Primary Prevention Nice Guidelines

Who to offer therapy to? Offer lipid-modification therapyto people aged 84 years and younger if their estimated 10-year risk of developing cardiovascular disease (CVD) using the QRISK®2 assessment tool is 10% or more.lipid-modification therapyQRISK®2 – If the person has type 2 diabetes, see Scenario: Managing lipids in the CKS topic on Diabetes - type 2 for information on lipid-modification therapy.Scenario: Managing lipidsDiabetes - type 2 Offer lipid-modification therapy (without the need for a formal risk assessment) to people with: – Type 1 diabetes — for more information, see the section on Lipid modification in the CKS topic on Diabetes - type 1.Lipid modificationDiabetes - type 1 – Chronic kidney disease — for more information, see the section on Prescribing a statin in the CKS topic on Chronic kidney disease - not diabetic.Prescribing a statinChronic kidney disease - not diabetic – Familial hypercholesterolaemia — for more information, see the section on Lipid-modification treatment in adults with heterozygous FH in the CKS topic on Hypercholesterolaemia - familial.Lipid-modification treatment in adults with heterozygous FHHypercholesterolaemia - familial Consider offering lipid-modification therapy (without the need for a formal risk assessment) to people who are 85 years of age or older, taking into account the benefits and risks of treatment and any comorbidities that make treatment appropriate.lipid-modification therapy

Holistic Approach Implement measures to reduce the risk of cardiovascular disease (CVD). These are : – Addressing other modifiable CVD risk factors, such as smoking, high blood pressure, and obesity. Wherever possible, the management of these modifiable risk factors should be optimized before offering lipid-modification therapy. – Identifying and managing secondary causes of hyperlipidaemia, such as excess alcohol consumption, uncontrolled diabetes mellitus, hypothyroidism, liver disease, and nephrotic syndrome.

Initial Blood Tests Lipid measurement — at least one lipid sample should be taken to measure a full lipid profile. This should include measurement of total cholesterol, high-density lipoprotein (HDL) cholesterol, non- HDL cholesterol (the difference between total and HDL-cholesterol), and triglycerides. A fasting sample is not needed. – For people with a total cholesterol of more than 7.5 mmol/L and a family history of premature coronary heart disease, consider the possibility of familial hypercholesterolaemia. For more information, see the CKS topic onHypercholesterolaemia - familial.Hypercholesterolaemia - familial – For people with a triglyceride concentration of more than 20 mmol/L that is not a result of excess alcohol or poor glycaemic control, refer for urgent specialist review. – For people with a triglyceride concentration between 10 and 20 mmol/L: Repeat the triglyceride measurement with a fasting test (after an interval of 5 days, but within 2 weeks). Review for potential secondary causes of hyperlipidaemia. Seek specialist advice (for example from a lipid clinic) if the triglyceride concentration remains elevated. – For people with a triglyceride concentration between 4.5 and 9.9 mmol/L, optimize the management of other CVD risk factors present. Seek specialist advice if non-HDL cholesterol concentration is more than 7.5 mmol/L in this group of people. Creatine kinase (CK) — ask the person if they have persistent generalized unexplained muscle pain (whether associated with previous lipid-lowering therapy or not). – If present, measure CK level: If the CK level is raised but is less than five times the upper limit of normal, start lipid-lowering treatment. If the CK level is five or more times the upper limit of normal, re-measure after 7 days. If levels are still five times the upper limit of normal, seek specialist advice (for example from a lipid clinic). – Do not measure CK in asymptomatic people being considered for statin treatment.

Initial blood tests Liver function tests (alanine aminotransferase or aspartate aminotransferase) — if these results are abnormal, perform further investigations to determine the cause of the abnormal test results (for example non-alcoholic fatty liver disease). – Do not routinely exclude from treatment people who have liver enzymes that are elevated but are less than three times the upper limit of normal. Renal function (including estimated glomerular filtration rate) — chronic kidney disease (CKD) does not preclude the use of a lipid-lowering drug. However, specific doses are recommended depending on the stage of CKD. For more information, see the section on Prescribing a statin in the CKS topic on Chronic kidney disease - not diabetic.Prescribing a statinChronic kidney disease - not diabetic HbA 1c — to diagnose diabetes mellitus. – HbA 1c of 48 mmol/mol is recommended as the cut point for diagnosing diabetes mellitus. HbA 1c of 42–47mmol/mol indicates high risk of diabetes mellitus and lifestyle advice is recommended. – However, lipid-lowering treatment should not be stopped due to acute elevations in blood glucose. – See the sections on lipid modification in the CKS topics on Diabetes - type 1 and Diabetes - type 2 for information on prescribing a lipid-lowering drug to a person with diabetes mellitus.Diabetes - type 1Diabetes - type 2 Thyroid stimulating hormone (if dyslipidaemia is present) — to detect a thyroid disorder.

