A Summary of the Evidence Used to Develop FATS5 from FATS4

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

INTRODUCTION3

SUPPORTING NOTES4

People with symptomatic or prior occlusive vascular disease4

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 group24

Summary form as quick reference guide26

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.

1

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 (mg) / Absolute total cholesterol reduction (95% CI) mmol/l / % reduction in total cholesterol (95% CI) mmol/l / Absolute LDL-C reduction (95% CI) mmol/l / % reduction in LDL-C (95% CI) 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.