rest. Walking, at a natural cadence, is equivalent to 3 METs or three times the energy cost of sitting, whereas jogging is equivalent to 7 METs.

Fitness (or exercise capacity) is often measured directly using treadmills or cycle ergometers, which enable physical fitness units (eg, time, speed, gradient, load, and distance) to convert to METs. There are compendiums outlining MET costs for all types of physical activity that can help clinicians tailor physical activity and exercise training prescriptions.164

NICE guidelines recommend the following for physical activity:165

• Over a week, this should add up to at least 150 min (2.5 h) of moderate intensity physical activity in bouts of 10 min or more.

• Alternatively, comparable benefits can be achieved through 75 min of vigorous intensity activity spread across the week or combinations of moderate and vigorous intensity activity.

• All adults should also undertake physical activity to improve muscle strength on at least 2 days a week.

• They should minimise the amount of time spent being sedentary (sitting) for extended periods.

There is recent evidence that certain ethnic groups (eg, South Asian men) may benefit from higher levels of physical activity to improve CVD risk profiles.166

Physical activity status plays a significant role in predicting CVD risk over time. If someone is physically active at the recommended level, they are much less likely to suffer a premature CVD event.159 ,161 Physical activity status (eg, frequency and duration of activity) has been successfully measured using motion devices (eg, pedometers or accelerometers). Alternatively, Leisure Time Physical Activity (LTPA) and sedentary behaviour questionnaires have been successfully used to assess the impact of interventions.

NICE guidance concludes that physical activity:165

• Prevents and helps to manage conditions such as CHD, type 2 diabetes, stroke, mental health problems, musculoskeletal conditions, and some cancers.

• Has a positive effect on wellbeing, mood, sense of achievement, relaxation, and release from daily stress.

In 2007, Haskell et al159 reviewed the evidence and concluded that physical activity interventions were effective, in adults, in the short term. In 2013, Shortreed et al161 investigated the impact of long term physical activity compared to long term inactivity on CVD risk, all-cause mortality, and CVD related mortality using Framingham observational data collected over 40 years. Over time, long term physical activity had a protective effect (stronger in men than women) seen through a lower incidence of all-cause and CVD related mortality compared with physical inactivity.

Cardiac rehabilitation and prevention programmes are proven interventions that improve health related lifestyle outcomes in people with established CVD,167 ,168 and improve risk profiles in those at risk of CVD.169 ,170 The evidence for physical activity and exercise training is presented in figure 29 where it is shown that moderate to high intensity, longer duration approaches are most beneficial.

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Figure 29

Cardiovascular disease risk reduction associated with physical activity and exercise training. CVD, cardiovascular disease; METs, metabolic equivalents.

1.5.5 Summary

• Prolonged sedentary activity should be reduced and interspersed with regular breaks that incorporate physical activity.

• Fitness levels and physical activity status are important in understanding CVD risk profiles and mortality trends.

• When combined with CVD risk scores, physical fitness improves the predictive capability of the estimation in terms of risk reduction and mortality benefit.

• Physical activity and exercise training approaches make a significant contribution to CVD risk reduction and should be included as part of a lifestyle approach.

1.6.1 Obesity in children

1.6.2 Obesity in adults

While there are no randomised trials demonstrating that obesity reversal or prevention lessens CVD, evidence from bariatric surgery,189 and more recently genetic studies,190 confirms that obesity is a causal risk factor for CVD. There is also recent evidence that obesity is causally linked to diabetes, hypertension, and abnormal lipids.191 Thus, prevention or treatment of obesity in adults remains an important means to lessen CVD risk. A discussion about obesity is possible anytime a heathcare professional (HCP) meets a patient, and in general, the HCP should take the following approach, which could be summarised as the 3A's. They should first Ask patients if they are happy and ready to discuss their weight, and potential interventions if required, as not all patients will be. If patients are happy to discuss, the HCP should Assess their BMI and then give Advice on the potential courses of action, dependent on the patients measured BMI and levels of comorbidity. Several clinical guidelines, for example, NICE CG43,185 ,192 ,193 exist for management of obesity in adults and HCPs are directed to these. It should also be recognised that some commercial weight loss providers can be superior to the NHS in helping patients lose weight,194 thereby providing another potential resource for evidence based weight management.

1.6.3 Summary

• While a large proportion of adults are overweight or obese, the increase in population levels of obesity has been fastest in children and young adults.

• Childhood obesity:

  • Tracks to adult obesity

  • Disturbs metabolic profile and BP, even over ‘normal’ BMI ranges

  • Accelerates development of type 2 diabetes

  • Is associated with premature CVD and death.

• Prenatal and early postnatal factors may ‘programme’ higher risk of childhood obesity and permanently alter morbidity and mortality in adult life.

• Early weight restoration may normalise CVD risk.

• Physicians need to play a major role in multidisciplinary approaches to obesity management in children and young adults with a ‘lifetime risk’ message.

• Obesity in adults leads to CVD risk in large part by affecting lipid values, BP, and diabetes risk. Targeting of adult obesity to lessen CVD is an important goal for many individuals.

• With appropriate training, all healthcare professions should be able to Ask, Assess and then Advise patients on evidence based ways to target weight change.

2.1.1 Background

There is a continuous relationship between cholesterol concentrations and CVD risk. This is principally determined by values of TC and HDL-c, both in people with and without CVD. The absolute benefit of cholesterol reduction is related to the level of baseline CVD risk. Compelling evidence for cholesterol lowering comes from statin trials in a range of populations with varying levels of CVD risk.

