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MeReC Bulletin Volume 19 Number 3
December 2008

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Lipid-modifying treatment

Introduction
What does NICE advise about primary prevention of cardiovascular disease?
What does NICE advise about secondary prevention of CV disease?
What does NICE advise about statins in acute coronary syndrome?
What does NICE advise about statins in type 2 diabetes?
What evidence is there for ?higher intensity? statins?
How reliable is a single cholesterol measurement?
Is there any new evidence for rosuvastatin?
What is the controversy over ezetimibe▼?
What about the side-effects of statins?

Summary

  • This MeReC Bulletin summarises the NICE guidance on lipid modification and addresses some important supplementary clinical questions.
  • Statin therapy should usually be considered for all adults who have established cardiovascular (CV) disease or who have a 20% or greater 10-year risk of developing it. Use a suitable risk calculator to estimate risk and explain likely risks and benefits to patients in absolute terms (see the patient decision aid on the lipids section of NPC).
  • A single cholesterol reading may well under- or over-estimate a person?s true average cholesterol by as much as 14%, so health professionals should be wary of making treatment decisions on the basis of single readings.
  • Simvastatin 40mg daily is the usual first-choice statin for most patients for primary and secondary prevention. If this is contraindicated or not tolerated, or if there are potential drug interactions, offer a lower dose or an alternative preparation, such as pravastatin.
  • For primary prevention in people without type 2 diabetes, no target for total or LDL-cholesterol is recommended. Do not use higher intensity statinsa routinely.
  • For secondary prevention in people without type 2 diabetes, consider increasing to simvastatin 80mg if both the total cholesterol and the LDL-cholesterol are greater than 4mmol/L and 2mmol/L, respectively, on simvastatin 40mg. These figures are intended to guide treatment and are not targets all patients are expected to attain. Most patients will not attain these levels on simvastatin 80mg and it is not cost-effective to try to take more patients to target using higher cost statins such as atorvastatin.
  • Offer people with acute coronary syndrome treatment with higher intensity statins but note that no target for total or LDL-cholesterol is recommended.
  • Any decision to offer a higher intensity statin should take into account the patient's informed preference, comorbidities, multiple drug therapy, and the benefits and risks of treatment.
  • Recommendations for primary and secondary prevention in people with type 2 diabetes are slightly different from those without diabetes (see text).
  • In the only published randomised controlled trial (RCT) of ezetimibe ▼ which examined patient-oriented CV outcomes, ezetimibe▼ plus simvastatin did not produce beneficial effects compared with double placebo treatment but raised safety concerns relating to cancer. Statins are usually well tolerated, but due consideration should be given to possible side-effects and the need for monitoring of enzyme levels (e.g. transaminases and creatine kinase) in certain circumstances.

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Introduction

This MeReC Bulletin summarises NICE guidance on lipid modification1-5 (see Panel) and addresses some important supplementary clinical questions. More information on lipid modification can be found on the cardiovascular section of NPC.

Panel: What NICE guidance is there relating to lipid modification?
The NICE clinical guideline on lipid modification was published in May 2008. It provides comprehensive guidance on CV risk assessment and lipid modifying treatment1. This guidance included and updated relevant previously published technology appraisals on statins2 and ezetimibe3. At the same time, NICE published updated guidance on management of type 2 diabetes.4 This included specific recommendations on management of lipids in people with diabetes (who were not included in the general lipid modification guidance). Finally, in August 2008, NICE published its clinical guideline on management of familial hypercholesterolaemia.5


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What does NICE advise about primary prevention of cardiovascular diseaseb?

