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Simvastatin over the counter

Abstract

In July 2004, simvastatin 10mg was reclassified in the UK from a Prescription-only medicine (PoM) to a Pharmacy (P) medicine and launched as Zocor Heart-Pro (Johnson & Johnson.MSD Consumer Pharmaceuticals). It is the first statin in the world to be sold without prescription. Zocor Heart-Pro is licensed to reduce the risk of a first major coronary heart disease (CHD) event in people likely to be at "moderate risk" of such problems. Here we review the rationale and process for reclassifying simvastatin 10mg as an over-the-counter product.

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Background

For the last few years, UK national guidelines have recommended that a statin should be prescribed for everyone with symptomatic cardiovascular disease (secondary prevention).13 A statin should also be prescribed for people without symptomatic disease (primary prevention) if their risk of experiencing a coronary event within the next 10 years is either at least 30%,1,3,4 or at least 15% if they have type 2 diabetes mellitus.5 More recent guidelines suggest prescribing a statin for primary prevention for people with elevated blood pressure plus a 10-year risk of a cardiovascular event of at least 20% (equivalent to a 10-year CHD risk of 15%).6 However, this lower threshold for treatment is controversial. All of these guidelines specify the need for a formal assessment of the patient's risk, using a chart or computer-based tool that takes into account factors including serum cholesterol concentrations and blood pressure.

The National Service Framework for CHD in England requires the NHS to reduce both the prevalence of risk factors for CHD and inequalities in risks of developing the disease across the population.1 These requirements, and the Government's aim to improve choice and access to medicines,7 appear to have been major influences in the decision to reclassify simvastatin 10mg tablets. It is also worth noting that the drug company's application for reclassification coincided with expiry of the patent for Zocor.

Who's in the target group?

Zocor Heart-Pro is meant to be taken as part of a programme of actions designed to reduce the risk of CHD.8 These actions include smoking cessation, a healthy diet, regular exercise and reducing obesity. Zocor Heart-Pro is licensed at a dose of one 10mg tablet each evening and has a recommended retail price of £12.99 for 28 tablets. It is indicated "to reduce the risk of a first major coronary event (non fatal myocardial infarction and coronary heart disease (CHD) deaths) in individuals who are likely to be at moderate risk (approximately 10-15% 10-year risk of a first major event) of CHD".8 This assumes that such individuals can be identified easily and reliably during a single visit to a pharmacy. In this regard, there are key weaknesses in the "pragmatic pharmacy model" suggested by the drug company to identify those in the target group. This model uses age, gender and self-reported risk factors (see box) rather than the formal risk-assessment required when a statin is prescribed at NHS expense. Sale of simvastatin 10mg daily without this more precise assessment of CHD risk could result in the under-treatment of people who are at substantially higher risk than suggested by the model. This includes, for example, those with unidentified high blood pressure or very high cholesterol concentrations (e.g. due to familial hypercholesterolaemia). In addition, people at lower risk than suggested by the model may be exposed to unnecessary treatment that they have to pay for.

The role of the pharmacist

Both the Royal Pharmaceutical Society of Great Britain (RPSGB) and the drug company have issued guidelines to pharmacists and their staff for the sale of Zocor Heart-Pro.9,10 These require pharmacists to be involved in all initial sales and to assess each customer's suitability for the medicine, with the aid of a questionnaire. The company also advises customers to register with its information service, the Healthy Heart Programme, by post or online. The RPSGB suggests that subsequent sales may be dealt with by a "suitably competent" medicines counter assistant. Zocor Heart-Pro can be bought from online pharmacies, but not all request information from the customer before a sale is made. This raises concerns about the lack of direct support and counselling for consumers. Both the RPSGB and the company recommend that a customer should be referred to a GP (rather than sold Zocor Heart-Pro) if he or she is known to have diabetes; established heart disease or peripheral vascular disease; familial dyslipidaemia; high blood pressure; abnormal liver function tests; hypothyroidism; renal impairment; a family history of muscle disorders; or a level of alcohol consumption above 4 units/day for men, or 3 units/day for women. The fact that people may unknowingly have one or more of these features again raises the possibility that some who are at high risk of a CHD event will not receive the most appropriate treatment by being sold Zocor Heart-Pro. Neither the RPSGB nor the company requires the pharmacist to measure the customer's blood pressure or blood cholesterol concentrations before a sale. The RPSGB recommends that such testing is good practice, but the company argues that cholesterol-testing before starting Zocor Heart-Pro is unnecessary.

Curently, most pharmacies do not stock Zocor Heart-Pro.

Is Zocor Heart-Pro effective?

