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Of the Trial to Assess Chelation Therapy, Bayes, the NIH, and Human Studies Ethics

An experiment is ethical or not at its inception; it does not become ethical post hoc—ends do not justify means.
~ Henry K. Beecher

tact

A couple of weeks ago, Dr. Josephine Briggs, the Director of the National Center for Complementary and Alternative Medicine (NCCAM), posted a short essay on the NCCAM Research Blog touting the results of the Trial to Assess Chelation Therapy (TACT) (italics added):

The authors found that those receiving the active treatment clearly fared better than those receiving placebo. The accompanying editorial in the AHJ reminds readers about the value of equipoise and the need to “test our beliefs against evidence.”

Most physicians did not expect benefit from chelation treatment for cardiovascular disease. I readily admit, initially, I also did not expect we would find evidence that these treatments reduce heart attack, strokes, or death. So, the evidence of benefit coming from analyses of the TACT trial has been a surprise to many of us. The subgroup analyses are suggesting sizable benefit for diabetic patients—and also, importantly, no benefit for the non-diabetic patient. Clearly subgroup analyses, even if prespecified, do not give us the final answer. But it is also clear that more research is needed to test these important findings.

And TACT findings are indeed a reminder of the importance of retaining equipoise [sic], seeking further research aimed at replicating the findings, and neither accepting nor rejecting findings based on personal biases. The scientific process is designed to weed out our preconceived notions and replace them with evidence.

Dr. Briggs concluded:

So, TACT is a reminder—an open mind is at the center of the scientific method.

Dr. Briggs’s title was “Bayes’ Rule and Being Ready To Change Our Minds”, a reference to a recent editorial that had accompanied one of the TACT papers. That editorial, by Dr. Sanjay Kaul, a physician and statistician from UCLA, begins with this quotation:

Preconceived notions are the locks on the door to wisdom.
~ Merry Browne

Here is the relevant passage from Dr. Kaul’s editorial (italics added):

Sixth, it has been argued that the trial was unethical because there was no compelling clinical or preclinical evidence that chelation therapy has significant efficacy against atherosclerotic cardiovascular disease, and given that chelation therapy can cause harm, the risk was not minimal. A Bayesian analysis would not look kindly on the results because of the low prior probability of treatment effect (the so-called implausibility argument).6 This is an uncharitable (and unwarranted) interpretation of the data because previous systematic reviews concluded, “insufficient evidence to decide on the effectiveness or ineffectiveness of chelation therapy in improving clinical outcomes among people with atherosclerotic cardiovascular disease.” It is axiomatic that absence of evidence of efficacy is not the same as evidence of the absence of efficacy.

From a Bayesian perspective, the strength of evidence is often summarized using a Bayes factor, which is a measure of how well 2 competing hypotheses (the null and the alternate) predict the data. The Bayes factor and the corresponding strength of evidence for the primary end point result in TACT overall, and diabetic cohorts are shown in Table 1. The p-value of 0.035 for TACT overall cohort translates into a Bayes factor of 0.108, which means the evidence supports the null hypothesis ≈1/9th as strongly as it does the alternative. This reduces the null probability from 50% pretrial (justified by suspension of one’s belief in treatment effect) to 10% post-trial. Although this does not represent strong evidence against the null, it does reduce the level of skepticism surrounding chelation therapy. In the diabetic cohort, the nominal p-value of 0.0002 translates into a Bayes factor of 0.002 (1/500), which reduces the extremely skeptical prior null probability of 95% to 4% post- trial, indicating very strong evidence against the null.

In concluding, Dr. Kaul states:

Finally, TACT highlights the double standard when it comes to accepting inconvenient results not aligned with our preconceived notions on so-called dubious quack cures such as chelation…

Closed minds?

Dr. Kaul’s reference “6” above is to a lengthy article that we published in 2008 titled “Why the NIH Trial to Assess Chelation Therapy Should Be Abandoned”. So, it seems, both Drs. Briggs and Kaul were chastising us for our biased, preconceived beliefs about so-called dubious quack cures. Our minds were, apparently, not open. Let’s examine this contention. (more…)

Posted in: Clinical Trials, Health Fraud, Medical Academia, Medical Ethics, Politics and Regulation

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More evidence that routine multivitamin use should be avoided

If scientific evidence guides our health decisions, we will look back at the vitamin craze of the last few decades with disbelief. Indiscriminate use is, in most cases, probably useless and potentially harmful. We are collectively throwing away billions of dollars into supplements, chasing the idea of benefits that have never materialized. Multivitamins are marketed with a veneer of science but that image is a mirage – rigorous testing doesn’t support the health claims. But I don’t think the routine use of vitamins will disappear anytime soon. It’s a skillfully-marketed panacea that about half of us buy into.

