FATS5; supporting notes - NESG



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FATS5

A strategy for the use of cholesterol lowering drugs in Newcastle, North Tyneside and Northumberland

A summary of the evidence used to develop FATS5 from FATS4

The recommendations are presented in summary form as a quick reference guide on the last page

FATS Steering Group February 2009

INDEX

Page

INTRODUCTION 3

SUPPORTING NOTES 4

People with symptomatic or prior occlusive vascular disease 4

People with diabetes (Type 1 of Type 2), or IGT (OGTT) 12

High risk people without symptomatic or prior occlusive

vascular disease and without diabetes / IGT (OGTT) 15

Additional notes 20

Appendix; Membership of the group 24

Summary form as quick reference guide 26

INTRODUCTION

FATS5 has been developed following a review of FATS4. The following have been published since the development of FATS4 and have been taken into consideration;

• NICE Lipid Modification Guideline, CG067[1].

• NICE Guideline for the Management of Type 2 diabetes, CG066[2]

• NICE Guideline for Chronic Kidney Disease, CG073[3].

• NICE Guideline for Identification and Management for familial hypercholesterolaemia, CG071[4]

• Important statin trials published / presented since the NICE lipid modification guideline.

As in previous iterations of the FATS guidelines, FATS5 not only incorporates new evidence, but also considers how the guideline will be implemented. The aim has been to provide a practical tool drawing on the evidence of clinical and cost effectiveness, which can be used in everyday practice. The FATS group recognised that occasional people as a result of their specific lipid abnormalities, drug intolerances and co-morbid conditions may need to be managed outside the guidelines, but this will usually be following specialist advice, and the reasons should be explicitly stated.

FATS5 is intended for all clinicians in the Newcastle, North Tyneside, Northumberland areas involved in treating people for primary and secondary prevention of cardiovascular disease, including coronary disease, cerebro-vascular disease and peripheral arterial disease.

How to use the FATS5 guideline

The guideline has two parts; the summary part, a quick reference guide which can be easily folded over and laminated into a double sided A5 sheet and kept readily available, is at the end of the supporting notes.

The notes contain each of the recommendations in the summary highlighted in bold in text boxes with background detail of how the decision to include the recommendation was reached, and in some cases expand the recommendation providing more detailed guidance.

The summary is intended as a quick reference guide and an everyday reminder. The notes contain additional supporting information and clinicians are encouraged to be familiar with these and use them to refer to for further clarification of management in individual people as needed. The BNF should be referred to as necessary.

SUPPORTING NOTES

FATS5 is a lipid lowering drug strategy which should only be used within an overall lifestyle and clinical management strategy

It is assumed that people with contraindications to specific drugs will be identified and excluded (refer to the BNF).

Statins and fibrates are contra-indicated in pregnancy. In all women in whom pregnancy is possible, the following should be specifically clarified before starting treatment; whether pregnant, contraceptive status and future pregnancy plans or possibility of pregnancy.

All people with symptomatic or prior occlusive vascular disease should be considered for lipid lowering drugs. This is consistent with FATS4 and with relevant NICE guidance. Occlusive vascular disease includes people with coronary heart disease, atheromatous stroke disease and people with peripheral arterial disease.

This is the same as in FATS4. The NICE lipid modification guideline recommends at least one fasting sample be measured and it was agreed that a fasting sample was preferred, but not mandatory and a non-fasting sample was acceptable. It is important to measure a full lipid profile including total cholesterol, HDL cholesterol and triglycerides. LDL cholesterol can only be calculated from a fasting sample. However, non-HDL cholesterol can be calculated from a non-fasting sample and may be used to monitor the response to treatment. If non-fasting triglyerides are markedly raised (> 4.5 mmol/l), a fasting sample is required for an accurate assessment.

All people presenting with ACS/acute MI should also have a full lipid profile measured on presentation, taking note of the timing of the sample from the onset of symptoms. The NICE lipid modification guideline did not recommend measuring a lipid profile prior to starting treatment in people with ACS/acute MI, but the FATS group felt that it was important to do so. Interpretation of the result should be made taking into account the duration from onset of symptoms. Studies have shown that lipid profiles taken in the first 6 to 12 hours after the onset of an acute MI are reflective of the patients’ baseline steady state lipid levels. After that time frame an acute phase response occurs, with a fall in total and LDL cholesterol levels. This can decrease the LDL cholesterol levels by as much as 50%. However, this fall does not protect from atherosclerosis as the acute phase response makes the LDL cholesterol more prone to oxidation and the HDL cholesterol pro-inflammatory. Following an acute MI, it can take up to 6 weeks for the lipid levels to return to baseline. Thus, a non fasting sample obtained on or shortly after admission can be used to assess the patients baseline lipid status, and aid in diagnosing lipid abnormalities. Lipid profiles taken 24 hours to 6 weeks after the onset of MI should be interpreted knowing that the usual LDL cholesterol may be as much as twice the measured value.

No change from FATS4 in patients treated with simvastatin 40 mg od or other low/moderate dose statins, but an additional recommendation to measure liver enzymes after 3 months in those treated with high dose statins (ie simvastatin 80 mg od, atorvastatin 80 mg od).

The FATS group discussed the recommendation in the NICE lipid modification guideline to measure LFTs at baseline, 3 months and 12 months in all patients. The evidence statements informing this recommendation were;

6.3.1.5 In a systematic review of cohort studies, randomised trials, voluntary notifications to regulatory authorities and published case reports, the incidence of major adverse events associated with skeletal muscle and the liver was low.

6.3.1.8 Elevations of the liver enzymes alanine aminotransferase and / or aspartate aminotransferase were reported more frequently in those treated with statins compared with placebo, especially at higher doses. Trials showed no excess of liver disease or chronic kidney disease in statin allocated participants.

The NICE lipid modification guideline also acknowledged that there was little evidence to support the recommendation to monitor LFTs in all patients and that this was reached by consensus. However, there is evidence of an increased risk of a sustained rise in liver enzymes in patients treated with high dose statins.

FATS5 recommends checking LFTs (ALT or AST) at baseline to identify those with raised levels before initiating treatment, but only recommends routine monitoring after 3 months in those treated with high dose statins. FATS5 also emphasises that if liver enzymes are abnormal during monitoring, the test must be repeated before any action based solely on the results of the blood test is taken. In many cases the abnormality may not be sustained, and the statin can be safely continued.

The main purpose of measuring ALT or AST before treatment is to identify people with abnormal results prior to starting drug treatment, but not to exclude them from treatment. Fatty liver is one cause of a raised ALT/AST and is certainly not an indication to exclude people from treatment.

Members of the FATS group felt that statins were sometimes inappropriately stopped in people who develop abnormal LFTs, and clinical status, repeat blood testing and other causes of abnormal LFTs should be considered before statins are stopped.

In some people with raised liver enzymes a lower dose of statin may be started initially, and liver function may be monitored during treatment. The locally available liver enzyme assay should be used.

