Cholesterol, Statins, Zetia,Niacin, ASCVD, and MI's

This blog was stimulated by several recent articles and studies about statins, zetia, Niacin, ASCVD, and MI's. We must not lose sight of the fact that virtually all researchers have concluded that an MI is triggered by the rupture of an atheromatous plaque in a coronary artery, although the actual rupture has not, I think, ever been seen dynamically. Nevertheless, when a coronary artery is found clotted off at autopsy, and the clot is adjacent to and newer than the plaque, and the surrounding tissue is necrosed, then the conclusion is probably correct.

The first fact to notice at such an autopsy is that the atheromatous-clotted artery, as a rule, has a larger diameter anatomically before and after the clot than does another coronary artery. In other words, the probability of a rupture-to-clot process does not seem to depend vitally on the pre-clot diameter, although there is, of course, some influence. Just recall how many times an artery with 97%-99% stenosis is not occluded, but is stented instead.

So we then come to the question: what causes (or prevents) the plaque in a coronary artery from rupturing, clotting off the artery, and causing an MI? Clearly there must be some degree of inflammation which sets the plaque up to be susceptible to the shearing force of coronary blood flow. So we can have some equation that the probability of clot formation varies as (C)x(probability of plaque)x(?thickness of plaque)x(probability of rupture), where C is a factor to indicate that an MI has occurred before; if C=1 we are dealing with primary prevention, and if C is greater than one, we are dealing with secondary prevention.

Since we have plenty of data on secondary prevention, I am going to concentrate on primary prevention. Now CRP, a measure of inflammation, has been variously correlated with the risk of MI as has 81 mg/day of ASA, with no clear-cut primary prevention shown by either lowering CRP or by daily ASA. But in experimental physics we have a saying: If you are arguing about the significance of data, then the data is not significant, similar to the last data point in a particle physics experiment.

We do know that diabetes, cigarette smoking and hypertension are synergistic with cholesterol levels in causing a plaque as well as a clot. This shows at least two mechanisms at work, since it is difficult to imagine that hypertension increases local plaque inflammation. Similarly Zetia, which lowers cholesterol, does not seem to increase coronary artery diameter, but these studies did not look at MI or CVA as an endpoint, so we don't know if Zetia affects plaque inflammation and rupture. A curious observation is that if your "native" cholesterol is 200, your risk of an MI is greater than if Crestor was used to lower your native cholesterol from 240 to 200. This clearly indicates to me that statins have an additional preventive effect, probably lowering inflammation of the plaque, over and above lowering cholesterol and/or reducing the size of the plaque. Similarly Niacin, which raises HDL, has a beneficial effect beyond its size effect, and probably lowers inflammation as well. And patients (usually female) with cholesterols over 300 and 85+ years old without and ASCVD are outside our explanations and models.

But to me, the most amazing drug is C2H5OH, or ethanol. In matched pairs, people who drink "moderately" (= 1 drink/day for men, and one every other day for women) have a lower heart attack rate and LARGER DIAMETER CORONARY ARTERIES AT AUTOPSY than do non-drinkers. This result holds for numerous studies with whiskey, beer, slivovitz (plum brandy), scotch, etc,in homogeneous populations (e.g.native-born Japanese males in Hawaii) and seems to be a pure alcohol effect. We have known this since 1974 (see article in JAMA). No one knows the mechanism by which this occurs, but I assume constant research is going on. Since young people already have atheromatous plaques, then if we want to reduce heart disease in our older population, it seems to me we should encourage a glass of wine with dinner starting with high school seniors. There is no argument in the literature about this effect, as there is about lowering CRP, adding ASA, or lowering salt in the diet.

With regard to lowering salt in the diet, there were two long articles (one pro and one con) about this subject published years ago in Lancet. The con argument was that just as eating sugar will not make you a diabetic, so will eating salt (with normal kidney function) not give you hypertension. I have a more fundamental ethical objection to imposing salt reduction. In hospitals and research clinics, when an experiment is performed on human subjects, it must be passed by the Institutional Review Board, and each subject must be warned of possible negative side effects and given a chance to withdraw. No such board will review the law if low salt diets are mandated, and I am concerned that 10 years down the road we may learn that we have done irreversible harm to the subjects, our fellow citizens, or to the children in school cafeterias.

