Statin therapy for healthy people with high cholesterol?

[SW VandeCarr]

There are lots of things you cannot randomize.

Of course. You do the best you can, but you may not get the most convincing results.

 

[SW VandeCarr]

It often does, but not always. What I do believe is that everytime I have seen someone object that causation does not imply correlation, that person was arguing against something where the correlation was clealy causal. (Ironically, that is an interesting correlation.)

We know that the relationship between LDL cholesterol and heart disease is causal because it occurs through all subgroups of people with elevated LDL, and because almost any way of lowering itlowers risk. This is unlike the correlation between coffee and lung cancer--the elevation is found only in one subgroup--smokers--and so we know it is not really coffee that is the cause. In the coffee case, the coffee is not harmful, but rather is correlated with the thing that is really harmful. But it does not work that way with cholesterol--the correlation with heart disease is unrestricted.

You can use the word any way you wish, but don't try publish in a medical journal that you've proved your causal hypothesis by means of a correlation. In the case of LDL-C, it is found in plaques, but there's still a lot of research regarding the stability of plaques. Stable plaques can remain asymptomatic for a long time. When they become unstable, there is a high risk of intimal rupture and inflammation leading to a clot. It's not known what causes this destabilization so you can't say cholesterol is involved at this stage for certain.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2659534/

 

[Evo]

This is in the first few paragraphs of the 2002 "cholesterol skeptic" paper that I posted and to which you seem to object to so much. I don't accept their full thesis, but they seem to have gotten that one right. They also claim that the method of measuring arterial wall media-intima thickness is inaccurate. I don't have an opinion on that.

Please quote what you are referring to so that we don't have to guess.

Thanks.

 

[SW VandeCarr]

Please quote what you are referring to so that we don't have to guess.

Thanks.

This is the third paper listed at the bottom of post 15. I mistook this one for the 2002 paper by the "cholesterol skeptic", published in the Oxford Journals. This is a 2003 paper which expresses similar points of view regarding the role of cholesterol but uses different arguments and may not be associated with the "cholesterol skeptics".

http://jcem.endojournals.org/content/88/6/2445.full Here's the quote:

"Atherosclerosis is a complex multifactorial disease. Lipids play an important, but not an exclusive, role in its development and progression. In some persons, lipids will be a major factor, and in some, lipids as we currently understand them will play a minor role. Outstanding advances have been made in understanding the biology of the vessel wall and of atherosclerosis, but there is still a long way to go. Our concepts of atherosclerosis and coronary heart disease (CHD) have dramatically changed, and we now know that coronary atherosclerosis is a diffuse multifocal inflammatory vasculopathy (1, 2, 3, 4). Rupture of nonocclusive lesions (<50% of the lumen) are often the most dangerous, abruptly causing sudden death or the acute coronary syndrome (ACS; Ref. 5). The important fact about these nonocclusive or culprit lesions is that there are many of them in the coronary circulation that are as dangerous as the one that causes the ACS. In fact, it is these lesions, and not necessarily the one causing the ACS, that are responsible for recurrent CHD events after myocardial infarction or the development of unstable angina (4). It is for this reason that antiatherosclerotic therapy (including lipid-lowering therapy) should be aggressive in patients with CHD or at high CHD risk. The most dangerous lesions are nonocclusive, asymptomatic, and not necessarily detected by stress testing, with or without imaging, or by coronary arteriography because the lesions may be accompanied by compensatory dilation with little or no encroachment on the lumen (6)."

 

[ApplePion]

I think the central issue in this thread is the recent evidence that cholesterol is not the whole story in CVD (CRP, inflammation, thrombus explanation)

I never claimed that cholesterol is the whole story--smoking, high blood pressure and diabetes are other factors. Indeed, smoking is a much more important factor for heart disease. Nor is the evidence "recent" that cholesterol is not the whole thing. What I claimed was that people with increased cholesterol are at increased risk for heart disease.

Again, consider my driving analogy. Drunk driving is not the whole thing for traffic deaths--there are traffic fatalities that do not involve alcohol. But a drunk driver is nevertheless at increased risk of dying in a traffic accident. And I also point out that there are no randomized studies on this--researchers cannot randomly select people to be told to either drive home drunk or to not drive home drunk.

It is for this reason that antiatherosclerotic therapy (including lipid-lowering therapy) should be aggressive in patients with CHD or at high CHD risk. The most dangerous lesions are nonocclusive, asymptomatic, and not necessarily detected by stress testing, with or without imaging, or by coronary arteriography because the lesions may be accompanied by compensatory dilation with little or no encroachment on the lumen (6)."

Doesn't this contradict your original claim that seemingly healthy people with high cholesterol should not be given medication to lower cholesterol?

 

[SW VandeCarr]

Doesn't this contradict your original claim that seemingly healthy people with high cholesterol should not be given medication to lower cholesterol

RE: It is for this reason that antiatherosclerotic therapy (including lipid-lowering therapy) should be aggressive in patients with CHD or at high CHD risk. The most dangerous lesions are nonocclusive, asymptomatic, and not necessarily detected by stress testing, with or without imaging, or by coronary arteriography because the lesions may be accompanied by compensatory dilation with little or no encroachment on the lumen (6)."

