Intended for healthcare professionals

Corrected version

Statins: under used by those who would benefit

People at high 10 year risk of cardiovascular disease deserve treatment

The United States Food and Drug Administration has recently rejected proposals by the manufacturers of lovastatin and pravastatin to make these drugs available over the counter without a doctor’s prescription. Advisers to the Food and Drug Administration decided that physicians should probably determine who should get the drugs as well as monitor them for side effects. The main arguments for allowing over the counter sales were summarised in a recent conference sponsored by the industry: statins are effective, easy to take, and relatively safe, and many people who should be taking these drugs are not doing so. (1)

The underuse of statins is most apparent in the secondary prevention of heart disease in patients with known atherosclerotic disease, for whom there is strong clinical trial evidence that statins are highly effective in preventing myocardial infarction, stroke, and death. (2) (3) In one recent survey, for example, only 37% of patients with recent myocardial infarction and blood cholesterol concentrations above 200 mg/dl had been given drugs to lower their lipid concentrations and few had reached their target cholesterol concentrations. (4) Most patients with heart disease have concentrations of low density lipoprotein cholesterol that warrant treatment, (5) and making statins available over the counter might increase their use (as has occurred with aspirin).

Undertreatment is also a problem for the much larger population of people who do not have manifest atherosclerotic disease (primary prevention). There is no longer any doubt that statins benefit those who are at substantial risk of developing coronary disease. The best evidence for this is presented in an updated meta-analysis in this issue of the BMJ, whichshows that statins prevent 35% of myocardial infarctions and coronary deaths. (6) The fact that the reduction in all cause mortality was only 11% and not statistically significant does not detract from the conclusion that statins are beneficial (it is due to dilution by the non-cardiovascular causes that account for as many as 73% of the deaths in primary prevention populations (7)). A key fact here is the absence of any increase in non-cardiovascular deaths in larger meta-analyses of the effects of statins. (2) (3)

Practice guidelines have been devised to identify patients who are at high enough coronary risk to need treatment. (8) The recently revised Sheffield table is easy to use and an excellent example. It provides cut-off points for the ratio of total cholesterol to high density lipoprotein cholesterol (taking into account age, sex, diabetes, hypertension, and smoking) that identify people whose coronary risk exceeds 30% per decade. (9) The table also gives cut-off points for treating the larger numbers of people whose coronary risk exceeds 15% per decade "where resources permit." (9) This lower cut-off point has the virtue of more closely resembling the 10 year coronary risk of participants in trials of primary prevention. (6)

Age is the most important determinant of coronary risk, (10) (11) and the two main primary prevention trials of statins both set the lower limit for enrolment at the relatively mature ages of 45 for men and 55 for women. (6) This decision made sense when designing these trials: younger participants would have too few coronary events to provide adequate power to detect an effect of treatment. But in clinical practice physicians may ask: "why not extrapolate these results and use statins to help prevent the few coronary events that do occur in younger people?" The answer is that treating younger people may be reasonable if they have other strong risk factors such as familial hypercholesterolaemia or diabetes. But the reasons for not doing so in most younger people are the remaining concerns about safety and the harsh realities of cost.

Statins do seem to be reasonably safe and are probably less likely to cause serious harm than aspirin. Earlier concerns that lipid lowering drugs might increase the risk of death from injuries were a false alarm. (2) (3) Serious adverse effects such as liver failure and rhabdomyolysis are extremely rare, and more common side effects such as raised serum transaminase activity are usually reversible. (7) (12)There remains the theoretical possibility that statins may have adverse effects years later. A recent follow up report from the first major trial of statins was reassuring on this point, showing trends toward continued benefits in survival and fewer cancer deaths for two years beyond the five years of randomised statin treatment. (13) The evidence for both safety and efficacy have led statins to outstrip other lipid lowering drugs and to eclipse the role of diet (which has a far smaller effect on low density lipoprotein concentration (14) and is resisted by many patients) in coronary prevention. However, there are two caveats about the safety of these powerful drugs. Firstly, not every statin has been studied in large clinical trials with disease end points; use of the newer formulations is based on studies of their effects on blood lipids. (15) And secondly, seven years is not long enough to eliminate concerns about long term adverse effects such as cancer. While we await the findings of continued follow up of the statin trials, it is prudent to hold back from prescribing statins for patients who have a low 10 year risk of coronary events.

Cost is the other reason to hesitate before recommending statins to people at low risk of heart disease. Coronary heart disease is so rare among young adults that starting drug treatment for life in people in their 30s costs up to £1m ($1.4m) per year of life extended. (16) Until the price of statins comes down a lot, this is not a reasonable expenditure of medical resources. Of course, people who are well off can ignore concerns of cost. In a world that allowed statins to be bought over the counter, they could also bypass the need to persuade a physician to prescribe them. But the Food and Drug Administration has decided against such a world for now, leaving decisions about who should be taking statins in the hands of healthcare providers.

However, this does leave physicians with the obligation to do it right. Most people who could substantially benefit from statins are not getting them, (4) (17) perhaps due to a lack of awareness by physicians and their patients or to organisational and fiscal policies that do not support prevention. It is time to get serious about identifying and removing these obstacles. Physicians must do a better job of following practice guidelines for using statins to treat undesirable cholesterol concentrations in people who have a substantial 10 year risk of coronary events; this includes most patients with a history of coronary disease and a good many (mostly older) people who may soon develop it.

Stephen B Hulley

chair, Department of Epidemiology and Biostatistics

Deborah Grady

professor, epidemiology and medicine

Warren S Browner

professor, medicine and epidemiology

Departments of Epidemiology and Biostatistics and Department of Medicine, University of California San Francisco, 500 Parnassus Avenue, San Francisco, CA 94143-0886, USA
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