A Cholesterol Treatment Trialists (CTT) collaboration meta-analysis, based on data from 170 000 participants in 26 RCTs, showed that standard statin regimens typically reduce LDL-c by approximately 30%, but that using either higher doses of traditional statins or utilising newer, more potent statins may reduce LDL-c by up to 50%.11 These most recent analyses show that further reductions in LDL-c (down to between 1 and 2 mmol/L) reduce the incidence of CVD events, and there is no heterogeneity in treatment effect in trials of statins versus placebo, and in the ‘more versus less intensive’ statin trials. The reduction in major CVD events is directly proportional to the absolute LDL-c lowering, with similar relative benefits across the distribution of LDL-c even when the starting LDL-c is already <2 mmol/L. Overall, for a 1 mmol/L reduction in LDL-c a 22% proportional reduction in major vascular events was observed. For a 2 mmol/L reduction in LDL-c a 40% proportional reduction was observed, while a 3 mmol/L reduction resulted in a 50% proportional risk reduction. There was no evidence that such reductions in LDL-c resulted in any adverse events, including haemorrhagic stroke, nor any adverse effect on cancer incidence. This, together with the good safety profile for most statins, supports the use of higher doses of statins in individuals who have sufficient CVD risk to warrant drug therapy.

2.1.2 Treatment approaches

Routine investigations for people with hypertension

People with hypertension should undergo a series of routine investigations to assess their CVD risk and target organ damage, to assist in their risk profiling and in making the decision to treat (box 3).

BP thresholds for treatment

People with a persistently high-normal clinic BP (135–139/85–89 mm Hg) have a high rate of progression to overt hypertension214 and should receive ‘lifestyle advice’ to help reduce their BP and CVD risk, using the JBS3 calculator.⁰³

Recommended lifestyle changes to reduce BP and CVD risk are shown in box 4. Lifestyle modification can also reduce BP and obviate the need for drug therapy in people with stage 1 hypertension, or reduce the number of drugs required to control BP in people with drug-treated hypertension.203 ,215 (For more detailed discussion or lifestyle interventions to reduce CVD see Lifestyle section.)

BP thresholds for intervention with drug therapy are outlined in table 3. People with stage 2 hypertension, including the very elderly (ie, aged ≥80 years), are at sufficiently high CVD risk on the basis of BP levels alone to require drug therapy to reduce their BP. The decision to treat people with stage 1 hypertension will depend on three factors: (1) the presence of clinical evidence of CVD or diabetes; (2) the presence of target organ damage (box 3); and/or (3) their estimated CVD risk using the JSB3 risk calculator. People with stage 1 hypertension and clinical evidence of CVD or diabetes or target organ damage or a 10-year CVD risk estimated to be ≥20%, or a high modifiable lifetime CVD risk, should be offered BP lowering drug therapy.203 People with stage 1 hypertension, but without CVD, diabetes or target organ damage, should have lifetime risk assessment on an individual basis to inform lifestyle strategies. They should have their BP and lifetime CVD risk reassessed annually, and be considered for BP lowering drug therapy based on the benefits of lifetime risk reduction for the individual.

BP treatment targets

The benefits of BP reduction are primarily driven by the quality of BP reduction.216 Systolic BP is generally more difficult to control than diastolic BP.217 Recommended treatment targets are shown in table 3. Although ABPM has been recommended to confirm the diagnosis of hypertension, there is insufficient evidence at present to use anything other than clinic BP to monitor the BP control of treated hypertension.203 Thus, seated clinic BP is recommended to monitor BP control. However, for patients noted to have a pronounced discrepancy between their clinic BP levels and those from ABPM or HBPM at the time of diagnosis, it may be necessary to use ABPM or HBPM to monitor their BP control.

The limited data available suggest that BP should be treated to a seated clinic systolic BP target of <140 mm Hg, aiming for a systolic BP of 130–135 mm Hg. The recommended diastolic BP treatment target is <90 mm Hg, aiming for a diastolic BP of 80–85 mm Hg. These treatment targets apply to all patients except those initiating treatment at the age of ≥80 years, in whom the BP target should be <150/90 mm Hg.203 If ABPM or HBPM monitoring is used to monitor BP control, the BP target would be <135/85 mm Hg, or <150/85 mm Hg in those aged ≥80 years.

Previous guidelines recommended lower clinic BP targets (ie, <130/80 mm Hg) for people with established CVD, diabetes or CKD. However, there are no reliable prospective clinical trial data to support such a recommendation. Furthermore, some post-hoc, retrospective data suggest that, among some subgroups of patients, a J-shaped relationship between systolic BP achieved and CVD risk may pertain.218 ,219 Hence, pending good prospective trial evidence, this lower BP target can no longer be recommended for all high risk patients. However, such treatment targets may still be appropriate in younger high risk patients, but this has not been confirmed in clinical trials. See sections for specific recommendations in diabetes and CKD.

Selection of drug therapy

Randomised controlled clinical trials have consistently demonstrated that BP lowering, based on various classes of drug therapy, is effective at reducing CVD, cerebrovascular and renal morbidity and mortality.207 ,216 Meta-analyses and overviews of treatment of hypertension have concluded that the main driver of benefit from antihypertensive therapy is BP lowering per se.205 ,207 ,216 Furthermore, most hypertensive patients require more than one drug to achieve BP control.220 Thus, the emphasis of treatment is on defining an optimal treatment strategy rather than an optimal drug therapy. The most cost effective drug treatments for hypertension are ACE inhibition or ARBs (A), CCBs (C), or the thiazide-like diuretics (D).203 β-blockers are significantly less cost effective, largely because of less effective stroke and CHD prevention than the aforementioned treatments. ‘No treatment’ is the least cost effective option of all.203 Thus, a trio of treatments A, C, and D should form the basis of the treatment strategy for most people with hypertension.

In clinical trials of BP lowering drugs, most people have required at least two BP lowering drugs to achieve recommended BP targets. In clinical practice in England, the majority (54%) of treated patients receive more than two drugs. Despite this, fewer than two thirds (63%) of treated hypertensive people in England have their BP optimally controlled. A key message is that monotherapy (currently used by 45% of treated patients in England) is usually insufficient therapy for hypertension.

