Lipid modification and cardiovascular risk assessment for the primary and secondary prevention of cardiovascular disease: summary of updated NICE guidanceBMJ 2014; 349 doi: https://doi.org/10.1136/bmj.g4356 (Published 17 July 2014) Cite this as: BMJ 2014;349:g4356
- Silvia Rabar, senior research fellow and project manager1,
- Martin Harker, senior health economist1,
- Norma O’Flynn, clinical director and guideline lead1,
- Anthony S Wierzbicki, professor of cardiometabolic disease 2
- On behalf of the Guideline Development Group
- 1National Clinical Guideline Centre, Royal College of Physicians, London NW1 4LE, UK
- 2Guy’s and St Thomas’ Hospitals, London, UK
- Corresponding author: S Rabar
Cardiovascular disease (CVD) is the leading cause of death in England and Wales, accounting for almost a third of deaths. An update of existing National Institute for Health and Care Excellence (NICE) guidance (published in 2008)1 was necessary in light of new evidence on the efficacy and safety of statin therapy,2 on the effects of combining statins with non-statin drugs,3 4 5 and on novel risk assessment tools for predicting risk of CVD.6 Since the previous guideline, more statins have become available as generic drugs, and this has changed the cost effectiveness of statin treatment. The scope of the update included risk assessment for CVD and the use of lipid modification in people with type 1 diabetes, type 2 diabetes, and chronic kidney disease.
This article summarises the most recent recommendations from NICE on lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease.7
NICE recommendations are based on systematic reviews of best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on the guideline development group’s experience and opinion of what constitutes good practice. Evidence levels for the recommendations are given in italic in square brackets.
Assessing the risk of CVD
Full formal risk assessment
Use the QRISK2 risk assessment tool6 to assess CVD risk for the primary prevention of CVD in the general population, including people with type 2 diabetes. QRISK2 cannot be used in people over 84 years of age.
The available risk tools do not adequately assess risk in certain people. Do not use a risk assessment tool to assess the risk of CVD in people with:
-Type 1 diabetes
-Evidence of estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2 or albuminuria (or both)
-Familial hypercholesterolaemia or other inherited disorders of lipid metabolism.
Use clinical judgment to interpret CVD scores because CVD risk assessment tools provide only an approximate value for CVD risk.
CVD risk may be underestimated in people with underlying medical conditions or treatments. These groups include:
-People being treated for HIV
-People with serious mental health problems
-People taking drugs that can cause dyslipidaemia such as antipsychotic drugs, corticosteroids, or immunosuppressants
-People with systemic inflammatory disorders such as systemic lupus erythematosus
-People who are already taking antihypertensives or lipid modifying drugs
-People who have recently stopped smoking
-Severely obese people (body mass index greater than 40).
(New recommendations.) [Based on low quality cohort studies and the experience and opinion of the Guideline Development Group (GDG)]
Communication about risk assessment and treatment
Set aside adequate time during the consultation to provide information on risk assessment and use everyday jargon-free language to communicate information on risk.
Offer people information about their absolute risk of CVD and about the absolute benefits and harms of an intervention over a 10 year period. This information should be in a form that:
-Presents individualised risk and benefit scenarios
-Presents the absolute risk of events numerically
-Uses appropriate diagrams and text.
To encourage people to participate in reducing their CVD risk:
-Find out what, if anything, they have already been told about their CVD risk and how they feel about this
-Explore their beliefs about what determines future health (this may affect their attitude to changing risk)
-Assess their readiness to change their lifestyle (diet, physical activity, smoking, and alcohol consumption), to undergo investigations, and to take long term drugs
-Assess their confidence in making changes to their lifestyle, undergoing investigations, and taking drugs
-Inform them of potential future management based on current evidence and best practice
-Involve them in developing a shared management plan
-Check with them that they have understood what has been discussed.
(These recommendations are from the 2008 guideline.)