Does having heart disease or being at high risk sound healthy to you? I agree that if they are symptomatic or have arterial blockage on testing, they should be treated with statins, but not if it's just a laboratory value and no other interventions have been tried. Only one statin has been approved for primary prevention because its maker did the trials and submitted the data. Maybe you don't like that, but that's the way it is. It's not my call.

 

[SW VandeCarr]

What I claimed was that people with increased cholesterol are at increased risk for heart disease

Yes, "increased risk" is the way to say it. I agree.

 

[ApplePion]

Does having heart disease or being at high risk sound healthy to you?

Does the term "seemingly healthy" sound like "healthy" to you?

I agree that if they are symptomatic or have arterial blockage on testing, they should be treated with statins, but not if it's just a laboratory value and no other interventions have been tried.

Are you not aware that you were responding to a post where I specifically quoted your post saying that often people with severe heart disease are completely undiagnosable because they have no symptoms and their disease will not show up on tests?

If you are not aware that you posted it, you should carefully look at my post labelled #37, where I quote you.

 

[SW VandeCarr]

Does the term "seemingly healthy" sound like "healthy" to you?

In the absence of any other information, yes.

 

[ApplePion]

This contradicts your claim in post 37:

"In the elderly without established [coronary artery disease], but with risk factors for coronary artery disease, drug treatment should be introduced when indicated by the high prevalence of subclinical disease. This recommendation is supported by the studies: Cardiovascular Health Study (CHS),[22] PROSPER,[14] and HPS.[13] The National Cholesterol Education Program III (NCEP III)[23] also recommends dyslipidemia treatment in elderly patients without CAD, since the studies above mentioned certify the efficacy of statin therapy in CAD high risk elderly, even without diagnosed disease."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418895/?tool=pubmed

In post 34 you post that people with very severe heart disease often seem healthy, and that tests often cannot detect the heart disease. In post 41 you say that if there is no appearance of of heart disease that a person should be considered to not have heart disease.

 

[SW VandeCarr]

I never claimed that cholesterol is the whole story--smoking, high blood pressure and diabetes are other factors. Indeed, smoking is a much more important factor for heart disease. Nor is the evidence "recent" that cholesterol is not the whole thing. What I claimed was that people with increased cholesterol are at increased risk for heart disease.

What you've been claiming was that high serum cholesterol caused CVD. Now you're saying that it increases the risk, which is correct. These concepts need to be distinguished by scientists if not lay people. High serum cholesterol is neither a necessary nor sufficient cause of CVD outcomes such as heart attacks or strokes.

Does the term "seemingly healthy" sound like "healthy" to you?

What does seemingly healthy mean? In the absence of more information, if a person appears healthy from whatever information base we have, say from a health status screening, should we assume that the person is not healthy? Are you arguing that everyone should be tested for every possible pathology without some basis for doing so?

Are you not aware that you were responding to a post where I specifically quoted your post saying that often people with severe heart disease are completely undiagnosable because they have no symptoms and their disease will not show up on tests?

If you are not aware that you posted it, you should carefully look at my post labelled #37, where I quote you.

I am aware that you quoted the author of the paper from which I posted an excerpt as requested by Evo. The author expressed an opinion about an elderly population which might be at high risk. In other words he made a presumption about a demographic which is not unreasonable. Moreover, there is one statin which is now approved for primary prevention.

In any case, because I posted a paper for its substantive value, are you suggesting I should agree with any or all opinions the author may express?

I don't intend to respond to any more of your posts because I believe your intentions are questionable. Your initial position was that I was an unconditional supporter of the so called "cholesterol skeptics". I'm not and in any case, some of their positions have been vindicated. You accused me of misinterpreting a study I posted. I did not. You failed to understand that I was talking about survival studies of familial hypercholesterolemia patients, not the study end point, even though it was clearly stated in the quote you posted. I could go on, but it's not worth my time.

 

[ApplePion]

What you've been claiming was that high cholesterol caused CVD. Now you're saying that it increases the risk, which is correct. These concepts need to be distinguished by scientists if not lay people. High serum cholesterol is neither a necessary or sufficient cause of CVD.

So when people say that drunk driving is a cause of accidents do you object, saying that it is not a cause, but only increases the risk, and that it is neither a necessary nor sufficient condition for an accident?

And if you agree high cholesterol increases the risk, why did you object to lowering cholesterol? I presume you do not object to decreasing the amount of drunk driving.

What does seemingly healthy mean? In the absence of more information, if a person appears healthy from what ever information base we have, should we assume that the person is not healthy?

If someone appears healthy but otherwise has high cholesterol we should assume he might be unhealthy.

In fact, that was a recommendation of a paper you yourself posted.

Do you also think that people with high blood pressure who seem healthy should not get their blood pressure under control?

 

[mazinse]

This phrase "appears healthy" really doesn't say much. Is this a subjective or objective thing. I am puzzled by its meaning. You can't see atherosclerosis plaque built up in coronary arteries with a bunch lab tests.