Recommended drug treatment algorithm

NICE, in its most recent hypertension guideline in collaboration with the British Hypertension Society (BHS), recommended a simple treatment algorithm based on the aforementioned trio of treatments (A, C, D) (figure 30), to assist practitioners in logical sequencing and combinations of drug therapy.203

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Figure 30

Hypertension treatment algorithm. ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; CCB, calcium channel blocker.

The recommended drug combinations and sequencing are similar to those used in many contemporary clinical trials of BP lowering drugs.207 ,216 People who are younger (ie, aged <55 years) are recommended to initiate therapy with an A drug (ie, an ACE inhibitor or ARB). This recommendation reflects the fact that younger people generally have a more active renin–angiotensin system, and thus an A drug is likely to be the most effective initial BP lowering therapy. The caveat to this recommendation relates to women of childbearing potential. ACE inhibitors or ARBs should be avoided in pregnancy. In women planning pregnancy or at risk of pregnancy, a β-blocker or methyldopa may be suitable alternatives.221 People aged ≥55 years should receive a CCB as initial therapy. In such patients, a thiazide-type diuretic (ie, chlorthalidone or indapamide) is a possible alternative in those with peripheral oedema, heart failure or at risk of heart failure, such as the very elderly or those intolerant of CCB. For thiazide-type diuretic therapy, low dose therapy with chlorthalidone (12.5–25 mg) or indapamide (2.5 mg or 1.5 mg SR (slow release)) is preferred to low dose conventional thiazide diuretic, for example, bendroflumethiazide or hydrochlorothiazide, as there is no evidence of benefit on CVD outcomes with the latter class of agents.203 A CCB (or thiazide-type diuretic) is also recommended as initial therapy for people of black African/Caribbean origin at any age.

Monotherapy is insufficient to control BP in most patients, and at step 2 a combination of A+C is recommended.220 This is the preferred two-drug combination, unless a thiazide-type diuretic has been indicated. For those in whom BP is still not controlled, step 3 treatment is indicated, that is, A+C+D.203 This treatment strategy should be sufficient to control BP in the majority of patients. Combination therapy can be prescribed as free combinations of drugs or as single pill combinations (hitherto frequently and inaccurately described as fixed dose combinations). Systematic reviews have suggested that single pill combination therapy may improve adherence to treatment,222 BP control,223 and to be cost effective.224 The use of single pill combinations should be preferred, unless a clear cost disadvantage to their use is apparent.

β-blockers are not recommended as part of the treatment algorithm because they are no more effective at preventing CVD events than the recommended alternatives and are less effective at preventing stroke.203 ,225 ,226 However, β-blockers should be considered for patients with others indications for their use, for example, patients with symptomatic angina, heart failure, or post-MI, or in women anticipating or at risk of pregnancy.

Recent trials have also demonstrated that combining ACE inhibitors and ARBs for the treatment of hypertension provides no additional CVD protection, and renal outcomes are worsened when compared with either agent used as monotherapy227; hence, this combination should not be used. Prescribing information for all BP medications should be considered before use.

Resistant hypertension

Resistant hypertension is defined as a BP that is not controlled (clinic BP >140/90 mm Hg) as confirmed by ABPM (daytime average BP >135/85 mm Hg), despite treatment with optimal or best tolerated doses of at least three medications (ideally A+C+D), having excluded treatable causes of secondary hypertension.203 ,228 The true prevalence of resistant hypertension is not known, but is likely to be <10% of patients. This is supported by data from the Health Survey for England, which showed 8% of patients with uncontrolled BP despite prescribed treatment with at least three BP lowering medications. True prevalence estimates for resistant hypertension are confounded by apparent treatment resistance being commonly as a result of poor adherence to treatment.228 ,229 ,230 There have been no formal clinical trials to define the optimal treatment strategy for resistant hypertension. Observational data suggest that further diuretic therapy, most commonly with low dose spironolactone (eg, 25 mg once daily), can be very effective,203 ,231 but renal function and potassium values must be monitored within a month of initiating therapy, and spironolactone should be avoided in people with significant renal impairment (stage III kidney disease) and/or a baseline potassium ≥4.5 mmol/L.203 Even at these low doses (12.5–25 mg once daily), a small proportion (∼6%) are unable to tolerate spironolactone due to gynaecomastia, and in such patients treatment with eplerenone or amiloride can be offered instead. Other treatments, such as α-blockers (based on observational data)232 or β-blockers can also be considered for the treatment of resistant hypertension.203 Patients with resistant hypertension should be referred to a BP specialist.

Renal denervation has emerged as a potential treatment strategy for true resistant hypertension.233 ,234 Data on the safety and efficacy of this technique suggest that the initial findings relating to efficacy may have been exaggerated.

Indications for specialist referral

Most patients with hypertension can be managed in primary care. Some patients, however, should be considered for specialist referral to evaluate further potential secondary causes of hypertension and for advice on the management of treatment resistance or complex cases of hypertension (box 5).

Going beyond BP to reduce CVD risk in hypertensive patients

Patients who present with hypertension should have their CVD risk assessed using the JBS3 risk calculator. Their lifestyle and drug treatment should be guided by their CVD risk, and treatments to reduce other CV risk factors may be beneficial. The Anglo-Scandinavian Cardiac Outcomes (ASCOT) trial demonstrated that statin therapy greatly reduced the risk of CHD and stroke in patients in whom average BP was controlled to the currently recommended BP target, irrespective of the baseline cholesterol value.235 Furthermore, antiplatelet therapy should also be considered in patients with established ischaemic heart disease or prior ischaemic stroke or TIA.

