Lipid Modification and Cardiovascular Risk Assessment

GUIDELINES

Lipidmodification and cardiovascular risk assessmentfor the primary and secondary prevention ofcardiovascular disease: summary of updated NICEguidance

Silvia Rabar senior research fellow and project manager 1, Martin Harker senior health economist 1,NormaOFlynn clinical director and guideline lead1, Anthony SWierzbicki professor of cardiometabolicdisease 2, On behalf of the Guideline Development Group

1National Clinical Guideline Centre, Royal College of Physicians, London NW1 4LE, UK; 2Guys and St Thomas Hospitals, London, UK

This is one of a series of BMJ summaries of new guidelines based onthe best available evidence; they highlight important recommendationsfor clinical practice, especially where uncertainty or controversy exists.

Cardiovascular disease (CVD) is the leading cause of death inEngland andWales, accounting for almost a third of deaths. Anupdate of existing National Institute for Health and CareExcellence (NICE) guidance (published in 2008)1was necessaryin light of new evidence on the efficacy and safety of statintherapy,2 on the effects of combining statins with non-statindrugs,3-5 and on novel risk assessment tools for predicting riskof CVD.6 Since the previous guideline, more statins havebecome available as generic drugs, and this has changed thecost effectiveness of statin treatment. The scope of the updateincluded risk assessment for CVD and the use of lipidmodification in people with type 1 diabetes, type 2 diabetes,and chronic kidney disease.

This article summarises the most recent recommendations fromNICE on lipid modification: cardiovascular risk assessment andthe modification of blood lipids for the primary and secondaryprevention of cardiovascular disease.7

RecommendationsNICE recommendations are based on systematic reviews of bestavailable evidence and explicit consideration of costeffectiveness. When minimal evidence is available,recommendations are based on the guideline developmentgroups experience and opinion of what constitutes goodpractice. Evidence levels for the recommendations are given initalic in square brackets.

Assessing the risk of CVDFull formal risk assessment

Use the QRISK2 risk assessment tool6 to assess CVD riskfor the primary prevention of CVD in the generalpopulation, including people with type 2 diabetes. QRISK2cannot be used in people over 84 years of age.

The available risk tools do not adequately assess risk incertain people. Do not use a risk assessment tool to assessthe 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)

-Pre-existing CVD

-Familial hypercholesterolaemia or other inherited disordersof lipid metabolism.

Use clinical judgment to interpret CVD scores becauseCVD risk assessment tools provide only an approximatevalue for CVD risk.

CVD riskmay be underestimated in people with underlyingmedical 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 asantipsychotic drugs, corticosteroids, orimmunosuppressants

-People with systemic inflammatory disorders such assystemic lupus erythematosus

Corresponding author: S Rabar [email protected]

For personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe

BMJ 2014;349:g4356 doi: 10.1136/bmj.g4356 (Published 18 July 2014) Page 1 of 6

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-People who are already taking antihypertensives or lipidmodifying drugs

-People who have recently stopped smoking

-Severely obese people (body mass index greater than 40).

(New recommendations.) [Based on low quality cohortstudies and the experience and opinion of the GuidelineDevelopment Group (GDG)]

Communication about risk assessment andtreatment

Set aside adequate time during the consultation to provideinformation on risk assessment and use everydayjargon-free language to communicate information on risk.

Offer people information about their absolute risk of CVDand about the absolute benefits and harms of an interventionover a 10 year period. This information should be in a formthat:-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 CVDrisk:-Find out what, if anything, they have already been toldabout 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), toundergo investigations, and to take long term drugs

-Assess their confidence in making changes to theirlifestyle, undergoing investigations, and taking drugs

-Inform them of potential future management based oncurrent evidence and best practice

-Involve them in developing a shared management plan

-Check with them that they have understood what has beendiscussed.

(These recommendations are from the 2008 guideline.)

Cardioprotective diet for prevention of CVD Take account of peoples individual circumstancesforexample, drug treatment, comorbidities, and other lifestylefactors when giving dietary advice.

Advise people at risk of CVD, or those with CVD, to:-Reduce saturated fat intake from animal sources: this alsoreduces monounsaturated fat levels

-Replace saturated and monounsaturated fats with oliveoil, rapeseed oil, or spreads based on these oils, and usethem in food preparation

-Choose wholegrain varieties of starchy food

-Reduce intake of sugar and food products containingrefined 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 portionof oily fish (pregnant women should limit oily fish to nomore 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 enrichedwith plant stanols and sterols because there is no evidencefor benefit on CVD outcomes.

