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Statins: when and how should they be used?

Dr Albert Ferro reviews clinical best practice in statin prescribing

In recent years it has become increasingly clear that the effects of statins on lipid profile cannot fully account for their cardiovascular protective action. Their beneficial effects are too rapid to be easily explained by their relatively slow action on atherogenesis and too large to be accounted for by their relatively small impact on plaque regression.

Experimental models have revealed statins exert a variety of other cardiovascular effects of predicted clinical benefit (see box right).

These were first brought to light in the mid-1990s with the publication of trials (such as 4S, WOSCOPS and CARE) showing their effectiveness in people with established coronary heart disease or at high risk of developing it ­ individuals with high serum cholesterol.

More recently, studies such as the Heart Protection Study have shown that beneficial effects ­ albeit smaller ­ extend even to those people previously judged to be at low cardiovascular risk, including people who used to be seen as having relatively 'normal' cholesterol levels.

Who should receive statin treatment?

Statins reduce coronary events, all cardiovascular events and total mortality, and are at least as effective in this regard in elderly as in younger patients. Age, therefore, should not be a consideration in the decision whether or not to use a statin.

Current guidance on statin use comes from the Joint British Societies, comprising the British Cardiac Society, British Hyperlipidaemia Association, British Hypertension Society and Diabetes UK. This guidance is set out below, and should be used in conjunction with the Joint British Societies Coronary Risk Prediction Chart, to be found in the back of every copy of the British National Formulary.

It is important to bear in mind, however, that the chart should only be used in patients without clinical evidence of established coronary disease.

Secondary prevention of coronary and cardiovascular events In patients with established CHD (including history of angina or acute myocardial infarction), peripheral arterial disease, or a history of stroke or transient ischaemic attack:

 · Statins produce benefits irrespective of the initial cholesterol concentration

 · Patients with a total serum cholesterol concentration of 5mmol/L or greater are likely to benefit most

 · Statins reduce the incidence of non-haemorrhagic stroke when used for secondary prevention in CHD

 · Most authorities now recommend that all patients with established atherosclerotic

disease should received statin treatment, unless there is a specific contraindication or they are not tolerated.

Primary prevention of coronary events

In patients at increased risk, as judged for example from the Joint Societies Chart:

 · Statins should particularly be considered when total serum cholesterol concentration is 5mmol/L or greater and the CHD risk is 30 per cent or greater over 10 years, in association with lifestyle measures and other appropriate interventions

 · Patients at an increased risk of CHD

(10-year risk of 15 per cent or possibly less), stand to benefit from primary prevention irrespective of the cholesterol concentration

 · The new BHS national guidelines on hypertension recommend that the threshold of risk requiring treatment comes down to 15 per cent over 10 years.

Targets and doses For primary and secondary prevention of CHD statin treatment should be adjusted to achieve:

 · A target total cholesterol concentration of less than 5mmol/L (or a reduction of

20-25 per cent if that produces a lower concentration)

 · The LDL-cholesterol should be below 3mmol/L (or a reduction of about 30 per cent if that produces a lower concentration)

 · It does not matter so much which statin is used, so long as it is used at a dose sufficient to achieve these cholesterol targets (all statins studied thus far appear to exert cardio- and vasculoprotective effects that seem to be directly related to the degree of cholesterol lowering)

 · It would seem sensible to commence the statin at the licensed starting dose, bearing in mind that serum lipid response must be monitored, with subsequent up-titration of the statin dose until the target cholesterol concentration is achieved.

How frequently should serum cholesterol be measured?

Unlike blood pressure, which tends to fall on repeated measurement in an individual,

there is no evidence to suggest the need to measure lipid profile more than once to judge the necessity for, or efficacy of, statin treatment. Following initiation of statin therapy, lipid profile should be measured again after two-three months and the dosage increased if necessary, based on this result.

After each dose increase, lipid profile should be reassessed after two-three months.

Once target cholesterol is reached, serum cholesterol should be checked on an annual basis. It is advisable also to check serum creatine kinase and liver function tests two-three months after initiation and after each dose increase, and thereafter at six-monthly intervals for one year, in view of the

occasional occurrence of myositis or hepatotoxicity.

Treatment should be discontinued if serum transaminase concentration rises to three times the upper limit of the reference range and/or if creatine kinase is elevated to 10 times the upper limit of normal.

Serum total cholesterol and LDL-cholesterol vary very little during the day (less than 15 per cent) ­ unlike triglycerides and HDL-cholesterol, whose serum concentration can vary widely during the day (up to

60-70 per cent). For initial assessment, therefore, a random total cholesterol will suffice.

If this is raised, a fasting lipid profile should be performed, since the total:HDL cholesterol ratio is needed for risk calculation.

A full fasting profile should be repeated following each increase in statin dose. Once target is reached, it is usually sufficient to monitor random total cholesterol on an annual basis, unless this rises to above target levels, in which case a full fasting profile should be remeasured. Cholesterol increases with age: in theory it ought to be measured every five years if normal.

What if target cholesterol is not reached, even with maximum recommended doses?