Background

Individuals with prior MI, stroke or AF have already manifest complications of established CVD and guidelines are consistent in prioritising lifestyle interventions and therapeutic prevention strategies. The risks of recurrence and of major complications are sufficiently high to justify secondary prevention treatment in all, except for those with isolated AF and no additional risk factors (CHADS₂VASc score=0).

Although these different CVD conditions share several pathogenic features, there are key differences in the contribution of CVD to their progression and to subsequent complications (figure 31). Thus, they share many secondary prevention strategies, but there are also differences that relate to CV organ specific mechanisms and comorbidity.

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Figure 31

Schematic representation of the contributions of cardiovascular disease to disease conditions manifest in different organ systems.

Treatment approaches to patients with established CVD

NICE, SIGN, and ESC guidelines are consistent in their major secondary prevention recommendations.236^–242

For all patients with established CVD, an intensive approach to risk factor modification is recommended, including lifestyle intervention and the use of pharmacological therapy for secondary prevention. As indicated previously, there are particular considerations for patients with other comorbidities, such as diabetes and CKD.

Nevertheless, the EUROASPIRE III survey reveals major shortfalls in achieving targets: for example, only 48% of those with established CVD achieved smoking cessation, only 34% had regular physical activity, and only 18% had a BMI <25 kg/m². Only 50% achieved BP levels of <140/90 mm Hg and only 55% achieved an LDL-c of <2.5 mmol/L.14

Lipid lowering therapy

Evidence for the benefits of statins in secondary prevention is robust and specific trials have shown early benefit and superiority of more intensive statin therapy.244 ,245 This is manifest by reductions in risk of CVD death, non-fatal MI, ischaemic stroke, and revascularisation. The proportional reductions are independent of the initial LDL-c concentration and hence treatment should be started early during admission, in all patients, with a treatment goal of at least LDL-c <1.8 mmol/L equivalent to non-HDL-c of <2.5 mmol/L. For those with true intolerance to statins, alternative agents including ezetimibe should be considered. Newer approaches to lower LDL-c, for example, PCSK9 inhibitors, are in development (see Lipid section).

There is evidence that low concentrations of HDL-c are associated with increased CVD events (mainly from epidemiological studies).14 Although in some studies, pharmacological approaches to raise HDL-c have shown evidence of improvement in intermediate endpoints, trials have not yet demonstrated improvements in rates of CVD death or MI.

Antithrombotic therapy

Life long aspirin treatment is recommended based upon a meta-analysis of all of the trials in secondary prevention after MI.14 ,236^–243 For long term treatment, lower doses of aspirin are generally used to minimise bleeding complications (70–100 mg). Patients with true intolerance of aspirin (rare) should receive clopidogrel (75 mg/day) as long term secondary prevention.245

Novel approaches to platelet inhibition, involving antagonism of the platelet thrombin receptor, for example, with vorapaxar, have not shown sufficient evidence of a favourable risk–benefit balance to be included in guideline recommendations.246 ,247 In all of the studies of more potent antiplatelet and antithrombotic therapy, there is evidence of a trade-off between efficacy and safety. Identification of suitable patients is critical and patients need to be selected on the basis of the potential for benefit with least increase in bleeding risk (using clinical risk scores for outcome and for bleeding risk). Some patients exhibit reduced inhibition of platelet aggregation with aspirin or with thienopyridines (especially clopidogrel), and it was hoped that in vitro assays of platelet aggregation might identify those with the potential for greater benefit from more potent antiplatelet therapy. Although patients with persistently upregulated platelet aggregation have more adverse CVD outcomes, trials of dose escalation and of more potent antiplatelet agents have not resulted in significantly improved outcomes, but have shown an increase in bleeding hazards.

Dual antiplatelet therapy

In the CURE trial, dual antiplatelet therapy with clopidogrel and aspirin was superior to aspirin alone in preventing a composite of outcome events.248 More potent platelet inhibitors (prasugrel or ticagrelor) have each been shown to be superior to clopidogrel in large scale trials in which the therapies were initiated in the acute phase and continued for approximately 12 months, and hence they are recommended in the guidelines.14 ,240^–243 There is no evidence to support dual antiplatelet therapy beyond 12 months and studies of aspirin plus clopidogrel in patients with CVD disease have not, overall, shown evidence of significant benefit.248 Nevertheless, further trials with novel agents are underway. Some test the novel agent without aspirin, with the aim of minimising bleeding risk.

In the ATLAS-ACS TIMI 51 study, the addition of a low dose of anticoagulation with rivaroxaban was tested on top of antiplatelet therapy, predominantly aspirin plus clopidogrel.249 The optimal balance of benefit versus risk was achieved with the lowest dose of 2.5 mg twice daily rivaroxaban (a quarter of the dose used in AF) and this therapy is approved by the European Medicines Agency. This combination provides an alternative treatment option without increased risks of bleeding. It remains unclear whether this combined therapy is better or worse than aspirin plus a newer antiplatelet agent (ticagrelor or prasugrel).

Stent implantation

Dual antiplatelet therapy is also required to reduce the risk of stent thrombosis and reinfarction. In trials, a thienopyridine plus aspirin was better than aspirin alone, and both prasugrel and ticagrelor have shown a reduced frequency of stent thrombosis compared with clopidogrel treatment (each on top of aspirin). As a consequence, patients who receive a bare metal stent should be prescribed dual antiplatelet therapy for a minimum of 1 month, versus a minimum of 6 months for those who receive a drug eluting stent.14 ,240 ,241 ,243^–245 Robust evidence for benefit compared to risk does not extend beyond 1 year of treatment. Thus, when considering the duration of treatment and, each patient should be assessed in relation to their underlying thrombotic and bleeding risks. Abrupt discontinuations, especially unplanned discontinuations, of dual antiplatelet therapy have been associated with increased risks and particular efforts are required to educate the patients and physicians to manage minor bleeding events without discontinuation of antiplatelet treatments, if possible.250

