Dr Alan Begg highlights the role of simvastatin 80 mg in clinical management and the trial evidence behind safety concerns over the use of this dosage
Simvastatin is by far the most commonly prescribed statin in the United Kingdom, with the highest number of prescriptions for the 40 mg dose. The QResearch Group, which examined prospective data on statin use collected from 368 general practices in England and Wales, found that approximately 70.7% of new users of statin in England and Wales were prescribed simvastatin.1 Figures from the Prescribing Information System for Scotland during the period October 2009 to September 2010 revealed that there were 35 times more prescription items for the 40 mg dose than for the 80 mg dose. There were, however, almost 60,000 prescription items for the 80 mg dose during the same period (pers. comm). This article discusses UK guidance that advocates the use of simvastatin 80 mg, and summarises trial data on the relationship between simvastatin and potential muscle injury.1
Guidance on the use of statins
Quality and outcomes framework
The quality and outcomes framework (QOF) guidance indicates that the use of a statin would be the most appropriate approach in the management of patients with high cholesterol. This particular drug treatment is included in the following QOF domains—coronary heart disease, diabetes, and stroke and transient ischaemic attack:2
- measurement of a patient's cholesterol level on a regular 15-month basis—a total of 12 points
- level of cholesterol (<5 mmol/l)—a total of 28 points.
The QOF highlights that stroke risk will be reduced with use of a statin in individuals at high risk of vascular disease. The guidance states that, based on trial data, there is a greater relative benefit for more potent cholesterol-lowering regimens.It also suggests that national guidelines may be amended to recommend starting all patients with coronary heart disease (CHD) on a statin irrespective of their starting cholesterol so that their risk of stroke will be reduced.2
NICE guidance: Clinical Guidelines 67 and 71
NICE Clinical Guideline 67 on lipid modification for the prevention of cardiovascular disease (CVD) recommends statin therapy for adults with clinical evidence of this condition.3 Treatment should be initiated with simvastatin 40 mg, but may be increased to 80 mg or a drug of similar efficacy and acquisition cost if the targets of total cholesterol <4 mmol>3
It is recommended that statin therapy should be initiated with a drug that has a low acquisition cost taking into account the required daily dose and product price per dose. This in effect means initiation with simvastatin 40 mg and not routinely offering a higher intensity statin for primary prevention of CVD.3
NICE Clinical Guideline 71 on familial hypercholesterolaemia (FH) advises that healthcare professionals should consider prescribing a high-intensity statin to achieve a recommended reduction in LDL-C concentration of >50% from baseline. A statin with a low acquisition cost should be offered if a diagnosis of FH is made in an adult aged over 60 years and if there is no evidence of CHD.4
Risk of myopathy
Guidance from Qresearch Group data
Data analysed by the QResearch Group showed that the risk of significant outcomes in terms of moderate or serious myopathy was higher in men than in women for both simvastatin and atorvastatin.1 Outcomes for patients receiving 10 mg and 20 mg doses of simvastatin were grouped together as were those for individuals taking 40 mg and 80 mg. There was no dose-response correlation between the two dosage groups in terms of increased cases of moderate or severe myopathy. However, the data indicated a possible dose response for the development of myopathy in men prescribed atorvastatin and pravastatin.1
US Food and Drug Administration warning
In March 2010, the US Food and Drug Administration (FDA) issued a warning about the increased risk of myopathy in patients receiving simvastatin 80 mg.5 It warned that there was a greater risk of developing muscle injury including rhabdomyolysis if simvastatin was prescribed at this higher dose. This information was derived from clinical trials, observational studies, event reports, and data on prescription use. The FDA is also reviewing results from the SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) trial, which includes data on muscle injury in patients taking simvastatin (see below and Table 1).5,6
SEARCH trial results
The SEARCH trial was a multicentre, double-blind, active-treatment, factorial-design study conducted at 88 sites in the UK. This trial investigated the effect of simvastatin 80 mg versus 20 mg on major cardiovascular events, defined as fatal coronary events, non-fatal myocardial infarction, a coronary revascularisation procedure, non-fatal or fatal stroke, or peripheral revascularisation procedure. It included 12,064 patients with a history of myocardial infarction and follow up was a median time of 6.7 years.6,7
The results from SEARCH showed that treatment with simvastatin 80 mg did not provide any significant benefit over a 20 mg dose. The incidence of major vascular events was similar for the 80 mg dose versus 20 mg. However, there were more cases of myopathy and rhabdomyolysis in patients receiving 80 mg compared with 20 mg simvastatin (see Table 1).6,7
Medicine and Healthcare products Regulatory Agency advice
Based on the SEARCH trial results, the Medicine and Healthcare products Regulatory Agency (MHRA) and Commission on Human Medicines (CHM) published an article in the May 2010 edition of Drug safety update. The MHRA highlighted the increased risk of myopathy for patients receiving an 80 mg dose of simvastatin.7 It recommended that this dosage should be considered only in patients with severe hypercholesterolaemia who are at a high risk of cardiovascular complications and have not achieved their treatment goals on lower doses, on the basis that the benefit of the higher dose is expected to outweigh the potential risks.7
The MHRA also advises that patients already taking 80 mg of simvastatin or those who have been considered for uptitration to this dosage, may need their medication reviewed to take this evidence into account.7
|Table 1: SEARCH data on the comparative effects of simvastatin 20 mg and 80 mg on major vascular effects, myopathy, and rhabdomyolysis6|
|Incidence||Simvastatin 20 mg||Simvastatin 80 mg||Risk ratio|
|Major vascular events||1553 (25.7%)||1477 (24.5%)||0.94 (95% confidence interval 0.88–1.01)|
|Myopathy||1 (0.02%)||53 (0.9%)||–|
Clinical evidence for the use of simvastatin
Prior to publication of the SEARCH study, the evidence for the effectiveness of simvastatin was based on the Heart Protection Study for primary prevention of CHD8 and 4S (Scandinavian Simvastatin Survival Study)9 for secondary prevention, although neither of these trials investigated the 80 mg dose.
