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Statins Are Better on JUPITER

Over 26 million Americans are taking statin drugs. Some people think they should be available over-the-counter without a prescription, and it has even been facetiously suggested that they should be added to our drinking water. The protective effect of statins in cardiovascular disease and in high-risk patients with high cholesterol levels is well established. But what about people with no heart disease and normal cholesterol levels – can they benefit too?

The New England Journal of Medicine has pre-released an important new study on statins online prior to its planned publication date of November 20, 2008. It is certain to stir up a lot of controversy, and the International Network of Cholesterol Skeptics will not be happy, because it contradicts some of their favorite arguments. They have claimed that statins do more harm than good, that reducing cholesterol levels is harmful to health, that the benefits of statins and/or cholesterol lowering do not extend to women and the elderly, and that studies showing benefits of statins are meaningless because they do not show reduction of overall mortality. This study indicates otherwise.

The JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) study looked at people with low levels of LDL cholesterol but high levels of C-reactive protein (CRP). CRP is a marker for inflammation, and elevated levels are a risk factor for cardiovascular disease. Since statins reduce CRP levels, the hypothesis was that statins would prevent heart attacks in these patients.

JUPITER was a well-designed study with nearly 18,000 subjects in 1315 sites in 26 countries. It was randomized, placebo-controlled, and double blind. It found that rosuvastatin significantly reduced the rate of cardiovascular events as well as the overall death rate.

They selected subjects with care to eliminate possible confounding factors, and they even did a 4-week placebo run-in trial to eliminate subjects who were not compliant about taking the pills. Subjects were men over the age of 50 and women over the age of 60 who had no history of cardiovascular disease, who had LDL cholesterol levels of 130 mg per deciliter or lower (usually considered normal), and who had elevated CRP levels of 2.0 mg per liter or greater. The primary endpoint was the occurrence of a first major cardiovascular event such as a heart attack or stroke. Secondary endpoints looked at specific individual events like nonfatal MI, and included overall death rate from any cause.

The results were overwhelming. 20 mg of rosuvastatin a day produced:

  • LDL cholesterol 50% lower than with placebo
  • CRP 37% lower
  • Reduction of first major cardiovascular event from 1.36 per 100 person-years to 0.77.
  • Reduction of MI from 0.37 to 0.17
  • Reduction of stroke from 0.34 to 0.18
  • Reduction of revascularization for unstable angina from 0.77 to 0.41
  • Reduction of all-cause death rate from 1.25 to 1.0

These were all highly significant, from p=0.02 to p=0.00001. Effects were similar for all subgroups evaluated:

These effects were consistent in all subgroups evaluated, including subgroups customarily considered to be at low risk, such as people with Framingham risk scores of 10% or less, those with LDL cholesterol levels of 100 mg per deciliter or less, those without the metabolic syndrome, and those with elevated levels of high-sensitivity C-reactive protein but no other major risk factor. The trial also showed robust reductions in cardiovascular events with statin therapy in women and black and Hispanic populations for which data on primary prevention are limited.

The rate of reported side effects was similar for both the rosuvastatin and the placebo group. Muscle side effects including rhabdomyolysis have been a great concern of statin critics, but in this study there was no difference between the statin and placebo groups and there was only one case of rhabdomyolysis and that was in a 90-year-old subject with febrile influenza, pneumonia, and trauma-induced myopathy. Some critics have claimed that statins cause cancer, but in this study there were fewer new diagnoses of cancer and significantly fewer cancer deaths in the rosuvastatin group (p=0.02). The only adverse finding was a higher rate of physician-reported diabetes in the rosuvastatin group; but there was no significant difference in blood glucose levels between the groups.

So rosuvastatin is effective and safe for primary prevention of heart disease in patients with normal cholesterol levels. Does that mean we should give it to everybody or put it in the drinking water? NO!

  • They estimated that 95 people would have to take rosuvastatin over 2 years or 25 people would have to take it over 5 years to prevent one new major cardiovascular event.
  • If I did the math right, 400 people would have to take it for a year to prevent one death.
  • Rosuvastatin costs $3.45 a day. That would add up to over half a million dollars for each death prevented. Who will pay?
  • This study only involved patients with high CRP levels. We don’t know if it would benefit those with normal CRP levels.
  • This was a short-term study and we don’t know what the long-term effects of rosuvastatin might be.
  • LDL cholesterol levels dropped to an average of 55 mg per deciliter – this is very low and we don’t know what the long term consequences of such low levels might be.
  • It studied a select group with no confounding factors; the results in the general population and in younger patients might be quite different.
  • We still don’t know the role of CRP and it’s not recommended as a screening test for the general population.
  • We can’t be sure we’d get the same results from other statins as from rosuvastatin.
  • We don’t know whether the benefits are due to lowered cholesterol or whether lowered cholesterol is a marker for other benefits of the drug.

In a thoughtful accompanying editorial, Mark Hlatky, MD says,

At this point, the current guideline for measurement of high-sensitivity C-reactive protein remains reasonable: a measurement may be obtained in asymptomatic individuals who have an intermediate level of risk, as estimated on the basis of standard clinical risk markers, if the decision to initiate drug treatment might change depending on the high-sensitivity C-reactive protein level. In my view, the evidence still favors this selective strategy for measuring high-sensitivity C-reactive protein, not routine measurement.

This study sounds almost too good to be true, and the drug company will inevitably be accused of trying to drum up business. Rosuvastatin is marketed by AstraZeneca under the brand name Crestor. The study was admittedly funded by the manufacturer, but 1315 separate sites were involved and AstraZeneca “played no role in the conduct of the analyses or drafting of the manuscript and had no access to the unblinded trial data until after the manuscript was submitted for publication.” It seems unlikely that they could have done anything to bias the results.

I hope this study doesn’t just encourage doctors to indiscriminately hand out more pills. Prevention should address all modifiable risk factors and should start with lifestyle changes like smoking cessation and exercise. In my view, this study is not enough to justify wholesale statin treatment, but it does give us more confidence that statins are safe and effective. And it shoots down some of the claims of anti-statin activists. It will be interesting to see if this study will change practice guidelines. The NEJM is conducting a poll to see if readers think it should. You can cast your vote here.

Posted in: Clinical Trials, Pharmaceuticals

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110 thoughts on “Statins Are Better on JUPITER

  1. qetzal says:

    On the other hand, I expect this will bolster those who think that cholesterol reduction is a red herring, and that inflammation is the true risk factor.

  2. frankzovko says:

    Thanks for your analysis, Harriet. I was wondering… was there any particular reason for the choice of a population with low LDL and no metabolic syndrome but high C-reactive protein? Is that an uncommon set of characteristics?

    Also, I have seen a fair amount of speculation suggesting that statins’ cardio-protective effects may very well have more to do with anti-inflammatory effects than LDL-lowering effects, and here, we have a group with already-low LDL seeing significant benefits while having their CRP decrease, where the latter is considered an inflammation marker. Perhaps we will see statins’ effectiveness attributed less to their cholesterol-lowering function and more to some sort of anti-inflammatory mechanism.

  3. Harriet Hall says:

    There were several criteria for exclusion, but metabolic syndrome was not one of them. 41% of subjects had metabolic syndrome. In the subgroup analysis, both those with and without metabolic syndrome benefitted; the response was marginally better in those who didn’t have metabolic syndrome.

    As I mentioned,

    We don’t know whether the benefits are due to lowered cholesterol or whether lowered cholesterol is a marker for other benefits of the drug.

  4. frankzovko says:

    Ah, my apologies- I’m not even sure where I got that idea- I should read the entire article from the journal before I misinterpret anything else! Thanks.

  5. delaneypa says:

    Thanks for the summary Dr. Hall. I agree with your earlier posts that, while often appropriate, statins are in over prescribed. When I calculate the Framingham Risk Score with real versus ideal cholesterol, the improvment that one could expect is often surprisingly small particularly for healthy women (of course, purists will argue the FRS is not meant for such “what-if” scenarios).

    I bet, though, this study will make overprescribing statins even worse. CRP is a nonspecific marker for cardiovascular disease…many conditions are associated with inflammation, and without careful thought some will “treat” acute inflammation with statins.

  6. EddieVos says:

    Hello Harriet, I am a member of THINCS and I read your article re JUPITER.

    The HICK in ALL statin trials is that statins have conclusively shown NOT ever to extend a life of a female. It is always with surprise and with me thinking of my late but activist mother, a pioneer like yourself, that female authors appear not to appreciate that medical certainty. A brief report I co-authored is here but it has the references: http://www.cmaj.ca/cgi/content/full/173/10/1207-a

    Statins are, among other things, mimics of nitroglycerin, and the use thereof, like COX-2 inhibitors, would send fewer patients to the hospital for a non fatal pain only to be duly recorded as having experienced a non fatal endpoint, be if for a knee problem or in this case for a stent intervention or a simple hospitalization. 55% of ‘event’ benefit in JUPITER was in revascularizations, a procedure, not a disease and not an MI or death preventing intervention [as per MASS-2, COURAGE]

    In JUPITER’s table 4: 12 DEATHS from stroke and MI in either group, again a failure to save lives in the cardiovascular department.

    More women than men die from cardiovascular disease than men. Therefore and especially in women, any drug class NOT reducing women’s mortality has limited use, if any, in my opinion. There are several much more effective ways of reducing arterial decline and that also reduce deaths thereof but that is not the topic at hand, but statins at least in women are not one of these ways, that is a mathematical certainty.

    You might want to elucidate that issue in a posting, or place this mail on the relevant blog if you see fit.

    Kind regards, Eddie Vos

    > http://www.health-heart.org
    > http://www.health-heart.org/author.htm [yours truly]
    > http://www.health-heart.org/why.htm [why arteries fail]
    > http://www.health-heart.org/cholesterol.htm [why not]
    > http://www.health-heart.org/HIPandHOPE.gif [pic du jour]
    > Nutrition, Health & Heart Disease; Cause & Prevention

  7. Harriet Hall says:

    EddieVos,

    Rosuvastatin reduced the actual numbers of:

    Deaths from any cause from 247 to 198. p=0.02
    Myocardial infarction, stroke, or confirmed death from cardiovascular causes from 157 to 83 p=<0.00001
    Nonfatal MI from 62 to 22 p=<0.00001
    Any MI from 68 to 31 p=0.0002
    Nonfatal stroke from 58 to 30 p=0.003
    Any stroke from 64 to 33 p=0.002
    Arterial revascularization or hospitalization for unstable angina from 143 to 76 p=<0.00001

    The NEJM article does not break down the deaths by male or female. It does look at women as a sub-group, and the overall benefit to women was very significant. In fact it was slightly greater than that for men.