β-blockers, ACE inhibitors, ARBs

Evidence supports the use of β-blockers after STEMI (for up to 1 year) but is not available beyond this or in other patient groups. β-blockers are indicated in the management of stable ambulant patients with heart failure (together with ACE inhibitors, ARBs, and aldosterone antagonists).245

Detailed consideration of each secondary prevention strategy is beyond the scope of this section and the reader is referred to specific national and international guidelines. 236^–242

Atrial fibrillation

Both rhythm and anticoagulation management are considered in recent ESC guidelines.251 There is robust evidence that AF remains undetected in many individuals and is untreated or poorly managed in many others. The ESC guidelines recommend opportunistic screening for AF in patients over 65 years of age, by taking the pulse and then performing an ECG, if an irregular pulse is detected. There is a class 1A recommendation for antithrombotic therapy to prevent thromboembolism and stroke in all patients with AF, except in those who are at very low risk (age <65 years and lone AF) or in those with contraindications. In those with very low risk (CHA₂DS₂ -VASc score of zero), no antithrombotic therapy is recommended. In those with a CHA₂DS₂-VASc score of ≥2, oral anticoagulation is recommended (class 1A recommendation). The novel anticoagulants show advantage over warfarin and all novel agents reduce the risk of intracranial haemorrhage (dabigatran, rivaroxaban, apixaban, edoxaban). They do not require dose adjustment and do not have the food and drug interactions of warfarin. The ESC guidelines recommend the approved novel agents, where available, over warfarin. For patients who are poorly controlled or unable to manage warfarin, a novel anticoagulant is recommended in the guidelines.

The role of aspirin has been downgraded in the ESC guidelines.251 Recent trials have shown that the risks of bleeding from aspirin can be as high as those of anticoagulation (eg, with a novel agent), and yet the stroke risks are higher with aspirin than with anticoagulation. Bleeding risk should be assessed (eg, HAS-BLED score) in all patients. This may influence the choice of anticoagulant and indicate whether the benefits may outweigh the risks.

AF in stroke patients

Anticoagulation should be considered for TIA or cerebral infarction patients with permanent or paroxysmal AF where underlying cerebral haemorrhage has been excluded.252 Anticoagulation should be delayed for 2 weeks in those with a severe disabling cerebral infarction.

Background

Despite the falling stroke incidence and mortality over the last decade,253 in the UK there are approximately 150 000 strokes per annum, nearly 50 000 of which are recurrent events. There are an additional 40 000 TIAs.

Treatment approaches

Ongoing and unresolved issues

The SPS3 trial in patients with lacunar stroke failed to show that BP treatment to lower levels (systolic BP <130 mm Hg) resulted in improved stroke prevention compared to higher treatment values (systolic BP 130–140 mm Hg). The study, however, was probably underpowered and there is a clear need to define appropriate BP targets after stroke for both cerebral infarct and PICH patients.268 Although lipid lowering with statins following ischaemic stroke is of benefit, optimal lipid levels and the timing of stating treatment after cerebral infarct remain unclear. The best treatment of patients who have a cerebral ischaemic event while on an antiplatelet agent is also unclear. The risks, especially in terms of significant haemorrhage on long term dual antiplatelet therapy (eg, aspirin plus clopidogrel), seem to outweigh any potential benefits. With the current ability to manage more intensively CVD risk factors, it is uncertain whether intensive medical treatment offers advantages compared to current standard therapy in secondary stroke prevention, while remaining cost effective and not increasing the risk of adverse side effects.

Smoking cessation

Smoking is the strongest risk factor for PAD and current smokers are almost four times as likely to develop asymptomatic PAD as non-smokers.281 However, no benefit of cessation on walking distance has been found in four cohort studies.282 Nevertheless, in terms of CVD and respiratory health, it remains an important part of management in PAD patients.283 ,284

Physical activity and exercise

The risk of PAD is inversely related to previous levels of physical activity, suggesting a protective effect of exercise.285 A Cochrane review of 22 studies showed that compared with usual care or placebo, exercise significantly improved maximal walking time and distance with an overall improvement in walking ability of 50%–200%.286 Supervised exercise therapy has the best effects.287

Antiplatelet therapy

Antiplatelet therapy can reduce the risk of fatal and non-fatal CVD events in PAD patients. Evidence from meta-analyses confirms that the long term use of antiplatelet agents reduces the rate of MI and ischaemic stroke in patients with symptomatic PAD.288 ,289 NICE recommends clopidogrel as the agent of choice in PAD, rather than aspirin.267

In the CAPRIE trial of clopidogrel versus aspirin, the benefits of clopidogrel over aspirin were most pronounced in the PAD subgroup (relative risk reduction 23.8%).290 In the CHARISMA trial of clopidogrel and aspirin versus aspirin alone, there was no benefit for dual antiplatelet therapy overall or in the PAD subgroup.291 In patients with intermittent claudication, antiplatelet therapies are associated with lower all-cause and CVD mortality compared with placebo. Compared with all antiplatelet therapies, the strongest evidence exists for thienopyridines, such as clopidogrel.292

Lipid lowering therapy

Statins have a wide range of benefits and all PAD patients should receive them, if tolerated.283 ,284 ,293 A systematic review of lipid lowering therapies in PAD, including 18 trials, found no significant effect on overall mortality or on total CVD events.294 However, a subgroup analysis did show a reduction in coronary events. Pooling of the results from several small trials of a range of lipid lowering agents indicated an improvement in total walking distance and pain-free walking distance but no significant impact on ankle brachial index (ABPI). The conclusion was that lipid lowering therapy is effective in reducing CVD mortality and morbidity in people with PAD, and may also improve local symptoms. A separate systematic review has confirmed the beneficial effect of statins on intermittent claudication (IC) distance.295 Currently, the use of a statin in people with PAD is recommended by most guidelines as an essential part of PAD management.283

Hypertension

Both the HOPE study and more recently the ASCOT trial have reported on subgroups of patients with PAD and have shown that they obtain the same benefit as other groups of patients with CVD, without an increase in adverse event rates.296^–298

In a Cochrane review of BP control in PAD, four studies were included.299 The conclusion was that evidence on various antihypertensive drugs in people with PAD is poor, so that it is unknown whether significant benefits or risks accrue from their use. However, lack of data, specifically examining outcomes in PAD patients, should not detract from the compelling evidence of the benefit of treating hypertension and lowering BP available from other sources.

