Map of life expectancy at birth from Global Education Project.

Monday, December 04, 2006

Just to make myself clear . . .

I did not say, and certainly do not believe, that everyone ought to take statins, or that we ought to put them in the water supply, or anything like that. What I did say is that research is showing, with an increasing degree of confidence, that certain categories of people who do not currently have symptoms of heart disease show a long-term benefit in terms of both reduced risk of cardiovascular events, and overall survival.

Commenters provided links to more information about statins, and if you are interested this is a group of researchers who are approaching these medications with skepticism, which is appropriate. We should approach everything with skepticism. Their web site has links to various studies and their own summaries of information. I would say that they do get a tiny bit tendentious about some issues. For example, the evidence that statins can cause cognitive or behavioral side effects is extremely weak and conflicting. They give this link to a study under the heading of "statins and memory loss," but when you actually read the abstract, this is the conclusion: "Treatment of hypercholesterolemia with lovastatin did not cause psychological distress or substantially alter cognitive function. Treatment did result in small performance decrements on neuropsychological tests of attention and psychomotor speed, the clinical importance of which is uncertain." These deficits don't apply to most subjects at all, but only emerge when you take the average of all participants, whereupon the investigators find tiny differences that may not even matter.

When you do a study like this and look at multiple endpoints, it is often the case that certain relationships appear to exist which are in fact spurious. This is called the problem of multiple comparisons. Drug companies often rely on such fishing for relationships to claim positive effects of drugs, but it works just as well in the opposite direction, i.e. it's easy to find spurious side effects as well. Obviously, if you think your prescription is having such effects on you, you can stop taking it. You can even do an experiment. Have your doctor ask the pharmacy to give you the drug for two months, and a placebo for two months, but not tell you which months are which. After four months, you'll have a much better idea of whether the drug is really causing problems for you.

The serious side effects of statins are well known, they occur in only a small minority of individuals, and they are usually recognizable well in advance of any long-term consequences. However, it is the case that one statin, Bayer's cerivistatin, posed a particularly high risk for myopathy. It was pulled from the market.

You can read the National Heart, Lung and Blood Institue's summary of what is known about the safety of statins here. (Small PDF) They say this:

More than 50,000 individuals have been randomized to either a placebo or statin in these trials, and no serious morbidity or increase in mortality was observed in the drug treatment groups. These agents reduce the risk of essentially every clinical manifestation of the atherosclerotic process; they are easy to administer, with good patient acceptance. There are very few drug to drug interactions. Although the experience with the safety of statin therapy outside of clinical trials has not been fully reported, it is reasonable to suspect that the incidence of side effects may be higher in clinical situations where patients are not monitored as closely as they are in clinical trials.

I should note that cardiologists have no profit motive here: they don't make much money by writing prescriptions, and if statins do indeed prevent heart attacks, it's costing them business, not helping them. It's not directly relevant to the issues I want to discuss here, but for the record, statins are more clearly beneficial for men than for women, and may not be a good idea for people older than 75 or so. (Which by the way is also the conclusion of the BMJ study I originally linked to.)

My point in reciting all this is not to defend or advocate for the drugs. Rather, it is, as before, to point up some of the epistemological, ethical and pragmatic problems posed by the continual advances in pharmacology -- and there are indeed advances, even though, as I have said many times, the drug companies invest a lot more in "me-too" drugs and "evergreening" old ones (maintaining marketing exclusivity by making tiny changes in formulations), and marketing aggressively to get people to buy their most profitable products, than they do in actually developing new therapies to meet real needs. If statins didn't appear to offer benefits to some people, we wouldn't have an issue. But they do.

So these drugs are an excellent example to focus our thinking about the following problems, among others.

1) Clinical trials are conducted under ideal conditions, and they are designed to look for expected benefits, and not as well designed to look for unexpected outcomes, including side effects. In the real world, drugs may be used less appropriately and less safely, and unanticipated side effects may also emerge, particularly if they are rare. We generally don't have any way of really knowing how safe drugs are when they are first marketed, and we also don't generally invest enough in post-marketing surveillance and further trials to evaluate side effects that we may start to suspect due to anecdotal evidence. There is a pro-drug bias in the way we collect, structure and use information. (That said, the overall safety and net benefit of statins is still holding up well -- but people who argue that we ought to be working harder to learn more certainly have a case.)

2) Drug company marketing often leads to drugs being prescribed more widely than they should be. Statins are certainly a prime candidate for such misuse because they are recommended for some people who don't have patent disease, which means it's easy for "prescription creep" to happen. As I noted before, statins are aggressively marketed because a drug you have to take more or less forever has great profit potential. Each new customer is worth a lot to the manufacturers. The bias that physicians have to "do something" doesn't help either.

3) People's typical personal evaluation of risk is not the same as the actuarial evaluation that is used to generate clinical guidelines. A pill that can reduce the risk of a natural event such as the development of heart disease and myocardial infarction, while posing a lesser risk of an event that would not occur if you didn't take the pill -- in this case myopathy -- might not look like a good tradeoff to the person taking it. This is especially true if there appear to be other ways of reducing the risk of heart disease, such as stringent diet, exercise, etc. -- even though the person is highly unlikely to do those things in reality.

4) The danger that some people may be prescribed statins inappropriately, or use them inappropriately (e.g., they are more risky for alcohol abusers and grapefruit juice drinkers) means that some individuals will suffer harm that can be anticipated, even if the population experiences a net benefit. Do these people deserve compensation? How do these risks affect our evaluation of the entire project of selling these drugs?

5) Is there a substantial hidden cost to labeling people without manifest illness with a disease label, such as hypercholesterolemia, and putting them on a treatment regimen? Do we somehow suffer morally or psychologically from this? Does it make us dependent, or self-involved, or anxious? Is it a misallocation of resources?

6) In the end, can we really depend on the NIH-FDA-medical-industrial complex to give us accurate and honest information so that we can make decisions with confidence? I have offered for your consideration consensus guidelines on statin use and the clinical advisory on adverse effects, but I know that many readers will simply not believe them. I personally am much less skeptical in this case than I am in the case of anti-depressants, for example, but I can understand why people are doubtful.

Further feedback is encouraged. Have at it.

1 comment:

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