At present, statins are often restricted to people who have heart disease and elevated cholesterol levels. But, new findings from the UK's 20,000-patient Heart Protection Study* show that statins also cut the risks of heart attacks and strokes in people who have diabetes, or have narrowing of arteries in their legs, or have had a stroke. Most remarkably, the study found substantial benefits even among those high-risk patients considered to have "normal" or "low" cholesterol levels. It provides definite evidence that guidelines should be changed so that – irrespective of the blood cholesterol level – a statin is considered for anybody at increased risk of either heart attacks or strokes.
"The clear message from this study is: 'Treat risk – not cholesterol level', "said Professor Sir Charles George, Medical Director of the British Heart Foundation – the UK's leading heart charity. He called for an urgent review of national and international guidelines on statin use by government organisations, such as the National Institute of Clinical Excellence (NICE) in the UK and the National Institutes of Health (NIH) in the USA, as well as by professional bodies, such as the European Society of Cardiology (ESC) and the American Heart Association (AHA).
The study overturns conventional wisdom in a number of other areas. For example, current guidelines say that there is little evidence that statins help older individuals. By deliberately studying large numbers of older people, the researchers were able to show that cholesterol-lowering with statins was just as effective for the over 70s as for those in middle age.
Likewise, not many women had been included in previous studies so there was little direct evidence on the benefits and safety of statins in women. With more than 5,000 women included in the Heart Protection Study, it has been able to show that statins work just as well for women as for men.
HPS lead investigator Professor Rory Collins said: " HPS shows unequivocally that statins can produce substantial benefit in a very much wider range of high-risk people than had been thought. These new findings are relevant to the treatment of some hundreds of millions of people worldwide. If now, as a result, an extra 10 million high-risk people were to go onto statin treatment, this would save about 50,000 lives a year – that's a thousand each week. In addition, this would prevent similar numbers of people from suffering non-fatal heart attacks or strokes."
The HPS team estimates that implementing these new findings fully would more than triple the numbers of people benefiting from statins. In the UK, the numbers treated with statins would increase from a current figure of less than 1 in 20 of the population aged over 40 (or about 1 million people) to about one in 8 (about 3 million people). This would save an extra 10,000 lives each year.
An outline of the study findings was presented at the American Heart Association conference in Los Angeles last November. Now that the detailed results are published in the Lancet, the way is open for a review of official guidelines and for doctors to change their prescribing practice. This could have a significant impact in reducing the high rates of heart attacks and strokes in the UK and other developed countries. It would also be important for many developing countries where the rates of heart attacks and strokes are already high or are rising rapidly, and where diabetes is becoming increasingly common.
Dr Richard Horton, editor of the Lancet, who chaired the news briefing, backed the call for a review of the guidelines. "These findings should tear up the rule-book on statin prescribing," he said. "They are the most important and far-reaching results for the treatment and prevention of heart disease and strokes that we have seen in a generation."
One of the most encouraging aspects of the study was that the majority of people now shown to benefit from statins would already be known to their doctors because of their past medical history. HPS clinical coordinator Dr Jane Armitage said: "Implementing these findings does not require massive public health education campaigns by governments. It simply needs the guidelines to be changed so that doctors check their medical records and identify those patients with vascular disease or diabetes who we now know would benefit substantially from statin therapy."
Sir George Radda, Chief Executive of the UK's Medical Research Council, said the implications for managing health were good for both patients and healthcare professionals alike. "Through a single large-scale, well-designed trial we have been able to identify a whole new set of patients with a variety of conditions who can be helped by statins," he said.
Another bonus from HPS was that it established firmly that statin treatment is safe. Professor Peter Sleight, deputy chair of the HPS Steering Committee, said: "HPS should reassure doctors and patients about both the safety and the benefits of statins. It provides clear evidence that statin use safely cuts the risks not just of heart attacks but also of future strokes by about one-third. These findings open the door to treatment for many patients who are currently unlikely to receive a statin in the UK or elsewhere." The research team is currently analysing the financial implications of such changes in prescribing patterns. Said Professor Collins: "We can't yet say exactly how cost-effective implementing these findings would be and we do recognise that the drug costs will be significant**. But, we believe that the level of benefit in these high-risk patients is so great that treating them will be extremely cost-effective. Moreover, the benefits of statins are additional to those of other treatments (such as aspirin) that are already used to prevent heart attacks and strokes."
HPS also assessed the effects of using antioxidant vitamin supplements (600mg vitamin E, 250mg vitamin C and 20mg beta-carotene daily) in people at high risk of vascular disease. Those results are also published today in the Lancet. Although this supplement did increase blood vitamin concentrations substantially, it did not produce any significant reductions in the five-year risk of heart attacks, strokes, cancers or other major outcomes. However, the study did provide strong 5-year safety evidence. In particular, the vitamins did not produce any excess risk of strokes due to bleeding or of cancers at any site. This contradicts the apparent adverse trends in some other studies of vitamin E and beta-carotene.