Cardioprotective diet for prevention of CVD
Take account of people’s individual circumstances—for example, drug treatment, comorbidities, and other lifestyle factors when giving dietary advice.
Advise people at risk of CVD, or those with CVD, to:
-Reduce saturated fat intake from animal sources: this also reduces monounsaturated fat levels
-Replace saturated and monounsaturated fats with olive oil, rapeseed oil, or spreads based on these oils, and use them in food preparation
-Choose wholegrain varieties of starchy food
-Reduce intake of sugar and food products containing refined sugars, including fructose
-Eat at least five portions of fruit and vegetables a day
-Eat at least two portions of fish a week, including a portion of oily fish (pregnant women should limit oily fish to no more than two portions a week and avoid marlin, shark, and swordfish)
-Eat at least four to five servings of unsalted nuts, seeds, and legumes a week
Do not advise people to take foods or supplements enriched with plant stanols and sterols because there is no evidence for benefit on CVD outcomes.
(New recommendations.) [Based on low and very low quality randomised controlled trials and the experience and opinion of the GDG]
Lipid measurement and referral
Measure a full lipid profile (total cholesterol, high density lipoprotein (HDL)-cholesterol, non-HDL-cholesterol, and triglyceride concentrations) before starting lipid modification therapy. A fasting sample is not needed.
Do not use lipid cut-off values alone to judge the likelihood of a familial lipid disorder but combine these with the clinical findings and family history. Exclude possible common secondary causes of dyslipidaemia (such as excess alcohol, uncontrolled diabetes, hypothyroidism, liver disease, and nephrotic syndrome) before referring for specialist review.
If total cholesterol concentration is more than 7.5 mmol/L (1 mmol/L=38.61 mg/dL) and the person has a family history of premature coronary heart disease, consider the possibility of familial hypercholesterolaemia.8
If total cholesterol concentration is more than 9.0 mmol/L, or the non-HDL-cholesterol concentration is more than 7.5 mmol/L, refer the person to specialist care even in the absence of a first degree family history of premature coronary heart disease.
If the triglyceride concentration is more than 20 mmol/L (1 mmol/L=88.5 mg/dL) and not a result of excess alcohol or poor glycaemic control, refer the person to specialist care.
If the triglyceride concentration is 10-20 mmol/L, repeat the measurement with a fasting test (after an interval of five days, but within two weeks) and review for potential secondary causes of hyperlipidaemia. Seek specialist advice if the triglyceride concentration remains above 10 mmol/L.
If the triglyceride concentration is 4.5-9.9 mmol/L, the CVD risk may be underestimated by risk assessment tools.
(New recommendations.) [Based on the experience and opinion of the GDG]
Statins for the prevention of CVD
For the purpose of the guideline, statins are grouped into three different intensity categories according to the percentage reduction in low density lipoprotein cholesterol. This grouping was agreed by GDG consensus, informed by analyses in the literature (table⇓).9
The decision about whether to start statins should be made after an informed discussion between the clinician and the person about the risks and benefits of statin treatment, taking into account factors such as potential benefits from lifestyle modifications, informed patient preference, comorbidities, polypharmacy, general frailty, and life expectancy.
Before starting statins perform baseline blood tests and clinical assessment, and treat comorbidities and secondary causes of dyslipidaemia. Include all of the following in the assessment:
-Body mass index or other measure of obesity11
-Total cholesterol, non-HDL cholesterol, HDL-cholesterol and triglycerides
-Glycated haemoglobin (HbA1c)
-Renal function and estimated glomerular filtration rate
-Transaminase level (alanine aminotransferase or aspartate aminotransferase)
-Thyroid stimulating hormone.
