I am sure that many if not all of you read or heard about the front page story in today's (Friday, May 27) NY Times that using Niacin to raise the level of HDL (the "good") cholesterol did NOT lower the incidence of heart disease. The false expectation of a benefit from raising HDL came from the common confusion (and wishful thinking, because doctors are always looking for ways to help their patients) between correlation and causation. Remember that just because taller people (on the average) weigh more than do short people, it does not therefore follow that the way to increase a person's weight is to increase his/her height.
We doctors have many suggestions to make to our patients about primary prevention of heart attacks . By primary, I mean prevention of the first heart attack. Since the biggest risk of having a heart attack resides in those who have already had one, we have been very aggressive and successful in finding ways to prevent a second heart attack (hence the phrase "secondary" prevention). This is why a patient who has been on no medicine at all and who enters the hospital with a heart attack usually goes home on five medicines, since each of them has been shown to greatly reduce the risk of having a second heart attack.
However, despite all our theories, and all our observations about commonalities in patients who have a first heart attack versus those "similar" patients who have not, very few interventions have been shown to reduce the risk of a first heart attack, and of these, stopping smoking leads the list. We also have over 30 years of strong evidence (but only in comparative studies) that mild intake of alcohol of any origin (beer, red or white wine, scotch, slivovits, etc.) reduces the relative and absolute risk of a first heart attack. Unfortunately, we have absolutely no idea how the C2H5OH molecule does this, and it certainly has not been linked to a reduction in cholesterol, but at autopsy mild alcohol ingesters have larger lumens (= less blockage) in their coronary arteries than do tee-totalers.We also have no strong evidence for the benefits of daily aspirin, and we certainly cannot explain the results of a 30 year epidemiological study published in Lancet as to why in the Far East patients with a higher BMI (i.e. heavier patients) had a reduced risk of heart attacks, nor can we explain the studies that demonstrate that patients who are somewhat overweight (BMI between 26 and 29) have the greatest survival rate if they have a heart attack. It is trivial to note that stopping smoking does not affect your total cholesterol, LDL cholesterol, or fasting glucose (except insofar as most ex-smokers gain 10 to 15 pounds the first year).
In approximate numbers, survivors of a first heart attack have at least a 10% chance of a repeat heart attack in the following two years, so the results of a pharmacological intervention are readily seen. But patients with a high cholesterol who have never had a heart attack have a comparative increased risk of a heart attack in the next TEN years of 10%, so the results of an intervention have to be stronger or longer to show a statistical benefit, which is why it is difficult to show the benefits of any primary prevention in any forward double-blind study. In fact, the first double blind study of cholesterol lowering, done on male smokers in Finland with gemfibrizol, showed no benefit of reducing heart attacks until the statistical method of analysis was altered. I do not have the space here that is necessary to demonstrate why it is statistically unsound to vary your method of statistical analysis if you don't like the result of the first analysis.
We are left with the result that elevated cholesterol, elevated LDL cholesterol and lowered HDL cholesterol are all statistically associated with an increased risk of a heart attack, but only lowering the LDL has been shown to lower the risk of heart attacks consistently. The Zetia study showed that Zetia lowered total cholesterol, but did not decrease the heart attack risk. (Which only means that this first Zetia study failed to show a benefit, and a second and possibly a third study would be needed to validate this result as a clinical conclusion.) It may well be that the real value in the use of statins to lower cholesterol lies in their anti-inflammatory properties. We now have a study that shows that raising HDL did not reduce the risk of heart attacks. We have also known for years that elevated triglycerides are a statistical risk factor for heart attacks, but no study as yet has shown that lowering the TGL level lowers the heart attack risk. (Some doctors empirically lower the TGL of all their diabetic patients because diabetics have an increased risk of heart attacks, and a relative insulin deficiency causes a rise in TGL, but there is no cause-and-effect proof yet.) We also definitely do not understand why many patients, especially females, can have total cholesterols of over 280 with no evidence of an increased heart attack risk in them or their mothers, and have very patent coronary arteries at autopsy, if one is done. We also don't know why (but we think we do) females have a lower risk for heart disease than do men, any more than we understand why lupus and anorexia are more common among women than men.
Again, we must be very careful of assuming that any and every statistical relationship is cause-and-effect, and that if elevated "A" is associated with disease "B" then pharmacologically lowering the value of "A" will lessen the incidence of disease "B". In other words, altering a statistical risk factor is not guaranteed to affect the incidence of the disease. Very few facts are "obvious" in medicine: just recall the universal advice to patients with calcium oxalate kidney stones to lower the amount of calcium in their diet to prevent a recurrence, until a physician at UTexas, Galveston showed conclusively that INcreasing the amount of calcium in the diet DEcreased the recurrence rate of calcium oxide kidney stones. It was also thought that anti-oxidants had a protective effect against cancer, but when 50% of a matched group of Finnish cigarette smokers were given daily doses of anti-oxidants, it was found that those who took daily anti-oxidants had an INcreased incidence of lung cancer, a result to which the American Cancer Society has not given proper importance.
Finally, we also have the Law of Unintended Consequences: When mothers throughout America gave their children pure bottled water to drink, there was an increase in the incidence of dental caries in children, until it was realized that bottled water contained no fluoride, so now they have returned to giving their children fluoride as prescription Poly-Vi-Flor fluoridated vitamins (or their equivalent), just as I did. And since they have lost the business of children with cavities, dentists are now pushing orthodontia and night guards in Medicare patients(!). In most states, when the mandatory drivers' seatbelt law was passed, the death rate for pedestrians INcreased in the first few years, and we still don't know why. And many, many doctors were guilty of prescribing combination estrogen-progesterone tablets for their post-menopausal female patients in an attempt to reduce their risk of a heart attack until the increased incidence of cancer was noted. When we advised patients to take daily Vitamin E (400 Units) on theoretical grounds to lower their heart attack risk, the first decent statistical analysis showed that daily pharmacological doses of Vitamin E INcreased the risk of having a heart attack. Similarly, when men with prostate cancer were given estrogen to decrease the effect of any androgen on the prostate, an increase in cerebral strokes was soon noted. And at the present, only God knows the effect of daily doses of CoEnzyme-Q, or the proper dosage if there is a benefit, or how many times a day it should be taken, if at all, and if so on an empty or a full stomach.