Evidence on simvastatin 10mg daily

No published clinical studies have determined what effect simvastatin 10mg daily has on CHD morbidity or mortality. The use of Zocor Heart-Pro is based instead on assumptions that reductions in LDL-cholesterol concentrations achieved with simvastatin 10mg daily will inevitably produce a corresponding fall in CHD events. Key to this rationale is a meta-analysis of short-term randomised statin trials (typically lasting a few weeks), which suggests simvastatin 10mg daily reduces total LDL-cholesterol concentration by 27%.11 A separate meta-analysis of longer-term studies of lipid-lowering by any means suggests a consistent relationship between reduction in cholesterol concentration and fall in CHD risk, irrespective of cholesterol concentrations or CHD risk before treatment.11 Through extrapolating the findings of the two meta-analyses, it has been suggested that a 27% fall in LDL-cholesterol concentration with simvastatin 10mg daily will produce a 30% relative reduction in the likelihood of a CHD event over 3 years.12 However, it is important to note that the meta-analyses included patients with clinical manifestations of CHD taking prescribed lipid-lowering therapy - people at higher risk than the target group for Zocor Heart-Pro. So the extrapolation of the meta-analyses may represent an over-optimistic prediction of the effect of over-the-counter simvastatin 10mg daily in people without evidence of CHD.

Evidence on other statins

Direct evidence on the efficacy of statins in primary prevention of CHD comes mainly from two double-blind randomised controlled trials.13,14 In one, 6,595 men (mean age 55 years) with a mean plasma cholesterol concentration of 7.0mmol/L were randomised to pravastatin 40mg or placebo, daily for a mean of 4.9 years.13 Pravastatin reduced the rate of non-fatal MI or death from CHD, the primary outcome measure (5.5% vs. 7.9% with placebo, p<.001). In the second trial, 6,605 men and women (mean age 58 years) with a mean cholesterol concentration of 5.71mmol/L but low HDL-cholesterol levels (0.94mmol/L for men, 1.03mmol/L for women) were randomised to lovastatin 20mg or 40mg (an unlicensed drug in the UK) or placebo, daily for a mean of 5.2 years.14 Lovastatin reduced the rate of acute major coronary events, the primary outcome measure (3.51% vs. 5.54% with placebo, p<.001). Taken together, the two studies suggest that the number-needed-to-treat (NNT) to prevent one coronary event was around 45 people treated for 5 years.15 In these studies, the 'baseline risk' of a CHD event (i.e. the rate in those allocated placebo) was 0.6-1.5% per year. This is roughly similar to a 10-year CHD risk of 5-15%.

Three other randomised controlled trials provide evidence on statins in primary prevention.1618 However, in all three, the patients either had symptomatic CHD or were known to be at increased risk of CHD. In a non-blind study involving patients (mean age 66 years) with high blood pressure, no added benefit was reported with pravastatin 40mg daily for a mean of 4.8 years, compared with usual care.16 In a double-blind study involving 5,804 patients (mean age 75 years) with a history of, or risk factors for, cardiovascular disease, pravastatin 40mg daily for 3.2 years reduced the rate of CHD death, non-fatal MI and fatal or non-fatal stroke, the primary outcome measure (14.1% vs. 16.2% with placebo, p=0.014).17 In a double-blind study involving patients (mean age 63 years) with hypertension, atorvastatin 10mg daily for a median of 3.3 years reduced the rate of non-fatal MI and fatal CHD, the primary outcome measure (6.0% vs. 9.4% with placebo, p=0.0005).18

Overview

In a meta-analysis of data from the five studies,13,14,1618 in which 84% of patients had no evidence of CHD, treatment with a statin (atorvastatin, lovastatin or pravastatin) at comparatively higher doses than simvastatin 10mg daily reduced the absolute incidence of cardiovascular events (MI and stroke) by 1.4% compared to placebo.19 This suggests that, overall, 71 mostly primary-prevention patients would have to be treated for around 3-5 years to prevent one event. (By comparison, statin therapy used in secondary prevention for 5 years offers an absolute risk reduction of 4.8% [NNT 21].19) On current evidence, it is questionable whether the limited benefit from primary prevention suggested by the meta-analysis will necessarily be achieved with use of over-the-counter simvastatin, particularly at a dose of 10mg daily.

How safe is Zocor Heart-Pro?

The widespread use of simvastatin, mostly at doses greater than 10mg daily for up to 14 years, has shown it to have a favourable safety profile.11 This was a key argument in the decision to reclassify the drug. Whether the safety profile will be different for more widespread, over-the-counter use is not known and guidelines direct pharmacists to warn customers about potential unwanted effects and interactions.9,10

Muscle problems

Myopathy and rhabdomyolysis are rare but severe unwanted effects of simvastatin.8 They can occur when the drug is used on its own, or be precipitated by co-administration of a drug that reduces liver metabolism of simvastatin by the cytochrome P450 3A4 enzyme, such as a macrolide antibacterial or an azole antifungal. The common use of such drugs presents problems for prescribers who may be unaware that their patient is buying simvastatin over the counter. The summary of product characteristics (SPC) states that all individuals starting therapy with Zocor Heart-Pro must be advised of the risk of myopathy and told to immediately stop taking the drug until they consult with a physician if they experience unexplained generalised muscle pain, tenderness or weakness. Simvastatin therapy should be discontinued immediately if myopathy is suspected or diagnosed. The SPC also advises against concomitant use of simvastatin with ciclosporin, clarithromycin, erythromycin, HIV protease inhibitors, itraconazole, ketoconazole, nefazodone or ▼telithromycin. Grapefruit juice can significantly increase the risk of toxicity with simvastatin, and should be avoided by people taking simvastatin.8,20