Background

An increased risk of CVD in type 1 diabetes was observed over 30 years ago.300 While earlier reports indicated a four- to 10-fold relative risk compared with a younger control population without diabetes,301^–307 a more contemporary large study in Scotland observed a lower relative risk of CVD of 2.3 in men and 3 in women.308 The risk of CVD is highest among those with diabetic nephropathy. A reduced incidence of nephropathy has been observed over this period, 301 ,302 ,30,9 so it appears that there has been a reduction in CVD incidence in the last 10–20 years.

There is uncertainty as to whether type 1 diabetes, acquired in childhood, accelerates CVD in all cases.3,10 Studies demonstrate that the most consistent predictors of CVD risk are age and markers of nephropathy, primarily albuminuria.302^–307 ,310^–31,2 Measures of dyslipidaemia, such as reduced HDL-c and hypertriglyceridaemia and, to a lesser extent, central adiposity, independently predict higher CVD risk.307 ,31,1 ,31,2 Although albuminuria has primacy in CVD risk prediction, the presence of proliferative retinopathy and autonomic neuropathy also independently added to the risk.307 ,3,10 ,31,1 There is a need to develop CVD risk scores specifically for patients with type 1 diabetes.

Treatment approaches

Background

Over 3 million (5%) of the UK population above the age of 17 years are now known to have diabetes. Type 2 diabetes had been considered as a CHD risk equivalent in terms of future CHD risk.325 It is now clear, however, that at point of diagnosis, diabetes is not a CHD risk equivalent condition,326 and certain features are required to escalate CHD risk, notably longer duration of diabetes,327 ,328 and/or presence of proteinuria.329

In the Emerging Risk Factor meta-analysis, the risk for CVD events in patients with diabetes patients was twice that of non-diabetic individuals330 and, at a population prevalence of 10%, diabetes accounts for 11% of CVD deaths. Individualisation of care in identifying cardiometabolic targets and choices of therapy is now recommended practice (NICE and ADA-EASD (European Association for the Study of Diabetes)-ESC), with a need for more intensive glucose lowering therapy earlier, especially in younger patients, and, in contrast a more conservative approach to glycaemic control and BP lowering in those aged >65 years, especially with established CVD.

Treatment approaches

Background

Several pieces of evidence suggest that aspirin efficacy in primary prevention of CVD in diabetes is compromised. A meta-analysis of >140 000 subjects reported that antiplatelet agents used in primary prevention (mainly aspirin) resulted in a 22% reduction in CVD events, but, in a subgroup of around 5000 diabetes subjects, the risk reduction was only 7% and not significant.347 In the Primary Prevention Project (PPP) trial involving 4495 subjects, aspirin treatment was associated with a 31% relative risk reduction of CVD events, but individuals with diabetes (n=1031) had an 11% relative risk reduction, which again did not reach statistical significance.348

Two other primary prevention studies, JPAD and POPADAD, failed to show an impact of aspirin on CVD events in diabetes.349 ,350 However, JPAD demonstrated an overall benefit in the older population and also a reduction in fatal CVD events in whole study cohort, without affecting total mortality. POPADAD was conducted in individuals with evidence of PAD and could thus be regarded as a secondary prevention study. Events rates were low in both studies.

In a meta-analysis of six studies, aspirin had no significant effect when used for primary prevention in diabetes.351 In the small Steno 2 study of high CVD risk in microalbuminuria, however, aspirin was part of a multiple risk reduction strategy and this approach was associated with a significant reduction in CVD.352 It is not, however, possible to determine the specific benefit attributable to aspirin. In contrast, it is generally accepted that aspirin is effective in secondary CVD prevention in diabetes.353

Treatment approaches

Aspirin therapy, for primary prevention of CVD in type 1 diabetes, is not currently indicated. The only potential exception is in patients with established nephropathy in whom CVD risks are very high, but further trial evidence is required to confirm this.

In type 2 diabetes, aspirin use for primary prevention is similarly no longer recommended.

Blood pressure

Most trials of BP lowering, involving people with CKD, have examined progression of kidney damage rather than CVD events as an outcome. These trials have assessed both optimal BP and how best to achieve BP control using available antihypertensive regimens. Long term follow-up of individuals in the Modification of Diet in Renal Disease (MDRD) study indicated that treatment to a tighter BP target of 125/75 mm Hg instead of 140/90 mm Hg slowed progression of kidney disease in non-diabetic individuals, but this benefit was only seen in those with proteinuria (>1 g/24 h).364 This finding was endorsed by a long term follow-up of participants in the African American Study of Kidney Disease and Hypertension (AASK) trial, among whom tighter BP control slowed progression, but again only in proteinuric individuals (protein: creatinine ratio (PCR) >350 mg/24 h).365

Trials involving people with proteinuric CKD who do not have diabetes have generally favoured the use of agents that block the renin–angiotensin–aldosterone pathway over alternative strategies, at least from the perspective of slowing kidney disease progression.297 ,366 It is less certain whether the use of ACE inhibitors or ARBs is associated with cardiovascular benefits in individuals with CKD without diabetes and/or proteinuria. Several large studies comparing these agents with alternative antihypertensive strategies have included people with CKD, but analysis of data from these subgroups is inconsistent.