What is first line Option Which first-line lipid modification therapy should I offer for primary prevention of CVD? Offer a high-intensity statin treatment with atorvastatin 20 mg unless this is contraindicated (for example in pregnancy).high-intensity statin treatmentcontraindicated Discuss the benefits and risks of statin treatment so that the person can make an informed choice about their treatment.Advise that: – High-intensity statin treatment is the most clinically effective option for the prevention of cardiovascular disease (CVD). However, statins at any intensity reduce CVD risk compared with no treatment.intensity – The adverse effects of statins are generally mild, reversible, and not medically serious, although some people may find them distressing.adverse effects – Myopathy and rhabdomyolysis are the most serious adverse effects of statins. However, they are rare, with estimated incidences of 5 cases per 100,000 person years and 1.6 cases per 100,000 person years, respectively. Myopathy and rhabdomyolysis If the person is willing to take a statin: – Prescribe atorvastatin 20 mg once a day. – Advise that: Statin treatment should be adhered to, and should be combined with lifestyle measures such as increased physical activity, reduction of alcohol consumption, and adoption of a cardioprotective diet. See the CKS topic on CVD risk assessment and management for more information.CVD risk assessment and management They should stop the statin and seek medical advice if they develop adverse effects such as unexplained muscle symptoms (pain, tenderness, or weakness).adverse effects – Follow up the person to assess the effectiveness and tolerability of treatment. Follow up – See Prescribing information for detailed information on the use of statins.Prescribing information

If statins are contraindicated, consider seeking specialist advice (for example from a lipid clinic). – Do not routinely prescribe fibrates. – Do not offer bile acid sequestrants, nicotinic acid, omega-3 fatty acid compounds, or a combination of a statin and another lipid-modifying drug. – Do not offer coenzyme Q10 or vitamin D to increase adherence to statin treatment. – People with primary hypercholesterolaemia can be considered for treatment with ezetimibe.primary hypercholesterolaemia If the person declines treatment with a statin, advise that their CVD risk should be reassessed again at a later date. Record their choice in their medical notes.

When statins are contraindicated The recommendation to seek specialist advice is based on what CKS considers to be good clinical practice. Regarding ezetimibe, the NICE guideline on lipid modification states that people with primary hypercholesterolaemia should be considered for ezetimibe treatment in line with recommendations in the NICE technology appraisal Ezetimibe for the treatment of primary (heterozygous-familial and non-familial) hypercholesterolaemia[NICE, 2014], which recommends ezetimibe as an option for the treatment of 'adults with primary (heterozygous-familial or non-familial) hypercholesterolaemia who would otherwise be initiated on statin therapy but who are unable to do so because of contraindications to initial statin therapy' [NICE, 2007]. For more information, see the NICE technology appraisal.NICE, 2014NICE, 2007NICE technology appraisal – Hypercholesterolaemia is defined as the presence of high concentrations of cholesterol in the blood. Primary hypercholesterolaemia is associated with an underlying genetic cause [NICE, 2007]:NICE, 2007 In heterozygous-familial hypercholesterolaemia, one of the pair of LDL cholesterol receptor genes is defective or mutated and impairs the LDL cholesterol receptor activity, resulting in markedly elevated LDL cholesterol levels (with other forms of cholesterol remaining normal). See the CKS topic on Hypercholesterolaemia - familial for more information.Hypercholesterolaemia - familial In non-familial hypercholesterolaemia (the more common form of primary hypercholesterolaemia), a number of genes interact with dietary and other factors such as smoking and physical inactivity.

