Prescribing Review - Lipid Regulating Drugs


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The National Institute for Health and Clinical Excellence (NICE) concluded that statin therapy is clinically effective and cost effective for people with clinical evidence of CVD; and that in primary prevention, statin therapy is most appropriate in people at a 20% or greater 10-year CVD risk.3 The risk of developing CVD can be estimated using an appropriate risk calculator in most patients. Clinical assessment should take place for those patients where a risk calculator is not appropriate (elderly patients, people with diabetes or people in high-risk ethnic groups).³ A CVD risk calculator for use in type 2 diabetes has been developed using data from the UK Prospective Diabetes Study and is freely available.⁴ The NICE guidance on the management of blood lipids in type 2 diabetes recommends prescribing statins only in patients at high risk.⁵

Cholesterol Targets
There is a strong relationship between total serum cholesterol concentration and CVD. The relationship between total cholesterol, low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol and the relative risk of CVD are similar in people with or without CHD. The NSF for CHD target for primary and secondary prevention of CHD is to reduce total cholesterol to < 5mmol/l or by 20 to 25% (LDL cholesterol to < 3mmol/l or by 30%) whichever results in the lowest level.⁶ NICE has included the same targets for total serum cholesterol and LDL cholesterol (< 5mmol/l and < 3mmol/l respectively or a 30% reduction) in its draft guideline for secondary prevention in primary and secondary care for patients following a myocardial infarction.⁷ Three QoF domains contain targets to achieve total cholesterol = 5mmol/l: secondary prevention of CHD, stroke or transient ischaemic attack and diabetes. If 60% of patients reach the target in each domain then maximum quality points are awarded. The NICE clinical guideline on lipid modification for the primary and secondary prevention of cardiovascular disease will confirm the targets for cholesterol lowering (due in December 2007).

Treatment with Statins
The effectiveness of statins in preventing cardiovascular events in people with and without established CVD is well supported by high quality evidence. A meta-analysis of 14 randomised statin trials found that the 5-year incidence of major coronary events, coronary revascularisation and stroke was reduced by about 20 to 35%.⁸ The reduction in LDL cholesterol achieved in these trials was 0.8 mmol/l on average. This translates into 48 fewer people having major cardiovascular events per 1,000 among those with pre-existing CHD at baseline compared with 25 per 1,000 in people with no history of CHD. Simvastatin 40mg daily has been shown to reduce the incidence of major vascular events in a wide population (including people with established CHD; people with atherosclerotic vascular disease but without diagnosed CHD; people aged up to 80 years and people with diabetes).⁹ Atorvastatin and pravastatin also have good outcome data in terms of reducing the number of vascular events. There is very little clinical evidence assessing morbidity and mortality outcomes for rosuvastatin, and therefore it seems sensible to reserve its use for difficult-to-treat cases.⁹ NICE recommends that statin therapy is usually initiated using a drug with a low acquisition cost.³ Simvastatin is the cheapest statin, followed by pravastatin (see Price Chart).

There is still debate about what dose of statin to initiate. Most trials have used a set dose whereas guidelines usually support starting with a low dose which is increased as required. Some people will require a high dose to achieve the targets for lowering cholesterol recommended in the NSF. In a meta-analysis of trials comparing high dose to standard dose statin therapy, a 16% reduction of coronary death or any cardiovascular event was found (32.3% v 28.8%, odds ratio 0.84, 95% CI 0.80 to 0.89).¹⁰ The patients included in this analysis either had stable CHD or acute coronary syndromes. There is no evidence for using aggressive statin therapy in primary prevention. The cost-effectiveness of high dose statin therapy has yet to be determined and the benefits need to be balanced against the greater risk of adverse events.⁹ The routine use of statins at very high doses is not recommended by NICE. A retrospective analysis of data from the Treating to New Targets study (a comparison of 10mg to 80mg atorvastatin) suggested that particular types of patient (those with diabetes and/or the metabolic syndrome) might be good candidates for intensive statin therapy.¹¹ Further trials are required to substantiate whether the degree of risk of CVD could be used to identify patients likely to benefit from more intensive lipid-lowering.

One of the NHS Institute Productivity Metrics measures the percentage of items for simvastatin and pravastatin as a percentage of all statin prescribing. Chart 3 shows that there is wide variation in this measure across PCTs (range 19% to 84%). In the quarter to June 2006 the most commonly prescribed strength of atorvastatin was 10mg (44% of items for atorvastatin) whereas the most common strength of simvastatin was 40mg (44% of items). There were low levels of prescribing of the highest strengths (80mg) of either atorvastatin or simvastatin (5% and 1% of items respectively). There is no evidence that 10mg atorvastatin is more effective than 40mg simvastatin.¹²

