After reading this article, you should be able to:
- Identify people at high risk of cardiovascular disease (CVD), or those with established CVD, who may benefit from lifestyle or pharmacological interventions to reduce their CVD risk;
- Support the implementation of lifestyle changes that will reduce a person’s individual CVD risk;
- Undertake a shared decision with a patient to initiate and monitor statin therapy for primary and secondary prevention of CVD;
- Consider alternative or additional lipid-lowering therapy if a person is not treated to target on maximum dose/maximum tolerated statin therapy.
Cardiovascular disease (CVD) is a general term for conditions affecting the heart or blood vessels. It is usually associated with a build up of fatty deposits inside the arteries (atherosclerosis) and an increased risk of blood clots. It can also be associated with damage to arteries in organs such as the brain, heart, kidneys and eyes. Four of the main types of CVD are coronary heart disease; stroke and transient ischaemic attack (TIA); peripheral arterial disease; and aortic disease.
CVD is a significant cause of mortality and morbidity, accounting for a quarter of all deaths in the UK. CVD death rates increase with age, male gender and in the winter months. Furthermore, death from CVD increases three-fold among people living in the most deprived communities compared to those living in more affluent areas. Within the UK, the highest rate of CVD mortality is in Scotland; although the lowest rate is in England, there is still a mortality variation between the highest (Yorkshire and Humber) and the lowest (south east of England) geographical areas.
Government policies have recognised the need to improve CVD outcomes, citing this as the single biggest area where the NHS can save lives, in addition to it being largely preventable through lifestyle changes, including smoking cessation, weight management, reducing alcohol misuse and improving food policies. These themes are also reflected in the Scottish ‘Heart Disease Action Plan 2021’ and the ‘Keep Well’ programme, which sets out the priorities to minimise preventable heart disease and ensure equitable and timely access to diagnosis, treatment, and care for people in Scotland[3,4].
The scale of the challenge has increased with the impact of COVID-19, which has led to the unintended consequence of worsening cardiovascular health within the UK population and hence renewed calls to focus on CVD prevention and treatment as a health priority.
This article will discuss opportunities to support:
- People at increased risk of CVD but who have not been diagnosed (primary prevention);
- People already diagnosed with CVD (secondary prevention).
Opportunistic testing may identify a person who is at increased CVD risk; however, a more systematic approach is required. Primary care services, including community pharmacy teams, have a vital role to play. This may be through formalised programmes, such as the NHS Health Check programme, which was introduced in England in 2009 with the ambition of detecting early signs of stroke, kidney disease, heart disease, type 2 diabetes mellitus and dementia in adults aged 40–74 years. The programme is aimed at people who do not have underlying CVD/CVD-related conditions and should be offered every five years. An infographic containing details of the programme is available from the NHS Health Check website. Depending on local commissioning, health checks may be delivered via a GP surgery, community pharmacy or other community- or work-based programme.
People already diagnosed with underlying CVD (secondary prevention) or those who have already been identified as being at high risk of CVD (e.g. people with diabetes or diagnosed hypertension) are excluded from the NHS Health Check programme as they should already receive regular monitoring and review.
During the COVID-19 pandemic, the NHS Health Check programme was suspended, and delivery dropped close to zero in the first quarter of 2020/2021(see Figure).
In addition, it is recognised that inequitable access to the NHS Health Check programme may have significant adverse effects on the health of certain populations. As a result, there is an added focus to extend the health check offer to:
- People with a learning disability, who often have poorer physical and mental health, as an annual health check from the age of 14 years (NHS target of 75% by 2024);
- Anyone aged 18 years or over who has schizophrenia, bipolar disorder, or psychosis through offering a free health check once per year.
All community pharmacies offer Healthy Living services, which give pharmacists the opportunity to initiate conversations around CVD risk. In addition, the Community Pharmacy Hypertension Case-finding service also provides an opportunity to identify people at increased risk of CVD through blood pressure checks. Further details on the management of high blood pressure and the service specification are beyond the scope of this article. This enhanced community pharmacy service targets people aged over 40 years who have previously not been diagnosed with hypertension, and allows onward referral to general practice for those requiring further management. These types of services may offer a gateway to wider conversations regarding CVD risk and prevention, and provide an opportunity to ask people about CVD risk factors (with the limitation of lack of access to the full clinical record). Pharmacy teams should be aware of services in their local area and use these conversations to signpost people to local and national services.