Liver problems

Hepatic reactions to simvastatin have been reported rarely in clinical trials.21 However, patients who may be more susceptible to liver toxicity (e.g. because of concomitant drugs or disease) have usually been excluded from such studies. If persistent increases in serum transaminase levels occur, they usually return to normal on stopping the drug. SPCs for prescribed statins, including simvastatin, require liver function testing before starting therapy and, possibly, at intervals thereafter, but the SPC for Zocor Heart-Pro makes no such recommendation.

Other concerns about Zocor Heart-Pro

People may presume wrongly that by taking Zocor Heart-Pro they are completely protected against CHD and can therefore avoid appropriate lifestyle changes.22 Also, given the strong inverse relationship between socio-economic status and CHD, it is possible that the people who can afford to purchase Zocor Heart-Pro will be those least likely to experience cardiovascular disease. The introduction of Zocor Heart-Pro might, therefore, increase social inequity.23 Another issue is that in order to obtain potential benefit (unproven by direct clinical trials) people would have to purchase Zocor Heart-Pro and take it daily over many years. The limited evidence available on adherence to prescribed statins suggests that it is greatest following an acute cardiac event and appears much lower in the context of primary prevention.24 It is possible that people who are prepared to pay for Zocor Heart-Pro may, by definition, be committed to persisting with such treatment long term. However, we know of no evidence to confirm this.

Consultation before reclassification

In November 2003, the Medicines and Healthcare products Regulatory Agency (MHRA) published a consultation document on the proposed reclassification of simvastatin 10mg.12 One hundred responses were received from a wide range of professional organisations, patient groups and individuals. The MHRA subsequently stated that no new issues were raised in the responses to the consultation and that "about two thirds of respondents were in favour of the proposal".25 However, our analysis of the 80 responses that the MHRA has made available for public scrutiny indicates that 31% of these respondents offered at least some support for the reclassification, 35% clearly opposed it and the rest offered no clear opinion either way. Most respondents raised concerns about the proposals. Typically, these included the lack of an evidence base, the lack of a requirement for measuring blood pressure, blood cholesterol concentration or liver function, and the low dose of simvastatin being suggested. Even if all 20 of the withheld responses are assumed to have been in favour of the reclassification, only 45% of all respondents at most could be described as supporting the proposal.

Promotion of Zocor Heart-Pro

The advertising of Zocor Heart-Pro to the public has focused on the fact that the risk of a heart attack for people in the target group is "as much as 1 in 7". In early advertisements, this claim was made without any explanation that this was actually a 10-year risk. DTB complained to the MHRA that this omission could have misled consumers as to their likelihood of experiencing a heart attack. Although this complaint has not been upheld, it is notable that more recent advertisements for the product have included the previously missing information that qualifies the risk as being for a 10-year period. Packaging and promotional materials for Zocor Heart-Pro state it "reduces the risk of a heart attack". In our view, this statement is unjustified given the lack of direct evidence on simvastatin 10mg daily as a means of reducing CHD morbidity or mortality in primary prevention. Furthermore, advertising for Zocor Heart-Pro does not alert potential buyers to the largely theoretical basis for the product's use nor indicate that the drug is intended to be taken indefinitely.

Conclusion

Zocor Heart-Pro, which contains simvastatin 10mg, is the first statin in the world to be sold in pharmacies without prescription. It is indicated for primary prevention of coronary heart disease (CHD) in people likely to be at moderate risk of a first major CHD event. Reclassification of simvastatin as a Pharmacy (P) medicine was approved in an attempt to increase choice for consumers and reduce inequalities in healthcare through improved access to medicines. In principle, we support these objectives. However, we believe that the reclassification of simvastatin was not based on robust evidence of clinical benefit. As a result, the UK population has, in effect, now been enrolled in a large experiment without adequate monitoring of benefits or risks. It is also worrying that the results of the consultation process which preceded the reclassification of simvastatin 10mg appear to have been inaccurately reported by the Medicines and Healthcare products Regulatory Agency. Assuming that Zocor Heart-Pro does reduce the likelihood of CHD events, its sale to people at moderate risk of CHD may create inequality for those who fall outside current national guidelines for statin use but who cannot afford to buy the product over the counter. In addition, we are concerned that protocols to support the sale of Zocor Heart-Pro do not require a formal calculation of an individual's cardiovascular risk: this could lead to inappropriate management of those not recognised as being at particularly high or low risk. For all these reasons, we believe the way simvastatin became an over-the-counter product was flawed and represents a poor model for future reclassifications of medicines.

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[M=meta-analysis; R=randomised controlled trial]

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