Not all vitamin and mineral supplementation is useless. They can be used appropriately, when our decisions are informed by scientific evidence: Folic acid prevents neural tube defects in the developing fetus. Vitamin B12 can reverse anemia. Vitamin D is recommended for breastfeeding babies to prevent deficiency. Vitamin K injections in newborns prevent potentially catastrophic bleeding events. But the most common reason for taking vitamins isn’t a clear need, but rather our desire to “improve overall health”. It’s deemed “primary prevention” – the belief that we’re just filling in the gaps in our diet. Others may believe that if vitamins are good, then more vitamins must be better. And there is no debate that we need dietary vitamins to live. The case for indiscriminate supplementation, however, has never been established. We’ve been led to believe, through very effective marketing, that taking vitamins is beneficial to our overall health – even if our health status is reasonably good. So if supplements truly provide real benefits, then we should be able to verify this claim by studying health effects in populations of people that consume vitamins for years at a time. Those studies have been done. Different endpoints, different study populations, and different combinations of vitamins. The evidence is clear. Routine multivitamin supplementation doesn’t offer any meaningful health benefits. The parrot is dead. (more…)

Posted in: Herbs & Supplements, Science and Medicine

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New Cholesterol Guidelines

On November 15, the American College of Cardiology and the American Heart Association released an updated guideline for the use of statins to prevent and treat atherosclerotic cardiovascular disease (ASCVD). The full report is available online. It has already generated a lot of controversy. The news media have characterized it as a “huge departure” from previous practice and have trumpeted that it will lead doctors to prescribe statins to millions more people. As usual, the truth is much more nuanced. There are some problems with the guidelines, but on the whole they represent an improved, more rational approach to prescribing statins.

Statins have always been a source of controversy: people seem to either love them or hate them, and discussions about them generate a lot of emotion. The International Network of Cholesterol Skeptics denies that cholesterol has anything to do with cardiovascular disease. An article on HuffPo calls statins “an unsafe, unnecessary product that will now be recommended to healthy people to make them sicker.” Mercola says they can actually make heart disease worse and cause premature aging, and no one should take them unless they have the genetic defect of familial hypercholesterolemia. A website collects patient self-reports of adverse effects; but like the vaccine reports on VAERS, these are only anecdotal reports of correlation, not evidence for causation.

At one time the evidence only supported using statins for secondary prevention and for men. We now have better evidence showing that they are effective for both primary and secondary prevention in patients of both sexes and all ages, and that they are more effective for those with higher risk factors. (more…)

Posted in: Pharmaceuticals

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Do vitamins prevent cancer and heart disease?

It is a triumph of marketing over evidence that millions take supplements every day. There is no question we need vitamins in our diet to live. But do we need vitamin supplements? It’s not so clear. There is evidence that our diets, even in developed countries, can be deficient in some micronutrients. But there’s also a lack of evidence to demonstrate that routine supplementation is beneficial. And there’s no convincing evidence that supplementing vitamins in the absence of deficiency is beneficial. Studies of supplements suggest that most vitamins are useless at best and harmful at worst. Yet the sales of vitamins seem completely immune to negative publicity. One negative clinical trial can kill a drug, but vitamins retain an aura of wellness, even as the evidence accumulates that they may not offer any meaningful health benefits. So why do so many buy supplements? As I’ve said before, vitamins are magic. Or more accurately, we believe this to be the case.

There can be many reasons for taking vitamins but one of the most popular I hear is “insurance” which is effectively primary prevention – taking a supplement in the absence of a confirmed deficiency or medical need with the belief we’re better off for taking it. A survey backs this up – 48% reported “to improve overall health” as the primary reason for taking vitamins. Yes, there is some vitamin and supplement use that is appropriate and science-based: Vitamin D deficiencies can occur, particularly in northern climates. Folic acid supplements during pregnancy can reduce the risk of neural tube defects. Vitamin B12 supplementation is often justified in the elderly. But what about in the absence of any clear medical need? (more…)

Posted in: Herbs & Supplements, Nutrition, Science and Medicine

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What Can We Learn from the Kitavans?