(New recommendations.) [Based on the experience and opinion of the GDG]
Discuss the benefits of lifestyle modification and offer people the opportunity to have their risk of CVD assessed again after they have tried to change their lifestyle before starting statins for primary prevention. If lifestyle modification is ineffective or inappropriate offer statin treatment after risk assessment. (New recommendation.) [Based on the experience and opinion of the GDG]
Offer atorvastatin 20 mg for the primary prevention of CVD to people who have a 10% or greater 10 year risk of developing CVD (estimated with QRISK2). (New recommendation.) [Based on high to moderate quality evidence from randomised controlled trials, cost effectiveness analysis, and the experience and opinion of the GDG]
In people with type 1 diabetes
Offer atorvastatin 20 mg for the primary prevention of CVD to people with type 1 diabetes who are over 40 years, have had diabetes for more than 10 years, have established nephropathy, or have other CVD risk factors. (New recommendation.) [Based on the experience and opinion of the GDG]
In people with type 2 diabetes
Offer atorvastatin 20 mg for the primary prevention of CVD to people with type 2 diabetes who have a 10% or greater 10 year risk of developing CVD (estimated with QRISK2). (New recommendation.) [Based on high to moderate quality evidence from randomised controlled trials, cost effectiveness analysis, and the experience and opinion of the GDG]
Start statin treatment for the secondary prevention of CVD with atorvastatin 80 mg.
Use a lower dose of atorvastatin if there are potential drug interactions (for example, with clarithromycin, systemic azole, antifungal agents), there is a high risk of adverse effects (for example, in older people, people with low muscle mass or impaired renal function), or because of patient preference. (New recommendations.) [Based on high to moderate quality evidence from randomised controlled trials, cost effectiveness analysis, and the experience and opinion of the GDG]
Do not delay treatment to manage modifiable risk factors. (New recommendation.) [Based on the experience and opinion of the GDG]
People with chronic kidney disease
Offer atorvastatin 20 mg for the primary or secondary prevention of CVD to people with chronic kidney disease. Increase the dose if a greater than 40% reduction in non-HDL-cholesterol is not achieved and eGFR is 30 mL/min/1.73 m2 or more. Agree the use of higher doses with a renal specialist if eGFR is less than 30 mL/min/1.73 m2. (New recommendation.) [Based on high to moderate quality evidence from randomised controlled trials, cost effectiveness analysis, and the experience and opinion of the GDG]
Follow-up of people started on statin treatment
Measure total cholesterol, HDL-cholesterol and non-HDL-cholesterol in all people who have been started on high intensity statin treatment at three months of treatment and aim for a greater than 40% reduction in non-HDL-cholesterol.
If a greater than 40% reduction in non-HDL-cholesterol is not achieved, discuss adherence and timing of dose and optimise adherence to diet and lifestyle measures. An increase in dose should also be considered if the person was started on less than atorvastatin 80 mg and is thought to be at higher risk of cardiovascular disease because of comorbidities or risk score, or using clinical judgment
Discuss with people who are stable on a low or medium intensity statin the likely benefits and potential risks of changing to a high intensity statin when they have a medication review, and agree with the person whether a change is needed.
Provide annual medication reviews for people taking statins.
-Use these reviews to discuss adherence to drugs, lifestyle modification, and CVD risk factors.
-Consider an annual non-fasting blood test for non-HDL-cholesterol to inform the discussion.
(New recommendations.) [Based on the experience and opinion of the GDG]
Advice and monitoring of adverse effects
Advise people taking statins that some drugs, foods, and supplements can interfere with statins and to consult the patient information leaflet, a pharmacist, or a prescriber for advice when starting other drugs or thinking about supplements.
Remind people to restart the statin if they stopped taking it because of drug interactions or to treat intercurrent illnesses.
Before offering a statin, ask people if they have had persistent generalised unexplained muscle pain, regardless of whether it was associated with previous lipid lowering drugs. If present, measure creatine kinase levels:
-If creatine kinase levels are more than five times the upper limit of normal re-measure within five to seven days. If creatine kinase levels are still five times the upper limit of normal, do not start treatment
-If creatine kinase is raised but less than five times the upper limit of normal, start statin treatment at a lower dose.
Advise people who are being treated with a statin to seek medical advice if they develop muscle symptoms (pain, tenderness, or weakness). If this occurs, measure creatine kinase.