This is consistent with FATS3 and FATS4, and is based on the recruitment criteria to the Heart Protection Study. In some people with raised liver enzymes a lower dose of statin may be started initially, and liver function may be monitored during treatment. The FATS group emphasised that people with raised liver enzymes should not be automatically excluded from statin treatment.

Background evidence

There is good clinical evidence that in people with coronary disease higher intensity statins and hence greater proportional reductions in LDL cholesterol, compared with lower intensity statins, are associated with a reduction in major vascular events. The NICE lipid modification guideline has analysed the cost effectiveness of higher intensity statins in different sub-groups, and concluded that treatment with either simvastatin 80 mg od or atorvastatin 80 mg od is cost effective when this is initiated in people with a spontaneous acute coronary syndrome / acute MI.

In people with established vascular disease (see above if ACS/acute MI, see below if diabetes), it is cost effective with current pricing in the setting of secondary prevention to titrate to simvastatin 80 mg od when treated with simvastatin 40 mg daily to achieve a target total cholesterol of 4 mmol/l. In people without diabetes it is not cost effective to use a non-generic statin.

Health economic analysis in the NICE type 2 diabetes guideline found that in people with type 2 diabetes and known vascular disease it was cost effective to further titrate to atorvastatin 80 mg od if total cholesterol remained > 4 mmol/l or LDL cholesterol remained > 2 mmol/l when treated simvastatin 80 mg od.

FATS5 does not make recommendations for treating people with familial hypercholesterolaemia in whom a non-generic statin may be required – see the NICE guideline for familial hypercholesterolaemia, CG071.

Acute coronary syndrome / MI in FATS5

The FATS group discussed whether people with an acute coronary syndrome / acute MI should be treated with simvastatin 80 mg od or atorvastatin 80 mg od. No published trials in people with acute coronary syndrome / acute MI have initiated simvastatin 80 mg od, (A-Z[5] titrated after a month), whilst PROVE-IT[6] initiated atorvastatin 80 mg od. The cost impact with atorvastatin 80 mg is higher than with simvastatin 80 mg od, but the number of people to be treated is relatively small and the patent expiry for atorvastatin is November 2011. The group also considered the results of SEARCH[7], a randomised trial of simvastatin 20 mg od compared to simvastatin 80 mg od in people with a past history of MI. The (non-peer reviewed), results indicate a higher incidence of myopathy and rhabdomyolysis with simvastatin 80 mg od compared to that reported in clinical trials with atorvastatin 80 mg od.

The consensus was to recommend early use of atorvastatin 80 mg od in people presenting with an acute coronary syndrome / acute MI, taking into account any potential interactions / increased risk of adverse side effects. Further titration is not recommended, although lipids should be monitored. There is no recommendation to routinely reduce the dose after an interval.

People without acute coronary syndrome / MI in FATS5

In people with vascular disease who do not present with an acute coronary syndrome/ acute MI, treatment should be initiated with simvastatin 40 mg od, with titration to simvastatin 80 mg od being considered if necessary to achieve a total cholesterol < 4 mmol/l, LDL cholesterol < 2 mmol/l or non-HDL cholesterol < 2.8 mmol/l. Reductions in total and LDL cholesterol with simvastatin 40 mg od and simvastatin 80 mg od (summary estimates from 164 randomised controlled trials) were included in the full version of the NICE lipid modification guideline[8];

|Statin |Daily dose |Absolute total cholesterol |% reduction in total|Absolute LDL-C reduction |% reduction in LDL-C |

| |(mg) |reduction (95% CI) mmol/l |cholesterol (95% CI)|(95% CI) mmol/l |(95% CI) mmol/l |

| | | |mmol/l | | |

|Simvastatin |40 |2.14 (1.99-2.28) |31% |1.78 (1.66-1.90) |37% |

|Simvastatin |80 |2.41 (2.20-2.63) |35% |2.01 (1.83-2.19) |42% |

The group discussed the results of SEARCH1 which had been presented, but not published. The group took note of the reported incidence of myopathy in people treated with simvastatin 80 mg od, particularly during the first year. The group reached the consensus that before considering titration the likely benefits of the dose increase and the risk of adverse effects should be taken into account. In some people, in whom the risk of treatment with simvastatin 80 mg od may be higher and the benefits lower, treatment with simvastatin 40 mg od may be continued rather than making any titration.

Thus in those not achieving a total cholesterol < 4 mmol/l, LDL cholesterol < 2 mmol/l or non-HDL cholesterol < 2.8 mmol/l, the following should be considered;

• The initial response in the lipid profile to treatment with simvastatin 40 mg od, and the likely benefits of further titration to simvastatin 80 mg od.

• The likely risk of adverse side effects from increasing the dose to simvastatin 80 mg od.

The risk of adverse side effects, particularly myopathy/rhabdomyolysis with high dose simvastatin, should be informed by an assessment of;

• The development of any mild myalgia taking simvastatin 40 mg od

• The presence of some co-morbidities (see below)

• Treatment with other drugs which interact (see below)

Further information about co-morbidities and drug interactions is given in the ‘Additional notes below’. The BNF should also be referred to.

Patients treated with simvastatin 80 mg od should be reviewed to assess the additional response from the increased dose, and ensure there has been additional demonstrable benefit and maintaining the higher dose is justified.

A lower dose of simvastatin may be considered initially in people with co-morbidity which increases the risk of adverse side effects or who are taking other drugs which interact with simvastatin. In some cases the maximum dose may also be lower.

Statin intolerance

The FATS group also further discussed the issues of tolerability and efficacy, and recognised the importance of equitable access to treatment. In FATS5 people intolerant of simvastatin, alternative statins, of similar cost, such as pravastatin, can be considered as recommended by the NICE lipid modification guideline. In some the addition of ezetimibe to lower dose generic statin may be needed as recommended by the NICE technology appraisal guidance, TA132, ‘Ezetimibe for the treatment of primary (heterozygous familial and non familial) hypercholesterolaemia’, although this has a higher acquisition cost at present. Pravastatin is not as efficacious in terms of cholesterol lowering, but seems better tolerated by some people than simvastatin. Tolerability includes people who develop adverse side effects as well as those treated with other drugs which interact with higher dose simvastatin. This is consistent with the NICE lipid modification guideline which recognises the need to consider patient preferences, co-morbidities, other drug treatment, and benefits and risks of treatment.

People intolerant of any statin should be assessed on an individual basis. A fibrate (fenofibrate is recommended) may be considered. The recommended initial dose is one capsule of Lipantil Micro 200 daily with food. Patients with more severe dyslipidaemia may require an increased dose of 267 mg daily (Lipantil Micro 267), which should always be taken with food as it is less well absorbed from an empty stomach. The dose should be reduced in patients with renal impairment (refer to the BNF, but in brief reduce dose to 2x67 mg capsules if eGFR < 60 ml/min/1.73m2, and to one 67 mg capsule if eGFR is < 20 ml/min/1.73m2, avoiding altogether if the eGFR is less than 10 ml/min/1.73m2). However, those people who have had a serious adverse reaction to a statin such as rhabdomyolysis should be referred to a lipid clinic for assessment first, if this is being considered. Ezetimibe 10 mg od is an alternative. There is far less clinical outcome data with either of these drugs than there is with statins. The table below includes estimates of the average change in total and LDL cholesterol with the two drugs.

|Drug |Mean change total cholesterol |Mean change LDL cholesterol |

|Fenofibrate 267 mg daily |- 22% |- 26% |

|Ezetimibe 10 mg daily |- 13% |- 19% |

Treatment with the combination of a fibrate and ezetimibe is not a licensed indication, although has been shown to be effective in a published clinical trial and may be considered in some circumstances.