"Life is short, art long, opportunity fugitive, experimenting dangerous, reasoning difficult....."--- Hippocrates
Showing posts with label cholesterol. Show all posts
Showing posts with label cholesterol. Show all posts
Saturday, May 28, 2011
Friday, January 22, 2010
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.
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.
Friday, May 8, 2009
Cholesterol and Heart Disease (1)
There have been many, many articles published, both in refereed medical journals and in newspapers, as well as reports from medical conferences about the correlation/statistical link between elevated cholesterol and heart disease, and about who would benefit from having his/her cholesterol lowered.
All commentators agree that elevated cholesterol is a "risk factor" for heart disease, in that, all else being equal, the higher the cholesterol, the greater the risk for plaque build-up in the coronary arteries. The real question, of course, is whether or not lowering the cholesterol lowers the risk for heart disease and/or heart attacks. The answer ab initio is far from obvious. No one would expect to lower an elevator in an office building by pulling down on the indicator arrow.
An excellent demonstration of the disconnect between risk indicators and risk improvement has been shown between high blood pressure, heart attacks, and strokes. Many studies have shown that untreated high blood pressure is a risk factor (i.e. is positively correlated with) both heart attacks and strokes, but, as far as I know, every study on the benefits of lowering elevated blood pressure only shows a reduction in the risk for strokes, and NOT a reduction in the risk of heart attacks. We may believe that we also help prevent heart attacks by lowering blood pressure, but there is no scientific data to support this belief. A doctor should only act on facts demonstrated by scientific research, or, to be fair to the patient, specify when he/she is acting on his own beliefs.
We also have to discriminate between primary prevention and secondary prevention. The greatest risk factor for having a heart attack is having had one already. Preventing a second heart attack would be called "secondary prevention", and since this group is at such high risk
it is easy to show the benefits or non-benefits of intervention. Showing the benefits of primary prevention is much more difficult, since the event rate is lower.
There has been a lot of argument in journals about various methods to obtain primary prevention, or reduction in primary risk. As a general rule, if scientists have to argue about the proper interpretation of data, then the data is probably useless. (Just try to follow any of the arguments of the use of meta-analyses.) Also, many studies confuse statistical significance (chance of interpretation being false less than 5%) with clinical significance (saves a significant number of lives in an absolute sense). For instance, if I could reduce your chance of being killed by a lightning bolt by 50% (relative benefit), but this meant a risk reduction from 1:1,000,000 to 1:2,000,000, you probably wouldn't be interested.
This initial blog is just setting up the framework for an in-depth discussion of cholesterol-lowering and heart disease prevention. Two caveats:(1) no one knows why lowering cholesterol with the use of Zetia or Vytorin showed no additional benefit, (2) the medical patients with the lowest total cholesterol levels, approx. 100, are patients with ulcerative colitis, who also have one of the highest rates of colon cancer.
All commentators agree that elevated cholesterol is a "risk factor" for heart disease, in that, all else being equal, the higher the cholesterol, the greater the risk for plaque build-up in the coronary arteries. The real question, of course, is whether or not lowering the cholesterol lowers the risk for heart disease and/or heart attacks. The answer ab initio is far from obvious. No one would expect to lower an elevator in an office building by pulling down on the indicator arrow.
An excellent demonstration of the disconnect between risk indicators and risk improvement has been shown between high blood pressure, heart attacks, and strokes. Many studies have shown that untreated high blood pressure is a risk factor (i.e. is positively correlated with) both heart attacks and strokes, but, as far as I know, every study on the benefits of lowering elevated blood pressure only shows a reduction in the risk for strokes, and NOT a reduction in the risk of heart attacks. We may believe that we also help prevent heart attacks by lowering blood pressure, but there is no scientific data to support this belief. A doctor should only act on facts demonstrated by scientific research, or, to be fair to the patient, specify when he/she is acting on his own beliefs.
We also have to discriminate between primary prevention and secondary prevention. The greatest risk factor for having a heart attack is having had one already. Preventing a second heart attack would be called "secondary prevention", and since this group is at such high risk
it is easy to show the benefits or non-benefits of intervention. Showing the benefits of primary prevention is much more difficult, since the event rate is lower.
There has been a lot of argument in journals about various methods to obtain primary prevention, or reduction in primary risk. As a general rule, if scientists have to argue about the proper interpretation of data, then the data is probably useless. (Just try to follow any of the arguments of the use of meta-analyses.) Also, many studies confuse statistical significance (chance of interpretation being false less than 5%) with clinical significance (saves a significant number of lives in an absolute sense). For instance, if I could reduce your chance of being killed by a lightning bolt by 50% (relative benefit), but this meant a risk reduction from 1:1,000,000 to 1:2,000,000, you probably wouldn't be interested.
This initial blog is just setting up the framework for an in-depth discussion of cholesterol-lowering and heart disease prevention. Two caveats:(1) no one knows why lowering cholesterol with the use of Zetia or Vytorin showed no additional benefit, (2) the medical patients with the lowest total cholesterol levels, approx. 100, are patients with ulcerative colitis, who also have one of the highest rates of colon cancer.
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