    I can’t understand the THINCS fixation on mortality. Drugs that decrease morbidity would be valuable even if they didn’t change the overall death rate. If a woman is going to die at age 80 either way, isn’t it better for her not to have a nonfatal stroke or a nonfatal heart attack at age 65?

  8. wertys says:

    THINCS remind me of ID proponents in that they find an anomaly and obsess over it, thereby missing the wood for the trees.

    While I completely agree that there are better value-for-money ways to reduce cardiovascular risk, they should at least have the scientific integrity to admit that there is compelling evidence of benefit for statins, and not a lot of equally compelling evidence to the contrary.

    Having spent time on a stroke rehabilitation unit, I agree that prevention of nonfatal stroke is a very worthwhile goal, and perhaps this should also be factored into the cost-benefit analysis. A four-week inpatient rehabilitation stay in my part of world costs the taxpayer around $16-20K, and there are ongoing expenses in terms of community services and outpatient rehabilitation. This is not even to mention the suffering and distress caused to families and survivors of stroke who have to deal with the abrupt onset of severe disability.

    So before THINC start trying to pick holes in a fairly tight study and quibble over statistical irrelevancies, they should look at the ways that this study could actually reduce harm and disability which occurs at far higher rates than severe statin myopathy.

  9. alec.elliott says:

    HELLO,
    How come you do not mention ABSOLUTE risk reduction ?
    Did you notice they are less than 1% ?
    You do notice death reduction is significant (18000 patients makes it easier) but is it relevant (0.5%)?

    The early stoppage has no justification even pre-planned, since the placebo group patients were not harmed by treatment and it is hardly justified to decide they should all be statin treated based on just one study. It is a short time to detect potential more relevant benefits (beyond 1% in absolute risk) or late side effets (mental status deterioration and cancer require a little more time to appear).

    One point makes me feel uncomfortable:
    The way the authors naively try and conceal the fact there is no difference in fatal strokes or myocardial infarction in table 3 : this is ridiculous , anyone can make the maths. This is lousy data presentation spinning. Why should they do that?

    Another point:
    More diabetes cases, but the authors try and minimise this, stating
    “minimal difference in the median glycated hemoglobin value (5.9% and 5.8%, respectively;P = 0.001).” So when that does not suit you , a significant result is tagged “minimal” ; And indeed it is minimal. They say mean glucose was not difference. But this and the glycated hemoglobin level are irrelevant to the matter of diabets. Diabetes is a qualitative diagnosis, you are or you aren’rt diabetic. The elevated glyc. haemoglobin or glucose levels from the diabetes diagnoses are very unlikely to impact on the average values for the group. I also call this a dishonnest presentation.

    Hence i see in this paper where a lot of money (incentives) are at stake, some indication of biased presentation.

    Now I acknowledge there are some significant results, but :

    1- When I calculate the absolute risks (that they don’t indicate, why ? ) I see nothing impressive , less than 1% reductions if i’m not mistaken (absolute risk is real life, relative risk is well known and shamefully accepted in great journals as a way to enhance a result’s appearance). Someone is trying to impress us. If they don’t give the absolute risk then they are not satisfied with it, this is the logical conclusion.

    2- When I read there aren’t more muscle complaints with the statin, I am amazed. Really ? Is this consistant with what is previously known?

    3 -When I compare this with the benefits of a healthy way of life (real Cretan diet or equivalent, not just olive oil, physical activity, not smoking) well I don’t exactly remember the figures but (I don’t have the figures to hand, so I hope I’m not wrong) if I remember well the order of magnitude of the benefits is much higher for no or little cost and extended benefits (bones, cancer , weight, glucose tolerance). This should have been mentionned in the discussion.

    4- My opinion on the early interim analysis is that it was unwarranted as stated above, and it feels lik a gambler who leaves the table early after a lucky hand. With more time, the results could have been more convincing with better improvements in absolute risk . With less time there is a lesser risk side effects such as cancer od cognitive decline may be detected.

    It is a pity and in my opinion, unethical, that this study was not carryed out longer.
    This and the aforementionned reasons make me feel someone is trying to manipulate me. This casts doubts on the study.

  10. pec says:

    The study only continued for 2 years, so you cannot conclude statins are safe over a lifetime. And it does not contradict the claims of the cholesterol skeptics at all — it shows that the main culprit in artery disease is inflammation, and that cholesterol may be irrelevant.

    It would make more sense to investigate the causes of chronic inflammation, and to find more natural ways of reducing it. Statins can have very serious side effects in some individuals, and they are usually taken for many years. The effects of statins over very long periods is not known.

  11. daedalus2u says:

    pec, they stopped the trial because the placebo leg was dying at a higher rate than the treatment leg. It is unethical to continue a trial when one of the legs has a statistically significant higher death rate. That is why the trial was stopped when p=0.02.

    If the trial were continued, more people in the placebo leg would have died. That isn’t what they signed up for. That isn’t what the clinicians signed up for, continuing an experimental trial when it is known that one leg will die at a higher rate than the other.

    Yes, statins can have side effects. Most people would rather avoid death than avoid the side effects of statins.

  12. Harriet Hall says:

    The study only continued for 2 years, so you cannot conclude statins are safe over a lifetime.

    I already pointed that out.

    And it does not contradict the claims of the cholesterol skeptics at all

    It contradicts the four claims of THINCS that I listed.

    — it shows that the main culprit in artery disease is inflammation, and that cholesterol may be irrelevant

    The main culprit may very well be inflammation, but it is not accurate to say that this study shows that. It merely shows that one drug that reduces both inflammation and cholesterol is effective in reducing risk.

    It would make more sense to investigate the causes of chronic inflammation,

    “More sense” than what? It is precisely studies like this that will help direct future investigation. Meanwhile, we can treat patients instead of doing nothing but investigating.

    and to find more natural ways of reducing it.

    I can understand using the knowledge for prevention, if that’s what you mean; but “natural” is not a meaningful concept for determining which treatments are safer or more effective.

    Statins can have very serious side effects in some individuals,

    This study does not bear that out: it showed no significant difference in side effects between the drug and the placebo.

    and they are usually taken for many years. The effects of statins over very long periods is not known.

    I already pointed that out.

  13. Fredeliot2 says:

    It would seem that determining the effectiveness of a low cost statin like simvastatin could make the cost benefit ratio more favorable, unless the large pills required would be a problem. The low reported rate of side effects in this study maybe will crimp the style of the lawyers trying the drum up business for Crestor lawsuits. There are claims that very low doses of Crestor have a significant effect and maybe fractional or alternate day dosages could make this approach more cost effective.

  14. marilynmann says:

    “We don’t know whether the benefits are due to lowered cholesterol or whether lowered cholesterol is a marker for other benefits of the drug.”

    I’m wondering if you meant “CRP” in this sentence instead of “cholesterol.” The reason I think that is that lowered CRP IS probable a marker for a variety of benefits that add up to lower inflammation. It is not likely that it is the lower CRP itself that directly causes the lower risk.

    Part of the evidence for that is that people with lifelong elevated CRP for genetic reasons don’t have a higher risk of heart disease. This is in contrast to people with lifelong elevated LDL for genetic reasons (i.e., familial hypercholesterolemia), who do have a higher risk. Most people think elevated LDL is actually one of the causes of atherosclerosis, rather than a marker of some other mechanism that causes atherosclerosis. I hope this made sense.

    http://www.theheart.org/article/914925.do

    Marilyn Mann

  15. pec says:

    pec: “Statins can have very serious side effects in some individuals”

    HH: “This study does not bear that out: it showed no significant difference in side effects between the drug and the placebo.”

    pec: “and they are usually taken for many years. The effects of statins over very long periods is not known.”

    HH: “I already pointed that out.”

    I said statins can have serious side effects, and you said no, not according to this study. But the study only ran for 2 years, as you pointed out. So you CANNOT conclude from this study that statins do not have side effects, if taken for long periods.

  16. Harriet Hall says:

    quetzal said,

    I expect this will bolster those who think that cholesterol reduction is a red herring, and that inflammation is the true risk factor.

    It may, but I don’t think they are justified in disregarding cholesterol just yet.

    1. There was evidence of benefit from pre-statin studies of lowering LDL cholesterol by other treatments that didn’t affect inflammation.

    2. In several studies the reduction in risk correlated to the amount of LDL cholesterol reduction, so cholesterol is at least useful as a marker for effective treatment.

    3. CRP is not recommended as a screening test for the general population; it is more of a tie-breaker and is not very specific for cardiovascular disease.

    Inflammation is a broad umbrella term. There are inflammatory conditions that don’t raise cardiovascular risk. Other anti-inflammatory drugs like NSAIDS don’t reduce risk. Just as we learned to distinguish between “good” and “bad”cholesterol, I think we will find that inflammation is complicated. Why does inflammation sometimes increase risk and other times not? Does high CRP cause heart attacks, or does cardiovascular disease cause high CRP? What exactly is the role of inflammation? Is there one inflammatory factor that’s more important than others? We have much to learn.

  17. Harriet Hall says:

    marilynmann,

    I did mean cholesterol. Studies show that the degree of cholesterol lowering correlates to the degree of risk reduction. That could mean that it is the lower cholesterol that reduced the risk, or it could mean that something else about the treatment reduced the risk and that the cholesterol reduction is just a marker.

  18. Harriet Hall says:

    pec said,

    I said statins can have serious side effects, and you said no, not according to this study. But the study only ran for 2 years, as you pointed out. So you CANNOT conclude from this study that statins do not have side effects, if taken for long periods.

    Please read more carefully and don’t put words in my mouth. I didn’t say statins can’t have serious side effects: I said this study didn’t show that they did. I not only didn’t conclude from this study that statins don’t have side effects, I pointed out that we don’t know what the long term effects might be. I also pointed out that the results from other statin drugs might be different.

  19. The Blind Watchmaker says:

    I will be interested to read this study in full when published. I am interested to know if they controlled for waist circumference.