If people report muscle pain or weakness while taking a statin and have previously tolerated statin therapy, explore other possible causes of muscle pain and raised creatine kinase. Do not measure creatine kinase in asymptomatic people who are being treated with a statin.
Measure baseline liver transaminase enzymes (alanine aminotransferase or aspartate aminotransferase) before starting a statin. Measure liver transaminase within three months of starting treatment and at 12 months, but not again unless clinically indicated.
Do not routinely exclude people from statin therapy if liver transaminase levels are raised but are less than three times the upper limit of normal.
Do not stop statins because of an increase in blood glucose level or HbA1c.
Statins are contraindicated in pregnancy. Advise women of childbearing age of the potential teratogenic risk of statins and to stop taking them if pregnancy is a possibility. Advise women planning pregnancy to stop taking statins three months before they attempt to conceive and to not restart them until breast feeding is finished.
(New recommendations.) [Based on high to moderate quality evidence from randomised controlled trials and the experience and opinion of the GDG]
Intolerance to statins
Aim to treat people with the maximum tolerated dose of statin.
Tell people that any statin at any dose reduces the risk of CVD. If someone reports adverse effects when taking high intensity statins discuss the following possible strategies:
-Stopping the statin and trying again when the symptoms have resolved to check if the symptoms are related to the statin
-Reducing the dose within the same intensity group
-Changing the statin to a lower intensity group.
Seek specialist advice about other options for treating people at high risk of CVD (such as those with chronic kidney disease, type 1 diabetes, type 2 diabetes, or genetic dyslipidaemias), and those with CVD who are intolerant to three different statins. Advice can be sought, for example, by telephone, virtual clinic, or referral.
Do not offer coenzyme Q10 or vitamin D to increase adherence to or to reduce muscle related adverse events from statin treatment because there is no evidence of benefit.
(New recommendations) [Based on low quality evidence from randomised controlled trials and the experience and opinion of the GDG]
Fibrates, nicotinic acids, bile acid sequestrants (anion exchange resins), and omega-3 fatty acid compounds
Do not routinely offer fibrates, and do not offer nicotinic acids, bile acid sequestrants (anion exchange resins), or omega-3 fatty acid compounds, alone or in combination with a statin, for the prevention of CVD because there is no evidence of benefit. (New recommendations.) [Based on high to very low quality randomised controlled trials and the experience and opinion of the GDG]
These recommendations introduce the use of non-HDL-cholesterol rather than low density lipoprotein-cholesterol and lower the threshold at which it is cost effective to offer statins for primary prevention. Those who are likely to be offered statins will already be identified using the NHS Health Check (a universal health screening programme for people aged 40-70 years designed to identify those with a high risk of developing CVD, diabetes, or renal disease).12 However, more people will require a meaningful explanation of their risk, lifestyle advice, explanation of the trade-off between benefits and potential harms, and monitoring for side effects. Tools have been developed to help explain cardiovascular risk and potential benefits of treatment13; NICE is currently developing a patient decision aid on risk assessment and preventive treatment for cardiovascular disease (publication expected autumn 2014).
A cost-utility analysis was conducted to compare the cost effectiveness of high intensity, medium intensity, and low intensity statins versus placebo in primary prevention; no total risk modification trial has looked at lifestyle and drug therapy simultaneously. The cost effectiveness analysis also took into account costs other than the price of the drug—for example, costs of consultations with a general practitioner, initial blood tests, and monitoring. It found that high intensity statins were cost effective at a cost effectiveness threshold of £20 000 (€25 040; $34 276) per quality adjusted life year gained compared with all other options for secondary prevention. High intensity statins were also cost effective for primary prevention in patients with CVD risk levels above thresholds that varied by age and sex from 2.4% to 7.3% for atorvastatin 20 mg and from 3.4% to 11.6% for atorvastatin 80 mg.