Higher risk people

The NICE lipid modification guideline reported that in people not presenting with an acute coronary syndrome / acute MI, routine titration beyond simvastatin 80 mg od is not cost effective. However, the NICE lipid modification guideline does not address the management of people with diabetes, and health economic analysis reported in the NICE guideline for the management of type 2 diabetes found that titration to atorvastatin 80 mg, if a total cholesterol < 4 mmol/l or LDL cholesterol < 2 mmol/l is not reached, was cost effective in people with type 2 diabetes and established vascular disease. The Markov model reported in the NICE type 2 diabetes guideline[9] assumed the risk of developing cardiovascular disease events in people with type 2 diabetes compared with non-diabetics was 1.9 fold. Evidence from the literature suggested the risk could be between 1.5 to 2.6 fold and in a sensitivity analysis the risk of developing cardiovascular disease events has to be at least 1.6 fold for two-step titration (to atorvastatin 80 mg od) to a total cholesterol < 4 mmol/l to be cost-effective at £20,000/QALY.

People with type 2 diabetes and established vascular disease are a higher risk group, and whilst titration to atorvastatin 80 mg od is not cost effective in ‘average people without diabetes’ being treated for secondary prevention, there will be some in whom the absolute risk is similar to that of people presenting with acute coronary syndrome/ acute MI, or of those with type 2 diabetes and established vascular disease. The FATS group felt that by extrapolation, titration in such people could be anticipated to be cost effective, and agreed to recommend titration to atorvastatin 80 mg od be considered in such people if total cholesterol remains ≥ 4 mmol/l, LDL cholesterol ≥ 2 mmol/l or non-HDL cholesterol ≥ 2.8 mmol/l. These people are strictly defined as those in the following groups: with diabetes, or with disease in more than 1 arterial disease location (coronary disease, cerebrovascular disease and PAD)[10], or after CABG or with recurrent acute events within a year (although these latter people may already be treated if they have an acute coronary syndrome). In other people statins should not be routinely titrated beyond simvastatin 80 mg od.

The FATS group discussed the option of titration to atorvastatin 80 mg od or to simvastatin 40 mg od plus ezetimibe 10 mg od if a two-step titration is being considered. There is good evidence for efficacy of atorvastatin 80 mg od in reducing cardiovascular events and this is the recommended option, unless tolerability of high dose statin is a concern.

Non-HDL cholesterol and assessing response to therapy

This is unchanged from FATS4. Some clinicians may prefer to use non-HDL cholesterol measurements instead of LDL cholesterol when assessing response to treatment. Total cholesterol includes the cardio-protective HDL cholesterol fraction, but it is the atherogenic fraction of total cholesterol, which needs to be the primary focus for treatment. LDL cholesterol is a major atherogenic fraction of total cholesterol and is calculated from the Friedewald formula using total cholesterol, HDL cholesterol and triglyceride. It requires a fasting sample, and is only valid when triglycerides are below 4.5 mmol/l. In some people (for example those with lower total and LDL cholesterol levels and those with diabetes), the triglyceride rich lipoprotein fraction, VLDL, accounts for a greater proportion of serum lipids. When enriched in cholesterol, VLDL fractions are considered to be atherogenic and use of LDL cholesterol as a therapeutic target may result in under treatment.

Non-HDL cholesterol includes LDL and VLDL cholesterol. A reduction in non-HDL cholesterol is associated with a reduction in coronary risk[11] and has been proposed in the US NCEP ATP III guidelines as an alternative to LDL cholesterol as a therapeutic target[12]. It has the advantage of not requiring a fasting sample and can be used in people with raised triglycerides. Non-HDL cholesterol is a simple calculated measure which is reported alongside LDL cholesterol by the biochemistry laboratories in Newcastle Hospitals and Northumbria Healthcare Trust and may be preferred as a therapeutic target.

Some clinicians measure cholesterol alone, and this may be used for monitoring purposes, but only if HDL cholesterol and triglycerides are known to be normal. A full lipid profile should always be measured at baseline.

Low HDL cholesterol

There is no new evidence for the clinical effectiveness of using drug therapy targeted at increasing HDL cholesterol and no changes have been made for FATS5, although the results of HPS2-THRIVE are awaited. In people with low HDL cholesterol, diet and physical activity should be specifically discussed, but routine initiation of drug treatment such as modified release nicotinic acid is not currently routinely recommended. Drug treatment targeted at raising HDL cholesterol per se should only be prescribed following recommendation from specialist care.

Statins and fibrates are contra-indicated in pregnancy. In all women in whom pregnancy is possible, the following should be specifically clarified before starting treatment; whether pregnant, contraceptive status and future pregnancy plans or possibility of pregnancy.

Impaired glucose tolerance (IGT) is diagnosed from a 75g oral glucose tolerance test (OGTT) and the indications for a OGTT are included in the local diabetes guidelines. People with IGT should be considered to have a similar vascular risk to those with Type 2 diabetes.

As in FATS4, all people with diabetes (Type 1 or Type 2) with microalbuminuria / proteinuria should be considered for statin treatment.

Those with Type 1 diabetes, Type 2 diabetes or IGT aged ≥ 40 years should be considered for statin treatment unless all of the following are present;

• Not overweight, tailoring this with an assessment of body weight associated risk according to ethnic group

• Normotensive ( 1.7 mmol/l (non-fasting > 2.5 mmol/l)

• Has no history of cardiovascular disease, and

• Has no family history of premature cardiovascular disease.

Those who are older may still be considered for treatment even if the above are the case, as cardiovascular risk increases with age.

Assessment of cardiovascular risk in people with Type 1 diabetes, Type 2 diabetes or IGT aged < 40 years remains difficult, and it was agreed to make a single recommendation for these people in FATS5. Clinical judgement is required, and treatment should be considered in those with one or more other cardiovascular risk factors, with the indications becoming stronger as the number of cardiovascular risk factors increases, and particularly as people near the age of 40 years.