    Abdominal obesity is associated with an increased number of macrophages meshed in with the adipose cells of the omentum. They can also be found in the liver of patients with “fatty liver”. It seems likely that these macrophages are the source of the inflammatory mediators that may contribute to the endothelial damage in the arteries. Some speculate that this is also related to the decrease in adiponectin produced by the abdominal fat cells. Low adiponectin causes insulin resistance, which leads to hyperglycemia and microvascular disease.

    Other damaging factors include hypertension and smoking.

    Damaged arterial linings (endothelium) then accumulate macrophages which release more inflammatory mediators. The arteries pick up cholesterol from circulating LDL particles.

    Statins certainly reduce LDL cholesterol and would therefore likely affect this latter step. If they reduce inflammation (as measured by a decrease in HS-CRP level) then they affect the chain of events lower down the chain too.

    So, likely statins decrease cardiovascular morbidity by decreasing inflammation AND LDL cholesterol. Perhaps we should be measuring the CRP levels in our patients with increased waist circumferences and considering statin therapy if it is elevated, even in the face of normal LDL levels.

    We’ll see.

  20. Dr*T says:

    Alec Elliott,

    Sceptical Rogue guestblogged on my site regarding Absolute Risk Reduction:

    Lies, Damned Lies & Statins

    Here is a small excerpt:

    In real, proper, everyday terms, this means that if I have normal cholesterol levels, but higher c-reactive protein levels, over 2 years:-

    - My risk of heart attack goes from a rather disappointingly low 0.76% to an indistinguishably lower 0.35%.

    - My risk of stroke goes from a most decidedly non-headline-grabbing 0.72% to a yippee-I’m-gonna-live-forever 0.37%.

  21. pec says:

    “Perhaps we should be measuring the CRP levels in our patients with increased waist circumferences and considering statin therapy if it is elevated’

    Maybe they should decrease their waist circumferences. And maybe lack of exercise contributes to both obesity and high CRP. And maybe insulin resistance, resulting from refined carbohydrates and lack of exercise, should be considered.

  22. qetzal says:

    Dr. Hall,

    Thanks for the additional comments on cholesterol and inflammation. I agree that the data doesn’t justify disregarding cholesterol.

    I was merely anticipating the reaction of those who claim that it is all about inflammation, and that cholesterol has nothing to do with cardiovascular disease. We had a discussion on a previous thread where another commenter (not pec, IIRC) claimed exactly that.

  23. Harriet Hall says:

    Blind Watchmaker said,

    I will be interested to read this study in full when published.

    It has been published in full online and there is a link to it in the second paragraph of my article. The exclusion criteria are listed; waist circumference was not one of them. However, waist circumference is part of the metabolic syndrome and benefits were similar in those with and without metabolic syndrome.

    I like your suggestion that both LDL and inflammation affect the same chain of events at different stages. That sounds very plausible.

  24. Harriet Hall says:

    pec said,

    Maybe they should decrease their waist circumferences. And maybe lack of exercise contributes to both obesity and high CRP.

    We went round and round with pec about this on another thread. No one is suggesting that prevention should be scrapped in favor of pills; in fact, I addressed that in the last paragraph of my article.

    Doctors all agree that it is better to prevent disease than to treat it once it has developed. Meanwhile, we have to deal with real patients in the real world. We have to treat the people who already have the disease while we’re working on preventing it from developing in others and while we’re working on preventing the disease from getting worse in those who already have it. It would be malpractice to hand out statins without addressing other modifiable risk factors like smoking, obesity, and sedentary life style.

  25. weing says:

    There is also a very high correlation between waist circumference and CRP. If I have a patient with increased waist circumference, I do not even bother to get a CRP.

  26. Harriet Hall says:

    Alec.Elliott:

    HELLO.
    I DID mention ABSOLUTE risk reduction, and so did the abstract of the study. For instance, “Reduction of first major cardiovascular event from 1.36 per 100 person-years to 0.77.” In case you are having trouble understanding the numbers, that shows an absolute risk reduction of 0.59 events per 100 person years. In other words, if 10,000 people took the drug for a year, 59 events would be prevented. That is highly statistically significant. Whether it is relevant to clinical decisions is a matter of opinion.

    The early stoppage was consistent with current research guidelines.

    The authors obviously did not “conceal” the numbers for fatal MIs and strokes, since you were able to easily find the data. The study was designed to show a reduction in major cardiac events, and fatal MIs and strokes were only one subset of that. There WAS a reduction in nonfatal MIs and strokes and there WAS a reduction in all-cause mortality.

    I think the presentation of the diabetes risk was fair. And diabetes is not a “qualitative” diagnosis.

    The lack of muscle complaints is interesting, and it contradicts other studies. Perhaps a low dose of this statin does not cause the same side effects as higher doses of other statins. Further study and long-term followup are certainly in order.

    It’s interesting that you mention cancer as a long-term concern, especially since there were fewer new diagnoses of cancer and significantly fewer cancer deaths in the rosuvastatin group in this study and since other evidence so far does not show an increase in cancer but suggests that statins may actually have a small anti-cancer effect.

    I can’t fault them for not mentioning the benefits of a healthy lifestyle: we are all well aware of that. This study did not attempt to compare the benefits of lifestyle changes with drugs and it certainly did not suggest that lifestyle changes should not be pursued before resorting to drugs.

  27. James Fox says:

    Good discussion Harriet
    If prevention is better than disease treatment what did this study say about assessment and screening criteria doctors use to determine who should be prescribed a statin??

    “If I did the math right, 400 people would have to take it for a year to prevent one death.”

    At what point does someone reasonably get moved into the 400 FBO (for benefit of) 1 group?
    It appears quite likely that as a result of this study more people will be prescribed statins and that NEJM is asking practitioners opinions begs the question of practice changes. But if the study does not provide some information as to who may be more likely to benefit, it seems a somewhat limited result if the overall benefit is only seen in a non real world broad herd prophylactic treatment. How is the assessment of the individual patient impacted?
    Just wondering.

  28. Harriet Hall says:

    The study did not address screening and clinical decision-making.
    The editorial did – did you read it? Current guidelines consider the patient’s overall risk, not just the LDL and/or CRP levels.

    It’s not a question of deciding when to move someone into the 400 FBO 1 group because the benefits of the drug are not limited to preventing death. A more appropriate consideration is

    25 people would have to take it over 5 years to prevent one new major cardiovascular event.

    From other studies it appears that patients with greater overall risk are more likely to benefit from statins, so it’s quite possible that the Number Needed to Treat (NNT) to prevent one major event over a 5 year period might be considerably smaller than 25.

    No one can say what NNT justifies recommending a drug, because that depends partly on the risk/benefit ratio and partly on other considerations like the patient’s philosophy. Some will fixate on the 24 people who take it for no benefit, others will fixate on the fact that they might be the 25th person who will benefit.

  29. pec says:

    “We went round and round with pec about this on another thread”

    Yes, we did, and it was not easy to convince anyone here that lifestyle changes should always be tried first.

  30. McDoctor says:

    As presented, this is not a very useful study. The authors don’t present event rates for low risk patients. They note a relative risk reduction of about 50% for those with a Framingham score less than 10%, but don’t give us the absolute numbers. this is the population wherein the benfits of treatment remain uncertain (or at least poorly quantified). prior to this study, there was already good evidence that high risk patients with normal LDL benefit from statins (see CARDS study for one).

    Also, are the authors suggesting that high risk individuals, (say a 58 year male with family history, hypertension and extensive smoking history), with normal CRP levels and LDL in the 100 to 130 range need not be treated?

    This study mostly lumps low risk people in with high risk people, and uses the benefit seen in high risk individuals to justify broadening our criteria for whom we treat with statins.

  31. marilynmann says:

    Harriet Hall wrote:
    “Studies show that the degree of cholesterol lowering correlates to the
    degree of risk reduction.”

    If you are comparing statin trials, this is generally true, although the JUPITER trial showed a bigger risk reduction than would have been expected based on the amount of LDL-lowering (the editorial in the NEJM points out that stopping the trial early may have exaggerated the treatment effect somewhat). However, if you are talking about non-statin drugs as well, the statement is true only if you ignore the time to benefit. While there are non-statin
    medications that lower LDL and reduce risk, the risk reduction takes
    much longer than it does with a statin. For example, the POSCH (ileal
    loop bypass) and LRC-CPPT (cholestyramine) trials took 9.4 and 7.4 years
    to become positive, whereas statin trials are usually positive within
    2-5 years. The POSCH and LRC-CPPT trials support the view that
    LDL-lowering contributes to CV benefits. However, the real question is
    whether all LDL-lowering modalities confer the same benefits. For
    example, there is a substantial question as to whether LDL-lowering with
    ezetimibe confers CV benefits.

    “That could mean that it is the lower cholesterol that reduced the risk,
    or it could mean that something else about the treatment reduced the
    risk and that the cholesterol reduction is just a marker.”

    I agree that in theory LDL could be just a marker. However, this seems
    unlikely. Children with homozygous familial hypercholesterolemia, who
    have LDL many times normal from birth, suffer heart attacks in
    childhood, and generally do not live beyond their 20s without treatment
    (usually LDL apheresis is necessary). These children usually have no
    other risk factors other than elevated LDL (and, in some cases, family
    history). In addition, persons with heterozygous FH have risk many
    times normal without treatment. In addition, cholesterol is a component
    of atherosclerotic plaque, and atherosclerosis can be easily produced in
    animal models. I guess it depends on what level of evidence is good
    enough for you, but to me it seems unlikely that LDL does not have a
    causal role in atherosclerosis.

    Some people (at least some members of THINCS, for instance) assert that
    the benefits of statins are unrelated to LDL-lowering. Again, that
    seems unlikely, since several other interventions that lower LDL reduce
    risk, including simply removing LDL from the blood through LDL
    apheresis. Rather, it seems most likely that statins lower risk through
    a combination of LDL-lowering and pleiotropic effects.