MRC/BHF Heart Protection Study
In the Medical Research Council/British Heart Foundation Heart Protection Study, participants were high-risk individuals aged between 40 and 80 years with either a history of CHD, occlusive arterial disease, diabetes, or hypertension who were allocated to receive either 40 mg of simvastatin daily or placebo.8 There was a higher but non-significant increase (p=0.2) in the number of individuals diagnosed as having myopathy—muscle symptoms plus a creatine kinase level >10 times the upper limit of normal as defined in the trial. Although none of these myopathy cases were fatal, some of them developed into rhabdomyolysis and a creatinine level >40 times the upper level of normal.8
Scandinavian Simvastatin Survival Study
The 4S trial was the first study to show the benefits of statin therapy in improving survival in patients with established CHD—either angina or previous myocardial infarction—who also have a cholesterol level of between 5.5 and 8.0 mmol/l.9 Patients were randomised to receive treatment with simvastatin 20 mg or placebo. The simvastatin doses were adjusted, if necessary, at 12 weeks and 6 months to reach a goal treatment reduction of 3.0–5.2 mmol/l; if the serum cholesterol was out of range they either had their dose increased to 40 mg daily by taking two 20 mg tablets or their dose was reduced to 10 mg if the cholesterol level was too low. In the 4S study, there was a single case of rhabdomyolysis, which occurred in a woman taking simvastatin 20 mg.9
Cholesterol Treatment Trialists Collaboration
In 2005, the Cholesterol Treatment Trialists' (CTT) Collaborators performed a meta-analysis on the efficacy and safety of using statins to lower cholesterol. There was information on rhabdomyolysis from all but one of the 14 trials; the 5-year excess risk with statin was small and not significant (absolute excess 0.01% [standard error 0.01], p=0.4).10
The most recent meta-analysis from the CTT collaborators was published in November 2010.11 It examined data from 170,000 participants in 26 randomised trials, which included the SEARCH study. Only cases of myopathy that had progressed to rhabdomyolysis were sought from the individual trials. All of the excess cases of rhabdomyloysis (10 versus no cases) occurred in the two trials (SEARCH and the A to Z6,12) of 80 mg versus 20 mg simvastatin daily. These two trials have also reported definite excesses in the incidence of myopathy with 80 mg simvastatin daily.11
ConclusionThe safety of drugs has recently been highlighted by the recent suspension of the marketing authorisation for rosiglitazone.13 A recent review has pointed out possible safety problems apparent in the data presented to the initial European Medicines Agency approval meeting for rosiglitazone.14 Similarly, acting on recent concerns over an increased incidence of muscle damage, the MHRA has given clear advice on the use of a 80 mg simvastatin dose. However, the NICE guidance at present has yet to reflect these concerns on the use of simvastatin at this dose.
- Hippisley-Cox J, Coupland C. Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database. BMJ 2010; 340: c2197.
- British Medical Association. Quality and outcomes framework guidance for GMS contract 2009/10. Delivering investment in general practice. London: BMA, 2009. Available at: www.bma.org.uk/images/qof0309_tcm41-184025.pdf
- National Institute for Health and Care Excellence. Cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. Clinical Guideline 67. London: NICE, 2008. Available at: www.nice.org.uk/CG67
- National Institute for Health and Care Excellence. Identification and management of familial hypercholesterolaemia. Clinical Guideline 71. London: NICE, 2008. Available at: www.nice.org.uk/CG71
- FDA US. Food and Drug Administration website. FDA warns about increased risk of muscle injury with zocor. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm205215.htm (accessed 2 December 2010).
- Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group, Armitage J, Bowman L, Wallendszus K et al. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet 2010; 376 (9753): 1658–1669.
- Medicines and Healthcare products Regulatory Agency. Drug safety update: Volume 3, Issue 10, May 2010. Available at: www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate/CON081863
- Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360 (9326): 7–22.
- The Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344 (8934): 1383–1389.
- Baigent C, Keech A, Kearney P et al; 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 (9493): 1267–1278.
- Cholesterol Treatment Trialists' (CTT) Collaboration, Baigent C, Blackwell L, Emberson J et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010; 376 (9753): 1670–1681.
- de Lemos J, Blazing M, Wiviott S et al; A to Z Investigators. 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 (11): 1307–1316.
- Cohen D. European regulatory body recommends suspension of rosiglitazone. BMJ 2010; 341: c5291.
- Cohen D. Rosiglitazone: what went wrong? BMJ 2010; 341: c4848.G