Assessment of cardiovascular disease risk
There are several CVD risk assessment tools available. The tools have some commonality, but are derived from different populations so have nuances in terms of the required data and outputs. Recommendations for the UK are detailed in National Institute for Health and Care Excellence (NICE) and Scottish Intercollegiate Guidelines Network (SIGN) guidance[8,9].
Cardiovascular risk assessment calculators are used to predict the likelihood of a cardiovascular event occurring over a given time period. The main risk calculator used in England and Wales is QRISK, which is derived from a UK population. This tool is used to generate an estimate of CVD risk (heart attack, angina, stroke or TIA) in the next 10 years in people aged 25–84 years. As the QRISK tool is designed to estimate CVD risk in the general population, it should not be used to estimate risk in groups where CVD risk factors are increased. These include:
- People who already have CVD (e.g. angina, heart attack, peripheral arterial disease, stroke or TIA). This group should receive secondary prevention and will have already been identified as being at increased risk. They should also have a specific treatment and follow-up plan in place;
- People who are at high risk of developing CVD because of familial hypercholesterolaemia (FH), or other inherited disorders of lipid metabolism, where the risk of premature CVD is increased and the QRISK tool will underestimate the person’s risk. Clinical guidelines for FH should be followed;
- Those aged 85 years or over. For this group, advanced age alone places them at high risk of developing CVD. An individualised management plan is needed depending on comorbidities and patient preferences;
- Patients with type 1 diabetes mellitus. The QRISK tool (or an alternative) has not been validated in this group;
- Chronic kidney disease (CKD) is a risk factor for CVD. The QRISK tool is not recommended for people with CKD with an estimated glomerular filtration rate of less than 60mL/minute/1.73m2 and/or albuminuria, as they are already identified to be at increased CVD risk.
Most of the information required to produce a QRISK score can be gained from a short conversation with the patient. In many instances, it will be possible to identify high-risk patients without needing to access their full medical record and signpost on for further intervention where appropriate.
Patient identification/risk stratification
The QRISK 2 tool is most commonly used in England and Wales as this is embedded in most GP practice clinical systems; however, the tool was updated in 2018 to QRISK 3. It was recognised that the QRISK 2 tool may underestimate CVD by as much as 10% in some patient groups. Box 1 outlines the additional risk factors included in QRISK 3, which is now recommended by NICE. It is important for any healthcare professionals still using QRISK 2 to be aware of these additional risk factors.
Box 1: Additional risk factors for cardiovascular disease added to QRISK 3
- Expanded definition of chronic kidney disease (CKD) to include CKD stages 3-5;
- Systemic lupus erythematosus;
- Severe mental illness;
- Erectile dysfunction;
- Prescription for regular corticosteroids;
- Prescription for atypical psychotics;
- A measure of systolic blood pressure variability.
A low QRISK 3 score of less than 10% risk of CVD over the next 10 years should still be seen as an opportunity to re-enforce lifestyle advice, with ongoing review, as future risk will change over time. However, if the QRISK 3 score is 10% or more, this should lead to a conversation regarding both lifestyle, consideration of statin therapy to reduce CVD risk and, where relevant, addressing other CVD risk factors, such as blood pressure or diabetes management. In Scotland, similar principles are applied in primary prevention and the ASSIGN risk calculator is used. Using the ASSIGN risk calculator, people should be considered at high risk if they are assessed as having a 20% or more risk of a first cardiovascular event within 10 years.
However, all of these calculators have limitations. Of note, CVD risk may be underestimated in young people, those who are already taking antihypertensives or lipid-regulating drugs, or those who have recently stopped smoking. Interpretation of risk scores as well as the need for further management of risk factors in those who fall below the CVD risk threshold should always reflect informed clinical judgement. To aid discussion with younger people, an option is to use the QRISK lifetime score or the Joint British Societies 3 Risk Calculator, which estimate short-term (10-year) and lifetime risk of CVD events[8,13].