    See, for example, these papers by James K. Liao:

    http://arjournals.annualreviews.org/doi/abs/10.1146/annurev.pharmtox.45.120403.095748?cookieSet=1&journalCode=pharmtox

    http://www.ingentaconnect.com/content/ben/iemamc/2008/00000008/00000002/art00003

    Marilyn Mann

  32. James Fox says:

    OK I read the editorial and the most meaningful statement that was made regarding changes in practice appeared to be a great big non statement as conclusion. And even more remarkable (to my layman’s mind) the distinctive characteristic of the study participants was that they did not meet any current criteria for statin intervention. Seems more studies aimed at identifying relevant risk factors for screening criteria is warranted before practice is changed to any significant degree.

    http://content.nejm.org/cgi/content/full/NEJMe0808320v1

    “JUPITER provides yet more evidence about the effectiveness of statin therapy in reducing cardiovascular risk, even among persons who would not currently be considered for pharmacotherapy.3 Guidelines for primary prevention will surely be reassessed on the basis of the JUPITER results, but the appropriate size of the orbit of statin therapy depends on the balance between the benefits of treatment and its long-term safety and cost. “

  33. The Blind Watchmaker says:

    @ Pec

    “We went round and round with pec about this on another thread”

    “Yes, we did, and it was not easy to convince anyone here that lifestyle changes should always be tried first.”

    Who exactly are you arguing with?? Lifestyle changes are ALWAYS first and foremost enforced. The discussion here is about the statin study. I mean, do you really think that doctors do not enforce healthy lifestyles? I talk myself blue in the face all day to patients about good diet and exercise. For the few that actually take this advice seriously, medications are often not needed. But visit after visit, people keep coming with their excuses and increasing girth. At some point, a good doctor has to treat the disease too.

    Oh, and sorry, Harriet. I missed the link to the online article the first time through.

  34. Harriet Hall says:

    pec said,

    it was not easy to convince anyone here that lifestyle changes should always be tried first.

    Nonsense. No one ever even so much as suggested that lifestyle changes should not always be tried first. You misinterpreted what others said and argued with a phantom.

  35. Harriet Hall says:

    McDoctor,

    I don’t understand your objections. The study showed risk reductions for all sub-groups: those with high and low Framingham scores, those with and without metabolic syndrome, etc. The study shows that patients with lower risk also benefit from statins.

    Of course the authors are not suggesting that high risk individuals should not be treated. I can’t imagine what gave you that idea.

  36. Harriet Hall says:

    Marilynmann,

    I agree with you that the effects of statins are probably due to a combination of both LDL lowering and anti-inflammatory effects. My point was that we don’t yet fully understand the details, and that even if the cholesterol skeptics were right about LDL lowering not being the significant factor, it would still be useful to measure the degree of LDL lowering as a marker for the other effects of statins.

  37. Harriet Hall says:

    James Fox said,

    I read the editorial and the most meaningful statement that was made regarding changes in practice appeared to be a great big non statement as conclusion.

    I thought the section I quoted from the editorial was quite clear: we still don’t have enough information to justify routine measurement of CRP but it can be used as a tie-breaker to make treatment decisions in intermediate-risk patients.

    And even more remarkable (to my layman’s mind) the distinctive characteristic of the study participants was that they did not meet any current criteria for statin intervention.

    That was the whole point of the study – to look at patients who did not meet current criteria for statins.

    Seems more studies aimed at identifying relevant risk factors for screening criteria is warranted before practice is changed to any significant degree.

    We already knew that CRP was a risk factor. And there are several concerns about changing practice, many of which I mentioned. The editorial and I agree that it would be premature to make any really significant changes in current recommendations based on this study alone.

  38. McDoctor says:

    The study doesn’t provide absolute numbers for those low risk patients. How can one gauge the NNT? A useful study would number of events in these individuals, and allow me to articulate to these types of patients the absolute benefits of taking a statin. I can’t do this from this study, since the absolute numbers are not presented from the subgroup analysis.

    I already tend to treat many individuals with a risk score above 10% to an LDL of 100. Not always, but generally, I would take a statin if I fell in that category. There was already reasonable evidence to support doing this.

    the question is whether those with a risk far less than 10% but elevated CRP would benefit. I generally don’t treat these individuals with statins. I’m interested in the absolute numbers in these individuals and whether or not this subgroup in the placebo group had events at the same rate as those with a Framingham score greater than 10%. perhaps you can answer that question. Did the low framingham score group have the same number of events as the high framingham score group?

    I suspect the low score subgroup had far fewer events than the higher score subgroup, and that saying both benefited equally is quite misleading. You may not have said this, but this is the way the study is being marketed and this is the way I saw it presented in the press.

    People with a risk score of 5% should have had events in 1% within the placebo arm and therefore about 0.5% in the treatment arm. this gives us a NNT of 200 over 2 years. I’m guessing because I couldn’t parse out this data from what is presented in the study. (I should clarify, I am not in academia and may just be looking in the wrong places.) People with a risk score of 15% would have had events 3% in placebo and 1.5 percent with treatment. This gives a NNT of 75. One subgroup clearly benefits more than the other in this scenario, both have relative risk reductions of 50%.

    In regards to my other comment, in this study, a 65 year old smoking male with hypertension, imapired glucose tolerance, and a family history of heart disease, HDL of 30 and LDL of 125, was potentially given a placebo. This type of patient clearly benefits from a statin, and there’s no reason to include this type of patient in the study. That question has already been answered. Wouldn’t you suggest a statin in addition to lifestyle modification in this type of patient regardless of his CRP even before JUPITER? this type of patient being in the study led to the early benefit observed, I’m sure.

    this study would be more useful if it just focused on low risk individuals. That’s where the data is lacking. I still have questions about the long term effectiveness of a statin in a 60 year old female with no other risk factors and a CRP of 2.0 or more. I only have less than 2 years of data, out of a planned 4, and I still don’t know the NNT for this type of patient.

  39. McDoctor says:

    I should say I generally don’t treat low risk patients with a statin with a Framingham Score well below 10% without a family history and an elevated CRP. This is the most common type of patient I see. I still don’t have an answer for this type of patient when they ask about the merits of a statin.

  40. Harriet Hall says:

    McDoctor,

    I think you are asking too much of this study. It was not designed or powered to draw NNT information from sub-group analyses.
    By the way, the subjects were not hypertensive nor did they have glucose intolerance.

    No, the study doesn’t give us much guidance for what to do for individual patients, but that was not its intent. It was designed to see whether statins were of benefit in patients with low cholesterol and high CRP – in general. We still have to make those tough clinical decisions on the basis of imperfect knowledge.

  41. oderb says:

    There are a couple of numbers that concern me.

    Why were only 75% still taking medication at the end of 2 years? That seems like a very high dropout rate for a very carefully screened population and makes me wonder about the validity of the adverse effect profile.

    It appears -as earlier posters have mentioned – that there were more fatal MI’s from Crestor (9 vs 6) than from placebo (though there were fewer fatal strokes on Crestor). So 29% of the MI’s that occurred on Crestor were fatal vs about 9% of MI’s that occurred on placebo. Is that statistical noise or significant?

    The number of cases of diabetes appears to be greater than the number of non fatal cardiovascular events.

    There were 90 non CVD deaths from placebo vs 115 from Crestor. That seems like a non trivial difference. Why were the causes of these deaths not discussed?

    There were 51 more patients with a family history of premature CVD and 71 more with metabolic syndrome in the placebo group, both being very significant risk factors for CVD. How much a difference would there be if those subgroup had been equalized?

    I’m not a statistician but I’d sure want answers to those questions before I accepted the conclusions of the study.

  42. McDoctor says:

    The exclusion criteria state “uncontrolled hypertension”, defined as greater than 190 SBP or 100 DBP. Diabetes Mellitus was an exclusion criteria, I didn’t see impaired fasting glucose as one.

    Patients with treated hypertension were eligible.

    You conceded my point, the study doesn’t give us much guidance on what to do in clinical practice for individual patients, and hence is not very useful to me as a clinician.

    Thanks for the great blog. Your posts do improve my ability to practice. I’m not just trying to anatagonize you.

  43. Harriet Hall says:

    McDoctor,

    Table 1 listed the median glucose as 94 and the interquartile range of blood glucose of 87-102. Unfortunately they don’t provide the entire range, so we can’t tell how many abnormals might have been included.

  44. Harriet Hall says:

    oderb,

    You ask some good questions, but I’m guessing they’re not enough to invalidate the study. For one thing, the absolute differences in family history and metabolic syndrome translate to percentages of 11.2 vs 11.8 and 41.0 vs 41.8. The percentage of females were 38.7 vs 37.9. I’m guessing these are acceptable differences. You will never get a control group that is exactly like the treatment group in every particular. I’m not a statistician either, and if one of our readers is, perhaps he can address these issues.

    The kind of questions you and others have asked are exactly why I don’t think this study should be used to justify significantly changing practice guidelines. I think the editorial got it just right. We should keep doing essentially what we’ve been doing, and use CRP levels as a tie-breaker in less clear-cut cases. This study at least makes us a bit more confident that statins are safe and effective and need not be restricted to only the highest risk patients.

  45. EddieVos says:

    Oderb, “deaths from cardiovascular causes” is part of the primary endpoint but they don’t give a number, however, subtracting the any MI + any stroke from the total in Table 3, we have 19 deaths from cardiovascular causes on rosuva and 25 on placebo, my P value = 0.37.

    Harriett, the list you gave confirms what I said: no difference in fatal MI and strokes [12 in each group]. Let’s agree, based on PROSPER, that statin is not a life saving chemotherapy in cancer and therefore remove the 23 fewer cancer deaths from the 49 difference in total deaths, gives us a P value of 0.17 for any other kind of death. Why was 47% of the mortality benefit in cancer? Well, like PROSPER, for example, they did not adjust for smokers, and a small difference here could explain much if not all.

    At 25% of participants on statin having LDL <44 mg/dL, this level in my opinion is not compatible with long healthy life, as indicated in massive studies [Vorarlberg population study; by memory, 1million years of follow-up] and in J-LIT [1/4 million years statin use fullow-up study]. Stopping at 1.9 years prevented any long term effect to manifest itself.

    It appears probable that the data entry was done by a pharma contracting firm and any one there seeing such minuscule LDL levels was thereby instantly unblinded to the study group. It would have been better had ALL data management been done by a university group.

    So: 19 deaths from CV causes + 35 from cancer = 54 [27%] which leaves 144 deaths [73%] from other causes on rosuva. What in the world did that group die of when excluding causes 1, 2 and 2 of deaths world wide, i.e. heart, stroke and cancer?

  46. HCN says:

    The Blind Watchmaker replying to pec said:
    ““Yes, we did, and it was not easy to convince anyone here that lifestyle changes should always be tried first.”

    Who exactly are you arguing with?? Lifestyle changes are ALWAYS first and foremost enforced. The discussion here is about the statin study. I mean, do you really think that doctors do not enforce healthy lifestyles? I talk myself blue in the face all day to patients about good diet and exercise.”