Primary prevention refers to reducing the risk of developing cardiovascular (CV) disease in the future (e.g. myocardial infarction [MI], stroke, angina, etc) in people who do not currently have it. NICE advises that all adults who have a 20% or greater 10-year risk of developing CV disease should be considered for statin therapy.1 More information on CV risk assessment can be found in a separate MeReC Bulletin6 and on the relevant section of NPC. Healthcare professionals should consider the possibility of familial hyper-cholesterolaemia (FH) in adults with raised cholesterol (total cholesterol typically greater than 7.5mmol/L), especially when there is a personal or a family history of premature coronary heart disease.5 Diagnosis and management of FH is addressed in a separate NICE clinical guideline and is not discussed further in this MeReC Bulletin.5

If statin treatment is appropriate for primary prevention, it should be offered as soon as practicable after full risk assessment. However, the decision to treat should follow an informed discussion with the patient about risks and benefits taking into account additional factors such as comorbidities and life expectancy. Patients should be offered information about their absolute risk of CV disease and the likely absolute benefits and harms of an intervention over a 10-year period. Information should present individualised risk/benefit scenarios, present the absolute risk of events numerically, and use appropriate diagrams and text.1 NICE makes particular reference to NPC, where there is a patient decision aid on the lipids section . More information on the use of patient decision aids was published in MeReC Extra 36.7

Patients should usually be prescribed simvastatin 40mg daily. If simvastatin 40mg is contraindicated or not tolerated or if there are potential drug interactions (see MHRA advice8), patients may be offered a lower dose or an alternative preparation, such as pravastatin. Higher intensity statinsa should not be used routinely.1 Fibrates or anion exchange resins may be considered if statins are not tolerated but the combination of an anion exchange resin, fibrate or nicotinic acid with a statin is not recommended.1

No target for total or LDL-cholesterol is recommended. Once a person has been started on a statin for primary prevention, repeat lipid measurement is unnecessary. Clinical judgement and patient preference should guide the review of drug therapy and whether to review the lipid profile (see section below on the reliability of single cholesterol levels).1

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What does NICE advise about secondary prevention of CV diseasec?

Statin therapy is recommended for adults with established CV disease. As with primary prevention, the decision to treat should follow an informed discussion with the patient about risks and benefits.1 Fibrates, anion exchange resins or nicotinic acid may be considered if statins are not tolerated.1

Patients should usually be prescribed simvastatin 40mg daily. If simvastatin 40mg is contraindicated or not tolerated or if there are potential drug interactions (see MHRA advice8), patients may be offered a lower dose or an alternative preparation, such as pravastatin.1 NICE advises that patients and prescribers should consider increasing to simvastatin 80mg if a total cholesterol of less than 4mmol/L or an LDL-cholesterol of less than 2mmol/L is not attained.1 Increasing the dose should be considered only for patients whose total cholesterol is greater than 4mmol/L and also whose LDL-cholesterol is greater than 2mmol/L. If either figure is below that level, then increasing the dose is not recommended [NICE. Personal communication, November 2008]. Moreover, these figures are intended to guide treatment. NICE lipid guidance sets no lipid targets which patients are expected to achieve.9 Most patients would not achieve these levels on 80mg simvastatin daily and modelling suggests that it is not cost-effective to try to take more patients to target using higher-cost statins such as atorvastatin.9 Any decision to offer simvastatin 80mg should take into account the patient's informed preference, comorbidities, multiple drug therapy, and the benefits and risks of treatment.1

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What does NICE advise about statins in acute coronary syndrome?

People with acute coronary syndrome (ACS) should generally be treated with a higher intensity statin; that is one which achieves greater lipid lowering than simvastatin 40mg daily.1 NICE says that atorvastatin 80mg and simvastatin 80mg daily are both cost-effective in ACS (but atorvastatin 80mg is not cost-effective in stable CV disease).9 The decision to use a higher intensity statin instead of simvastatin 40mg should take into account the patient?s particular circumstances and preferences, as with other patients requiring secondary prevention.1 It is important to note that no lipid target is specified in ACS. NICE does not give guidance on how long patients with ACS should take a higher-intensity statin; that is, at what point after their ACS event they should be treated in the same way as other secondary prevention patients, and whether and when those receiving atorvastatin 80mg should transfer to simvastatin, and at what dose.