Thus, recommendations for the management of BP in people with CKD stage 3–5 are largely based on our understanding of the cardiovascular benefits of BP reduction in non-CKD populations, the knowledge that ‘tighter’ control of BP slows progression of kidney damage, and that agents that block the renin–angiotensin–aldosterone system may have clinical benefits over other BP lowering agents, particularly in proteinuric individuals. The NICE CKD guideline recommends controlling BP to <140/<90 mm Hg in people with CKD, unless the ACR is ≥70 mg/mmol or PCR ≥100 mg/mmol, in which case the BP should be <130/<80 mm Hg.356 These levels are endorsed by an international guideline published by Kidney Disease: Improving Global Outcomes (KDIGO) in which the albuminuria ‘cut off’ for the lower BP target was 30 mg/day.367 Both the NICE and KDIGO guidelines recommend offering agents that block the renin–angiotensin–aldosterone system to individuals with albuminuria/proteinuria, although again the thresholds for intervention are somewhat different. The more recent KDIGO guideline suggests that these agents should be used even in the presence of microalbuminuria (urinary albumin excretion 30–300 mg/day).

Lipids

CKD is generally associated with elevated triglyceride and low HDL-c values.368 Except in people with heavy proteinuria, total and LDL-c are normal or low compared to a matched population without CKD.369 Furthermore, the value of measuring TC and LDL-c concentrations in an effort to stratify CVD risk, particularly in advanced CKD, is uncertain.370 Although elevated lipid concentrations may not be the main driver of CVD in the context of CKD, the available data generally support the use of lipid lowering regimens to reduce the risk of CVD events. Post hoc identification of people with CKD stages 1–3 recruited into large ‘statin’ trials suggest that lipid lowering therapy reduces the risk of CVD events, as in individuals with normal kidney function.371 More robust, prospectively collected data are available from the SHARP study in which 9270 people with CKD (including 6247 with predominantly stages 3–5 disease not receiving dialysis at the time of recruitment) were randomised to receive either the combination of ezetimibe 10 mg plus simvastatin 20 mg or placebo.372 With an average LDL-c difference of 0.85 mmol/L (with about two thirds compliance) during a median follow-up of 4.9 years, there was a highly significant 17% reduction in major CVD events among those randomised to ezetimibe/simvastatin, as would be predicted from a meta-analysis of existing LDL lowering trials in predominantly non-CKD populations.244 Subgroup analysis on baseline total and LDL-c showed the expected trends with a greater proportional effect observed among those with higher baseline values. The approach to LDL lowering used in SHARP using a statin/ezetimibe combination avoided exposing patients to high doses of statin. Whether a similar reduction in CVD events could have been achieved with a high dose of statin alone (achieving an equivalent LDL-c reduction), with an acceptable number of adverse events, is uncertain. Recent international guidelines from KDIGO recommend that people with stages 3–5 CKD not receiving dialysis are offered a statin (or statin/ezetimibe combination), particularly if >50 years of age or at an arbitrary higher level of risk based on risk prediction equations.373

Aspirin

There have been no appropriately sized trials of aspirin examining CVD clinical endpoints in any CKD population. Some data are available from post hoc analyses of large trials. For example, in the Hypertension Optimal Treatment trial, aspirin was of benefit in a subgroup of individuals with stage 3 CKD at the time of recruitment.374 There is very little information about the effects of aspirin among those people with CKD stages 4–5 and an increased risk of minor bleeding is recognised which may offset any benefits.375 A recent Cochrane review concluded that this hazard may outweigh any benefits of aspirin in people with CKD.376

Cardiovascular impact of obstructive sleep apnoea

Obstructive sleep apnoea (OSA) is part of a spectrum of sleep related breathing disorders ranging from simple snoring through to obesity related hypoventilation syndrome. It is defined and diagnosed by the presence of apnoeic/hypopnoeic episodes that occur during sleep that are associated with oxygen desaturations followed by an arousal characterised by sympathetic nervous system activation. These are caused by either cessation of airflow (apnoeas) or reduction in airflow (hypopnoeas). The most common presenting symptoms are daytime sleepiness and loud snoring associated with witnessed apnoeas. This comprises obstructive sleep apnoea/hypopnoea syndrome (OSAHS). Severity is assessed by a combination of symptoms and objective evidence of apnoeas/hypopnoeas measured during an overnight sleep study. An apnoea/hypopnoea index (the number of events per hour slept) of <5 is considered normal; 5–14, mild; 15–30 moderate; and >30 severe.399 OSAHS is common in obese patients with multiple cardiometabolic risk factors and therefore included in JBS3. It is not yet clear to what extent it may contribute directly to CVD events or be a marker for increased CVD risk.

The overall population prevalence of OSAHS in adults is around 4% in men and 2% in women, but it is much more common in the obese; about 1% of men will have moderate to severe OSAHS. Epidemiological studies have shown associations with cardiometabolic risk factors, including hypertension, dyslipidaemia, insulin resistance, and the development of type 2 diabetes that is partly independent of adiposity400 ,401; this has also been observed in well matched case–control studies.402^–404

This increase in risk factors translates into increased CVD risk. The magnitude of the effect depends on the severity of OSAHS and the presence or absence of preceding CVD, but overall a diagnosis of OSAHS results in a two- to fourfold increase in CVD events, including MI, stroke, CVD mortality, and sudden death.405 ,406

Mechanisms

There are several possible mechanisms by which the presence of OSAHS might adversely affect CVD risk, but their relative importance is uncertain. The cardinal features of OSAHS are intermittent nocturnal hypoxia and sleep disturbance, both of which might directly and indirectly influence CVD risk.402

Identified mechanisms for which there is supporting experimental evidence include:

• Increased sympathetic nervous system activity as a result of repeated arousals from sleep—this may contribute to rise in BP and heart rate, and potentially increase risk of cardiac arrhythmias; it could also contribute to increased insulin resistance and impaired insulin secretion.