    After I was first diagnosed with high cholesterol I was given a set of dietary guidelines, which I followed very closely. I no longer eat eggs, bacon (wah!), butter and cheese, which is difficult since I am married a Dutch fellow whose cholesterol levels are naturally low (his grandparent’s family recipes always seemed to start with “first melt half a kilo of butter in a pan”).

    I also increased my exercise routine, and now swim 2000 yards two to three times a week, and walk when I can (audio books on an mp3 player are great, along with weekly podcasts like “The Skeptics Guide to the Universe”, SETI’s “Are We Alone” and NPR’s “Wait, Wait, Don’t Tell Me!:).

    The first year my levels dropped, and it was a big YAY!… then they rose again as my liver made up for the loss by making more. I spent a total of three years trying to get it down with diet and exercise.

    Mdoctor said “I should say I generally don’t treat low risk patients with a statin with a Framingham Score well below 10% without a family history and an elevated CRP. ”

    Unfortunately, due to the closed adoption records of the early part of the last century and losing my possibly adopted only-child mother to a vehicular accident when she was 42… I do not have a good family history background. I just found out my dad’s mother was also adopted! Plus his overweight brother died in his mid-40s while watching TV with a lit cigarette in his hand.

    That is what put it over the edge, and even though my numbers were about 240 with high HDL (74), I am now on a low dose of statins (generic symvastatin… I can’t speel it!). My numbers are now just under 200, and the HDL dropped to 68 or so.

    I am still avoiding eggs, butter, cheese and bacon (wah!)… and keeping up the exercise routine (it is not helping me get svelte, but my back no longer goes out).

  47. Harriet Hall says:

    EddieVos said,

    Let’s agree, based on PROSPER, that statin is not a life saving chemotherapy in cancer and therefore remove the 23 fewer cancer deaths from the 49 difference in total deaths

    How ridiculous! Just cut anything out of the data that you don’t agree with! That’s not how science works.

    It appears probable that the data entry was done by a pharma contracting firm and any one there seeing such minuscule LDL levels was thereby instantly unblinded to the study group. It would have been better had ALL data management been done by a university group.

    This ridiculous accusation shows that you failed to read the next-to-the-last paragraph of my article.

  48. EddieVos says:

    Dear Harriett, are you proposing that the finding that rosuvastatin lowers deaths from cancer in 1.9 years is a hard study finding that merits considering statin a life extending chemotherapy in primary prevention for heart disease? All this regardless the fact that statins did not lower cardiovascular deaths in this study? Did you ever read the PROSPER study mortality and cancer data?

    Why do you ridicule my personality? I had thought you were an MD concerned about the mathematical certainty that statins have never lowered deaths in women from the disease that kills more of them than anything else. You care about having less ‘events’, no matter how non life threatening and, since statins don’t lower deaths in women but lower non fatal ‘events’, SOMEBODY should be concerned as to why that is.

    People that take the effort to respond to your blog don’t deserve to be called “ridiculous” by the moderator. Have a happy blog without me, clearly you don’t consider opposing views that may indicate your prescribing habits and/or opinions may have been less than science based.

    Finally, YES I was very aware of your second to last paragraph but that does not negate possible iffy data entry by the pharma contractor: we’ve seen misclassification before and no study involved author could have picked that up. I simply said it would have been BETTER if all data forms would have wound up in a university; they did not.

  49. Harriet Hall says:

    EddieVos,

    I did not ridicule your personality; I ridiculed what you said.
    If you said the Moon was larger than the Earth, I would be quite justified in pointing out that your statement was ridiculous. Now you ask,

    are you proposing that the finding that rosuvastatin lowers deaths from cancer in 1.9 years is a hard study finding that merits considering statin a life extending chemotherapy in primary prevention for heart disease?

    The reduction in cancer deaths was not a “hard” finding in the sense that the study was not designed or powered to determine whether cancer deaths were affected by rosuvastatin. OF COURSE I’m not proposing that a reduction in cancer deaths in this study justifies using statin to prevent death from heart disease!! That wouldn’t be logical. The study showed that rosuvastatin was effective in reducing cardiovascular events and all-cause mortality. Even if it didn’t reduce mortality, reducing morbidity is a worthwhile outcome. Its role in primary prevention was already well established before this study: the study suggested that it may be even more effective and safer than we thought.

    You are nitpicking to try to discredit a study that contradicts your beliefs. You CAN’T throw out part of the data and recalcuate based on your prejudices. And unless you have any evidence of misconduct, your insinuations about data manipulation are nothing but inappropriate conspiracy-mongering.

    It’s ironic that you cite the PROSPER study, because that study showed a reduction in coronary mortality of 24%! And its abstract says incorporation of its cancer data in a meta-analysis of all pravastatin and all statin trials revealed no overall increase of cancer risk. A recent systematic review concluded that the evidence on potentially protective or harmful effects is inconclusive.

    http://www.ncbi.nlm.nih.gov/pubmed/18707867?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

    Just curious – perhaps you would care to share with us your rationale for accepting the PROSPER cancer data but ignoring the fact that it showed reduced coronary mortality?

  50. EddieVos says:

    Hello Harriett, there was no mortality benefit in PROSPER since effectively the fewer deaths from heart disease were offset by the nearly significant increase in cancer deaths. Delta deaths for the whole study, group size adjusted is 6. One Lancet respondent: “it changed the way people died, from heart to cancer.”
    Moreover, there were 51 fewer [life-long] smokers in the statin group, yet more cancer deaths; had they adjusted for that “natural” variation that can happen by chance [no mischief here], the P for more cancer deaths probably would have been below P=0.05. The P for more “new” cancer was 0.02 and, for me, most interestingly, there was more new cancer in each of the 4 years of observation.

    You’re right, cancer was not exhaustively looked at in JUPITER, or smoking and other effect, but fewer cancer deaths, however extraneously explained, sent the total deaths to be significant. Your Abstract shows no evident link, = or -

    In PROSPER, they post-hoc meta analyzed the significantly greater cancer incidence away with studies in younger populations, and where evidently cancer is rare. That was scientifically scandalous, and, as you said, it appeared in the Abstract. Cancer is the #1 cause of death in the U.S. and Canada, but in the older, the population PROSPER is the only study specifically targeting. Let’s agree, JUPITER saved nobody from CV death.

    Now, how does one reduce the 48% of revascularization ‘events’ by ninety [90] % in an entirely safe manner, in fact it showed a mortality benefit at 6 months out: in an ‘Acute Cardiac Event’, take an ambulance FIRST to a non cath lab equipped hospital: http://www.bmj.com/cgi/content/full/330/7489/441 Clearly, angioplasties are a soft endpoints in the big scheme of things, doctor decided, and not necessarily [in an ACE] a survival benefit or medical necessity.

  51. EddieVos says:

    Harriett, incidentally, I’ve met 4 of the authors of JUPITER so I’m not questioning their motives. I said that they did not control the data from start to finish. I do question however the quality of the protocol designed by the 1st author.

  52. pec says:

    ” I talk myself blue in the face all day to patients about good diet and exercise.”

    Maybe you do, but patients get other messages from TV drug ads, news shows, and other doctors. They get the message that statins are safe and effective. Not that statins appear to be safe and slightly effective over short periods.

    Lifestyle changes have to be drastic. I know heart disease patients who were advised to exercise 20 minutes 3 times a week.

    People who have not exercised in 20+ years usually find it painful or boring. They are reassured that, as the ad says, you can always take a pill if diet and exercise fail. As long as MDs and marketers think statins are ok for life-long use, most patients won’t bother with lifestyle changes.

  53. Harriet Hall says:

    This 2008 systematic review concluded that the evidence that statins have either cancer protective or cancer-causing effects is inconclusive.

    http://www.ncbi.nlm.nih.gov/pubmed/18707867?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

    If you add the JUPITER study in, that would tend to tip the balance towards cancer protection.

    There was no overall mortality benefit in the PROSPER study, but there was a significant benefit for coronary mortality, and there was a significant benefit for non-fatal MIs. The PROSPER study was in older individuals (70-82) and included subjects who already had cardiovascular disease. Other studies (not limited to this older age group) have shown reduction in all-cause mortality for secondary prevention. Most studies have not shown a reduction in all-cause mortality for primary prevention, but the benefits for reducing morbidity are clear.

  54. Harriet Hall says:

    pec,

    We all recognize that it is easier to take a pill than to change your lifestyle. Patients know about statins. I’m sure way too many people are taking statins instead of doing everything possible to reduce modifiable risk factors without drugs.

    What is your point? Are you implying that we should deny patients effective treatment with statins if they are unwilling or unable to make drastic enough changes in their lifestyle? Don’t patients have the right to make that choice as long as they know the facts?

  55. pec says:

    I said: “As long as MDs and marketers think statins are ok for life-long use, most patients won’t bother with lifestyle changes.”

    You said: “Don’t patients have the right to make that choice as long as they know the facts?”

    My point is that patients are not really getting all the facts, since most doctors don’t know all the facts.

  56. EddieVos says:

    Dear Harriet, great, now we’re talking MORTALITY. There are ONLY 3 studies ever showing mortality benefit but in men only, LIPID, HPS, 4S and in the latter 2, that benefit started 1.5 years out and disappeared <3 years later. LIPID was contradicted by US’s largest study using the same statin, ALLHAT, that found ZIP benefit in ANY health department.
    Women never benefit in mortality [and second MI's] as per stuff in JAMA/JACC; links here: http://www.cmaj.ca/cgi/content/full/173/10/1207-a
    Incidentally, this is how I see Lipitor:
    http://www.health-heart.org/LipitorDoesNotSaveLives.gif and
    this is yours truly with links to my material in journals
    http://www.health-heart.org/author.htm
    Please note that NON fatal endpoints are often in the eyes of the beholder [protocol writer] and much result from where in the world one is and what kind of disease care provider one winds up at. If it is an interventional cardiologist, it’ll be a stent, if not, you may live longer, such is the science. Stable angina is a pain one can live to old age with [like knee pain or migraine].
    Unless you deal with CAUSE [and cholesterol*) has no evident link to a declining artery structure unlike homocysteine, i.e. lack of relevant B-vitamins, and glycation damage in diabetes], we are treating symptoms.
    *) Cholesterol crystal ‘clefts’ first appear in stage IV of the Stary classification of arterial decline; ditto for calcium; nothing in stages I to III. No cholesterol again in type VII. With the same logic, why not treat calcium?