Cardiovascular risk factors include:

• Family history of premature coronary disease; first degree relative in men< 55 years, women< 65 years)

• Of ethnic group with high risk, eg those of South Asian origin

• More severe abnormalities of blood lipids; total cholesterol ≥ 6 mmol/l, HDL < 1.0 mmo/l in men, < 1.2 mmol/l in women, fasting triglycerides > 1.7 mol/l (non-fasting > 2.5 mmol/l)

• Blood pressure ≥ 140/90 mmHg or requiring anti-hypertensive treatment

• Current or recent smoking

• Two or more features of the metabolic syndrome which are;

o Raised blood pressure (requiring anti-hypertensive treatment)

o Excess body fat, particularly abdominal fat – ‘central obesity’ ie BMI ≥ 30 kg/m2, or BMI < 30 kg/m2 with increased waist circumference (Caucasian men ≥ 102 cm (40 in), women ≥ 88 cm (35 in), Asian men ≥ 90 cm (35 in), women ≥ 80 cm (32 in))

o Low HDL-cholesterol (< 1.0 mmol/l in men and < 1.2 mmol/l in women)

o High triglycerides (fasting triglycerides > 1.7 mmol/l, non-fasting triglycerides > 2.5 mmol/l)

A non-fasting triglyceride level has been included for those in whom fasting samples may be particularly difficult to obtain.

It was noted that some features of the metabolic syndrome are alone also included as cardiovascular risk factors.

The NICE guideline for management of type 2 diabetes reports that initiation of simvastatin 40 mg od with a 1 step titration to simvastatin 80 mg od if total cholesterol remains above 4 mmol/l, LDL cholesterol > 2 mmol/l is cost effective in people with type 2 diabetes without known symptomatic vascular disease, but that a 2 step titration to atorvastatin 80 mg od is not. However, in people with type 2 diabetes who have established vascular disease a second titration to atorvastatin 80 mg od is cost effective.

If total cholesterol remains ≥ 4 mmol/l, LDL cholesterol ≥ 2 mmol/l, non-HDL cholesterol ≥ 2.8 mmol/l when treated with simvastatin 40 mg od, FATS5 recommends titration to simvastatin 80 mg od, but with a second titration to atorvastatin 80 mg od only in those with established vascular disease. Titration to simvastatin 80 mg od should take into consideration the benefits and risks of this. In people intolerant of simvastatin other statins may be considered. Refer to the section entitled ‘People with symptomatic or prior occlusive vascular disease’.

Previous iterations of FATS have not recommended combinations of statins and fibrates unless recommended by specialist care. The NICE guideline for the management of Type 2 diabetes recommends a combination of a statin and a fibrate be considered in people with diabetes if triglycerides are raised. The FATS group discussed this and came to the following consensus;

• If triglycerides are > 10 mmol/l seek specialist advice, eg by phone, as these people are at risk of acute pancreatitis.

• Look for and address secondary causes of high triglycerides, including poor glycaemic control, (others include untreated hypothyroidism, renal impairment and liver inflammation, particularly from alcohol) and make recommendations for intensive therapeutic lifestyle interventions (diet, alcohol reduction and physical activity).

• Consider treatment with a combination of statin and fibrate if fasting triglycerides remain > 4.5 mmol/l, or if fasting triglycerides are between 2.3 and 4.5 mmol/l if known cardiovascular disease or particularly high cardiovascular disease risk. The BNF recommends adding a fibrate to a statin after 6 months of therapeutic lifestyle interventions, if triglycerides remain high and it was agreed to adopt this time interval.

• A fasting lipid profile should be measured prior to considering combination treatment. However, raised triglycerides may be noted on an initial non fasting sample, and treatment with a statin, lifestyle interventions, and optimising glycaemic control could be initiated with the aim of arranging a fasting sample at the 6 month assessment when, if triglycerides remain raised, a fibrate might be added.

• It was recognised that whilst it is ideal that glycaemic control is optimised prior to treating with the combination of a statin and fibrate, this is not always achievable (although should be aspired to).

• Fenofibrate (such as 200 mg micronised fenofibrate) is the preferred fibrate, and if combined with a statin this should only be simvastatin 40 mg od, not higher intensity statins such as simvastatin 80 mg od or atorvastatin 80 mg od (unless following specialist recommendation). It was noted that fenofibrate has some LDL cholesterol lowering effect, which will offset the impact of any reduction in the dose of the statin. Higher doses of fenofibrate are not recommended in combination with a statin.

• Gemfibrozil should not be prescribed in combination with a statin (increased risk of myopathy).

• The combination of a statin and fibrate is associated with an increased risk of adverse effects, and this should be taken into account when considering whether to initiate combination therapy.

FATS advice is based on risk not cholesterol, discuss risk not just cholesterol

Overall vascular risk should be discussed, not just cholesterol. Clinicians should consider carefully how they are going to do this with people and the tools they will use to support the discussion.

A non-fasting sample is acceptable, but as above a fasting sample is required to accurately assess triglycerides, and for calculation of LDL cholesterol.

A cholesterol cannot be interpreted in isolation when assessing people for primary prevention and a full lipid profile must be measured.

There are different cardiovascular risk assessment tools available. The NICE lipid modification guideline recommends adopting a risk assessment tool based on Framingham. QRISK was discussed by the FATS group, but the consensus was to recommend Framingham risk assessment as the preferred option, although acknowledging other risk assessment methods exist.

Any initial cardiovascular risk assessment should incorporate;

• Age

• Gender

• Total to HDL cholesterol ratio (prior to treatment)

• Blood pressure (prior to treatment)

• Smoking status

A total to HDL cholesterol ratio and blood pressure before treatment may not always be available. In this case, available measurements should be used, recognising that the calculated risk will be lower than if pre-treatment levels had been used, and clinical judgement used to incorporate this into the overall assessment.

In people with hypertension an ECG is required to look for left ventricular hypertrophy (LVH). Some risk calculators may already include LVH in the 10 year CVD risk estimate, but if not, the 10 year CVD risk estimated from the risk factors age, gender, total cholesterol to HDL cholesterol ratio, blood pressure and smoking status should be doubled. Possible LVH on an ECG is not an indication to double the risk.

• Possible ECG-LVH with only voltage criteria for LVH is not associated with a marked excess vascular risk over and above that associated with the raised blood pressure, and should not be included as an additional factor in the risk assessment.

• Definite ECG-LVH with ST depression / T wave flattening or more marked ST / T wave changes as well as increased voltages is associated with a significantly increased risk, independent of the raised blood pressure, and should be included as an additional risk factor in the risk assessment.

• If the significance of the voltages on an ECG is uncertain, the ECG might be repeated after 2 years looking for progression of ECG changes of LVH and thus an increased risk, particularly if this would lead to a change in treatment.

In the Framingham Study, the criteria for definite ECG-LVH included some, but not all, of the following:

• an increased R wave amplitude in leads reflecting potentials from the left ventricle associated with S-T segment depression and T wave flattening or inversion;

• deep S waves over the right precordial leads;

• left axis deviation (> - 30 degrees);

• prolongation of the QRS complex duration;

Possible ECG-LVH was defined if tracings showed similar abnormalities which were less marked and for which the principal findings included in this category were increased R wave amplitude without prominent ST and T wave abnormalities[13].

After adjustment for blood pressure, vascular risk became markedly attenuated or disappeared in those with possible ECG-LVH. In those with definite ECG-LVH, the four fold increased risk was reduced by about 25% after adjustment for blood pressure[14].

People with the greatest increases in voltages and those with the most marked repolarisation changes are at greatest risk[15]. Serial change in voltages and repolarisation changes also predicted future risk, with a reduction associated with a lower risk and an increase with a higher risk[16].