(New recommendations.) [Based on low and very lowquality randomised controlled trials and the experienceand opinion of the GDG]

Lipid measurement and referral Measure a full lipid profile (total cholesterol, high densitylipoprotein (HDL)-cholesterol, non-HDL-cholesterol, andtriglyceride concentrations) before starting lipidmodification therapy. A fasting sample is not needed.

Do not use lipid cut-off values alone to judge the likelihoodof a familial lipid disorder but combine these with theclinical findings and family history. Exclude possiblecommon secondary causes of dyslipidaemia (such as excessalcohol, uncontrolled diabetes, hypothyroidism, liverdisease, and nephrotic syndrome) before referring forspecialist review.

If total cholesterol concentration is more than 7.5 mmol/L(1 mmol/L=38.61 mg/dL) and the person has a familyhistory of premature coronary heart disease, consider thepossibility of familial hypercholesterolaemia.8

If total cholesterol concentration is more than 9.0 mmol/L,or the non-HDL-cholesterol concentration is more than 7.5mmol/L, refer the person to specialist care even in theabsence of a first degree family history of prematurecoronary 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 alcoholor poor glycaemic control, refer the person to specialistcare.

If the triglyceride concentration is 10-20 mmol/L, repeatthe measurement with a fasting test (after an interval offive days, but within two weeks) and review for potentialsecondary causes of hyperlipidaemia. Seek specialist adviceif the triglyceride concentration remains above 10mmol/L.

If the triglyceride concentration is 4.5-9.9 mmol/L, theCVD risk may be underestimated by risk assessment tools.

(New recommendations.) [Based on the experience andopinion of the GDG]

Statins for the prevention of CVDFor the purpose of the guideline, statins are grouped into threedifferent intensity categories according to the percentagereduction in low density lipoprotein cholesterol. This groupingwas agreed by GDG consensus, informed by analyses in theliterature (table).9

The decision about whether to start statins should be madeafter an informed discussion between the clinician and theperson about the risks and benefits of statin treatment,taking into account factors such as potential benefits fromlifestyle modifications, informed patient preference,comorbidities, polypharmacy, general frailty, and lifeexpectancy.

Before starting statins perform baseline blood tests andclinical assessment, and treat comorbidities and secondary



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causes of dyslipidaemia. Include all of the following in theassessment:-Smoking status

-Alcohol consumption

-Blood pressure10

-Body mass index or other measure of obesity11

-Total cholesterol, non-HDL cholesterol, HDL-cholesteroland triglycerides

-Glycated haemoglobin (HbA1c)

-Renal function and estimated glomerular filtration rate

-Transaminase level (alanine aminotransferase or aspartateaminotransferase)

-Thyroid stimulating hormone.


Primary prevention Discuss the benefits of lifestyle modification and offerpeople the opportunity to have their risk of CVD assessedagain after they have tried to change their lifestyle beforestarting statins for primary prevention. If lifestylemodification is ineffective or inappropriate offer statintreatment after risk assessment. (New recommendation.)[Based on the experience and opinion of the GDG]

Offer atorvastatin 20 mg for the primary prevention ofCVD to people who have a 10% or greater 10 year risk ofdeveloping CVD (estimated with QRISK2). (Newrecommendation.) [Based on high to moderate qualityevidence from randomised controlled trials, costeffectiveness analysis, and the experience and opinion ofthe GDG]

In people with type 1 diabetes Offer atorvastatin 20 mg for the primary prevention ofCVD to people with type 1 diabetes who are over 40 years,have had diabetes for more than 10 years, have establishednephropathy, or have other CVD risk factors. (Newrecommendation.) [Based on the experience and opinionof the GDG]

In people with type 2 diabetes Offer atorvastatin 20 mg for the primary prevention ofCVD to people with type 2 diabetes who have a 10% orgreater 10 year risk of developing CVD (estimated withQRISK2). (New recommendation.) [Based on high tomoderate quality evidence from randomised controlledtrials, cost effectiveness analysis, and the experience andopinion of the GDG]

Secondary prevention Start statin treatment for the secondary prevention of CVDwith atorvastatin 80 mg.