Further information on the guidance
This update makes a clear recommendation for the use of QRISK2 as the preferred cardiovascular disease (CVD) risk assessment tool, including people with type 2 diabetes. The threshold for consideration of statin treatment has dropped from 20% CVD risk in the next 10 years in the previous guideline to 10% CVD risk. The guideline recommends the use of non-HDL-cholesterol rather than low density lipoprotein-cholesterol because non-HDL-cholesterol does not require a fasting sample. This should make assessment and monitoring easier.
The Guideline Development Group (GDG) followed standard NICE methods in the development of this guideline.14 The GDG comprised two consultants in metabolic medicine and chemical pathology, two consultant physicians with an interest in diabetes, a cardiologist, two general practitioners, a medicines information pharmacist, two patient or carer members, and a lipid nurse specialist. The group also co-opted a dietitian, a consultant in renal medicine, and a statistician expert in risk assessment.
The group developed clinical questions, collected and appraised clinical evidence, and evaluated the cost effectiveness of proposed interventions through systematic literature review and original economic modelling. The draft guideline went through a rigorous reviewing process, in which stakeholder organisations were invited to comment; the group took all comments into consideration when producing the final version of the guideline. Quality ratings of the evidence were based on GRADE methodology.15 These relate to the quality of the available evidence for assessed outcomes rather than the quality of the clinical study.
NICE has produced three different versions of the guideline: a full version; a summary version known as the “NICE guideline”; and an online version for people who have or are at risk of developing CVD, their family and carers, and the public. All of these versions, as well as a pathway, are available from the NICE website. Further updates of the guideline will be produced as part of NICE’s guideline development programme.
Future research and remaining uncertainties
The GDG identified the following areas for further research:
What is the comparative effectiveness of age alone and other routinely available risk factors versus formal structured multifactorial risk assessment for identifying people at high risk of developing CVD?
When evaluating cost effectiveness for statin therapy in reducing CVD, is prediction improved by the use of a complete meta-analysis dataset based on individual patient outcomes rather than published outcomes data from individual trials?
What is the effectiveness of statin therapy in older people?
What is the effectiveness of statins or other treatments that lower low density lipoprotein-cholesterol in people with type 1 diabetes?
What is the clinical effectiveness and rate of adverse events of statin therapy using atorvastatin 20 mg per day compared with atorvastatin 40 mg per day and atorvastatin 80 mg per day in people without established CVD?
Cite this as: BMJ 2014;349:g4356
This is one of a series of BMJ summaries of new guidelines based on the best available evidence; they highlight important recommendations for clinical practice, especially where uncertainty or controversy exists.
The members of the guideline group were: Anthony Wierzbicki, Rajai Ahmad, Lindsay Banks, Liz Clark, Martin Duerden, Eleanor Grey, Michael Khan, Emma McGowan, Dermot Neely, Nadeem Qureshi, and Alan Rees. The technical team at the National Clinical Guideline Centre were Angela Cooper, Lina Gulhane, Martin Harker, Norma O’Flynn, and Silvia Rabar.
Contributors: SR wrote the first draft. All authors reviewed the draft, helped write further drafts, and reviewed and approved the final version for publication. SR is guarantor.
Competing interests: We have read and understood BMJ policy on declaration of interests and declare the following interests: ASW declares contracts held by his institution and a role as principal site investigator for phase II and phase III studies on lipid lowering agents sponsored by Merck-Sharp-Dohme, Amgen, and Pfizer; these include phase III outcome studies that were sponsored by these companies but whose design and analysis are independent. These agents are not mentioned in the article because they are not licensed and are not likely to be licensed before the guideline is reviewed (2017). NICE did not consider these declared interests to be competing interests for this guideline. SR, MH, and NO’F are employed by the National Clinical Guideline Centre, which was funded by NICE to develop this guideline. The authors’ statements can be viewed at www.bmj.com/content/bmj/349/bmj.g4356/related#datasupp.
Provenance and peer review: Commissioned; not externally peer reviewed.