The current national recommendation is to consider statin treatment in people with a 10 year cardiovascular disease risk of 20% or more. In addition to the conventional risk factors used in the Framingham assessment, other factors increase cardiovascular risk. These include the factors above.

The presence of other co-morbid conditions such as CKD, inflammatory arthritis, connective tissue disease, and severe mental illness increase cardiovascular risk. Other inflammatory conditions may be associated with an increased risk, and for example, people with severe psoriasis which requires systemic treatment may also have a higher risk. People with HIV also have a heightened cardiovascular disease risk, but drug treatment needs tailoring (avoiding simvastatin because of drug interactions).

It was uncertain how useful the FATS4 recommendation to add 5% to an initial cardiovascular risk assessment had been if additional markers of risk were present. The NICE lipid modification guideline recommends that the risk is 1.5 fold higher with a family history of premature coronary heart disease with one family member affected and between 1.5 and 2.0 fold higher if more than one family member is affected.

The NICE lipid modification guideline distinguishes South Asian men from South Asian women and recommend an incremental risk only in men, recommending a 1.4 fold increased risk. The FATS group further considered the available evidence and agreed that both men and women of South Asian origin should be considered as being at increased risk.

There was general agreement that clinical judgement was required. An initial risk assessment should be made using conventional risk factors, incorporating additional risk factors using clinical judgement. For example, a statin would be recommended in a patient with an initial 10 year cardiovascular disease risk of 18% if there was also an additional risk factor such as a family history of premature coronary heart disease.

As a general guide, a statin should be considered in those with additional risk factors when 10 year cardiovascular disease risk estimated from conventional risk factors is 15% or more. However clinical judgement is required, particularly when there are multiple additional risk factors.

Communication and negotiation with people to explain and agree a management plan, and encourage concordance is important.

The NICE lipid modification guideline recommends simvastatin 40 mg od as first line. If simvastatin 40 mg od is not tolerated, a lower dose may be considered, or an alternative statin, with similar acquisition costs, such as pravastatin. In all people secondary causes should be excluded, and the NICE lipid modification recommends a fasting lipid profile is measured before a statin is initiated.

The NICE lipid modification guideline does not recommend that the lipid profile is monitored in people treated for primary prevention. However, there was a consensus to recommend this for FATS5, with the rationale that high risk people being treated for primary prevention with drug treatment will require review, and the purpose of monitoring is to review the response to treatment. If the fall in cholesterol is < 1 mmol/l, concordance both with drug treatment and with diet should be reviewed, as well as ensuring secondary causes have been excluded. However, routine titration of statins is not recommended in this group of people, consistent with the NICE lipid modification guideline.

All people being treated with drugs for primary prevention should have an annual review.

People with a combination of factors which increase the future risk of cardiovascular disease and diabetes may be diagnosed as having the metabolic syndrome. The metabolic syndrome is diagnosed when 3 or more of the following are present;

• Excess body fat, particularly abdominal fat – ‘central obesity’.;

BMI ≥ 30, or

BMI < 30 with increased waist circumference (Caucasian men ≥ 102 cm (40 in), women ≥ 88 cm (35 in), Asian men ≥ 90 cm (35 in), women ≥ 80 cm (32 in))

• Raised fasting triglycerides > 1.7 mmol/l

• Low HDL cholesterol < 1.0 mmol/l in men and < 1.2 mmol/l in women

• Blood pressure ≥ 130/85 mmHg (using the large cuff if appropriate), or treated hypertension

• Impaired fasting glycaemia (see local diabetes guidelines), or diagnosed diabetes or IGT

Lifestyle interventions are recommended for all people treated for cardiovascular prevention, as part of an overall management plan, but in FATS5, as in FATS4, the particular importance of therapeutic lifestyle interventions in those with the metabolic syndrome, and impaired fasting glycaemia, as well as in those with diabetes and IGT, is emphasised.

Vascular risk factors in people with the metabolic syndrome and impaired fasting glycaemia are usually particularly responsive to intensive therapeutic lifestyle changes which include;

• Reduced intake of total and saturated fat

• Increased physical activity

• Weight reduction

Thus, intensive therapeutic lifestyle changes are particularly emphasised, with cardiovascular risk assessed annually. Any hypertension should be appropriately managed and lipid lowering drugs offered as appropriate, based on an overall cardiovascular risk assessment.

ADDITIONAL NOTES (SEE FULL SUPPORTING NOTES FOR MORE INFORMATION):

These thresholds are included as people with very high total cholesterol and/or triglycerides may require different drug therapies to those routinely recommended in FATS5, and some may have familial conditions and also require family screening. It is recommended that the Simon Broome criteria are used for a clinical diagnosis of familial hypercholesterolaemia (FH) (see NICE guideline CG071 for details). In brief that is in adults;

Definite FH

Total cholesterol > 7.5 mmol/l (either pre-treatment or highest on treatment) in adults over 16 years, or LDL cholesterol > 4.9 mmol/l

plus

Either tendon xanthomata in the person or 1st or 2nd degree relative and/or DNA- based evidence of an LDL receptor mutation or familial defective apoB-100.

Possible FH

Total cholesterol > 7.5 mmol/l (either pre-treatment or highest on treatment) in adults over 16 years, or LDL cholesterol > 4.9 mmol/l

plus one of the following

Family history of myocardial infarction before age 50 years in 2nd degree relative or before 60 years in 1st degree relative

Family history of raised total cholesterol > 7.5 mmol/l in 1st or 2nd degree relative.

People with definite or possible FH should be considered for referral to the lipid clinic for confirmation of the diagnosis and initiation of family cascade testing, where appropriate.

High triglycerides

People with high triglycerides require individual assessment and management. Those with triglycerides above 10 mmol/l are at risk of acute pancreatitis and specialist advice should be obtained urgently. In others, intensive therapeutic lifestyle changes should be recommended (diet, alcohol, physical activity), and some will require specialist referral. See above for management of people with Type 2 diabetes.

Local advisors

These can be contacted by email;

Dr Neely in Newcastle upon Tyne Hospitals NHS Foundation Trust (fatsinfo@nuth.nhs.uk)

Dr McKenna in Northumbria Healthcare NHS Foundation Trust (paul.mckenna@northumbria-healthcare.nhs.uk)

This is consistent with previous iterations of FATS. All people with hyperlipidaemia being considered for lipid lowering drug treatment should have secondary causes of dyslipidaemia excluded. The table below describes some of the causes of secondary dyslipidaemia.