A person with established CVD will already be identified as being at increased risk of future CVD; therefore, risk assessment tools are not required. However, it is essential that pharmacy teams provide support for lifestyle modification and the prescription of, and ongoing support for adherence to, lipid-lowering therapy.
Management (primary and secondary prevention)
Irrespective of the individual patient’s level of risk, lifestyle modification is considered an integral part of CVD management.
Alongside general practice, which has embraced social prescribing to help support patients, community pharmacy teams have an important role in supporting and signposting patients to national and local services. Lifestyle modification includes weight management, healthy eating, alcohol moderation, increasing exercise/physical activity and smoking cessation.
With the prevalence of obesity increasing in both adults and children, tackling obesity is a national priority. There are various sources of support available, including the NHS Digital Weight Management programme — a 12-week, online programme. General practice and community pharmacies can refer people over the age of 18 years with a body mass index (BMI) of 30kg/m2 or more (adjusted to ≥27.5kg/m2 for people from black, Asian and ethnic minority backgrounds) with a diagnosis of diabetes mellitus (type 1 or type 2), hypertension or both. Some people may be prescribed medication to support weight loss, such as orlistat or semaglutide (2.4 mg by subcutaneous injection once a week), and/or be referred to specialist weight loss services where they may be considered for surgical intervention[17–20].
‘Heart-healthy’ eating has been promoted for many years in the UK and the Eatwell Guide (not suitable for children aged under 2 years) outlines the main recommendations. In addition, it is recommended that adults should have no more than 6g of salt (around 1 level teaspoon) in their food per day. This includes the salt that is already in our food as well as the salt added during and after cooking. Vegetable oil that are high in saturated fats, such as coconut oil and palm oil, should also be avoided.
Men and women are advised not to drink more than 14 units of alcohol per week, which should be spread across 3 days or more, and to avoid binge drinking. People should be encouraged to have several alcohol-free days each week. In general practice, the AUDIT C tool is often used to support conversations around alcohol usage.
Increasing exercise/physical activity
For good physical and mental health, adults should aim to be physically active every day. The guidance for adults is:
- At least 150 minutes of moderate or 75 minutes of vigorous activity/week;
- Strength building exercise at least twice per week;
- Minimise sedentary periods — break up periods of inactivity;
- In older adults, undertake activity to improve balance and reduce the risk of falls.
The General Practice Physical Activity Questionnaire is commonly used to support conversations in general practice around physical activity.
In the UK, in 2021, 13.3% of people aged 18 years and over smoked cigarettes, which equates to around 6.6 million people in the population. Incidence is higher in males than females, with the highest proportion in those aged 25–34 years. In addition, around 4 million adults report daily or occasional e-cigarette use and, while vaping is not completely risk free — with the long-term effects still unknown — it is thought to be significantly less harmful when compared with cigarette smoking[26,27]. Community pharmacy teams are ideally placed to deliver smoking cessation services and are often commissioned to do so.
Lipid modification therapy
The aim of lipid modification is to reduce CVD risk. The risk assessment tools outlined above are used to identify people without established CVD who may benefit from pharmacological intervention for primary prevention (in addition to lifestyle modification). People at higher risk of CVD where these risk tools are not appropriate (e.g. those with established CVD, FH or CKD) should also be offered lipid-lowering medication. The NHS has produced a summary of national guidance for lipid management for primary and secondary prevention of cardiovascular disease, which can be used in everyday practice.
Statins as first-line therapy
Since the publication of the first statin trial for secondary prevention in 1994, several statin-based trials have been published across a range of CVD risk populations. The Cholesterol Treatment Trialists’ Collaboration meta-analysis of data from 22 trials of statin therapy versus control (n=134,537) and five trials of more-intensive versus less-intensive statin therapy (n=39,612) confirmed that, for prevention of major vascular events, statin therapy is of similar effectiveness in males and females, with a 22% relative risk reduction with each mmol/L drop in low-density lipoprotein cholesterol (LDL-C).
NICE recommend prescribing a statin that will result in a reduction in non-high-density lipoprotein (non-HDL-C) of at least 40%. Table 2 details the relative potencies of statins. Atorvastatin 20mg once per day is recommended as the first-line option for all primary prevention indications. For secondary prevention, a high-intensity, high-potency statin is the first-line option with atorvastatin 80mg once per day recommended, unless there is a high risk of adverse effects, potential drug interactions, patient preference, or CKD (where 20mg is recommend as the starting dose). Rosuvastatin offers a cost-effective alternative (with the caveat of a starting dose of 5mg once per day and maximum dosage of 20mg once per day in patients of Asian ethnicity).