A Swedish researcher, Staffan Lindeberg, has been studying the inhabitants of Kitava, one of the Trobriand Islands of Papua New Guinea. He claims that sudden cardiac death, stroke, and exertion-related chest pain never occur in Kitava; and he attributes this to their eating a Paleolithic diet.

2,250 people live on Kitava. They are traditional farmers. Their dietary staples are tubers (yam, sweet potato and taro), fruit, fish, and coconut. They don’t use dairy products, alcohol, coffee, or tea. Their intake of oils, margarine, cereals, and sugar is negligible. Western foods constitute less than 1% of their diet. Their activity level is only slightly higher than in Western populations. 80% of them smoke daily and an unspecified number of them chew betel. The macronutrient composition of the Kitavan diet was estimated as 21% of total calories from fat, 17% from saturated fat, 10% from protein, and 69% from carbohydrates.

Lindeberg’s Kitava study examined a sample of 220 Kitavans aged 14-87 and compared them to healthy Swedish populations. They found substantially lower diastolic blood pressure, body mass index, and triceps skinfold thickness in the Kitavans. Systolic blood pressure was lower in Kitava than in Sweden for men over 20 and women over 60. Total cholesterol, LDL cholesterol, and apolipoprotein B were lower in men over 40 and in women over 60. Triglycerides were higher in Kitavans aged 20-39 than in Swedes of the same age. HDL was not significantly different. (more…)

Posted in: Nutrition

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The deceptive rebranding of aspects of science-based medicine as “alternative” by naturopaths continues apace

That naturopathy is a veritable cornucopia of quackery mixed with the odd sensible, science-based suggestion here and there is not in doubt, at least not to supporters of science-based medicine (SBM). However, what naturopaths are very good at doing is representing their pseudoscience as somehow being scientific and thus on par with conventional SBM. So how do they accomplish this? Certainly, it’s not through the validation of any of the cornucopia of pseudoscience and quackery that naturopaths apply to their patients as though picking “one from column A and one from column B” from a proverbial Chinese menu of woo. Naturopaths’ favored modalities include homeopathy (which remains to this day an integral part of naturopathy that all naturopaths are taught), acupuncture and traditional Chinese medicine (TCM), “detoxification” practices (a key precept of a lot of naturopathy) such as juicing, enemas, and chelation therapy, and the various other quack modalities that make up the practice of naturopathy. Treatments like these (especially homeopathy, whose precepts would require a massive rewriting of the laws of physics and chemistry for it to work) have not been and almost certainly cannot ever be scientifically validated with an evidence base of the quality and quantity supporting SBM.

So, instead naturopaths play a very clever game. In all fairness, naturopaths are not the only practitioners of so-called “complementary and alternative medicine” (CAM) or “integrative medicine” who play this game, but from my observations they appear to be the most talented at it. Their skill at obfuscating the line between SBM and naturopathy is evidenced by the success they have had in state legislatures in expanding their scope of practice, most recently in Colorado, where, if there is not a groundswell of support urging the Governor to veto SB-215 (or, as Jann Bellamy aptly called it, the quack full employment act), consumer protections against quackery in Colorado will be laid waste. At the same time, there is a naturopath licensing act (HB-1111) sitting on the Governor’s desk as well that would license naturopaths and give them the path to mandatory reimbursement from insurance companies. Instructions to write to the Governor opposing both bills can be found here and here; they would be disastrous for efforts to keep full vaccination in Colorado. A direct link to write the Governor can be found here.
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Posted in: Clinical Trials, Homeopathy, Naturopathy, Nutrition, Science and the Media

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AAFP CME Program Succumbs to “Integrative Medicine”

For many years I have been using Continuing Medical Education (CME) programs offered by the American Academy of Family Physicians (AAFP). The FP Essentials program consists of a monthly monograph with a post-test that can be submitted electronically for 5 hours of CME credit. Over a 9-year cycle, a complete family medicine curriculum is covered to prepare participants for the re-certification board exams. Some examples of typical subjects are skin cancer, hand and wrist injuries, valvular heart disease, and care of the newborn. I rely on these programs to learn, review, and keep up-to-date in my specialty. Imagine my dismay when I opened the latest package to find a monograph on Integrative Medicine.