Secondary causes of dyslipidaemias

|Condition / drug treatment |Lipid change |Lipoprotein elevated |

| |Cholesterol |Triglycerides |HDL cholesterol | |

|Diabetes mellitus | |++/+ |- |VLDL |

|Untreated hypothyroidism |++ | | |LDL |

|Alcohol excess | |++/+ |+ |VLDL |

|Obesity | |+ |- |VLDL |

|Chronic renal failure |+ |++ |- |VLDL/ LDL |

|Nephrotic syndrome |++ |+ | |VLDL/ LDL |

|Cholestasis |++ | | |LDL |

|Gout | |+ | |VLDL |

|Pregnancy |+/- |+/++ | |VLDL |

|Anorexia nervosa |+ | | |LDL |

|Hypopituitarism |+/+++ |++/+ |- |VLDL/ LDL/ IDL |

|Long term drug treatment | | | | |

|Anticonvulsants | | |+/++ |HDL |

|Androgens | | |-/-- |Lowers HDL |

|Atypical antipsychotics |+/+++ |+/+++ |- |VLDL/LDL |

|Beta blockers | |+ | |VLDL |

|Corticosteroids |+ |+ |- |VLDL/ LDL |

|Ciclosporin |+ |+ |- |LDL/ VLDL |

|HIV/anti-retroviral drugs | |+/++ | |VLDL |

|Oral oestrogens | |+ |+ |VLDL |

|Retinoids | |++/+ |- |VLDL |

No revision has been made about this for FATS5. Some people may be at increased risk of adverse side effects with higher doses of simvastatin and it is recommended that lower doses of simvastatin be considered in such people, and simvastatin 80 mg is only recommended after careful consideration of the risks and benefits (see above).

• CKD with eGFR ≤ 30 ml/min/1.73m2 (initial dose of simvastatin 10 mg od, higher doses with caution)

• Older people particularly those who are frail and or have a low muscle mass

• Untreated muscle disorder, or other conditions which may be associated with ‘vulnerable’ muscles eg PMR (CK measurement recommended at baseline in these groups, but not in all people)

• Untreated hypothyroidism (until corrected)

• Alcohol abuse

Grapefruit juice should be avoided, as it interferes with simvastatin metabolism.

All statins and fibrates are contra-indicated in pregnancy.

A number of other drugs interact with simvastatin and dosage modifications may be required. Information is available in the BNF. Examples are included in the table below (the list is not exhaustive, but includes some of the commoner drugs used, and the BNF should be referred to);

|Drug |Recommended doses of simvastatin |

|Amiodarone |Maximum simvastatin 20 mg od |

|Anti-fungal agents (ketocoanzole, |Avoid concomitant use, temporarily discontinue simvastatin during treatment with |

|itraconazole, miconazole, posaconazole) |anti-fungal agents |

|Ciclosporin |Maximum simvastatin 10 mg od |

|Danazol |Maximum simvastatin 10 mg od |

|Diltiazem |Maximum simvastatin 40 mg od |

|Erythromycin / clarithromycin / |Avoid concomitant use. Temporarily discontinue simvastatin during treatment with |

|telithromycin |erythromycin, clarithromycin or telithromycin |

|Fibrates |Combination treatment generally following recommendation from specialist care only. |

| |Increased risk of myopathy |

|Gemfibrozil |Avoid concomitant use |

|HIV protease inhibitors |Avoid concomitant use. Consider alternative statin. Refer to BNF |

|Nicotinic acid |Combination treatment generally following recommendation from specialist care only. |

| |Increased risk of myopathy. Maximum dose of simvastatin 10 mg od |

|Verapamil |Maximum simvastatin 20 mg od |

The interaction between simvastatin and warfarin has been addressed in previous iterations of FATS. Simvastatin modestly potentiates warfarin, but can still be used in combination. Fenofibrate also potentiates warfarin. People should be advised to start or up-titrate simvastatin or fenofibrate 3 to 5 days before the date of the next INR and a note made in the ‘yellow book’ that the drug has been started or dose changed. Clinical judgement should be used to decide if an adjustment in the warfarin dose is required prior to starting treatment, particularly when starting fenofibrate.

It is anticipated that in the majority of people treated with simvastatin 40 mg daily or higher intensity statin, total cholesterol and non HDL cholesterol will fall by at least 1 mmol/l from baseline, and usually more. Evidence from the Heart Protection Study is that the average cholesterol lowering during the trial with simvastatin 40 mg daily was about 1.8 mmol/l In a summary estimate from 164 trials reported in the full version of the lipid modification guideline, the average fall in total cholesterol was 2.14 mmol/l. If cholesterol fails to fall, it is recommended that the notes are reviewed to ensure secondary causes have been excluded and concordance is reviewed with the patient. In people being considered for further increments in the drug flow concordance with medication and lifestyle should be considered at each step.

This was discussed for FATS4 and is maintained for FATS5. The following was noted;

• Life expectancy in people of different ages (this included all people, not just those who are well) was reviewed. At the age of 80 years, the average life expectancy in men is about 7 years and in women 9 years. At the age of 90 years, the average life expectancy in both men and women is about 4 years

• People who are older are more likely to have a circulatory death than those who are younger. If statins are of benefit, that benefit may be greater in an older person than a younger

• Correcting for frailty, co-morbidity and first year events, cholesterol is a risk factor in older people

• The statin trials show no trend in difference in efficacy of statin treatment with older age

People with occlusive vascular disease and diabetes / IGT should be offered treatment irrespective of age. For those without known vascular disease or diabetes, the cardiovascular risk assessment tools are not validated and the recommendation in the NICE lipid modification guideline is appropriate. People aged 75 years and over should be considered to be at increased risk, particularly those who smoke and or have hypertension. People should be assessed for the benefits and risks of treatment, including considering any co-morbidities and the preferences of the patient, when deciding about treatment.

Older people have a higher risk of drug side effects and a lower initial dose of simvastatin may be preferred in this group.

APPENDIX

Membership of the FATS steering group

Dr Jane Skinner, Consultant Community Cardiologist, Newcastle upon Tyne Hospitals NHS Foundation Trust (guideline co-ordinator)

Dr Phil Adams, Consultant Cardiologist, Newcastle upon Tyne Hospitals NHS Foundation Trust

Dr Stuart Bennett, Consultant in Diabetes, Northumbria Healthcare NHS Foundation Trust

Dr Sibal Bharat, Consultant in Public Health Medicine, North Tyneside PCT

Dr Steve Blair, GP, Village Green Surgery

Dr John Bourke, Consultant Cardiologist, Newcastle upon Tyne Hospitals NHS Foundation Trust

Dr Andrew Chalmers, GP, Beaumont Park, Whitley Bay

Dr Richard Curless, Northumbria Healthcare Trust

Dr J Colin Doig, Consultant Cardiologist, Northumbria Healthcare NHS Foundation Trust

Tim Donaldson, Medicines Management Lead, Northumberland Tyne and Wear NHS Trust

Christine Dryden, Community Cardiology, North Tyneside PCT

Dr Sharon Gandy, GP, North Shields

Dr Akif Gani, Consultant in Elderly Care, Newcastle PCT

Dr Ifit Haq, Consultant Cardiologist, Newcastle upon Tyne Hospitals NHS Foundation Trust

Dr Gillian Hawthorne, Consultant Community Diabetologist, Newcastle PCT

Prof Philip Home, Consultant in Diabetes, Newcastle upon Tyne Hospitals NHS Foundation Trust

Zahra Irranejad, Pharmaceutical Advisor, Newcastle PCT

Dr Suren Kanagasundaram, Consultant in Renal Medicine, Newcastle upon Tyne Hospitals NHS Foundation Trust