Use a lower dose of atorvastatin if there are potential druginteractions (for example, with clarithromycin, systemicazole, antifungal agents), there is a high risk of adverseeffects (for example, in older people, people with lowmuscle mass or impaired renal function), or because ofpatient preference. (New recommendations.) [Based onhigh to moderate quality evidence from randomised

controlled trials, cost effectiveness analysis, and theexperience and opinion of the GDG]

Do not delay treatment to manage modifiable risk factors.(New recommendation.) [Based on the experience andopinion of the GDG]

People with chronic kidney disease Offer atorvastatin 20 mg for the primary or secondaryprevention of CVD to people with chronic kidney disease.Increase the dose if a greater than 40% reduction innon-HDL-cholesterol is not achieved and eGFR is 30mL/min/1.73 m2 or more. Agree the use of higher doseswith a renal specialist if eGFR is less than 30 mL/min/1.73m2. (New recommendation.) [Based on high to moderatequality evidence from randomised controlled trials, costeffectiveness analysis, and the experience and opinion ofthe GDG]

Follow-up of people started on statintreatment

Measure total cholesterol, HDL-cholesterol andnon-HDL-cholesterol in all people who have been startedon high intensity statin treatment at three months oftreatment and aim for a greater than 40% reduction innon-HDL-cholesterol.

If a greater than 40% reduction in non-HDL-cholesterol isnot achieved, discuss adherence and timing of dose andoptimise adherence to diet and lifestyle measures. Anincrease in dose should also be considered if the personwas started on less than atorvastatin 80 mg and is thoughtto be at higher risk of cardiovascular disease because ofcomorbidities or risk score, or using clinical judgment

Discuss with people who are stable on a low or mediumintensity statin the likely benefits and potential risks ofchanging to a high intensity statin when they have amedication review, and agree with the person whether achange is needed.

Provide annual medication reviews for people takingstatins.-Use these reviews to discuss adherence to drugs, lifestylemodification, and CVD risk factors.

-Consider an annual non-fasting blood test fornon-HDL-cholesterol to inform the discussion.


Advice and monitoring of adverse effects Advise people taking statins that some drugs, foods, andsupplements can interfere with statins and to consult thepatient information leaflet, a pharmacist, or a prescriberfor advice when starting other drugs or thinking aboutsupplements.

Remind people to restart the statin if they stopped takingit because of drug interactions or to treat intercurrentillnesses.

Before offering a statin, ask people if they have hadpersistent generalised unexplained muscle pain, regardlessof whether it was associated with previous lipid loweringdrugs. If present, measure creatine kinase levels:



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-If creatine kinase levels are more than five times the upperlimit of normal re-measure within five to seven days. Ifcreatine kinase levels are still five times the upper limit ofnormal, do not start treatment

-If creatine kinase is raised but less than five times theupper limit of normal, start statin treatment at a lower dose.

Advise people who are being treated with a statin to seekmedical advice if they develop muscle symptoms (pain,tenderness, or weakness). If this occurs, measure creatinekinase.

If people report muscle pain or weakness while taking astatin and have previously tolerated statin therapy, exploreother possible causes of muscle pain and raised creatinekinase. Do not measure creatine kinase in asymptomaticpeople who are being treated with a statin.

Measure baseline liver transaminase enzymes (alanineaminotransferase or aspartate aminotransferase) beforestarting a statin. Measure liver transaminase within threemonths of starting treatment and at 12 months, but notagain unless clinically indicated.

Do not routinely exclude people from statin therapy if livertransaminase levels are raised but are less than three timesthe upper limit of normal.

Do not stop statins because of an increase in blood glucoselevel or HbA1c.

Statins are contraindicated in pregnancy. Advise womenof childbearing age of the potential teratogenic risk ofstatins and to stop taking them if pregnancy is a possibility.Advise women planning pregnancy to stop taking statinsthree months before they attempt to conceive and to notrestart them until breast feeding is finished.

(New recommendations.) [Based on high to moderatequality evidence from randomised controlled trials and theexperience and opinion of the GDG]

Intolerance to statins Aim to treat people with the maximum tolerated dose ofstatin.

Tell people that any statin at any dose reduces the risk ofCVD. If someone reports adverse effects when taking highintensity statins discuss the following possible strategies:-Stopping the statin and trying again when the symptomshave resolved to check if the symptoms are related to thestatin

-Reducing the dose within the same intensity group

-Changing the statin to a lower intensity group.

Seek specialist advice about other options for treatingpeople at high risk of CVD (such as those with chronickidney disease, type 1 diabetes, type 2 diabetes, or geneticdyslipidaemias), and those with CVD who are intolerantto three different statins. Advice can be sought, forexample, by telephone, virtual clinic, or referral.

