Tuesday, March 29, 2011

Statins, cholesterol and medical science

Do statins work? Does high cholesterol cause heart disease? Are people who doubt the conventional wisdom on these two topics excessively skeptical conspiracy wonks? Or is big pharma pulling a fast one on the public by pushing statins?

See also this paper which is mentioned in the article below and which summarizes results of studies from 2008-2010 (response by authors to criticism). See here for earlier discussion on the overall quality of medical research.

MedConnect: ... Dr. Kausik K. Ray of the University of Cambridge (England) and his associates performed a meta-analysis of 11 randomized controlled trials that assessed the effects on all-cause mortality of statins versus a placebo or control therapies on all-cause mortality. They restricted their analysis to data on high-risk patients with no known cardiovascular disease and included previously unpublished data, “to provide the most robust information to date” on statins as primary prevention in this patient group.

The metaanalysis involved 65,229 men and women in predominantly Western populations, with approximately 244,000 person-years of follow-up. There were 2,793 deaths during an average of 4 years of follow-up.

All-cause mortality was not significantly different between patients taking statins and those taking placebo or control therapies. This suggests that “the all-cause mortality reduction of 20% reported in JUPITER is likely to be an extreme and exaggerated finding, as often occurs when trials are stopped early,” Dr. Ray and his colleagues said (Arch. Intern. Med. 2010;170;1,024-31).

This meta-analysis shows that statin therapy as primary prevention in high-risk patients is less beneficial than is generally perceived, and it can be inferred to be even less helpful in low-risk patients, they added.


LondonYoung said...

"Does high cholesterol cause heart disease?" I don't think this question is specific enough. I think you need to ask "if a given subject takes action to lower their "bad" cholesterol level, will they decrease their risk of heart disease?" I think there are very limited categories of subjects for which the answer is "yes", but that the majority of patients currently receiving treatment do not fall into one of those categories. The fact that many people go from being obese to being merely overweight when they "get a scare" and begin treatment damages the usefulness of most studies.

steve hsu said...

"majority of patients currently receiving treatment"

Does that mean statins?

DK said...

Do statins work?
Yes. They inhibit HMGCR just fine.

Does high cholesterol cause heart disease?
Not directly.

Are people who doubt the conventional wisdom on these two topics excessively skeptical conspiracy wonks?
Not all of them.

Or is big pharma pulling a fast one on the public by pushing statins?
Yes but not as much as conspiracy wonks want you to believe.

esmith said...

I left a response in the other thread, but it disappeared for some reason. I'm too lazy to type it up again. The gist of it: JUPITER was the largest (if not the only) serious study since 2005 looking at statins in healthy people. Most others looked at statins in people with some kind of preexisting problem. Statins reduce the risk of stroke and AMI, but lowering the cholesterol won't keep you from dying from heart failure or cure your aortic valve stenosis. And, since studies of people with systolic heart failure or aortic valve stenosis tend to be small, you may end up seeing a 20% reduction in the rate of AMI that also happens not to be statistically significant at the group size, and give fuel to people like de Lorgeril who'd use it to argue that statins don't work.

With regard to the link above, I don't think that anybody, certainly not JUPITER, ever claimed a 20% _all-cause_ mortality reduction from statins. This has always been a 20% cardiovascular mortality reduction.

steve hsu said...

If I read the criticism correctly if appears even the 20% cardiovascular mortality reduction might be an artifact of their stopping the study early.

What do you think of the Ray et al. meta-analysis, which covered high risk but healthy (no cardiovascular disease) subjects?

esmith said...

What do I think of the Ray et al meta analysis? The first thing I think is that "all-cause mortality was not significantly different between patients taking statins and those taking placebo or control therapies" does not mean that "statins have no effect". It means that "there may be an effect here, but our study was not precise enough to confirm or deny its existence."

All these studies were designed primarily to count cardiovascular events. They were only big enough to make reliable conclusions about incidence of miocardial infarctions & such. They are less useful to estimate CV mortality, and even less useful to analyze all-cause mortality. Even constructing a meta-analysis out of them that covers 240,000 person-years, you can't do much better than a +/-0.10 confidence interval, which happens to cover the entire interesting area, from JUPITER's 20% reduction to lack of any effect at all.

I found the full text of the meta-analysis: http://www.courses.ahc.umn.edu/pharmacy/5822/Ray_Statins%20and%20all-cause%20mortality%20in%20high-risk%20primary%20prevention_Arch%20Int%20Med%202010.pdf. Look at the table on page 3.

The second largest study (ALLHAT) did not test statins vs. placebo. It tested statins vs. "usual care". What did they mean by usual care? "The usual care group was treated for LDL-C lowering according to the discretion of their primary care physicians." "The usual care" was effective enough to lower patients' LDL cholesterol 20 points over 6 years.

In AFCAPS/TexCAPS, there was a substantial (25% to 40%) and highly statistically significant reduction in all sorts of cardiovascular events, but only 42 deaths across the entire test population. "and as predicted, the study was not adequately powered to detect treatment differences in the low frequency end points of cardiovascular mortality and CHD mortality." http://jama.ama-assn.org/content/279/20/1615.full.pdf+html

In PROSPER, once again, there was a substantial reduction in CV events and deaths, counterbalanced by an increase in cancers; which, as they say, is not borne out in other double-blind studies. (The overall death rate was still lower in statin group than in placebo group, I have no idea where Rey et al got their numbers.)

Anton Mescheryakov said...


LondonYoung said...

I am thinking "anything intervention aimed at cholesterol levels" ... physicians prescribing drugs or just diets or what-not ... correcting for everything the doctor's office does for you, does anything help with heart disease beyond just managing obesity? what do statins really do anyway? drug research is a kinda joke if you are trained as a physicist - no experiments, no controls....

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