Margaret King, Programme Co-ordinator, Community Cardiac Care, Newcastle PCT

Dr Nick Lewis-Barned, Consultant in Diabetes, Northumbria Healthcare NHS Foundation Trust

Dr Paul Mackin, Consultant Psychiatrist, Northumberland Tyne and Wear NHS Trust

Dr Paul McKenna, Consultant Chemical Pathologist, Northumbria Healthcare NHS Foundation Trust

Dr Dermot Neely, Consultant in Clinical Biochemistry and Metabolic Medicine, Newcastle upon Tyne Hospitals NHS Foundation Trust

Dr Wan-Fai Ng, Consultant Rheumatologist, Newcastle upon Tyne Hospitals NHS Foundation Trust

Dr Matthew Pettifer, GP, Northumberland

Dr Mike Scott, GP, Newburn Surgery, Newcastle

Dr Caroline Sprake, GP, North Tyneside

Prof Gerry Stansby, Consultant Vascular Surgeon, Newcastle upon Tyne Hospitals NHS Foundation Trust

Deb Stone, Dietician, Healthy Hearts, Northumbria Healthcare NHS Foundation Trust

Dr Simon Thomas, Consultant Physician, Newcastle upon Tyne Hospitals NHS Foundation Trust

Mr Glyn Trueman, Formulary Pharmacist, Newcastle upon Tyne Hospitals NHS Foundation Trust

Susan Turner, Pharmaceutical Advisor (commissioning), NHS North of Tyne

Dr John Waddell, GP, Northumberland

Dr Mark Walker, Consultant Physician, Newcastle upon Tyne Hospitals NHS Foundation Trust

Rachael Wiedmann, Pharmacist, Northumbria Healthcare NHS Foundation Trust

Dr Azfar Zaman, Consultant Cardiologist, Newcastle upon Tyne Hospitals NHS Foundation Trust

Declared conflicts of interest

JSS has received travel grants and honoraria from various pharmaceutical companies that manufacture lipid lowering drugs. PCA has received support from drug companies involved in statin and ezetimibe trials and promotion for research, travel and received honoraria for speaking. CD has received funding support for training from various pharmaceutical companies that manufacture lipid lowering drugs. JCD has received honoraria from various pharmaceutical companies which manufacture lipid lowering drugs and has participated in advisory boards for Merck and Astra-Zenica. IUH has received travel grants and honoraria from various pharmaceutical companies that manufacture lipid lowering drugs, and is an investigator for sponsored trials which include simvastatin and ezetimibe. PH has declared non-personal, non-specific duality of interests as various manufacturers of blood lipid modifying drugs support educational and research activities of his University, Trust, the International Diabetes Federation, the Worldwide Initiative for Diabetes Education in regard of diabetes products and activities, and was the clinical advisor for the NICE guidelines for management of Type 2 diabetes. NL-B has participated in an independent advisory board meeting for Astra-Zeneca. ST was an ASCOT investigator (Pfizer) and has received travel grants and honoraria from various pharmaceutical companies that manufacture lipid lowering drugs. PM was an investigator in the HPS and SEARCH trials, and is an investigator for HPS2-THRIVE trial organised by the CTSU, Oxford, and has received travel grants from various pharmaceutical companies that market lipid lowering drugs. RGDN is chair of Heart UK and has received travel grants and honoraria from various pharmaceutical companies that manufacture lipid lowering drugs and has participated in advisory boards for MSD-Schering Plough and Pfizer. MS has received honoraria for speaking and educational grants from various pharmaceutical companies, and works for Mediproof which is funded by pharmaceutical companies. GS has received honoraria from various pharmaceutical companies for speaking and chairing meetings

Date of review

February 2012, or earlier if required by new evidence.

• This is a lipid lowering drug strategy which should only be used within an overall lifestyle and clinical management strategy

• It is assumed that people with contraindications will be identified and excluded (refer to the BNF).

• This summary should be used with the supporting documentation

People with symptomatic or prior occlusive vascular disease

• Measure lipid profile (total cholesterol, HDL cholesterol, triglycerides)

• Measure ALT or AST at baseline (and after 3 months if high dose statin)

• If ALT or AST < 2 fold normal, prescribe a statin as below

• In acute coronary syndrome/ acute MI ; Atorvastatin 80 mg od

• In all others; Initiate simvastatin 40 mg od

Consider titration to simvastatin 80 mg od (benefits/risks)

• Repeat lipid profile 8 weekly until TC < 4 mmol/l, or LDL-C (fasting) < 2 mmol/l, or non-HDL-C < 2.8 mmol/l or maximum drug flow reached (see supporting notes)

• People intolerant of recommended statin; see supporting notes

• Higher risk people ie diabetes, disease in > 1 arterial bed (CHD, cerebrovascular, PAD), after CABG and recurrent spontaneous acute CVD events within a year, consider titration to atorvastatin 80 mg od / simvastatin 40 mg plus ezetimibe 10 mg od; see supporting notes.

People with Type 1, Type 2 diabetes, or IGT (OGTT)

Consider drug treatment in people with;

• Type 1 and Type 2 diabetes with microalbuminuria/proteinuria

• Type 1 diabetes / Type 2 diabetes / IGT aged ≥ 40 years

• Type 1 diabetes / Type 2 diabetes / IGT aged < 40 years if other cardiovascular risk factors present using clinical judgement

• Drug flow; Simvastatin 40 mg od

Consider simvastatin 80 mg od (benefits/risks)

Atorvastatin 80 mg od / simvastatin 40 mg plus ezetimibe 10 mg od only if established CVD

• Threshold for titration and additional notes; see other sections

• Type 2 diabetes and triglycerides > 1.7 mmol/l < 10 mmol/l; therapeutic lifestyle measures for 6 months, then consider adding a fibrate (see supporting notes)

High risk people without symptomatic or prior occlusive vascular disease and without diabetes / IGT (OGTT)

FATS advice is based on risk not cholesterol, discuss risk not just cholesterol

In people at high risk of developing vascular disease

• Measure total and HDL cholesterol, triglycerides (non-fasting acceptable)

• Estimate 10 year CVD risk (Framingham)

• If definite LVH on ECG, double 10 year CVD risk (if not already included)

Consider other additional risk factors:

Family history of premature CHD (men< 55 yrs, women< 65 yrs)

South Asian origin

Fasting triglycerides > 1.7 mmol/l

High level of deprivation

Premature female menopause aged ≤ 45 years

Other conditions (eg CKD, inflammatory arthritis, connective tissue disease, severe mental illness, other severe inflammatory conditions)

Consider simvastatin 40 mg od if 10 year CVD risk ≥ 20%, or ≥ 15% with additional risk factors (use clinical judgement, discussion with patient)

3 month lipid profile to assess concordance, not for dose titration, then annual review

• If metabolic syndrome or impaired fasting glycaemia; ensure intensive therapeutic lifestyle interventions (see supporting notes)

Additional notes (see full supporting notes for more information):

1. Consider familial hypercholesterolaemia (FH) if total cholesterol > 7.5 mmol/l, LDL cholesterol > 4.9 mol/l. Suspected FH or if triglycerides > 4.5 mmol/l, treat individually, consider discussion with local advisor.

