MeReC Bulletin Volume 19 Number 3
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?
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 ezetimibe▼3. 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|
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
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
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.
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.
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.
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.
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.
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
The National Institute for Health and Clinical Excellence (NICE) is associated with MeReC Publications published by the NPC through a funding contract. This arrangement provides NICE with the ability to secure value for money in the use of NHS funds invested in its work and enables it to influence topic selection, methodology and dissemination practice. NICE considers the work of this organisation to be of value to the NHS in England and Wales and recommends that it be used to inform decisions on service organisation and delivery. This publication represents the views of the authors and not necessarily those of the Institute.
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