Treatment with Other Lipid Regulating Drugs
Other lipid-regulating drugs may be required for people who cannot reach their cholesterol targets with a statin alone. They may also be prescribed instead of a statin when the person is intolerant of statins. Fibrates are indicated primarily to manage mixed lipaemia and hypertriglyceridaemia. Fibrates (except gemfibrozil) can be used in combination with statins but this increases the risk of rhabdomolysis. Ezetimibe selectively inhibits intestinal cholesterol absorption which reduces blood cholesterol concentration. The combination of ezetimibe and a statin will further reduce cholesterol concentrations but there are no trial data in relation to CVD morbidity or mortality.¹³ Omega-3 fatty acids at doses of 2 to 4g/day or omega-3 marine triglycerides at a dose of 5 to 10g/day are licensed for lowering triglycerides. The draft NICE guidelines on secondary prevention for patients following a myocardial infarction recommend that a lower dose of 1g/day of omega-3 fatty acids is started within 3 months of a myocardial infarction.⁷

PCT Distribution of Prescription Items for Simavastatin and Pravastatin as a % of all Statins Items for Quarter to June 2006 (Chart 3)

Prices based on Drug Tariff November 2006

Prescribing data
Prescribing of cardiovascular drugs has risen by 63% over the last 5 years to 58 million items while cost has risen by 32% to £472 million, quarter to June 2006. Lipid-regulating drugs account for 18% of all cardiovascular drugs by volume (10.3 million items per quarter) and 33% of cost (nearly £158 million). Statins account for 94% of items for lipid-regulating drugs and 90% of cost. Simvastatin is most often prescribed (52% of items). Over the last 5 years prescribing of simvastatin has risen more than four-fold to 5.4 million items per quarter, however cost has reduced by 43% to £25 million per quarter. Atorvastatin accounts for a third of statin prescribing, 3.4 million items per quarter, and 72% of cost, £102 million per quarter. Pravastatin items have risen by 27% over the last 5 years to almost 0.5 million items per quarter, cost has decreased by 87% to £1.8 million. There are 0.41 million items per quarter for rosuvastatin costing £10.5 million.

Fibrates account for 2% of all prescribing and spending on lipid-regulating drugs (217,000 items, £3.8 million quarter to June 2006). Prescribing of bezafibrate has fallen slightly over the last 5 years but it is still the most commonly prescribed fibrate (107,000 items per quarter, £1.2 million). Prescribing of fenofibrate has more than doubled over the last 5 years to 84,000 items costing £2 million per quarter. In the quarter to June 2006 there were 0.25 million ezetimibe items (costing £8.8 million), 57,000 items for omega-3 fatty acid compounds (£1.6 million), and 26,000 items (£1.3 million) for Inegy® (simvastatin with ezetimibe).

1. Allender S, Peto V, Scarborough P, Boxer A and Rayner M. Coronary heart disease statistics. British Heart Foundation : London. 2006
2. Department of Health. Coronary Heart Disease National Service Framework. Leading the way - Progress report. March 2005. www.dh.gov.uk/assetRoot/04/10/52/82/04105282.pdf?bcsi_scan_6196D1819D1DE478=0&bcsi_scan_filename=04105282.pdf
3. NICE. Statins for the prevention of cardiovascular events. Technology Appraisal 94. January 2006 www.nice.org.uk/page.aspx?o=TA094guidance
4. Diabetes Trial Unit, Oxford Centre for Diabetes, Endocrinology & Metabolism. UKPDS risk engine. www.dtu.ox.ac.uk/riskengine/index.php
5. NICE. Management of type 2 diabetes - management of blood pressure and blood lipids. October 2002. www.nice.org.uk/page.aspx?o=38564
6. Department of Health. National Service Framework for coronary heart disease. March 2000 www.doh.gov.uk/pdfs/chdnsf.pdf
7. NICE. Post Myocardial Infarction: Secondary prevention in primary and secondary care for patients following a myocardial infarction. Full Guideline. First Draft. August 2006. www.nice.org.uk/page.aspx?o=352622
8. 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: 1267-1278
9. National Prescribing Centre. Update on Statins. MeReC Briefing 2005; 28: 1 - 8 www.npc.co.uk/MeReC_Briefings/2004/briefing_no_28.pdf
10. CP Cannon, BA Steinberg, SA Murphy et al. Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy. J Am Coll Cardiol 2006; 48: 438-445
11. Deedwania P, Barter P, Carmena R et al. Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease and metabolic syndrome: analysis of the Treating to New Targets study. Lancet 2006; 368: 919-928
12. Moon JC. Switching statins. BMJ 2006; 332: 1344-1345
13. Anonymous. Ezetimibe - a new cholesterol-lowering drug. DTB 42; 9: 65-67

SUMMARY

• Statins are recommended for patients with clinical evidence of CVD and for primary prevention of CVD for adults where their risk of developing CVD is 20% or greater over 10-years.
• The current NSF target for primary and secondary prevention of CHD is to reduce total cholesterol to < 5mmol/l or by 20 to 25% whichever results in the lowest level.
• Statin therapy should usually be initiated with the drug with the lowest acquisition cost, which is currently simvastatin.
• Some patients will benefit from high dose statin therapy for secondary prevention of CVD but more evidence is needed to identify which types of patient.
• People who cannot meet their cholesterol targets with statins alone may require other lipid-regulating drugs.