Of the available statins, the most potent appear to be atorvastatin and (more recently) rosuvastatin; more potent statins will be marketed in the near future.

One can consider switching to one of these, although it should be borne in mind that, since rosuvastatin has only very recently been released, definitive long-term safety and clinical outcome data have yet to be obtained.

Another option is to add in a cholesterol absorption inhibitor (the only one currently available is ezetimibe); the evidence suggests a combination of this with a statin gives rise to marked reductions in serum cholesterol, although whether this translates into

long-term clinical benefit remains to be determined.

Finally, it is worth referring patients with stubbornly resistant hypercholesterolaemia to one of the specialist lipid clinics that have sprung up all over the country in recent years.

This should be considered also when there is a mixed hyperlipidemia ­ in other words where triglycerides are also high ­ in which case combination therapy with a fibrate may be considered and will require specialist monitoring.

Beneficial cardiovascular

effects of statins

 · They change lipid profile, reducing LDL and to a lesser degree raising HDL cholesterol and reducing triglyceride

 · They possess anti-inflammatory properties, reducing the accumulation of inflammatory cells in atherosclerotic plaques

 · They inhibit vascular smooth muscle cell proliferation, a key event in atherogenesis

 · They inhibit platelet function, thereby limiting both atherosclerosis and superadded thrombosis

 · They improve vascular endothelial function, largely through augmentation of nitric oxide generation

Key clinical points

 · Statins should always be prescribed to patients with established atherosclerotic disease, unless there is a contraindication or they are not tolerated

 · In patients without established atherosclerotic disease, the Joint Societies Chart in the BNF is a useful means of establishing 10-year coronary risk

 · Patients with a 10-year risk of 30 per cent or greater, and a total serum cholesterol of 5mmol/L or greater, should receive statin treatment

 · For both primary and secondary prevention, statins should be titrated to a dose that achieves a total cholesterol of less than 5mmol/L or a reduction of

20-25 per cent, whichever is the lower;

for LDL-cholesterol, the target is less than 3mmol/L

or a reduction of 30 per cent, whichever is the lower

 · It does not matter which statin is used so much as whether these cholesterol targets are achieved

 · Statin therapy should be commenced at the licensed starting dose, with subsequent up-titration until target cholesterol is reached

GP comment

Beware of false economies

Dr Anthony Cummins describes how good prescribing of the right drugs can cut mortality from CHD

This is both an exciting time and a turbulent one for GPs. On top of all the changes in how general practice operates, all the national service frameworks, guidelines and targets to be achieved, in coronary heart disease we are faced with a bewildering array of treatment options.

We now also have the new GPs with a specialist interest (GpwSI). What role do they have in improving quality of care, and how do they influence the wider implementation of evidence-based treatments, such as statins?

Wallasey Heart Centre opened four years ago. The service provides GPwSI assessments, a cardiac rehabilitation programme, weight management service, ECG reporting, a cardio-memo service and a vascular specialist nurse service for claudication patients. We have begun using BNP testing as a heart failure triage and will soon add echocardiography.

The service has created new partnerships between health professionals. We updated all our primary care teams in cardiovascular medicine via a regular symposium held every three months. Locally-produced guidelines were made available to all practices.

So what has been the outcome? The SMR for CHD has fallen to below the UK average for the first time ever; less than 10 per cent of referrals to the GPwSI service have been subsequently referred on to secondary care more than 90 per cent are dealt with by their own GP/practice nurse, informed by management advice from the centre.

Patient satisfaction is high and there is improved concordance with drug treatments following the use of patient-held records. Independent evaluations have been positive, and by comparison to the average STAR prescribing rates Wallasey GPs prescribe evidence-based drugs to a higher level.

This is particularly so for statins. This is good implementation of drugs of proven effectiveness: note the benefits obtained by patients with pre-existing CHD or diabetes when treated with simvastatin in the Heart Protection Study (although their cholesterol level wasn't necessarily especially abnormal).

In some practices in Wallasey over the past two years, while cardiovascular prescribing has increased markedly, overall prescribing costs have fallen. Despite national concerns about costs of drugs, the cost of inpatient care is the big problem. The national cost of treating angina is approximately £670 million, of which 33 per cent is due to procedures (CABG and angioplasty), 32 per cent to 'hotel' costs and only 12-16 per cent to drugs. In heart failure inpatient care accounts for 67 per cent of overall costs.

Although drug costs are sometimes used to criticise GPs' prescribing habits, the nation appears happy to spend vastly more on potentially avoidable hospitalisation. Politicians seem less enthusiastic about tackling this costlier aspect of the overall situation than the more expedient one of allegedly extravagant GPs.

Our experience in Wallasey suggests that increasing GPs' drug budgets may actually lead to improved prescribing and better quality of care, often more locally accessible than through traditional secondary care.

So the fat of the land can and should be treated in primary care:

a more cost effective, patient-focused, quality-driven model has

yet to be found.

Anthony Cummins is a GP specialist in cardiology and clinical director,

Wallasey Heart Centre, Merseyside

Albert Ferro is consultant in clinical pharmacology, Guy's Hospital, London

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