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What does NICE advise about statins in type 2 diabetes?

NICE guidance on type 2 diabetes also contains recommendations on lipid modification.4 These are slightly different from the recommendations for people without diabetes. People with diabetes aged 40 years or older should usually be considered for simvastatin 40mg daily.4 If their CV risk from non-hyperglycaemia-related factors is low, their risk should be assessed using the UKPDS risk engine. Simvastatin 40mg should be offered if the estimated 10-year risk of developing CV disease exceeds 20%.4 Simvastatin 40mg should be considered for people younger than 40 years whose CV risk profile appears to be particularly poor.4 NICE advises that the dose should be increased to simvastatin 80mg daily unless the person?s total cholesterol is less than 4mmol/L or the LDL-cholesterol is less than 2mmol/L.4 If either figure is below that level, then increasing the dose is not recommended [NICE. Personal communication, November 2008].

For people with type 2 diabetes who have established or newly diagnosed CV disease, or an increased albumin excretion rate, NICE recommends initiating treatment with simvastatin 40mg daily. Patients and prescribers should consider intensifying treatment with a higher intensity statina or ezetimibe▼ to achieve a total cholesterol of less than 4mmol/L (and an HDL-cholesterol not exceeding 1.4mmol/L) or an LDL-cholesterol of less than 2mmol/L.4

What evidence is there for ?higher intensity? statinsa?
A large meta-analysis of 14 randomised controlled trials (RCTs), including 90,056 patients, found that an initial 1mmol/L reduction in LDL-cholesterol is associated with about a 20% relative reduction in major vascular events after one year of treatment.10 No trials have examined the use of higher intensity statinsa for primary prevention. In secondary prevention, no trials have evaluated the comparative merits of treating to different target lipid levels, but some have compared different doses of statins.11,12,13,14 Some of these have shown a benefit from higher doses over lower doses in terms of reducing the risk of CV events,12,13 but others have not,11,14 and none has shown a reduction in all-cause mortality. In the studies in people with stable CV disease, those taking higher dose statins were more likely to stop treatment due to side-effects.13,14 The preliminary results of the SEARCH study of high dose simvastatin (which were discussed in a recent MeReC Stop Press blog15) are in keeping with these findings. A major limitation of the studies is that none used the ?gold standard? comparator, simvastatin 40mg daily. These trials are discussed further on the lipids section of NPC.

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How reliable is a single cholesterol measurement?

A recent study has found that the 95% confidence interval on a single cholesterol measurement was about ?14% of the person?s true average cholesterol.16 In practical terms, this means that for every 100 people with a single cholesterol measurement of 5.65mmol/L, we would expect the true average cholesterol levels of 95 of them to be in the range from 4.85mmol/L to 6.45mmol/L. Five people in the 100 will have true average levels outside this range. This study and its implications were discussed further in a MeReC Rapid Review blog.17 Health professionals should be wary of adjusting a patient?s lipid-lowering treatment on the basis of a single cholesterol measurement.

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Is there any new evidence for rosuvastatin?

The JUPITER study was the first published clinical trial to find a beneficial effect of rosuvastatin on patient-oriented CV outcomes.18 As discussed in a MeReC Rapid Review blog,19 this study compared rosuvastatin 20mg daily with placebo in people with few elevated CV risk factors apart from a raised high sensitivity C-Reactive Protein (hs-CRP). In absolute terms, for every 1,000 people who took rosuvastatin 20mg daily for two years, eight people avoided having an MI or a stroke or dying from CV causes, but six people developed physician-reported diabetes who would not have done so otherwise. Although JUPITER provides some reassurance about using rosuvastatin where no other statin is suitable, it provides no reason to depart from NICE guidance on choice of statin, the degree of cholesterol lowering for which to aim, or which patients to treat.

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What is the controversy over ezetimibe▼?