  57. weing says:

    And the facts are?
    Life style changes do not have to be drastic. They can be gradual. Statins are given in addition to lifestyle changes and not instead of. I was conflicted about giving statins to smokers until I read a study that even in smokers there was a benefit derived from statins. Of course, not as great if they would stop smoking.

  58. qetzal says:

    EddieVos wrote:

    Please note that NON fatal endpoints are often in the eyes of the beholder [protocol writer] and much result from where in the world one is and what kind of disease care provider one winds up at. If it is an interventional cardiologist, it’ll be a stent, if not, you may live longer, such is the science. Stable angina is a pain one can live to old age with [like knee pain or migraine].

    Is this meant to show some failing of the the JUPITER study, and why are you so fixed on mortality to the exclusion of other endpoints? Are you suggesting that heart attack and stroke aren’t clinically important endpoints? Or that they’re too subjective and subject to biased classification by the (supposedly blinded) researchers?

    Suppose we knew with “certainty” that rosuvastatin substantially reduced non-fatal MIs and strokes, but had zero effect on either CVD or all-cause mortality. Assuming an acceptable cost and risk profile (whatever that might be), wouldn’t that alone be an enormous benefit?

  59. EddieVos says:

    Dear qetzal, I am indeed saying that. It is easy to drop your chance of an MI or second MI by using plant and fish based omega-3′s [for example] but there is little evidence that taking statin will do so long-term: http://www.bmj.com/cgi/content-nw/full/337/nov11_1/a2423/FIG4 Here, ALL benefit in heart attacks in this SUPER high cholesterol group happened in the fist 2.5 years: then nothing more.
    I agree that stroke is nasty and SPARCL showed that Lipitor reduced clotting strokes but significantly increased bleeding strokes [the worst kind]. HPS [post hoc] also found that increase in bleeding strokes.
    I am indeed fixated on deaths when medicating in arguably the world’s top killing disease. PROSPER in 75.4 year olds +/- ~5 years resulted in the same 10% tomb stones at study end. Same dates of death but one reading died in his sleep from a heart attack and the other died after a 2 month heroic battle with cancer. I’m not kidding: read the full data in The Lancet about pravastatin / Pravachol in this case.
    My take about why there is cardiovascular decline is here:
    http://www.health-heart.org/why.htm or with an extra page:
    http://www.health-heart.org/why.pdf

  60. Harriet Hall says:

    EddieVos has made his prejudice quite clear and I will not be responding to him again.

    He is not just critiquing the JUPITER study. He disagrees with the current recommendations for using statins, recommendations that the scientific community agree are based on good evidence. His arguments are those of the activist group he belongs to, THINCS. I have addressed those arguments elsewhere. I have been involved in lengthy citation battles with other members of the organization: the evidence they cite doesn’t hold up against an unbiased review of the entirety of the published evidence. They believe the studies that they think support their point of view and they tend to disregard, discredit, and misrepresent studies that say otherwise.

    JUPITER was not a perfect study (no study is) but it was a good one and its findings are significant. It is clear that statins reduce morbidity in most populations at risk, and they reduce all-cause mortality in some populations. The devil is in the details. No study can tell us what to do for an individual patient. Studies like JUPITER can’t tell us what we should do, but they can help inform those difficult clinical decisions. If you are like Eddie Vos and have already decided that statins should never be prescribed, neither JUPITER nor any other study is likely to change your mind.

  61. pec says:

    It seems that Eddie Vos cited a lot of evidence for his opinion, and it does not seem to me that you have said anything specific to address his concerns about statins.

    “It is clear that statins reduce morbidity in most populations at risk, and they reduce all-cause mortality in some populations. ”

    Only all-cause mortality matters. Why use a drug if it decreases the chance of one cause of death but increases the chance of another?

    Saying “some populations” is awfully vague. Does the evidence suggest a great decrease in mortality for most people over many years?

    Or not.

  62. qetzal says:

    EddieVos wrote:

    Dear qetzal, I am indeed saying that.

    That’s not a useful response, given that I asked about multiple possibilities.

    Let me make it easier:

    Q1: Are heart attack and/or stroke clinically important endpoints? Yes or no?

    Q2: Are heart attack and/or stroke too subjective to be useful endpoints in clinical trials? Yes or no?

    Q3: If a hypothetical drug reduced non-fatal MIs and strokes but had no effect on mortality, would that be clinically valuable (assuming acceptable cost and risk)? Yes or no?

    If you want to engage in discussion, I would very much appreciate clear answers to each of these specific questions.

  63. Harriet Hall says:

    pec,

    You read that Eddie Vos cited a lot of evidence, but did you read what I said about there being a lot of other evidence that he has ignored – evidence that the scientific community looked at along with Eddie’s evidence before they formulated the current recommendations. I said plenty to address his concerns, both in this thread and in the one on THINCS. His concerns are not unbiased scientific concerns, but biased ideologic concerns, and nothing I could say at this point and no amount of solid evidence is going to make a dent in his opinion. It’s all been covered before, and this is not the place to repeat history.

    Only all-cause mortality matters.

    Can you really seriously mean this? Don’t you think morbidity matters? Isn’t it better that someone doesn’t live the last few years of his life incapacitated from heart disease or a stroke?

  64. EddieVos says:

    Dear qetzal, a major heart attack iS important, but minor occlusions leading to 100 of ‘necrozettes’ upon autopsy are not, The hick is to avoid the larger and more likely to be fatal heart attacks. There is a HUGE spectrum of ischemic stroke and MI.
    Strokes: an ischemic TIA is not important, a larger ischemic event IS; the trouble, statins increase the bleeding ones
    Q2: when not more defined than you do: NO, they are iffy endpoints; deaths are never iffy and that is where 100% of the studies in women for cholesterol-lowering are conclusive not to be beneficial.
    Q3: Evidently YES, the problem is that when using statin, CoQ10 production [needed for cell energy] and the whole isoprenoid tree is affected, i.e. side effects. No side effects apart from “gas” were resins, NOT absorbed and excreted. The result in 2×1990 mean 49 year old average cholesterol 280 ml/dL: after 7.5 years, the difference in deaths was 3.
    To Dr. Hall, so I am prejudice and you are right, while you base your opinion on the authorities of ATP III. Well, these men have 10 financial conflicts on average and when one author was flown over by Pharma to give a cardiology grandrounds [great shushi], it turned out he was not even aware of the existence, less the result, of the J-LIT study, the study on pravastatin, marketed by the Pharma that paid for his trip, and that showed that the “the lower is better” message caused greatest deaths in this majority women study, most from cancer. Somebody has to care about women dying or not being saved by ANY kind of cholesterol lowering. Some women do not. Pity.

  65. pec says:

    “Only all-cause mortality matters.”

    “Can you really seriously mean this? Don’t you think morbidity matters? Isn’t it better that someone doesn’t live the last few years of his life incapacitated from heart disease or a stroke?”

    I meant to say all-cause mortality and all forms of morbidity. If statins decrease heart attacks but cause other diseases, then the benefits of statins are not so clear.

    The statement “reduce all-cause mortality in some populations” implies that in most populations the death rate is not decreased by statin use. That implies that all-cause morbidity is also only decreased in some populations. If mortality is not decreased, morbidity is probably not decreased either.

    So it matters a lot what you mean by “some populations.” Only a small minority of all patients?

  66. pec says:

    And over 26 million Americans are taking these drugs! Do you really think that makes sense? Especially since the long-term effects are not known?

    The apparent benefits of statins may result mostly from their anti-inflammatory effect. It would be much more reasonable to use anti-inflammatory substances that are more natural and less harmful. And it makes even more sense to consider the causes of chronic inflammation, and to focus on lifestyle improvements.

    Furthermore, MDs often neglect to inform patients that their symptoms may be side effects of statins. For example, I know someone who suddenly experienced horrible muscle pains after taking statins for years, and his MD never suggested it might be a side effect. The pains disappeared after discontinuing the drug. Another patient I know could barely walk even with a walker, and everyone assumed it was her advanced age. After stopping statins she could walk almost normally, without a walker.

    These are only two anecdotal examples, but there are many thousands of similar stories on web sites.

  67. Harriet Hall says:

    pec said

    If mortality is not decreased, morbidity is probably not decreased either.

    Pec, I know you are not stupid or ignorant, and I can’t understand why you keep saying things like this. Morbidity IS decreased. The evidence is overwhelming.

    When I referred to different populations, I meant things like primary prevention vs secondary prevention and high-risk vs intermediate risk. The information for different populations was considered in formulating the treatment guidelines.

    The reason we aren’t using other anti-inflammatory substances is that we don’t have any evidence that they reduce cardiovascular morbidity or mortality. For some of them, we have evidence that they don’t.

    If your anecdotes are accurate, all they show is that those patients’ doctors made mistakes. Good clinicians do not disregard reports of muscle symptoms in patients taking statins. Anecdotes like these are all over the Internet, but controlled studies clearly show that the rate of side effects is far lower than the alarmists would have us believe.

  68. weing says:

    EddieVos,
    So a heart attack that kills you is bad, but one that leaves you with 20% of your heart function is acceptable? Hey, if you think getting short of breath on walking to the bathroom is fine, fine. Me, I’ll take the statin. Going on 14 years now and no recurrent MI. Regarding strokes, I recommend good blood pressure control and a handful of walnuts a day and blithely continue the statin.

  69. EddieVos says:

    Hello pec what I mean with ‘some populations’ and any-cause mortality benefit is essentially men under age 60ish when considering all studies ever done. When mashing everything together in a mega meta-analysis, the benefit of few is extended to all. I once authored this letter to the editor: “Statins in women, elderly: malpractice? This was published in a cardiovascular journal, copy here: http://www.health-heart.org/malpractice.pdf

    When I can get this into such Journal, clearly the evidence for benefit for all is debatable. That JUPITER study had at least one participant with a very serious side effect at age 90. If I’d be on the jury, I’d consider convicting for malpractice: this is entirely outside Evidence Based Medicine.

    About the quality of life issue, the Brits have given us a hard to understand measure called QALY [quality adjusted life year] but that measure has not been systematically applied, I believe to the statin issue, less in subgroups [for example women, elderly]. What has been done in that field is calculate cost effectiveness but the measure always stumbles on the definition of ‘event’ and how to “qualityfy” such event.
    Your anecdotes are real: my guess is that 50% of those on Lipitor experience muscle unease after about 6 weeks of use and if that does not show up in the side effects, the question simply was not asked properly. Ask the next 10 guys on Lipitor.