An alternative strategy to percentage reductions in non-HDL-C or LDL-C is to use target lipid levels — a strategy (combined with percentage reductions) used in other guidelines, including those from the European Society of Cardiology. Anecdotally, many clinicians prefer target levels, as calculation percentage reductions can be complex to work from in everyday practice.
Targets to improve lipid management in patients with established CVD have also been introduced into primary care as part of the Quality Outcomes Framework (QOF) indicators for primary care in England. In April 2023, each GP practice in England was able to earn up to 30 QOF points (see Table 3) if certain percentage thresholds were met. This represents a £36m investment in lipid management within England for 2023/2024.
Starting a statin
The decision whether to start statin therapy should be made after an informed discussion between the clinician and patient about the risks and benefits of statin treatment, considering additional factors, such as benefits from lifestyle modification, informed patient preference, comorbidities, polypharmacy, general frailty and life expectancy. This shared decision-making process is essential as the ‘nocebo effect’ (negative expectations of the patient regarding a treatment leading to reporting more negative effects, even if they are prescribed a placebo) and ‘statin reluctance’ (an attitudinal state of aversion to taking statins, often without prior exposure) can act as barriers to the clinical effectiveness of statin therapy.
In addition to the lipid profile, baseline blood tests should include liver blood tests, renal function, thyroid function (as hypothyroidism is a secondary cause of hyperlipidaemia and will increase the risk of statin induced myopathy) and HbA1c. This will help identify any contra-indications and rule out any secondary causes of high cholesterol, such as untreated hypothyroidism, nephrotic syndrome, or liver and/or alcohol-related issues.
A baseline creatine kinase (CK) is not required unless the person has generalised unexplained muscle symptoms (e.g. pain, tenderness or weakness), whether associated or not with previous lipid-lowering therapy.
Drug interactions with statins
There are some significant drug interactions with statins that may affect choice of statin or limit the maximum dosage that can be prescribed. Many, but not all, of the interactions are owing to inhibition of the cytochrome P450 3A4 pathway. Simvastatin is the most affected in the class, but atorvastatin is often also affected. In 2014, an alert from the Medicines and Healthcare products Regulatory Agency highlighted medicines that commonly interact with simvastatin and atorvastatin. These include macrolide antibiotics, antifungal agents, medicines for HIV, calcium channel blockers, amiodarone, warfarin and ciclosporin; this is not an exhaustive list and up-to-date information should be consulted, as well as consideration of potential interactions with herbal and over-the-counter medicines.
Grapefruit/grapefruit juice also inhibits statin elimination via the P450 pathway, so should be avoided when taking simvastatin and limited to no more than a small glass of juice per day in patients taking atorvastatin.
Adverse effects of statins
Some people who take statins experience muscle pain and/or weakness. Although data from clinical trials suggest that the numbers do not differ much between those patients allocated to active treatment or placebo, in clinical practice, a significant minority of patients will complain of this side effect. It is most likely to occur in the first 3–12 months of treatment and may be more common in people with underlying comorbidities, such as increasing age, renal impairment, hypothyroidism, Asian ethnicity or female gender, or as a result of drug interactions. It tends to affect the large muscle groups and to be symmetrical in nature. Rarely, some people taking statins have developed rhabdomyolysis — abnormal muscle breakdown, which can lead to kidney problems and be life threatening. If a patient reports side effects suggesting muscle problems with a statin, a blood test for CK should be undertaken. If there is only a mild increase in CK (less than four times the upper limit of normal) with tolerable symptoms, the patient can be reassured and, in most cases, the statin can be continued unchanged. For more symptomatic patients or those with a larger rise in CK, alternative strategies will be needed, depending on severity of the symptoms, magnitude of the rise in CK and clinical urgency. More detailed guidance can be found in the national statin intolerance pathway.