Although ezetimibe▼ lowers LDL-cholesterol levels, until recently there have been no published data to say whether or not ezetimibe? alone or added to a statin reduces the chance of having a CV event. The ENHANCE study, in people with familial hypercholesterolaemia, found no beneficial effects of ezetimibe▼ plus simvastatin 80mg versus simvastatin 80mg plus placebo on carotid intima-media thickness20 (see the relevant MeReC Rapid Review blog for more details21) Recently, the SEAS trial in people with asymptomatic aortic stenosis found no benefit from simvastatin plus ezetimibe▼ versus double placebo on the risk of major CV events.22 However, SEAS unexpectedly raised concerns about the safety of ezetimibe▼, because it found a 55% relative increase in the risk of new cancers in the active treatment group (NNH = 26 over 52.2 months, P=0.01). An analysis of interim data from two much larger ongoing studies of simvastatin plus ezetimibe▼ did not find an increased risk of cancer,23 but there are limitations to this analysis.24 A previous very large meta-analysis had shown that statins alone do not increase the risk of cancer.10 The SEAS trial and its implications are discussed further in a recent MeReC Rapid Review blog.25 All suspected adverse reactions to ezetimibeq should be reported through the yellow card scheme.

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What about the side-effects of statins?

The most well established side-effects of statins are their effects on muscle and on liver enzymes. Although widely believed, there is no clear evidence from randomised clinical trials that statins cause myalgia (muscle pain, tenderness or weakness without creatine kinase levels greater than 10 times the upper limit of normal [ULN]).26 However, many statin studies included a run-in period so people who were very sensitive to statin side-effects may not have been included in the trial follow-up.

The risk of myopathy (muscle symptoms with creatine kinase levels >10 times ULN) is very low at standard doses (typically less than 1 in 10,000 patient-years) and the risk of rhabdomyolysis is about a third of that.26 The risk increases with higher doses, in patients with certain risk factors such as renal impairment, and when statins are used in combination with drugs such as fibrates.8,26,27 In particular, gemfibrozil should not be used alongside a statin.27 Statins should be used with caution in those with risk factors for myopathy or rhabdomyolysis. The MHRA have also issued specific warnings and advice regarding drug interactions, especially but not only with atorvastatin and simvastatin,8 and the need to be particularly cautious in escalating the dose of rosuvastatin.28 Myalgia is not necessarily an indicator of myopathy, but NICE advises that creatine kinase should be measured in people who develop muscle symptoms while taking statins.1 Routine monitoring of creatine kinase in asymptomatic people is not recommended.1

Statins currently in use can increase liver enzymes (especially transaminases) but do not seem to be hepatotoxic.26 NICE advises that baseline liver enzymes should be measured before starting a statin. Transaminases should be measured within three months of starting treatment and at 12 months, but not again unless clinically indicated.1 People who have transaminases that are raised but are less than three times the ULN should not be routinely excluded from statin therapy.1

Less well known side-effects of statins as a class include depression, sleep disturbances, memory loss, and sexual dysfunction. Statins may also very rarely be associated with interstitial lung disease.29 Patients should be advised to seek help if they develop presenting features of interstitial lung disease such as dyspnoea, non-productive cough, and deterioration in general health.29 The incidence of peripheral neuropathy during statin therapy is similar to that of myopathy.9 NICE advises that if a person taking a statin develops an unexplained peripheral neuropathy, the statin should be discontinued and specialist advice should be sought.1 Any suspected adverse drug reactions with statin treatment should be reported through the yellow card scheme.29

Notes

  1. ‘Higher intensity statins’ are statins used in doses that produce greater cholesterol lowering than simvastatin 40mg, for example simvastatin 80mg.
  2. In people without diabetes or familial hypercholesterolaemia
  3. In people without diabetes or acute coronary syndrome

