25 May 2010
The May edition of Drug Safety Update includes an article advising healthcare professionals that the product information for simvastatin has been updated to highlight the increased risk of myopathy associated with the 80mg dose. This blog examines this issue in more detail. The other topics in the May DSU are discussed in a separate MeReC Stop Press.
Health professionals should follow NICE guidance on lipid management and use simvastatin 40mg for most people. NICE lipid guidance explicitly sets no lipid targets that patients are expected to achieve, for either primary or secondary prevention. High dose statin therapy should not be automatic but may be considered in certain circumstances, taking into account the patient’s informed preference, including the benefits and risks of treatment. Statin-related myopathy occurs with all statins and appears to be related to dose. There is no good evidence to suggest that any one statin has any advantages over another in this regard at a population level. There are more than 30 times as many primary care prescriptions issued for atorvastatin 10mg and 20mg as there are for simvastatin 80mg. As well as noting and where appropriate acting upon this new MHRA advice, there seems to remain significant scope for reviewing patients taking the lower doses of atorvastatin and where appropriate revising those prescriptions so they are in line with NICE guidance.
What does the MHRA say?
The product information for simvastatin now recommends that the 80mg dose should be considered only in patients with severe hypercholesterolaemia at high risk of cardiovascular complications who have not achieved their treatment goals on lower doses, when the benefits are expected to outweigh the potential risks. Similar changes are being made to the product information for combination products that contain simvastatin. The MHRA/CHM advises that prescribers treating patients who are taking simvastatin 80mg or who are being considered for an up-titration to that dose may need to review their treatment during their next visit, to take into account the new evidence. Patients who are currently taking simvastatin 80mg should not stop taking their medicine. However, they should be advised to contact their doctor immediately if they experience unexplained muscle pain, tenderness, or weakness.
What is the background to the MHRA advice?
The MHRA advice follows consideration of interim results of the SEARCH study in patients with a history of myocardial infarction (MI). The SEARCH study is complete but has not yet fully reported. It found that, over mean of 6.7 years, myopathy occurred in 0.9% of patients who received simvastatin 80mg compared with 0.02% in those taking simvastatin 20mg (number needed to harm [NNH] 114). An estimated 0.2% patients in the simvastatin 80mg group developed rhabdomyolysis compared with none in the 20mg group.
Another RCT has previously reported on rates of muscle problems with different doses of simvastatin. The A to Z study compared simvastatin 40mg for one month followed by 80mg thereafter with placebo for four months followed by simvastatin 20mg in patients with acute coronary syndrome (ACS) for a median of 1.98 years. More patients in the high dose group than in the lower dose group developed myopathy (0.4% vs 0.04%, P=0.02, NNH 278), but there were no statistically significant differences in rates of treatment discontinuation due to muscle-related adverse events (1.8% vs 1.5%, P=0.49).
What data are there on other statins at high doses?
There are no head-to-head RCTs which compare one statin with another at equivalent doses. As we discussed in a previous blog, statin-related myopathy occurs with all statins and appears to be related to dose. There is no good evidence to suggest that any one statin has any advantages over another in this regard at a population level.
Three RCTs have compared high dose atorvastatin (80mg) with atorvastatin or other statins at lower doses. The IDEAL study compared atorvastatin 80mg with simvastatin 20mg in people with a history of MI over a median of 4.8 years. At 24 weeks the dose of simvastatin could be increased to 40mg if the patient’s cholesterol level remained greater than 5mmol/L, and the atorvastatin dose could be reduced to 40mg if there were adverse events. More patients on high-dose atorvastatin discontinued treatment because of adverse effects compared with those taking simvastatin 20mg or 40mg (9.6% vs. 4.2%, P<0.001, NNH 19), and more people had raised liver enzyme levels (e.g. alanine aminotransferase >3 times the upper limit of normal 0.97% vs. 0.11%, P<0.001, NNH 116).
The TNT study compared atorvastatin 80mg with atorvastatin 10mg in people with stable coronary heart disease, over a median of 4.9 years. There were no excess cases of myalgia or rhabdomyolysis in the atorvastatin 80mg group compared with the 10mg group. However, more people in the atorvastatin 80mg group stopped treatment because of adverse effects than in the 10mg group (7.2% vs. 5.3%, P<0.001, NNH 53). Persistent elevations in liver enzymes were also more common in the high dose group (1.2% vs. 0.2%, P<0.001, NNH 100).
The PROVE-IT study compared atorvastatin 80mg with pravastatin 40mg in people with acute MI or high risk unstable angina for a mean of 24 months. Rates of discontinuations for adverse effects were similar in both groups. However, more patients taking atorvastatin had raised liver enzyme levels compared with those taking pravastatin (3.3% vs. 1.1%, P<0.001, NNH 45).
The MHRA have previously warned about the risk of muscle side effects with rosuvastatin: patients should start on 10mg (5mg for Asian patients and those with pre-disposing factors for myopathy), including patients switched from other statins, and the dose should be titrated up if necessary only after a four week trial.
What does NICE guidance say about statin doses and lipid targets?
NICE guidance on lipid management in people without type 2 diabetes advises that simvastatin 40mg/day should be prescribed for primary and secondary prevention of cardiovascular 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). It is important to note that NICE lipid guidance 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. It is important to note that these are 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 guidance.
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 usual choice and dose of 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 cardiovascular 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 blog.
Healthcare professionals should follow NICE guidance when looking after 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 previous blog .
When is co-prescribing ezetimibe an option?
NICE guidance on ezetimibe states that ezetimibe monotherapy is an option only if statins are contraindicated or not tolerated, and ezetimibe in combination with a statin is an option in some limited circumstances where statins have not appropriately controlled cholesterol levels, despite appropriate dose titration and consideration of switching statins. As discussed above, checking concordance and repeating cholesterol levels would seem prudent. There is no good evidence that ezetimibe, either alone or added to a statin, reduces the risk of CV events compared to a statin alone. Adding ezetimibe to statin therapy also substantially increases the cost to the NHS.
What are the priorities for prescribers and medicines managers in this area?
More than 6million items of simvastatin 40mg are prescribed in primary care in England each quarter. In March 2010 only 1.29% of simvastatin prescriptions (44,487 items) were for the 80mg strength. This is approximately equivalent to 1 prescription per general practitioner. In contrast there are more than 700,000 items of atorvastatin 10mg prescribed and more than 800,000 items of atorvastatin 20mg each quarter. As well as disseminating this new MHRA advice on high dose simvastatin, there seems to remain significant scope for reviewing patients taking the lower doses of atorvastatin and where appropriate revising those prescriptions so they are in line with NICE guidance.
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