Treatments not recommended Fibrates: the NICE GDG agreed that the limited evidence for benefits from fibrate trials does not support their widespread use for the primary prevention of CVD. Bile acid sequestrants: due to the lack of evidence for efficacy, the NICE GDG does not recommend bile acid sequestrants as an option for the primary prevention of CVD. Nicotinic acid: NICE did not identify any studies on nicotinic acid for primary prevention of CVD. However, after considering the common occurrence of adverse effects with nicotinic acid treatment, the NICE GDG agreed that there was no role for the use of nicotinic acids in the primary prevention of CVD. Coenzyme Q10 and vitamin D: NICE found no clinical evidence in favour of benefit from the use of coenzyme Q10 to improve adherence to statin treatment. The GDG agreed that the general measures to improve adherence outlined in the NICE Medicines Adherence guideline [NICE, 2009] should be used instead. No evidence was found on the use of vitamin D.NICE, 2009 Combination treatment: the GDG considered that there was insufficient evidence to recommend combining a statin with a fibrate, anion exchange resin, omega 3 compounds, or nicotinic acid. Evidence from a study that combined a fibrate with a statin found no benefit from addition of the fibrate [NICE, 2014]. In addition, there is a possible increased risk of myopathy when statins are given with other lipid- regulating drugs [BNF 68, 2014].NICE, 2014BNF 68, 2014

Follow up What follow up is recommended after initiation of statin therapy for primary prevention? Measure total cholesterol, high-density lipoprotein (HDL) cholesterol, and non-HDL cholesterol (total cholesterol minus HDL cholesterol) levels after 3 months of atorvastatin treatment. The aim of treatment is to achieve a greater than 40% reduction in baseline non-HDL cholesterol levels.atorvastatin treatment – If a greater than 40% reduction in non-HDL cholesterol is not achieved: Discuss adherence and timing of dose. Reinforce adherence to diet and lifestyle measures. Consider increasing the dose of atorvastatin if the person is judged to be at higher risk of cardiovascular disease (CVD) because of comorbidities or risk score, or using clinical judgement. – If a greater than 40% reduction in non-HDL cholesterol is still not achieved after appropriate dose titrations of atorvastatin, or because dose titration is limited by adverse effects: Ezetimibe, co-administered with atorvastatin, can be considered for people with primary hypercholesterolaemia(consider seeking specialist advice).primary hypercholesterolaemia Recheck liver function tests (LFTs) within 3 months of starting treatment, and again at 12 months. Further monitoring is not necessary unless clinically indicated (for example symptoms or signs of hepatotoxicity develop). – If LFTs are abnormal, see the section on Managing abnormal LFT results for information on management.Managing abnormal LFT results Review statin treatment annually. – Prior to the annual review, consider performing a non-fasting blood test for non-HDL cholesterol to inform the discussion. – During the annual review, discuss adherence to treatment and lifestyle modification, and address CVD risk factors. See the CKS topic on CVD risk assessment and management for more information.CVD risk assessment and management

Routinely monitor for adverse effects of lipid-modification therapy. – If unexplained muscle symptoms (such as pain, tenderness, or weakness) develop: Check creatine kinase (CK). Stop statin treatment immediately if muscle symptoms are intolerable or if CK is five or more times the upper limit of normal. For further information, see the section on Managing raised creatine kinase.Managing raised creatine kinase – If muscle pain develops but statin treatment was previously tolerated for more than 3 months, explore other possible causes of myalgia and raised CK, such as vigorous physical activity, hypothyroidism, infection, recent trauma, and drug or alcohol misuse. If the statin is suspected to be the cause of muscle pain and CK is five or more times the upper limit of normal, stop statin treatment immediately. For further information, see the section on Managing raised creatine kinase.Managing raised creatine kinase – If other adverse effects are reported, discuss the following possible strategies with the person:adverse effects Stopping statin treatment and trying again when the symptoms have resolved to check if the symptoms are related to statin use, or Reducing the dose within the same intensity group, orintensity group Changing to a statin in a lower intensity group.lower intensity group – If treatment is still not tolerated after three different statins have been tried, seek specialist advice (for example from a lipid clinic) about treatment options for people at high risk of CVD, for example people with chronic kidney disease, diabetes mellitus, or genetic dyslipidaemias. See the CKS topics on Chronic kidney disease - not diabetic, Diabetes - type 1, Diabetes - type 2, and Hypercholesterolaemia - familial for more information.Chronic kidney disease - not diabeticDiabetes - type 1Diabetes - type 2Hypercholesterolaemia - familial People with primary hypercholesterolaemia who have clinically significant adverse effects with statin treatment can be considered for treatment with ezetimibe.primary hypercholesterolaemia