First it was called various names like folk medicine, quackery, and unproven/untested treatments, then all of those (the less rational right along with the more rational) were lumped together under the umbrella term “Alternative Medicine,” then it became “Complementary and Alternative Medicine” (CAM), and now it has been re-branded as “Integrative Medicine.” The term is designed to make unscientific treatments seem more acceptable to science-based doctors. “Integrative Medicine” is a marketing term, not a meaningful scientific category. It is a euphemism for combining Complementary and Alternative Medicine (CAM) with mainstream medical practice, unproven with proven, magic with science.  It has been critiqued many times on this blog. We have stressed that there is only one medicine, and that when a treatment is proven to work by good evidence, it is just “medicine.” When the evidence for a CAM treatment is not good, it essentially amounts to experimental treatments and/or comfort measures. Worse, sometimes CAM even persists in using treatments that have been proven not to work or that are totally implausible, like therapeutic touch or homeopathy. (more…)

Posted in: Acupuncture, Cancer, Energy Medicine, Medical Academia

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It’s a part of my paleo fantasy, it’s a part of my paleo dream

There are many fallacies that undergird alternative medicine, which evolved into “complementary and alternative medicine” (CAM), and for which the preferred term among its advocates is now “integrative medicine,” meant to imply the “best of both worlds.” If I had to pick one fallacy that rules above all among proponents of CAM/IM, it would have to be either the naturalistic fallacy (i.e., that if it’s natural—whatever that means—it must be better) or the fallacy of antiquity (i.e., that if it’s really old, it must be better). Of course, the two fallacies are not unrelated. In the minds of CAM proponents, old is more likely to have been based on nature, and the naturalistic fallacy often correlates with the fallacy of antiquity. Basically, it’s a rejection of modernity, and from it flow the interest in herbalism, various religious practices rebranded as treatments (thousands of years ago, medicine was religion and religion was medicine—the two were more or less one and physicians were often priests as well), and the all-consuming fear of “toxins,” in which it is thought that the products of modernity are poisoning us.

Yes, there is a definite belief underlying much of CAM that technology and pharmaceuticals are automatically bad and that “natural” must be better. Flowing from that belief is the belief that people were happier and much healthier in the preindustrial, preagricultural past, that cardiovascular disease was rare or nonexistent, and that cancer was seldom heard of. Of course, it’s hard not to note that cancer and heart disease are primarily diseases of aging, and life expectancy was so much lower back in the day that a much smaller percentage of the population lived to advanced ages than is the case today. Even so, an implicit assumption among many CAM advocates is that cardiovascular disease is largely a disease of modern lifestyle and diet and that, if modern humans could somehow mimic preindustrial or, according to some, even preagricultural, lifestyles, that cardiovascular disease could be avoided. Not infrequently, evolutionary and genomic arguments are invoked, claiming that the estimated 10,000 years since the dawn of human agriculture is not a sufficiently long period of time for us to have evolved to handle diets rich in grains and meats and that we are “genetically wired” to exist on a diet like those of our paleolithic hunter-gatherer ancestors. For instance, in 2004, James H. O’Keefe Jr, MD and Loren Cordain, PhD wrote an article in the Mayo Proceedings entitled Cardiovascular Disease Resulting From a Diet and Lifestyle at Odds With Our Paleolithic Genome: How to Become a 21st-Century Hunter-Gatherer that asserted in essence, just that. Over the last decade, Cordain has become the most prominent promoter of the so-called “Paleo diet,” having written The Paleo Diet: Lose Weight and Get Healthy by Eating the Foods You Were Designed to Eat and multiple other books advocating a paleolithic-mimetic diet as the cure for what ails modern humans. Meanwhile, diets thought to reflect what our hunter-gatherer ancestors ate, such as the Paleo Diet consisting largely of animal and fish that can be hunted and fruits and vegetables that can be foraged for in the wild, have been promoted as a near-panacea for the chronic diseases of aging, such as cardiovascular disease and cancer.

