The aim of the recently reported Heart Protection Study1 in the United Kingdom, with over 20 000 participants aged 40–80 years, was to establish whether statin therapy is of benefit to people who are at high risk of cardiovascular disease (CVD) but have average-to-low levels of total cholesterol and LDL-cholesterol. High-risk patients (defined as those having previous coronary heart disease, diabetes, stroke, or peripheral vascular disease) were treated with simvastatin (40 mg daily), antioxidant vitamins (20 mg beta-carotene, 250 mg vitamin C and 600 mg vitamin E daily) or placebo in a 2 × 2 factorial design.

Among patients allocated to the antioxidant arm of the trial, there was no change in incidence of any prespecified endpoints, and there were small but significant increases in blood levels of LDL-cholesterol and triglycerides, which have the potential to increase CVD risk with long-term antioxidant use.2 High-dose antioxidant therapy is therefore not recommended.3

Reductions in cardiovascular events (including myocardial infarction, stroke and either coronary or peripheral arterial revascularisation) occurred with simvastatin therapy in women, elderly people, and people with previous cerebrovascular disease, peripheral artery disease, renal impairment or diabetes (see Box).

Translating the results of the HPS into clinical practice, patients with an absolute overall CVD risk of more than 17% over five years (the lowest rate occurring in any subgroup of the HPS treated with placebo) should receive

• high-dose statin therapy, equivalent to 40 mg/day simvastatin, independent of baseline levels of total cholesterol; and

• other cardioprotective therapy, such as β-blockers and aspirin.

Overall CVD risk can be estimated with the National Prescribing Service charts,4 which refer to CVD rather than coronary heart disease risk — a strategy flowing from the HPS outcomes.1,4 These charts, based on the Framingham study, provide only an approximation of absolute risk, but serve as a useful guide. Examples of patients with five-year CVD risk above 17% include most men over 60 years who smoke and have diabetes, and a 60-year-old non-smoking, non-diabetic man with blood pressure of 160/95 mmHg and a total cholesterol/HDL-cholesterol ratio of 6: 1.4

Benefits are likely to occur after 12 months of statin therapy, with greater benefits occurring the longer therapy is continued. Allowing for non-compliance, the HPS showed that about a third of major CVD events are likely to be prevented by statin therapy over five years. In the HPS, 23% of patients in the simvastatin group were smokers, 22% were being treated with antihypertensive agents, 20% with β-blockers, 25% with angiotensin-converting enzyme inhibitors (ACE inhibitors) and 21% with aspirin. Relative risk reductions in CVD incidence of up to 80% may be expected when statins are combined with standard cardioprotective agents (aspirin, β-blockers and ACE inhibitors) and stopping smoking.3

Given that CVD reduction in the HPS was independent of baseline cholesterol levels, it has been suggested that lipid levels need not be measured before commencing statin therapy in high-risk patients.3 However, fasting levels of triglycerides and HDL-cholesterol should be measured after 1–2 months, as therapy may need to be modified if these lipids are inadequately controlled by statin therapy alone. For example, gemfibrozil therapy may be considered for patients with low HDL-cholesterol levels.5

The HPS included about 6000 individuals with diabetes — the largest number in any statin trial reported to date. The CVD event rate for placebo-treated diabetics without coronary heart disease was 18.6%, compared with 22.5% for non-diabetics with coronary heart disease. Thus, the HPS confirms diabetes as a "coronary-equivalent" risk disorder for CVD.6 However, risk of CVD may vary from low to very high, depending on age and other risk factors, so it is still necessary to determine the global risk of CVD for an individual with diabetes when assessing the need to treat with a statin.4

Subjects at highest risk of CVD in the HPS had slightly elevated baseline serum creatinine levels (> 200 μmol/L), although only results of univariate analysis have been provided. The HPS confirms the high CVD risk in patients with impaired renal function and also supports the need for treatment of their dyslipidaemia.7 Caution is required in giving statin therapy to patients with more severe renal impairment, as they are at increased risk of myopathy.8

In the HPS, the safety profiles for statin and placebo therapy were similar. This finding may partly be a consequence of the exclusion of patients who showed adverse reactions to simvastatin during a 4–6-week run-in period leading up to the trial. However, only 32% of 63 603 screened patients were allocated to receive simvastatin in the study, so the low adverse event rate in the study may not necessarily apply to an unselected population.

Of particular importance with regard to safety was the low incidence of myopathy (defined as serum creatine kinase levels exceeding 10 times the upper limit of normal), which occurred in only 11 simvastatin-treated patients and six placebo-treated patients. These results are reassuring, but muscle symptoms and creatine kinase levels should still be monitored periodically, and withdrawal of statin therapy should be considered if myalgia occurs or creatine kinase levels rise to more than three times the upper limit of normal.9

There were no apparent safety concerns in patients with low baseline LDL-cholesterol levels (< 3 mmol/L), in whom average LDL-cholesterol levels during the trial were 1.8 mmol/L in the simvastatin-treated group and 2.7 mmol/L in the group receiving placebo. The association between low levels of total cholesterol and increased cerebral haemorrhage found in a study by Iso et al10 was not borne out by the HPS.

The safety and efficacy of treatment with 40 mg/day of simvastatin demonstrated by the HPS will probably result in a higher average dose being used in Australia, where the current average dose is 25 mg/day (Glen Godresse, Specialist/Hospital Product Manager, Merck Sharp and Dohme Australia Pty Ltd, personal communication). The benefits of statin therapy do not come without financial cost, although the long-term savings as a result of statin therapy are very likely to outweigh that cost.11 As CVD remains the single most important cause of mortality in Australia, consideration should be given to extending the availability of statins under the Pharmaceutical Benefits Scheme to include patients shown in the HPS to benefit from therapy: diabetics, women over 40 years, elderly people, and those with peripheral vascular disease, renal disease and low-to-average cholesterol levels, if their estimated global CVD risk exceeds 17% over five years.4