2. Consider secondary causes of hyperlipidaemia – alcohol / thyroid / diabetes / nephrotic syndrome / liver disease / drug induced

3. Initiate with a lower dose if increased risk of adverse side effects or treated with other drugs which may interact (eg verapamil, diltiazem, amiodarone, fibrates, ciclosporin). Temporarily stop simvastatin if treated with erythromycin, clarithromycin, some anti-fungals (supporting notes/BNF)

4. Simvastatin/fibrate potentiate warfarin – initiate 3 - 5 days before INR check

5. Review concordance and lifestyle if initial total cholesterol and non HDL cholesterol falls < 1 mmol/l

6. Treatment in older people; see supporting notes

FATS5 developed in the light of new evidence and monitoring of FATS1,2, 3 & 4

Agreed with Primary and Secondary Care Users North of Tyne

-----------------------

[1]

[2]

[3]

[4]

[5] JAMA 2004;292:1307-1316

[6] NEJM 2004;350:1495-1504

[7] accessed 9/1/2009

[8] accessed 9/1/2009

[9] National Collaborating Centre for Chronic Conditions. Type 2 diabetes: national clinical Guideline for management in primary and secondary care (update). London: Royal College of

Physicians, 2008. Appendix D accessed .uk on 21/12/2008.

[10] Steg PG et al for the REACH Registry One year cardiovascular event rates

in outpatients with atherothrombosis. JAMA 2007;297:1197-1206.

44% of patents had diabetes at baseline and the rate of cardiovascular death, acute MI and stroke at 1 year was 2.15% for patients with at least 3 risk factors only, 3.06% (PAD), 3.64% (coronary artery disease), 5.54% (cerebrovascular disease) for patients with one, 5.54% (PAD and coronary artery disease), 7.35% (coronary artery disease and cerebrovascular disease), 7.76% (PAD and cerebrovascular disease) in patients with two, and 9.21% for patients with three symptomatic arterial disease locations. The rate of cardiovascular death, MI, stroke or hospitalisation for an atherothrombotic event at 1 year was 5.31% for patients with at least 3 risk factors only, 17.44% (PAD), 13.04% (coronary artery disease), 9.87% (cerebrovascular disease) for patients with one, 23.11% (PAD and coronary artery disease), 19.81% (coronary artery disease and cerebrovascular disease), 21.95% (PAD and cerebrovascular disease) in patients with two, and 26.29% for patients with three symptomatic arterial disease locations.

[11] JACC 2009;53:316-322

[12] Although is not included in the NICE lipid modification guidelines

[13] Kannel WB Ann Intern Med 1970;72:813

[14] Kannel WB Ann Intern Med 1970;72:813

[15] Levy D Circulation 1994;90:1786-1793

[16] Levy D Circulation 1994;90:1786-93

-----------------------

FATS5 : 2009

Measure lipid profile (total cholesterol, HDL cholesterol, triglycerides)

Measure ALT or AST at baseline (and after 3 months if high dose statin)

If ALT or AST < 2 fold normal, prescribe a statin as below

In acute coronary syndrome/ acute MI ; Atorvastatin 80mg od

In all others; Initiate simvastatin 40mg od

Consider titration to simvastatin 80mg od (benefits/risks)

Repeat lipid profile 8 weekly until TC < 4 mmol/l, LDL-C (fasting) < 2 mmol/l, or non-HDL-C < 2.8 mmol/l or maximum drug flow reached (see supporting notes)

People intolerant of recommended statin; see supporting notes

Higher risk people ie diabetes, disease in > 1 arterial bed (CHD, cerebrovascular, PAD), after CABG or recurrent spontaneous acute CVD events within a year, consider titration to atorvastatin 80 mg od / simvastatin 40 mg plus ezetimibe 10 mg; see supporting notes

Consider drug treatment in people with;

• Type 1 and Type 2 diabetes with microalbuminuriople with;

Type 1 and Type 2 diabetes with microalbuminuria/proteinuria

• Type 1 diabetes / Type 2 diabetes / IGT aged ≥ 40 years

• Type 1 diabetes / Type 2 diabetes / IGT aged < 40 years if other cardiovascular risk factors present and using clinical judgement

Drug flow; Simvastatin 40 mg od

Consider simvastatin 80 mg od (benefits/risks)

Atorvastatin 80 mg od / simvastatin 40 mg plus ezetimibe 10 mg od only if established CVD

Threshold for titration and additional notes see other sections

In people at high risk of developing vascular disease

Measure total and HDL cholesterol, triglycerides (non-fasting acceptable)

Estimate 10 year CVD risk (Framingham)

If definite LVH on ECG, double 10 year CVD risk (if not already included)

Consider other additional risk factors:

Family history of premature CHD (men< 55 yrs, women< 65 yrs)

South Asian origin

Fasting triglycerides > 1.7 mmol/l

High level of deprivation

Premature female menopause aged ≤ 45 years

Other conditions (eg CKD, inflammatory arthritis, connective tissue disease, severe mental illness, other severe inflammatory conditions)

Consider simvastatin 40 mg od if 10 year CVD risk ≥ 20%, or ≥ 15% with additional risk factors (use clinical judgement, discussion with patient)

3 month lipid profile to assess concordance, not for dose titration, then annual review

If metabolic syndrome or impaired fasting glycaemia; ensure intensive therapeutic lifestyle interventions (see supporting notes)

Consider familial hypercholesterolaemia (FH) if total cholesterol > 7.5 mmol/l, LDL cholesterol > 4.9 mol/l. Suspected FH or if triglycerides > 4.5 mmol/l, treat individually, consider discussion with local advisor - see supporting notes

Consider secondary causes of hyperlipidaemia – alcohol / thyroid / diabetes / nephrotic syndrome / liver disease / drug induced

Initiate with a lower dose if at increased risk of adverse side effects or if treated with other drugs which may interact (eg verapamil, diltiazem, amiodarone, fibrates, ciclosporin. Temporarily stop simvastatin if treated with erythromycin, clarithromycin, some anti-fungals. ) See supporting notes/BNF

Simvastatin/fibrate potentiates warfarin – initiate 3 - 5 days before INR check

Review concordance and lifestyle if initial cholesterol or non HDL cholesterol falls < 1 mmol/l

Treatment in older people; see supporting notes

Type 2 diabetes and triglycerides > 1.7 mmol/l < 10 mmol/l; therapeutic lifestyle measures for 6 months then consider adding a fibrate (see supporting notes)

PEOPLE WITH SYMPTOMATIC OR PRIOR OCCLUSIVE VASCULAR DISEASE

PEOPLE WITH DIABETES (Type 1 or Type 2), OR IGT (OGTT)

HIGH RISK PEOPLE WITHOUT SYMPTOMATIC OR PRIOR OCCLUSIVE VASCULAR DISEASE AND WITHOUT DIABETES / IGT (OGTT)

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