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Posted in: Evolution, History, Nutrition

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Calcium supplements and heart attacks: More data, more questions

Why take a drug, herb or any other supplement? It’s usually because we believe the substance will do something desirable, and that we’re doing more good than harm. To be truly rational we’d carefully evaluate the expected risks and benefits, estimate the overall odds of a good outcome, and then make a decision that would weigh these factors against any costs (if relevant) to make a conclusion about value for money. But having the best available information at the time we make a decision can still mean decisions turn out to be bad ones: It can be that all relevant data isn’t made available, or it can be that new, unexpected information emerges later to change our evaluation. (Donald Rumsfeld might call them “known unknowns.”)

As unknowns become knowns, risk and benefit perspectives change. Clinical trials give a hint, but don’t tell the full safety and efficacy story. Over time, and with wider use, the true risk-benefit perspective becomes more clear, especially when large databases can be used to study effects in large populations. Epidemiology can be a powerful tool for finding unexpected consequences of treatments. But epidemiologic studies can also frustrate because they rarely determine causal relationships. That’s why I’ve been following the evolving evidence about calcium supplements with interest. Calcium supplements are taken by almost 1 in 5 women, second only to multivitamins as the most popular supplement. When you look at all supplements that contain calcium, a remarkable 43% of the (U.S.) population consumes a supplement with calcium as an ingredient. As a single-ingredient supplement, calcium is almost always taken for bone health, based on continued public health messages that our dietary intake is likely insufficient, putting women (rarely men) at risk of osteoporosis and subsequent fractures. This messaging is backed by a number of studies that have concluded that calcium supplements can reduce bone loss and the risk of fractures. Calcium has an impressive health halo, and supplement marketers and pharmaceutical companies have responded. There are pills, liquids, and even tasty chewy caramel squares embedded with calcium. It’s also fortified in foods like orange juice. Supplements are often taken as “insurance” against perceived or real dietary shortfalls, and it’s easy and convenient to take a calcium supplement daily, often driven by the perception that more is better. Few may think that there is any risk to calcium supplements. But there are now multiple safety signals that these products do have risks. And that’s cause for concern. (more…)

Posted in: Herbs & Supplements, Nutrition

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The result of the Trial to Assess Chelation Therapy (TACT): As underwhelming as expected

Chelation therapy.

It’s one of the most common quackeries out there, used by a wide variety of practitioners for a wide variety of ailments blamed on “heavy metal toxicity.” Chelation therapy, which involves using chemicals that can bind to the metal ions and allow them to be excreted by the kidneys, is actually standard therapy for certain types of acute heavy metal poisoning, such as iron overload due to transfusion, aluminum overload due to hemodialysis, copper toxicity due to Wilson’s disease, acute heavy metal toxicity, and a handful of other indications.

My personal interest in chelation therapy developed out of its use by unscrupulous practitioners who blamed autism on the mercury-containing thimerosal preservative that used to be in many childhood vaccines until 2001 but has since all but disappeared from such vaccines except for one vaccine (the flu vaccine, for which a thimerosal-free alternative is available) and in trace amounts in some other vaccines. Mercury became a convenient bogeyman to add to the list of “toxins” antivaccinationists hype in vaccines. In fact, my very first post after I introduced myself on this very blog discussed the idea that mercury in vaccines was a significant cause of autism and autism spectrum disorders, and I’ve periodically written about such things ever since, in particular the bad science of Mark and David Geier, whose idea that chemical castration of children with Lupron “works” against “mercury-induced” autism is based on a chemically ridiculous idea that somehow testosterone binds mercury and makes it harder to chelate. Unfortunately, this particular autism quackery has real consequences and has been responsible for the death of a child.

Chelation isn’t just for autism, however. Despite many practitioners advertising it for autism, cancer (often with dubious studies that I might have to take a look at), Alzheimer’s disease (which Hugh Fudenberg has blamed on the flu vaccine, a claim parroted by Bill Maher, of course!), and just about every ailment under the sun, it’s easy to forget that the original use for chelation therapy promoted by “alternative medicine” practitioners was for cardiovascular disease. When it is used for coronary artery disease or autism, on a strictly stoichiometric and pharmacological basis, it is extremely implausible. Moreover, it is not without potential complications, including renal damage and cardiac arrhythmias due to sudden drops in calcium levels. Such arrhythmias can and have led to death in children, and in adults complications such as renal failure and death.
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Posted in: Clinical Trials

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