    My personal guess, having looked at the CHD issue for over 3 decades: mortality would not change if statins would disappear tomorrow, and there are MUCH more effective strategies to prevent a heart attack or a stroke. I’d start with omega-3s, multivitamins on the long run and assuring you get the RDA/DV for magnesium, strategies that have been shown but were over run by the cholesterol hypothesis, declared dead in 1977 NEJM but on profitable life support by the statin/low-cholesterol food lobbies.

    Let me quote from once the top man at Mass. General Hosp, and Harvard’s medical department, Alex Leaf, in Circ. about omega-3′s, : “…relatively simple dietary changes achieved greater reductions in risk of all-cause and coronary heart disease mortality [deaths that is] .. than any of the cholesterol-lowering studies to date. This is emphasized by the finding that the unprecedented reduction … was not associated with differences in total cholesterol.” Source:
    http://circ.ahajournals.org/cgi/content/full/99/6/733
    Worrying about cholesterol distracts from that science-based medical approach, the purpose of this website.

  70. EddieVos says:

    Dear weinig, evidently a heart attack can be debilitating, but how many men in their mid lives will have to take statin to prevent such debilitation?
    This is between you and your doctor, taking statin that is; I’d worry about cancer. Personally I OTC niacin myself since I think high HDL is a good thing, for many reasons, and niacin does NOT have that potential risk.
    Walnuts!! Great, the only nut with 10% omega-3 in its oil. You must have been reading A. Leaf, the LYON study and for fish oil, the GISSI study.
    How do you know it was the statin and not the omega-3 that kept the ticker going? The omega-3′s are arrhrythmia preventive, an action is well established [not if you have an implanted defibrillator]. Best wishes.

  71. pec says:

    I would also like to know if weing gets at least an hour of aerobic exercise every day.

  72. weing says:

    I exercise 7 days a week. Half hour aerobics. Twenty minutes of weights and 5 minutes of stretches.

  73. oderb says:

    Well I hope that the supporters of SBM will be just as enthusiastic to support a study of Vit C comparable to Jupiter now that a study just published

    http://www.sciencedaily.com/releases/2008/11/081113091630.htm

    shows that 1000 mg daily reduces inflammation in study participants with elevated CRP about as much as Crestor.

    After reading the comments about multivitamins and quackery in

    http://www.sciencedaily.com/releases/2008/11/081113091630.htm

    I wonder whether you would still characterize moderate dose Vitamin C as quackery ( the study cited in that blog used 500 mg of C, not 1000)

    Imagine at least the possibility of reducing CVD by half or so with a substance that costs pennies and has virtually no adverse affects. Wonder what pharm would say about that?

  74. nwtk2007 says:

    The vitamin C connection with CTP makes since. Vit C strengthens connective tissue. Stronger connective tissue means less micro-trauma and that translates into lower inflammation levels.

  75. EddieVos says:

    Dear nwtk2007, the problem is that vitamin C now costs ~$2/1000 grams wholesale and cannot be patented. You have the key point: without adequate C all the time, our 2 main arterial proteins cannot be made with optimal qualities, collagen and elastin that is.
    To x-link either, we then also need lysyl-oxidase, irreversibly destroyed by homocysteine, which is higher than minimal when not taking a multivitamin. Also, lysyl-oxidase it needs vitamin B6 in amounts of 5 – 25 mg/day, levels only obtainable form multivitamins.
    Arterial decline is a problem of structure. Therefore the problem is simple considering it to be a decades-long sub-optimal multiple micro-nutrient deficiency disease. The human data, epidemiology, animal and cell culture data is elegant, rock solid and represents biochemistry 101. Cholesterol, the pure C27H45OH, simply plays no role in building or maintaining the structure of heart and of blood vessel.
    http://www.health-heart.org/why.htm has some of the basics.

  76. weing says:

    oderb,
    You are comparing a study that shows a change in a lab value to a study that shows change in mortality and morbidity. Studies of Vitamin C and E affects on morbidity and mortality have been disappointing.

  77. EddieVos says:

    Weing, re E and C and other vitamins, an important point is at which stage of decline do we intervene. For example, high homocysteine by insufficient B vitamins for one’s genome is probably THE main cause for arterial decline [and it's related to >100 other diseases and conditions], but lowering homocysteine with vitamins is NOT the cure for existing atheroma and other arterial decline.
    Salt water causes rust holes but putting the car in a dry garage does not fix the rust hole.
    Quitting smoking causes cancer but quitting does not cure cancer.
    In people, we do get some repair, quicker in fast turnover tissue like bone, then in stroke and, as per the CDC, there was a greatly increasing decline in heart and stroke deaths after folate was added to our grain products [nothing but hard epidemiology, plausible and nothing to lose].
    http://www.health-heart.org/HIPandHope.gif shows the effects.

    The problem with M.D.s: they are expected to “cure” decline in order to prevent disease and deaths from it. Cure with drugs is not so easy and evidently impossible when dealing with a deficiency disease, such as heart disease, goitre, rickets, pellagra, bone fractures, other] so doctors get easily side tracked by the beauty of the drugs: statins shine ever more brightly and when you don’t prescribe, you’re frowned upon or worse, and in many places you lose prescribing income. Clearly, such frustration shows in the fairly typical doctor’s attitude of our hostess and when doctors have nothing else approved in their tool kit they tend to denigrate those questioning their wisdom.

  78. weing says:

    EddieVos,
    Where are the studies to back up your claims? The addition of folate to foods was to prevent neural tube defects. There are many other variables that can better account for decreased stroke and coronary deaths. The main ones being the widespread use of statins and improved control of blood pressure. Hard epidemiology? That’s a new one. I think it may need some Viagra.

  79. EddieVos says:

    Here’s the CDC on the topic:
    http://www.ncbi.nlm.nih.gov/pubmed/16534029?dopt=AbstractPlus
    and here’s a follow-up
    http://www.medicalnewstoday.com/articles/6369.php

    You’re right, it was done to prevent neural tube defects, it did, it also lowered U.S. homocysteine levels about 10%, an unexpected side effect of -60% neuroblastoma [the most common solid cancer in neonate and the very young] and since the drugs you mention were present before and/or don’t save lives in the groups most dying from heart and stroke deaths, that theory stands until a better one comes up.

  80. weing says:

    “and since the drugs you mention were present before and/or don’t save lives in the groups most dying from heart and stroke deaths, that theory stands until a better one comes up.”
    Huh? That makes no sense at all. You still need proof for your claims. Something with viagra.

  81. EddieVos says:

    As the CDC authors say: “The accelerating improvement in death rates due to stroke and ischemic heart disease could not be explained by changes in other major risk factors, such as cigarette smoking, hypertension, diabetes and total serum cholesterol levels, many of which did not improve or worsen during the period studied …
    I did say it was epidemiology but we DO need an explanation for fewer deaths, and blood pressure drugs have never done so and statins, ah, well: never in elderly, women and in JUPITER: minus 6 deaths from cardiovascular causes in 8900 people treated for 1.9 years. The CDC could not have picked that up as a trend and indeed they did not.
    So, what’s your explanation?
    It’s just an other piece in the puzzle of ’cause’ that is missing a few center pieces but the frame and the picture is clear as spring water.

  82. oderb says:

    weing,

    If you read my post you will see that I was explicitly NOT comparing the Vitamin C study to Jupiter. I was commenting that now that there appears to be a solid study showing Vitamin C at 1 gram lowering CRP shouldn’t resources be found to do a Jupiter like study with C? I don’t know the literature all that well but if there has been studies of 1 gram of C that show no effect on mortality or morbidity it would be useful to know of them, and further if such studies have been done, I wonder why the study I cited was funded?

  83. pec says:

    “shouldn’t resources be found to do a Jupiter like study with C?”

    Yes of course, but there is less financial motivation. And it just seems more modern and scientific to use synthetic drugs.

  84. EddieVos says:

    Vitamin C has long been considered as antiinflammatory, antiviral agent and all mammals but few including primates make gram amounts/day on the human weight basis.
    There are many reasons to take a couple of grams/day, not only because it drops C-RP but it makes sure we always have enough to make strong connective tissue, even when under severe stress/ injury or other situation.
    That study will never be done: statins profit margin ~4000%, ascorbic acid: very little and no patent to protect unique rights.
    As I tried to say before, micro-nutrients in ‘age-related’ diseases are no rapid cure; mostly, they prevent bad things from happening in the first place. Being in the top 25% for homocysteine [unlikely when taking a multivitamin pill]: double the Alzheimer’s 8 to 16 years later, as per Framingham. Proof not, prevention just maybe.
    Also, the mother of the vascular diseases is lack of vitamin C by poor collagen synthesis [evidenced in capillary break down]. Extrapolate and we have arteries, containing the same collagen rope structures, as does heart [35% of protein is collagen. Think: congestive heart failure at age 75].

  85. weing says:

    Of course there is no motivation to do studies on Vitamin C. The vitamin sellers are raking in dough already. Why risk proving that it doesn’t do the job and lose sales? As I said, all the real (viagra) studies with Vitamins for coronary mortality and stroke have been disappointing. All you have now is a study showing that Vitamin C lowers the CRP, a lab test, as much as Crestor. Interesting, but I am not impressed. I find clinical endpoints much more convincing. My bank account is decreased by my mortgage payment. When my daughter gets her hands on my bank card, my bank account drops by the same amount. I will not assume that my mortgage payment has been made.

  86. weing says:

    EddieVos,
    The CDC link you give is about 4 years old and it was not a study. It was speculation. The folic acid studies have not panned out either. I have since stopped recommending folate supplementation. I don’t forbid patients, I just can’t in good conscience recommend it. I just tell them the studies don’t support the use of folate. Some of them continue to take it.