 

[SW VandeCarr]

If someone appears healthy but otherwise has high cholesterol we should assume he might be unhealthy.

In fact, that was a recommendation of a paper you yourself posted.

Do you also think that people with high blood pressure who seem healthy should not get their blood pressure under control?

Despite what I said, I must respond to this because it is so obviously wrong. I never said high cholesterol in "healthy" people should not be treated. First there is diet, exercise and life style modifications such as in alleviating high stress situations to the extent possible. Secondly, there are other non-statin drugs approved for reducing cholesterol. Thirdly, there is now is one statin that is approved for primary prevention in the US.

BTW, since this is available, if a physician prescribes another statin for an off-lable indication and has a treatment failure, he or she could be hauled into court, at least in the US. That's not a good situation, but other manufactures have either not yet gotten approval based on the trials they've done or the trials they have started that have not yet been completed and analyzed.

 

[bohm2]

Despite what I said, I must respond to this because it is so obviously wrong. I never said high cholesterol in "healthy" people should not be treated.

Just to comment on this issue. The 3 studies mentioned before by ApplePion (HPS, PROSPER and the prospective Cardiovascular Health Study (CHS) are not particularly convincing, in my opinion.
1. The PROSPER study showed no benefits in terms of all-cause mortality in the treatment group
2. The HPS study was a secondary prevention study so it's difficult to extrapolate for primary prevention
3. The CHS study was a prospective study not a controlled clinical trial.
I do think this topic is debatable and difficult particularly because 2 recent reviews/meta-analysis question or at least caution against the use of such drugs for primary prevention:

In conclusion, based on aggregate data on 65 229 men and women from 11 studies, yielding approximately 244 000 person-years of follow-up and 2793 deaths, we observed that statin therapy for an average period of 3.7 years had no benefit on all-cause mortality in a high-risk primary prevention population. Current prevention guidelines endorse statin therapy for subjects at high global risk of incident CVD as a means to reduce fatal and nonfatal vascular events. Due consideration is needed in applying statin therapy in lower-risk primary prevention populations.

Statins and All-Cause Mortality in High-Risk Primary Prevention
http://www.courses.ahc.umn.edu/phar...risk primary prevention_Arch Int Med 2010.pdf

Although reductions in all-cause mortality, composite endpoints and revascularisations were found with no excess of adverse events, there was evidence of selective reporting of outcomes, failure to report adverse events and inclusion of people with cardiovascular disease. Only limited evidence showed that primary prevention with statins may be cost effective and improve patient quality of life. Caution should be taken in prescribing statins for primary prevention among people at low cardiovascular risk.

Statins for the primary prevention of cardiovascular disease.
http://www.ncbi.nlm.nih.gov/pubmed/21249663

 

[ApplePion]

Hi bohm2. I'm short on time now, so I might not be able to give you a detailed response for several days. But just quickly looking at the studies you posted I see that one of the studies has a Relative Risk for all cause mortalty of of .91 and the other one has an RR of .83. That means that in one study the people taking statins had a reduced risk of dying of all causes of 9 percent and in one they had a reduced risk of dying of all causes of 17 percent. Under the (unfortunate) rules of "statistical signficance" it was not statistically significant because the sample size was not large enough. But clearly the people in the studies taking statins did significantly better.

If I played chess with you and you beat me in 3 games out of 3, it would not be statistically significant because the number of games was too small, but nevertheless it would be serious evidence that you were a better chess player than me...despite that lack (under the rules) of statistical significance.

I am under the impression that the benefits of statins have indeed been demonstrated to be "statistically significant"--I will look into it when I have time... but regardless, if I had high cholesterol and was told that after confounding variables were accounted for, people in those two studies taking statins had a lower total death rate by 9 or 17 percent I would think it would be an extremely illogical move not to take statins.

 

[bohm2]

Note, that a relative risk reduction is far less impressive than an absolute risk reduction. Also note and as reported in the Cochrane review, if one considers known "publication bias" in pharmaceutical research that will likely to lead to over-representing positive results, the small, statistically, non-significant, relative reduction is likely to be nil. It's well known that,

Published pharmaceutical industry–sponsored trials are more likely than non-industry sponsored trials to report results and conclusions that favor drug over placebo.

Similarily,

RCTs of head-to-head comparisons of statins with other drugs are more likely to report results and conclusions favoring the sponsor’s product compared to the comparator drug. This bias in drug–drug comparison trials should be considered when making decisions regarding drug choice.

Factors Associated with Findings of Published Trials of Drug–Drug Comparisons: Why Some Statins Appear More Efficacious than Others
http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0040184

Just to give 1 example, consider the HPS study you mentioned which was statistically significant and showed a relative risk reduction (RRR) of 11.5 % for secondary (not primary) prevention. What that translates to (in terms of number neeeded to treat (NNT) is 57 patients for 5 years to prevent 1 death). Then there is the question of how much longer will that person live? And there's the publication bias problems. One can argue that the "true" NNT is higher than the one published.

 

[berkeman]

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