Do not offer coenzyme Q10 or vitamin D to increaseadherence to or to reduce muscle related adverse eventsfrom statin treatment because there is no evidence ofbenefit.

(New recommendations) [Based on low quality evidencefrom randomised controlled trials and the experience andopinion of the GDG]

Fibrates, nicotinic acids, bile acidsequestrants (anion exchange resins), andomega-3 fatty acid compounds

Do not routinely offer fibrates, and do not offer nicotinicacids, bile acid sequestrants (anion exchange resins), oromega-3 fatty acid compounds, alone or in combinationwith a statin, for the prevention of CVD because there isno evidence of benefit. (New recommendations.) [Basedon high to very low quality randomised controlled trialsand the experience and opinion of the GDG]

Overcoming barriersThese recommendations introduce the use ofnon-HDL-cholesterol rather than low densitylipoprotein-cholesterol and lower the threshold at which it iscost effective to offer statins for primary prevention. Those whoare likely to be offered statins will already be identified usingthe NHSHealth Check (a universal health screening programmefor people aged 40-70 years designed to identify those with ahigh risk of developing CVD, diabetes, or renal disease).12

However, more people will require a meaningful explanationof their risk, lifestyle advice, explanation of the trade-offbetween benefits and potential harms, and monitoring for sideeffects. Tools have been developed to help explaincardiovascular risk and potential benefits of treatment13; NICEis currently developing a patient decision aid on risk assessmentand preventive treatment for cardiovascular disease (publicationexpected autumn 2014).

A cost-utility analysis was conducted to compare the costeffectiveness of high intensity, medium intensity, and lowintensity statins versus placebo in primary prevention; no totalrisk modification trial has looked at lifestyle and drug therapysimultaneously. The cost effectiveness analysis also took intoaccount costs other than the price of the drugfor example,costs of consultations with a general practitioner, initial bloodtests, and monitoring. It found that high intensity statins werecost effective at a cost effectiveness threshold of 20 000 (25040; $34 276) per quality adjusted life year gained comparedwith all other options for secondary prevention. High intensitystatins were also cost effective for primary prevention in patientswith CVD risk levels above thresholds that varied by age andsex from 2.4% to 7.3% for atorvastatin 20 mg and from 3.4%to 11.6% for atorvastatin 80 mg.

The members of the guideline group were: Anthony Wierzbicki, RajaiAhmad, Lindsay Banks, Liz Clark, Martin Duerden, Eleanor Grey,Michael Khan, Emma McGowan, Dermot Neely, Nadeem Qureshi, andAlan Rees. The technical team at the National Clinical Guideline Centrewere Angela Cooper, Lina Gulhane, Martin Harker, Norma OFlynn, andSilvia Rabar.

Contributors: SR wrote the first draft. All authors reviewed the draft,helped write further drafts, and reviewed and approved the final versionfor publication. SR is guarantor.

Competing interests: We have read and understood BMJ policy ondeclaration of interests and declare the following interests: ASW declarescontracts held by his institution and a role as principal site investigatorfor phase II and phase III studies on lipid lowering agents sponsoredby Merck-Sharp-Dohme, Amgen, and Pfizer; these include phase IIIoutcome studies that were sponsored by these companies but whosedesign and analysis are independent. These agents are not mentionedin the article because they are not licensed and are not likely to belicensed before the guideline is reviewed (2017). NICE did not considerthese declared interests to be competing interests for this guideline.SR, MH, and NOF are employed by the National Clinical Guideline



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Further information on the guidance

Whats new

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 10years in the previous guideline to 10% CVD risk. The guideline recommends the use of non-HDL-cholesterol rather than low densitylipoprotein-cholesterol because non-HDL-cholesterol does not require a fasting sample. This should make assessment and monitoringeasier.

Methods

The Guideline Development Group (GDG) followed standard NICE methods in the development of this guideline.14 The GDG comprised twoconsultants in metabolic medicine and chemical pathology, two consultant physicians with an interest in diabetes, a cardiologist, two generalpractitioners, a medicines information pharmacist, two patient or carer members, and a lipid nurse specialist. The group also co-opted adietitian, 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 proposedinterventions through systematic literature review and original economic modelling. The draft guideline went through a rigorous reviewingprocess, in which stakeholder organisations were invited to comment; the group took all comments into consideration when producing thefinal version of the guideline. Quality ratings of the evidence were based on GRADEmethodology.15 These relate to the quality of the availableevidence 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 onlineversion 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 apathway, are available from the NICE website. Further updates of the guideline will be produced as part of NICEs guideline developmentprogramme.