Rechecking lipids The NICE GDG considered that a non-fasting lipid profile should be taken 3 months after starting a statin, with the aim of a 40% reduction in non-high density lipoprotein (HDL) cholesterol levels [NICE, 2014].NICE, 2014 – If this reduction in non-HDL cholesterol is not achieved, the GDG thought it was appropriate to consider increasing the dose of atorvastatin (in people on a lower dose) if the person is judged to be at higher risk of cardiovascular disease (CVD) because of comorbidities or risk score, or using clinical judgement, after reinforcing adherence to drug treatment and lifestyle measures. – The recommendation that ezetimibe can be co-administered with atorvastatin if a greater than 40% reduction in non-HDL cholesterol is still not achieved is based on the NICE technology appraisal Ezetimibe for the treatment of primary (heterozygous-familial and non- familial) hypercholesterolaemia, which states that [NICE, 2007]:NICE, 2007 'Ezetimibe, coadministered with initial statin therapy, is recommended as an option for the treatment of adults with primary (heterozygous-familial or nonfamilial) hypercholesterolaemia who have been initiated on statin therapy when serum total or low-density lipoprotein (LDL) cholesterol concentration is not appropriately controlled either after appropriate dose titration of initial statin therapy or because dose titration is limited by intolerance to the initial statin therapy'. For more information, see the NICE technology appraisal.NICE technology appraisal – The recommendation to consider seeking specialist advice is based on what CKS considers to be good clinical practice.

Repeat liver function tests (LFTs) The NICE GDG noted that transaminase elevations usually occur on initiation of statin treatment; repeat LFTs are therefore recommended 3 months after initiation of statin treatment, and again at 12 months. Further monitoring is not necessary unless there are other hepatic comorbidities warranting more frequent monitoring [NICE, 2014].NICE, 2014 Annual medication review NICE recommends an annual medication review once a person is stable on their tolerated dose of statin [NICE, 2014]. This is an opportunity to review adherence and reinforce lifestyle modification.NICE, 2014 NICE advises that a measurement of non-HDL cholesterol at this review may be useful to inform the discussion. However, repeated measurements more regularly than this are not recommended unless required for dose adjustment [NICE, 2014].NICE, 2014

Routine monitoring for adverse effects NICE recommends routine monitoring for adverse effects of lipid- modification therapy [NICE, 2014].NICE, 2014 The recommendations on how to manage people with muscle symptoms are based on the expert opinion of NICE [NICE, 2014], advice issued by the MHRA [MHRA, 2014], the British National Formulary (BNF) [BNF 68, 2014], expert opinion in a Canadian Working Group Consensus update on the diagnosis, prevention, and management of statin adverse effects and intolerance [Mancini et al, 2013], and expert opinion in review articles on lipid management [Smellie et al, 2005; Smellie, 2006; Guyton et al, 2014].NICE, 2014MHRA, 2014BNF 68, 2014Mancini et al, 2013Smellie et al, 2005Smellie, 2006Guyton et al, 2014 For people with other adverse effects, the NICE GDG recommends the following strategies [NICE, 2014]:NICE, 2014 – Stopping the statin and trying again when the symptoms have resolved — the GDG decided that the person should be re-challenged with a statin, given the non-specific nature of many statin-related adverse effects. – Reducing the dose within the same intensity group — the GDG agreed that for people who are unable to take a high dose of a high-intensity statin, a lower dose is preferred to any other lipid-lowering drug. – Changing to a statin in a lower-intensity group — the GDG agreed that for people who are unable to take a high-intensity statin, a lower intensity statin is preferred to any other lipid-lowering drug.

Statin Intolerance Statin intolerance The recommendation to seek specialist advice about other possible treatment options for people at high risk of CVD who are intolerant to three different statins is based on the NICE guideline on lipid modification, which states that specialist advice should be sought about 'options for treating people at high risk of cardiovascular disease such as those with chronic kidney disease, type 1 diabetes, type 2 diabetes or genetic dyslipidaemias, and those with cardiovascular disease, who are intolerant to 3 different statins' [NICE, 2014].NICE, 2014 The recommendation to consider ezetimibe for people with primary hypercholesterolaemia who have clinically significant adverse effects with statin treatment is based on the NICE technology appraisal for ezetimibe, which states that 'ezetimibe monotherapy is recommended as an option for the treatment of adults with primary (heterozygous-familial or non-familial) hypercholesterolaemia who are intolerant to statin therapy' [NICE, 2007].primary hypercholesterolaemiaNICE, 2007 – The NICE technology appraisal defined intolerance to initial statin therapy 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 compliance with therapy being compromised. Adverse effects include evidence of new-onset muscle pain (often associated with levels of muscle enzymes in the blood indicative of muscle damage), significant gastrointestinal disturbance or alterations of liver function tests' [NICE, 2007].NICE, 2007