• Increased activity of the hypothalamic–adrenal axis—this occurs as a result of sleep disruption and could contribute to development of hyperglycaemia and dyslipidaemia.

• Intermittent hypoxia—this occurs as a direct result of apnoeic episodes and may contribute to insulin resistance and development of an inflammatory state (a recognised feature of sleep apnoea) in adipose and other tissues.

Chronic kidney disease

Even modest impairment of kidney function increases CVD, but the mechanisms linking CVD mortality and CKD remain poorly understood. Current treatment strategies rely on close attention to conventional CVD risk factors in the CKD population. Nevertheless, epidemiological evidence suggests that there are other factors over and above these that confer particular CVD risk and further research is needed to identify them.

Chronic inflammatory disease

The pathophysiological basis for the well established link between chronic inflammatory disease and increased CVD risk is poorly understood and has been complicated by the relatively recent recognition that some NSAIDs can increase CVD event rates, independently from their effects on the underlying inflammatory disease. There is limited evidence on which to base CVD prevention strategies specifically in patients with chronic inflammatory diseases and much more research needs to be done in this group of patients. The opportunity to reduce CVD risk by anti-inflammatory agents, in patients with CVD but no other chronic inflammatory disorders, is currently being tested in large randomised trials. The findings will be important both for the understanding of pathophysiology and potentially for treatment.

Obstructive sleep apnoea/hypopnoea syndrome

Patients with OSAHS are at increased risk of CVD events, but the underlying mechanistic links remain poorly understood. There is no research based evidence to guide preventive treatment of this group. Further research is therefore clearly needed to determine whether the increased CVD risk is mediated through conventional risk factors that can be addressed with existing treatment approaches, or whether managing the apnoea itself, for example, with CPAP, confers any independent protection against future CVD events.

Peripheral arterial disease

PAD is common and frequently undetected despite there being a cheap and reliable clinical tool to identify it—measurement of ABPI. Patients with PAD are at high risk of future heart attacks and strokes, yet ABPI is rarely measured in primary care. Research is needed to establish whether ABPI can meet the criteria needed for recommendation by the National Screening Committee. In comparison with coronary disease and cerebrovascular disease, less research has been performed on risk factor modification in PAD. Studies are needed to determine the most effective preventive strategies in patients with PAD, who are often older and may have more advanced disease at the time of detection.

Cerebrovascular disease

While most of the measures taken to prevent ischaemic heart disease have similar or equivalent protective effects against stroke, many questions remain unanswered on how best to approach prevention in someone who has already experienced a stroke. Thus further studies are needed to determine the choice and timing of statins, antihypertensive and antiplatelet therapies following the initial event.

The past decade has seen an unprecedented increase in the prescription of drugs to healthy individuals, in the expectation that future CVD events will be delayed or averted. But drugs can have side effects and unexpected consequences, both beneficial and detrimental, that randomised clinical trials are sometimes unable, for a variety of reasons, to identify. Most such effects become apparent long after the drug has been in widespread clinical use. For example, evidence gained from patient databases has pointed to an unexpected potential protective effect of aspirin against the incidence and dissemination of some cancers, while similarly derived data on ARBs, used widely in the treatment of hypertension and heart failure, failed to confirm a postulated link between these drugs and cancer. Observations like these provide a powerful argument in favour of the current move in England to making anonymised NHS patient data more readily available to researchers. The emphasis in JBS3 in long term management of CVD risk should encourage more research in the population and in primary care.

The approach to CVD prevention tends to be similar in men and women and in different ethnic groups, yet there is substantial evidence that both CVD risk and possibly also response to preventive medication may differ by gender and ethnic origin. Further research is therefore needed both in the form of prospective randomised trials and in the form of patient data surveillance to establish how best to achieve equitable CVD prevention across both genders and different ethnic groups.

Diet

While it is beyond doubt that diet has a significant influence on health, the evidence base for the contribution of specific dietary components to the development of CVD is not generally based on outcomes of randomised clinical trials, but is derived primarily from epidemiological observations. For this reason, dietary guidelines are necessarily based on expert interpretation of available data and will consequently be subject to challenge. Hence debates are likely to continue on the relative importance of different dietary components such as saturated fats, salt and sugar to the development of CVD. Access to large, population based datasets, linked to better biomarkers of dietary exposure and related genetic signals, may help to improve evidence to help refine future recommendations.

Physical activity

The effectiveness of exercise based rehabilitation is well established in research populations, but more studies are needed to test whether it delivers equivalent benefits in wider populations. Greater emphasis should be placed on high quality observational audit based research which uses data collected from patients accessing cardiac rehabilitation and prevention programmes. Further research using objective measures of activity as well as further high quality trials would also be beneficial.

Multifactorial programmes

A comprehensive, multifactorial programme to improve lifestyle and adherence to treatments is recommended, but currently, evidence for the effectiveness for this approach is weak. Further research is needed to determine how best to translate the impact of single factor interventions to multifactorial prevention programmes.

Recommendations

• The new JBS3 risk calculator should be assessed formally in different populations and the attitude of the public to CVD prevention over lifetime needs to be evaluated.

• The role of genetic testing, novel circulatory biomarkers and imaging for subclinical CVD to refine risk estimation needs to be determined, particularly in subjects at ‘intermediate risk’.

• The mechanisms by which a variety of associated diseases, eg, CKD, adversely affect CVD needs further study. This should provide novel targets for treatment.

• Research is required on how best to deliver sustained improvements in CVD outcomes from multifactorial prevention programmes involving lifestyle change and drug treatments.