* The MRC/BHF Heart Protection Study involved more than 20,000 volunteers aged 40-80 who were at high risk of coronary heart disease, but for whom there was substantial uncertainty about the balance of benefits and safety of cholesterol-lowering therapy. It specifically targeted groups in which there was little direct evidence of benefit – including women, the over 70s, people with diabetes, those with non-coronary vascular disease, and those with average or below-average cholesterol levels. Volunteers were randomly allocated to receive either 40mg daily simvastatin as cholesterol-lowering therapy, or matching dummy tablets (and, separately, were randomly allocated to receive vitamin supplements or matching dummy capsules). Study treatment and follow-up continued for an average of five years in 69 UK hospitals.
Funding of £21 million was provided by the UK's Medical Research Council, the UK British Heart Foundation, and the pharmaceutical companies Merck & Co. Inc. and Roche Vitamins Ltd. The study was, however, designed, conducted and analysed entirely independently of all funding sources by the Clinical Trial Service Unit of Oxford University.
** Currently, 40mg daily simvastatin (or an equivalent dose of another statin) costs approximately £1 per day in the UK and $4 per day in the US. The patent for lovastatin (Mevacor) expired at the end of 2001, and the patent for simvastatin (Zocor) expires in most of Europe (including the UK) in mid-2003 and in the US in 2006.
Summary of major findings of the Heart Protection Study
• Cholesterol-lowering with statin treatment reduced the risk of heart attacks and strokes by at least one third, as well as reducing the need for arterial surgery, angioplasty and amputations.
• Substantial reductions in these "major vascular events" were found in a very wide range of high-risk patients for whom there had previously been uncertainty about using cholesterol-lowering treatment, including:
- women as well as men;
- people aged over 70 as well as younger people;
- people who have diabetes, narrowing of arteries in their legs or a history of stroke, as well as those who already have heart disease;
- people with blood levels of total cholesterol below 5 mmol/l (approx. 200 mg/dl) or 'bad' LDL cholesterol below 3mmol/l (approx. 120mg/dl), as well as those considered to have 'high' levels.
• About 5 years of statin treatment typically prevented these major vascular events in:
- 100 of every 1,000 people who have previously had a heart attack
- 80 of every 1,000 people with angina or some other evidence of coronary heart disease
- 70 of every 1,000 patients who have previously had a stroke
- 70 of every 1,000 patients with occlusive disease in leg or other arteries
- 70 of every 1,000 people with diabetes
- In addition, continued treatment with a statin prevented further major vascular events and deaths in those people who had already had one heart attack or stroke.
- The benefits of treatment increased throughout the 5-year study treatment period, so more prolonged use of a statin would be expected to produce even bigger benefits.
- The benefits of statins were additional to those of other treatments used to prevent heart attacks or strokes, such as aspirin and blood pressure-lowering drugs
- The trial provides uniquely reliable evidence about the safety of the 40 mg simvastatin daily regimen used. There was no support for previous concerns about possible adverse effects of lowering cholesterol on particular non-vascular causes of death, on cancers or on strokes due to bleeding.
Implications
Based on WHO estimates of the numbers of people with coronary heart disease, stroke and diabetes, it can be estimated that the results are relevant to the treatment of some hundreds of millions of people worldwide (see table). If an extra 10 million high-risk people were to start statin treatment this would save about 50,000 lives each year and would prevent similar numbers from suffering non-fatal heart attacks or strokes.
Global statistics
| Region of the world |
|
||
|
CHD
|
Stroke
|
Diabetes
|
|
| Established Market Economies† |
8.2
|
9.5
|
37.9
|
| Former Socialist |
5.8
|
4.4
|
11.0
|
| India |
6.6
|
2.7
|
18.1
|
| China |
4.5
|
7.4
|
10.3
|
| Other Asia & Islands |
2.4
|
2.3
|
13.0
|
| Sub-Sahara Africa |
1.1
|
1.3
|
3.9
|
| Latin America/Caribbean |
2.0
|
1.6
|
11.2
|
| Middle East Crescent |
3.3
|
1.6
|
13.0
|
| World total |
34.0
|
30.9
|
118.3
|
*WHO Global Health Statistics (Murray CJL & Lopez AD, 1996): Estimates of numbers of people at all ages with coronary heart disease (angina), with stroke and with diabetes in 1990. NOTE: Some people may have more than one of these conditions and so be included in more than one column (i.e. there is some "double counting" due to overlap), but similar statistics are not readily available for people with other occlusive arterial disease (which would tend to under-estimate the size of the population to which the study results are relevant).
†Established Market Economies are Australia, Canada, Europe, Japan, New Zealand and US. WHO prevalence estimates for countries or areas within regions are not currently available, but (based on population size) the numbers of people with these conditions would be expected to be about 17M in US, 26M in Europe and 4M in UK alone.
Journal
The Lancet