Other adverse effects or cautions with statins include:
- Hepatic toxicity: statins are contra-indicated in active liver disease. Minor increases in liver enzymes (transaminases) are often seen in the first three months of statin therapy. Temporary discontinuation and further assessment is recommended if levels exceed three time the upper limit of normal;
- New onset diabetes: some people who take statins are at greater risk of diabetes (whether they take a statin or not). It is considered that the risk of statin-induced diabetes is low and outweighed by the potential benefits of reduced CVD risk;
- Common side effects (one in ten) include allergic reactions, headache, nausea, gastrointestinal disturbances, inflammation of the nasal passages, pain in the throat or nose bleeds. Statins are contraindicated in pregnancy and those breastfeeding[8,34,37].
Statin intolerance is defined as the presence of clinically significant adverse effects from statin therapy that are considered to represent an unacceptable risk to the patient or that may result in adherence to therapy being compromised. For people who are intolerant of the initial recommended statin, treatment options may include trying a lower dose of the same statin or switching to an alternative statin (in the absence of contraindications; ideally, at least three different statins should be tried).
In some patients, alternate day, or once or twice weekly, dosing strategies may be tolerated and can then be successfully up-titrated. More details can be found in the statin intolerance pathway.
Alternative or additional lipid-lowering treatment to lower cardiovascular disease risk
Two to three months after starting treatment, the lipid profile should be reviewed to assess response to therapy. For those people who do not achieve the required reduction in LDL-C or non-HDL-C, despite the maximum or maximum tolerated dose of statin, or who are unable to tolerate statins at all, additional or alternative options should be considered. In the past two years, treatment options have expanded with the introduction of new medicines, many of which can be used in combination.
Treatment options include:
Ezetimibe — the addition of ezetimibe to a statin will result in a further 15–20% reduction in LDL-C and, with proven tolerability alongside outcome data from the Improve-IT trial, is usually the next option[8,38].
Alirocumab or evolocumab — these are monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) from binding to LDL-receptors, which results in an increase in the number of LDL-receptors available to remove LDL-C from the circulation. The patient self-administers by subcutaneous injection every two to four weeks. These treatments result in a 50–60% reduction in LDL-C (in addition to that achieved by a statin), have outcome data and are approved by NICE and the Scottish Medicines Consortium (SMC) for high-risk patients[39–42]. They are currently restricted to initiation by specialists.
Bempedoic acid — licensed for the treatment of primary hypercholesterolaemia and approved by NICE and SMC (albeit with different approval criteria) as an adjunct to treatment with ezetimibe[43,44]. It does not have the muscle side effects of statins but may increase the risk of gout. The first outcome trial for bempedoic acid was recently published, providing data to support the use of bempedoic acid in statin-intolerant patients to reduce CVD events.
Inclisiran — another injectable option that works by harnessing the intrinsic process of RNA interference to increase hepatic LDL-C uptake and reduce LDL-C levels in the bloodstream. Clinical trial data show a reduction of LDL-C of around 50%. There should be a clear discussion with the patient that while current trials demonstrate the effectiveness in LDL-C reduction, data relating to the effect on CVD events is still awaited. Currently, inclisiran has been approved for secondary prevention by NICE and the SMC for high-risk secondary prevention patients, and for primary prevention for people with FH[46,47]. The recommeded schedule is for a single subcutaneous injection initially, again at three months and then followed by every six months[46,47].
Icosapent ethyl — a highly purified eicosapentaenoic acid ethyl ester, which lowers triglycerides. The REDUCE-IT trial demonstrated that addition of icosapent ethyl in patients with elevated triglyceride levels, despite the use of statins, reduced the risk of ischemic events, including cardiovascular death. Icosapent ethyl has been approved by NICE and SMC for this secondary prevention cohort[49,50].
Identification and appropriate intervention for people at increased CVD risk will help to improve their chances of living longer, healthier lives and reduce the burden of CVD on the healthcare system. There are many opportunities in everyday practice for pharmacy teams to make a significant contribution to this important public health goal.
Lifestyle modification is essential, but identification of people that would benefit from medication for primary or secondary prevention is also needed. Statins are the first-line medication, but an increasing number of other therapies are now available to use in addition or as alternatives to stain therapy. To maximise the benefits primary and secondary prevention measures, ongoing support for adherence to lifestyle and pharmacological treatments is vital.
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