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References

  1. National Institute for Health and Clinical Excellence. Lipid modification. Cardiovascular risk assessment: the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. Clinical Guideline 67. May 2008
  2. National Institute for Health and Clinical Excellence. Technology Appraisal Guidance 94. Statins for the prevention of cardiovascular events in patients at increased risk of developing cardiovascular disease or those with established cardiovascular disease. January 2006
  3. National Institute for Health and Clinical Excellence. Technology Appraisal Guidance 132. Ezetimibe for the treatment of primary (heterozygous-familial and non-familial) hypercholesterolaemia. November 2007
  4. National Institute for Health and Clinical Excellence. Type 2 diabetes: the management of type 2 diabetes (update). Clinical Guideline 66. May 2008
  5. National Institute for Health and Clinical Excellence. Identification and management of familial hypercholesterolaemia. Clinical Guideline 71. August 2008
  6. National Prescribing Centre. Assessing and communicating the risk of cardiovascular disease. MeReC Bulletin 2008;19(1)
  7. National Prescribing Centre. Using patient decision aids. MeReC Extra 2008; No. 36
  8. MHRA and CHM. Statins: interactions, and updated advice for atorvastatin. Drug Safety Update, January 2008;1(6):2-4
  9. National Collaborating Centre for Primary Care and the Royal College of General Practitioners. Lipid Modification. Cardiovascular risk assessment: the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. Full Guideline. May 2008
  10. Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-78
  11. de Lemos J, Blazing M, Wiviott S, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z Trial. JAMA 2004;292:1307-16
  12. Cannon CP, Braunwald E, McCabe C, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. New Engl J Med 2004;350:1495-1504 (the PROVE-IT study)
  13. LaRosa J, Grundy S, Waters D, et al Intensive lipid lowering with atorvastatin in patients with stable coronary disease. New Engl J Med 352:1425-35 (the TNT study)
  14. Pedersen T J, Faergeman O, Kastelein J, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA 2005;294:2437-45
  15. National Prescribing Centre. Is lower cholesterol better? – the SEARCH continues. MeReC Stop Press Blog 238. November 18th 2008
  16. Glasziou P, Irwig L, Heritier S, et al. Monitoring cholesterol levels: measurement error or true change? Ann Intern Med 2008;148:656-61
  17. National Prescribing Centre. Cholesterol measurements in the first few years of statin treatment may mislead. MeReC Rapid Review Blog 165. August 8th 2008
  18. Ridker P, Danielson E, Fonseca F, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. New Engl J Med 2008;359:2195-207 (the JUPITER study)
  19. National Prescribing Centre. Higher dose rosuvastatin in lower risk patients. MeReC Rapid Review Blog 236. November 12th 2008
  20. Kastelein J, Akdim F, Stroes E, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. New Engl J Med 2008;358:1431-43 (the ENHANCE study)
  21. National Prescribing Centre. What does ENHANCE tell us about the place in therapy of ezetimibe? MeReC Rapid Review Blog 97. April 16th 2008
  22. Rossebø A, Pedersen T, Boman K, et al for the SEAS Investigators. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008;359:1343-56
  23. Peto R, Emberson J, Landray M, et al. Analyses of cancer data from three ezetimibe trials. N Engl J Med 2008;359:1357-1366
  24. Fleming T. Identifying and addressing safety signals in clinical trials. New Engl J Med 2008;359:1400-02
  25. National Prescribing Centre. SEAS and ezetimibe: no benefits on CV endpoints, questions raised over cancer risk. MeReC Rapid Review Blog 199. September 15th 2008
  26. Armitage J. Safety of statins in clinical practice Lancet 2007;370:1781-90
  27. MHRA and CHM. Fibrates: new prescribing advice. Drug Safety Update, November 2007;1(4):2-3
  28. MHRA and CHM. Rosuvastatin (Crestor): introduction of 5 mg starting dose Current Problems in Pharmacovigilance May 2006;31:4
  29. MHRA and CHM. Statins: class effects identified. Drug Safety Update, February 2008;1(7):2-4

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