23 August 2010
A review of lipid lowering therapy argues that lipid modification should focus on strategies that are known to improve patient-oriented outcomes (e.g. simvastatin▼* 40mg daily), rather than focusing on interventions such as ezetimibe that improve biomarkers (e.g. LDL-cholesterol), but have not been shown to improve patient outcomes. Treating patients to achieve a specific lipid target is not supported by clinical trial evidence.
*Note: The MHRA has advised that the black triangle (▼) refers to intensive monitoring being requested only when simvastatin is used in children and adolescents (10–17 years), in line with the recently licensed paediatric dosing recommendation.
Health professionals should follow NICE guidance on lipid modification. Simvastatin 40mg daily is the first choice lipid lowering drug for most people, in both primary and secondary prevention of cardiovascular (CV) events. NICE lipid modification guidance explicitly sets no lipid targets that patients are expected to achieve, for either primary or secondary prevention.
More intensive statin treatment, fibrates, ezetimibe and other treatments for cardiovascular risk reduction or hyperlipidaemia have discrete but a limited roles. Ezetimibe is an option where statins are contraindicated or not tolerated, and for the treatment of primary hypercholesterolaemia. Addition of ezetimibe to simvastatin 40mg increases the acquisition cost considerably over simvastatin 40mg and has not been demonstrated to deliver better patient-oriented outcomes. Prescribers should review, and where appropriate, revise prescribing of ezetimibe to ensure it is in line with NICE guidance.
What does this review say?
This review published in the BMJ discusses the use of lipid lowering therapy to improve patient outcomes, rather than focusing on achieving ‘target’ cholesterol levels. The ‘treat to target’ approach assumes that changes in risk factors by an intervention (e.g. LDL-cholesterol reduction) will translate into a reduction in patient risk (e.g. reduction in CV events).
However, many interventions that lower cholesterol levels, and particularly LDL-cholesterol levels, have not been shown to reduce patient orientated outcomes. For example, questions are being raised about ezetimibe. Millions of prescriptions have been written for ezetimibe, which effectively reduces LDL-cholesterol, but no published clinical trial of ezetimibe has examined patient outcomes. The uncertainty about benefit and the limitations of the studies should be disclosed to patients when treatment strategies are being discussed. The prescribing of ezetimibe is discussed in more detail in a recent MeReC Rapid Review .
The authors comment that the focus on targets is out of alignment with the evidence from clinical trials. The trials of lipid lowering treatments tested the effect of fixed doses of drugs, not a strategy of progressively intensifying lipid therapy to reach a specific lipid target. No trial has yet examined progressive lowering or shown that combination lipid therapy improves patient outcomes.
Trial evidence most strongly supports the use of statins. Statins reduce the risk of major coronary events, revascularisation, and stroke, regardless of the initial lipid level. The best preventive strategy may be to use the patient’s global CV risk to determine treatment. Those at highest risk (e.g. patients with ACS) would have the highest probability of benefiting from higher dose or higher potency statins.
For people who still have high cholesterol levels after treatment with statins, the choice of which other drugs to use will be made with more uncertainty about the net benefit. Patients may wish to stay with strategies that have proven benefit to patient outcomes and patient preferences should be respected.
What does NICE guidance say?
This review supports recommendations in the NICE guidance on lipid modification for people without type 2 diabetes. NICE advises that simvastatin 40mg daily should be prescribed for primary and secondary prevention of CV events for most people. (If there are potential drug interactions, or simvastatin 40 mg is contraindicated, a lower dose or alternative preparation such as pravastatin may be chosen). The NICE lipid guidance does not recommend a ‘treat to target’ approach and explicitly sets no lipid targets that patients are expected to achieve, for either primary or secondary protection. It does advise certain lipid levels which may be useful to guide treatment.
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.
In secondary prevention patients without ACS, prescribers should consider increasing the dose of simvastatin to 80mg only in 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. These are the lipid levels which should prompt prescribers to consider increasing the dose. They are not targets patients are expected to achieve. Moreover, NICE states (in the full guideline) “Most patients would not achieve a target of 4mmol/L total cholesterol [on simvastatin 80mg] and modelling suggests that it is not cost-effective to try to take more patients to target using higher cost statins such as atorvastatin.” NICE also advises that any decision to offer a higher intensity statin should not be automatic, but should take into account the patient’s informed preference, including the benefits and risks of treatment. This is entirely consistent with the recent MHRA advice regarding the use of simvastatin 80mg.
In people with ACS, NICE found that atorvastatin 80mg and simvastatin 80mg are both cost effective, if more intensive statin treatment is chosen. Again, NICE advises that the decision to offer a higher intensity statin should take into account the patient’s informed preference, as above. In addition, NICE does not recommend target lipid levels in people with ACS. NICE does not give guidance about how long ACS patients 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.
NICE guidance on lipid management in people with type 2 diabetes recommends simvastatin 40mg as the first choice statin, with an increase to 80mg if the total cholesterol is more than 4mmol/L and also the LDL-cholesterol is more than 2mmol/L on treatment. In people with type 2 diabetes and existing or new CV disease, or increased albumin excretion, NICE advises considering intensifying lipid lowering treatment to achieve a total cholesterol of less than 4mmol/L or an LDL-cholesterol of less than 2mmol/L. However, in line with good medical practice, such a decision should take into account the patient’s informed preference, including the benefits and risks of treatment.
If statins seem ineffective in lowering cholesterol it is advisable to check the patient’s concordance as a first step. It is also important to bear in mind that a single cholesterol reading may over- or under- estimate a person’s true average cholesterol by up to 14%, and health professionals should be wary of increasing a patient’s lipid-lowering treatment on the basis of a single cholesterol test, if they are reasonably confident that the patient is taking the medication as prescribed. This is discussed in a previous MeReC Rapid Review.
Healthcare professionals should follow NICE guidance when managing people with familial hyperlipidaemia. This includes using the maximum licensed or tolerated dose of statins, plus ezetimibe if necessary, to try to achieve at least a 50% reduction in LDL-cholesterol from baseline. However, if a patient cannot tolerate or does not wish to take such intensive treatment, more moderate doses and reductions in LDL-cholesterol may still be beneficial. This is discussed in another MeReC Rapid Review.
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