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 multifactorialrisk 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-analysisdataset 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 withatorvastatin 40 mg per day and atorvastatin 80 mg per day in people without established CVD?

Centre, which was funded by NICE to develop this guideline. Theauthors statements can be viewed at www.bmj.com/content/bmj/349/bmj.g4356/related#datasupp.

Provenance and peer review: Commissioned; not externally peerreviewed.

1 National Institute for Health and Clinical Excellence. Lipid modification: cardiovascularrisk assessment and the modification of blood lipids for the primary and secondaryprevention of cardiovascular disease. (Clinical guideline 67.) 2008. www.nice.org.uk/guidance/CG67.

2 Baigent C, Blackwell I, Emberson J, Holland LE, Reith C, Bhala N, et al; CholesterolTreatment Trialists (CTT) Collaboration. Efficacy and safety of more intensive loweringof LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomisedtrials. Lancet 2010;376:1670-81.

3 Ginsberg HN, Elam MB, Lovato LC, Crouse JR 3rd, Leiter LA, Linz P, et al; ACCORDStudy Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl JMed 2010;362:1563-74.

4 Bosch J, Gerstein HC, Dagenais GR, , Daz R, Dyal L, Jung H, et al; ORIGIN TrialInvestigators. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia.N Engl J Med 2012;367:309-18.

5 Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, KoprowiczK, et al; AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levelsreceiving intensive statin therapy. N Engl J Med 2011;365:2255-67.

6 Hippisley-Cox J, Coupland C, Vinogradova Y, Robson J, Minhas R, Sheikh A, et al.Predicting cardiovascular risk in England andWales: prospective derivation and validationof QRISK2. BMJ 2008;336:1475-82.

7 National Institute for Health and Care Excellence. Lipid modification: cardiovascular riskassessment and the modification of blood lipids for the primary and secondary preventionof cardiovascular disease. (Clinical guideline 181.) 2014. www.nice.org.uk/guidance/CG181.

8 National Institute for Health and Clinical Excellence. Identification and management offamilial hypercholesterolaemia (FH). (Clinical guideline 71.) 2008. www.nice.org.uk/guidance/CG071.

9 Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoproteincholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis.BMJ 2003;326:1423.

10 National Institute for Health and Clinical Excellence. Hypertension: the clinical managementof primary hypertension in adults. (Clinical guideline 127.) 2011. www.nice.org.uk/guidance/CG127.

11 National Institute for Health and Clinical Excellence. Obesity: the prevention, identification,assessment and management of overweight and obesity in adults and children. 2006.(Clinical guideline 43.) www.nice.org.uk/guidance/CG43.

12 Department of Health. Putting prevention first. NHS Health Check: vascular riskassessment and management best practice guidance. 2013. www.nhshealthcheck.nhs.uk/default.aspx?aID=103.

13 Joint British Societies recommendations on the prevention of cardiovascular disease.JBS3 risk calculator. 2014. www.jbs3risk.com/pages/risk_calculator.htm.

14 National Institue for Health and Care Excellence. Developing NICE clinical guidelines.2013. www.nice.org.uk/aboutnice/howwework/developingniceclinicalguidelines/developing_nice_clinical_guidelines.jsp.

15 GRADE Working Group. The Grading of Recommendations Assessment, Developmentand Evaluation (GRADE) Working Group website. www.gradeworkinggroup.org/.

Cite this as: BMJ 2014;349:g4356

BMJ Publishing Group Ltd 2014



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Table

Table 1| Grouping of statins9

Dose (mg/day)Statin

804020105

33%27%*21%*Fluvastatin

29%*24%*20%*Pravastatin

42%37%32%27%*Simvastatin

55%49%43%37%Atorvastatin

53%48%43%38%Rosuvastatin

*20-30% reduction in low density lipoprotein (LDL) cholesterol: low intensity statin.

31-40% reduction in LDL cholesterol: medium intensity statin.

Above 40% reduction in LDL cholesterol: high intensity statin

Advice from the Medicines and Healthcare Products Regulatory Agency: there is an increased risk of myopathy associated with high dose (80 mg) simvastatin.

The 80 mg dose should be considered only in patients with severe hypercholesterolaemia and a high risk of cardiovascular complications who have not achieved

their treatment goals on lower doses, when the benefits are expected to outweigh the potential risks.



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Lipid Modification and Cardiovascular Risk Assessment