Mammograms, Zetia/Vytorin, Proscar,Folic Acid

I have received many phone calls from my patients and e-mails from readers on my bloglist about 3 different reports about medical research results: an article in the NY Times by Gina Kolata(Proscar), a report from a cardiac conference(Zetia/Vytorin), and recommendations from a medical study group (mammograms). I received no inquiries about an article in Lancet (folic acid), but I guess few people read British medical journals, even though Lancet antedates both NEJM and JAMA, and their letters to the editor are invaluable. My comments on these are probably applicable to many reports of medical results, and I leave it to my readers to evaluate any such reports.

First, some general comments. In many areas of non-precise science (I am therefore excluding mathematics, chemistry and physics) when recommendations are made, there is both a majority report/recommendation, and a minority report. However, in medicine, except as a rebuttal to a journal article (e.g. the discussion in Lancet as to whether or not reducing total salt in the diet saves lives) we never see the minority report. I doubt that 20 doctors (or 20 anyones) ever agree 100% on a committee report, and it would be nice to see the minority report (cf. the arguments about global warming) so we can try to make our own decision. Furthermore, most refereed journal articles require the authors to make the source data available on request, but this does not happen with medical committee recommendations, so we have no way to judge how they arrived at their recommendations, or what compromises were made (e.g. how did the government first decide that total cholesterol levels should be below 240?). Was it the same way that Congress decided on 27.5% as the oil depletion allowance, i.e. a compromise?

The recent recommendations on the starting age and frequency of mammograms are a case in point. There was no minority report, and the data on which the recommendations were made are not available. I only fear that HMO's will seize on this report to pay for fewer mammograms, as Medicare once did. I have never had a problem with ordering a test for a patient even if I was absolutely certain the result would be negative, because the patient's peace of mind is important to me.
There is absolutely no way to know for a given individual how often a mammogram should be done (why not every 6 months to detect fast-growing cancers?), or at what age the mammograms should start. I also have some 90 year old women who have never had a mammogram, and have never had breast cancer, and so far they are right as well.

The article about men not taking Proscar even though men on Proscar have a lower incidence of prostate cancer did not properly emphasize the fact that if prostate cancer does occur when a man is taking Proscar it is much more aggressive, and has a higher Gleason score. On the other hand, taking both Proscar and Flomax decreases a man's probability of needing a TURP of the prostate to relieve blockage caused by a growing prostate. Also, some men do not like taking Proscar because it diminishes the amount of fluid in the ejaculate by at least 50%, and these men do not enjoy the different sensation, because their orgasms are therefore shorter. Why not just say that men who do not take Proscar are "pharmacologically autonomous"?

Both Zetia and Vytorin decrease cholesterol, which is all the FDA required them to do. Studies on other statins as well as on Niacin showed that lowering cholesterol by these chemicals reduced the risk of second heart attacks and strokes, as well as the risk of first heart attacks. (I have never seen a study on diet, lower cholesterol, and heart attacks.) The FDA then assumed that any chemical lowering of cholesterol was beneficial, as does the entire medical establishment.
The study of Zetia/Vytorin showed that they did not cause regression of the narrowing of the intima of a major artery. However, this is a secondary surrogate marker for strokes and heart attacks. If heart attacks are caused by rupture of plaque (as many cardiologists believe) then stabilizing the plaque (are statins anti-inflammatory as aspirin is?) is more important than the lumen diameter, after a certain narrowing. No one has shown that lowering the cholesterol with Zetia or Vytorin does NOT reduce the risk of heart attack or stroke, just as no one has shown that intimal regression is a valid surrogate for MI's and CVA's.

The latest issue of Lancet reported a large study that showed that fortifying the diet with folic acid, which successfully lowered neural tube defects in infants, INCREASED the risk of cancer. I wonder what the USA and FDA will do with this study. It certainly should be repeated. But studies showing that vitamin ingestion can cause problems rarely make headlines in America. Maybe we should revise the recent recommendations which raised the RDA for folate from 0.4mg to 0.8mg?

Thought for the month: Why does the full moon appear larger when it rises in the East than it does when it is directly overhead?