  87. EddieVos says:

    Dear weing, I answered a question re epidemiology and I DID say it was that, not a randomized study but clearly the hard findings needs an explanation.
    The randomized trials show first benefit in bone, then in stroke [several studies] and no harm in CV departments.
    A bottle of 1 mg folic acid may cost about the same as a multivitamin such as this no iron one [best in the U.S.]:
    http://www.vitacost.com/Twinlab-Daily-One-Without-Iron
    It contains all the levels of B2, B6, folate and B12 and some co-factors that lower homocysteine. $0.11/day. Take AFTER or late in a meal. Always NO IRON unless there is a reason.
    You are talking about some, not all randomized studies in late primary or secondary prevention. THERE, the benefit is evidenly slow in coming but having minimal homocysteine is a benefit no matter what.
    Two randomized trials with benefit:
    http://www.health-heart.org/HIPandHOPE.gif
    Again, it’s no quick cure, but it lowers a natural blood toxin that reacts with the lysine, arginine and cysteine residues in all or most of our proteins and that is not a health benefit.
    Heart disease is rarely if ever reported in groups where the level is below 7 micromoles.
    Once the arteries have serious atheromatous thickening and/or fibrous caps, the trick is to keep the heart going when an ACE happens and here antiarrythmic omega-3′s and probably RDA amounts of magnesium play those roles. That would be the equivalent of keeping the rusty car moving when bad things happen.
    Incidentally, vitamin C may well exert a role in strengthening the fibrous cap [made of collagen], but that should be properly investigated some day.

  88. weing says:

    EddieVos,
    Here is a link to the study that made me stop recommending vitamins for coronary prevention about 3 years ago http://news.bbc.co.uk/1/hi/health/4218186.stm

  89. pc says:

    Weing said: “All you have now is a study showing that Vitamin C lowers the CRP, a lab test, as much as Crestor. Interesting, but I am not impressed. I find clinical endpoints much more convincing.”

    I totally agree. Changing a value without measuring the benefit of this change is meaningless. It proves nothing. However, the point of the JUPITER study was to prove that people with elevated CRP but normal to low cholesterol would benefit from Crestor. The results seem to show a (small) improvement in these people on Crestor, with the authors strongly suggesting that the CRP lowering effect of the statin was a major reason for this. If you accept this explanation then you have to ask yourself; would you rather take a cheap harmless vitamin or an expensive higher risk option of a statin to achieve the same endpoint?

  90. EddieVos says:

    Dear Weing, may I refer you to Refsum in the correspondence section of NORVIT here:
    http://content.nejm.org/cgi/content/full/355/2/205
    I agree that the results are not great in late secondary prevention, as would be bringing the car into the garage to cure existing rust.
    Part of the problem with promoting methylation pathways i.e. supplying folate+B12 is that it allows healthy cell replication. This is evidently a benefit in gestation, in early life and during later years including the years that atheroma or cancer tends to form [we have to rely on epidemiology and excellent animal studies though].
    However, a theoretical harm would be when ‘bad’ cells replicate, i.e when artery cells are ‘tickled’ by a metal stent [Lange] rather than by a balloon [Schnyder], or in cancer when receiving anti-folate treatment [however poorly these drugs aid survival, they stop normal cell replication].
    The key is the point in time we intervene: when early, vitamins prevent; late, they may not. Then again what to do? It’s unethical to do trials with dummy vitamins in humans, a species with a life span twice that of the average researcher. We have to rely on the balance of the data and where the prevention by micro/minor nutrients is excellent.
    Late in the game, it’s the impossible dilemma: how to feed the patient without feeding the ‘cancer’. In cancer itself, half die from basically malnutrition; what would have been better.

  91. weing says:

    pc,

    If my bank account decreases by the same amount as my mortgage payment after my teenage daughter used my credit card, can I assume that my mortgage payment has been made? Should I risk foreclosure? Anyway, you can get some statins for about 13 cents a pill.

  92. weing says:

    EddieVos,
    You are talking about primary prevention with vitamins. There are no studies to supporting this. I wish there were. From what you have written, you think you have an explanation of how they should work to prevent disease and until a better explanation comes along this explanation is somehow proof. Unfortunately it doesn’t work that way. The next thing to do is a study designed to disprove your hypothesis. If it doesn’t, the hypothesis stands. That’s the way to avoid the trap of epistemic arrogance.

    In the observation from the CDC that you mentioned previously it was noted that there was a decline in stroke related deaths that preceded the supplementation with folate. What caused this decline? Statins? Could the wider application of what caused the decline not have accelerated the decline? Why did the decline occur so soon after institution of folate supplementation if vitamins work at an earlier stage to prevent atherosclerosis?

  93. EddieVos says:

    Dear weing, what is ‘epistemic arrogance’ and what does it have to do with the much increasing RATE of decline of heart and stroke deaths as of 1998 [here, not in the U.K]? That general decline was indeed one that started in the U.S. in about 1965*). When the CDC implies it was not drugs, look at THEIR data and reasonings would be my suggestion but mine are at the end.

    Why do doctors hide behind the notion that we need placebo controlled trials in primary prevention in a human disease that in all likelihood is a long latency multi-nutrient deficiency disease before accepting that there are about a dozen existing scientific pathways that support that hypothesis of cause? The HIP part of the gif I referenced to above is such primary prevention vitamin/placebo study, be it in hip fractures [80% less!].

    In heart disease, such trials are impossible and unethical unless you find kids to be randomized to dummy vitamins or not and then to volunteer their arteries at different stages of life for autopsy.
    We already know how to mimic human arteriosclerosis in primate by simply restricting vitamin B6; we know the pathways that destroy the elastic components of artery by homocysteine and that should be enough to recommend us to obtain the levels of B vitamins that minimize homocysteine. Best available evidence.

    There are no placebo controlled statin studies in teenagers or in the very old but with little question, their mevalonate pathways are slashed to abide by a flawed hypothesis. What if you are trying to prevent a deficiency disease with life-long drugs? Is not there the ‘do no harm first’ principle?

    There is RCT evidence that while preventing stroke and TIA by statin, we are significantly promoting bleeding strokes and likely deaths by the latter offset lives extended by the former. In fact, the study of Lipitor vs placebo in stroke, SPARCL, ended with numerically more dead on statin, i.e. no explanation for the CDC finding. The P value in JUPITER for CV/heart deaths was 0.37, again no support for the decline found by the CDC. Lipitor has never postponed a death [in those ever qualifying for a clinical trial that is]. Time to face those mathematical certainties. Remember, that the 2 mega-trials with the first statin ended with more statin deaths but that was after 1990, not before.

    *) You asked why the earlier decline. Well, about 3 years before 1965, ready-to-eat junk breakfast cereals were introduced with an obligate multivitamin pill included in order not to kill people outright. Some have suggested it was this, in particularly B6, that initiated the decline.
    Then, we have the initially slow [re]introduction of omega-3 over the last 65 years [from soybean/canola oils] exerting an antiarrhythmic effect that also probably affected fewer deaths.

  94. weing says:

    EddieVos,
    Relying on your speculations as proof instead of experimental evidence is epistemic arrogance. Why would it be unethical to do a study on the usual diet + a dummy pill and the usual diet + a vitamin pill? Come to think of it, haven’t parents been giving their kids vitamins for decades already and haven’t been people using vitamins themselves for decades already in the belief they are preventing disease and warding off old age? I have not problem with fish oil and do recommend it. I am not surprised at the SPARCL, showing increased hemorrhagic stroke. I recall reading a good study, about 13-14 years ago, in JAMA that showed the same results using an extremely low fat diet and not statins. They found that adding a handful of walnuts a day led to loss of this increase in hemorrhagic stroke without increasing coronaries. If I get a chance, I’ll see if I can find the reference. I have been eating a handful daily ever since and recommend it to my patients. If I find studies showing otherwise, I’ll change my recommendations. Speculations will not do the job.

  95. pc says:

    weing said: “If my bank account decreases by the same amount as my mortgage payment after my teenage daughter used my credit card, can I assume that my mortgage payment has been made? Should I risk foreclosure? Anyway, you can get some statins for about 13 cents a pill.”

    No you do not risk foreclosure but you check your financial statements so that you know the root cause of your money withdrawals.
    If you read my argument properly I quite clearly state that to accept the Vitamin C argument you have to accept the CRP lowering hypothesis of the study ie you know that simple CRP lowering works and that it does not matter by what method this is achieved. I take it you do not accept the CRP hypothesis? I have no problem with that because as I far as I am concerned the data is insufficient to totally support the idea.
    I am also no advocate of supplements, but I do take statins and know all too well their health advantages and disadvantages.

  96. weing says:

    pc,
    You are correct. Sorry for the misunderstanding.

  97. EddieVos says:

    weing: “Come to think of it, haven’t parents been giving their kids vitamins for decades already and haven’t been people using vitamins themselves for decades already in the belief they are preventing disease and warding off old age?
    Guess, what: that’s why we have ~66% fewer deaths/100,000 age adjusted from CVD than at the peak of the epidemic. Call it speculation, I call it biochemistry.

    Currently, U.S. youth below age 18 have Hcy of 6. In India it’s about 22 [!!] at age ~22. You may argue such trial is ethical in India, it’s probably not ethical, if feasible, in the U.S. NOBODY would fund it if it could be done but that does not void other evidence.
    I looked up “epistemic” i.e. the systematic using of formal logic, physiology, knowledge. Arrogance has nothing to do with that method of analysis, one that is in my view based on a ‘dozen pathways’.

    Walnuts at 10% omega-3 is fine but expensive and high [>55%] in inflammatory omega-6. The poor man’s best plant omega-3: canola oil and flax [seed or oil].

  98. EddieVos says:

    $0.13/pill vs $3.45 for Crestor .. The WHO reported the lowest world retail price of $4.99/YEAR supply or $0.013/day. If only they would save people.
    Whatever the heart attack epidemic that started with Herrick’s 1912 JAMA article [great reading] was caused by, it was not the lack of circulating statins. Cheaper is not better. Hope springs eternal but fear motivates people, however little science-based.

  99. EddieVos says:

    That $0.13/pill vs $3.45 for Crestor .. The WHO reported the lowest world retail price of $4.99/YEAR supply or $0.013/day. If only they would save people.
    Whatever the heart attack epidemic that started with Herrick’s 1912 JAMA article [great reading] was caused by, it was not the lack of circulating statins. Cheaper is not better. Hope springs eternal but fear motivates people, however little science-based.

  100. weing says:

    EddieVos,
    Sorry, I base my recommendations on data that I have and not on just knowledge of possible mechanisms. If I had data that cigarette smoking prevented aging, I would recommend it, although I can’t think of a plausible mechanism for it. I never thought walnuts were expensive. Whether it’s the omega-3 in them or something else, I don’t know. All I know is what the effects of walnuts were. If you have outcome data on canola oil and flax seed oil, please share and I will gladly review them.

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