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Gold, incentives and meh

Statins

Dr Matt Doyle gives a round-up of the latest thinking on another key nMRCGP subject

Dr Matt Doyle gives a round-up of the latest thinking on another key nMRCGP subject


Statins have become the most ubiquitous drugs used in modern medicine. Their mechanism of action causes upregulation of LDL receptors and reduction in levels of LDL cholesterol.

They were first isolated from Penicillium citrinum in the 1970s forming the agent mevastatin (precursor of pravastatin).

The amount of statins prescribed has increased by 150% in the past five years and cost the NHS about £600m in 2005.

Five statins have UK marketing authorisation for the NHS: simvastatin, rosuvastatin, pravastatin, atorvastatin and fluvastatin. Pravastatin is a natural statin, simvastatin is semi-synthetic and the others are synthetic in their manufacture.

NICE published guidance on statins for the prevention of cardiovascular events in January 2006.

The increasing amount of data on statins suggests that their role may extend beyond cholesterol lowering with recent studies making claims as varied as reduction of mortality in COPD and influenza and reducing hospitalisation for sepsis in dialysis patients.

Who should have statins?

According to NICE, the following should be prescribed statins:

• all patients with CVD

• all patients with 20% or greater 10-year risk of developing CVD using appropriate risk calculator or by clinical assessment.

In addition, statins have important roles in patients with stroke, diabetes, metabolic syndrome and renal disease.

Target cholesterol

There is great worldwide and ethnic variation in cholesterol levels (MONICA, WHO 2004).

The most often quoted target is the '5 and 3' rule (total and LDL cholesterol levels). However JBS2 suggests 4 and 2 or 25% reduction in total cholesterol and 30% reduction in LDL, whichever is greater.

Side-effects

The side-effects of statins have recently been given a great deal of press coverage, with some writers suggesting that more patients are affected than previously thought (see 'If you want to feel younger, forget your statins', Dr James Le Fanu, Daily Telegraph, 3 April 2007). Key side-effects are considered to be myalgia, myositis and myopathy, with gastrointestinal upset and arthralgia also often described.

In addition, haemorrhagic stroke and diminished cognitive function have been suggested.

However, in cohort studies and RCTs the data appears different. The UK General Practice Research Database suggests the incidence of myopathy is significantly low at 11 per 100,000 patient years.

The Heart Protection Study showed no significant difference at five years between simvastatin and placebo. An increase in haemorrhagic stroke seems to be linked to cholesterol lowering rather than statins per se.

A well-written overview of arguments against statin therapy is made in The Great Cholesterol Con by Dr Malcolm Kendrick (John Blake Publishing 2007 ).

Over-the-counter statins

In 2004 the UK became the first country in the world to have statins (simvastatin 10mg) available without prescription (though with the intervention of a pharmacist).

No other country has followed suit and the decision has generated a great deal of criticism; not only for the questioned benefit of a 10mg dose of simvastatin but also for the potential for misuse (the 'I've had a steak, now I'll take a statin' idea) and cost (£10 a month).

Dr Matt Doyle passed the MRCGP last year and works as a full-time partner in St Ives, Cambridgeshire

Key statin studies

4S

4,444 patients with known IHD and elevated cholesterol (5.5-8.0) were put on either simvastatin or placebo. Follow-up was for 5.4 years. The treatment group had a reduction in major coronary events (such as MI), reduced coronary and total mortality.

Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-9

WOSCOPS

6,595 men aged between 45 and 64 were put on placebo or pravastatin 40mg od. The study was looking at primary prevention; however many of the subjects were high risk for cardiovascular disease (more than 30% were smokers, average cholesterol was >7.0). The study showed a reduced coronary mortality of 32%, with similar reductions in the number of coronary events (31%).

Prevention of coronary heart disease with pravastatin in men with hypercholesterolaemia. N Engl J Med. 1995;333:1301-7

CARE

4,159 subjects with prior history of MI but normal average cholesterol levels (around 5.3) with pravastatin vs. placebo. Showed reduction in coronary death or non-fatal MI of 24%. However there was no significant difference in total or coronary mortality.

The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;355:1001-9

LIPID

9,014 patients with cholesterols between 4.0 and 7.0 and a prior history of IHD. Pravastatin vs placebo. Coronary mortality and total mortality reduced (24% and 22% respectively). Number of coronary events reduced by 24%.

Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group. N Engl J Med. 1998;339:1349-57

AFCAPS/TexCAPS

5,608 men and 908 women with average cholesterol (about 5.7). Lovastatin vs placebo. Endpoint of first cardiac event was significantly reduced (RR 0.63, 95% CI 0.50-0.79).

AFCAPS/TexCAPS. JAMA. 1998;279:1615-22

Heart Protection Study

20,536 patients with a five-year follow-up at high risk of IHD (such as prior event, diabetes). Simvastatin 40mg vs placebo reduced coronary mortality by 18% and also showed significant reductions in total mortality, cardiovascular events and stroke). Benefit also applied to patients with initially low levels of cholesterol/LDL.

Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22

Several studies have shown halting or reversal of atherosclerosis with high-dose statin therapy, including REVERSAL (JAMA 2004) and ASTEROID (JAMA 2006). Other studies to be aware of include PROSPER, ASCOT-LLA, PROVE IT-TIMI 22 and CARDS.

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