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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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The return of the revenge of high dose vitamin C for cancer

Somehow, I’ve a feeling we’re not in Kansas anymore—except that we are, as you will soon see.

Because I’m the resident cancer specialist on this blog, it usually falls on me to discuss the various bits of science, pseudoscience, and quackery that come up around the vast collection of diseases known collectively as “cancer.” I don’t mind, any more than my esteemed colleague Dr. Crislip minds discussing infectious diseases and, of course, vaccines, the most effective tool there is to prevent said infectious diseases. In any case, there are certain things that can happen during a week leading up to my Monday posting slot on SBM that are the equivalent of the Bat Signal. Call them the Cancer Signal, if you will. One of these happened last week, thus displacing that post I’ve been meaning to write on a particular topic once again. At this rate, I might just have to find a way to write an extra bonus post. But not this week.

In any case, this week’s Cancer Signal consisted of a series of articles and news reports with titles like:

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Posted in: Basic Science, Cancer, Clinical Trials

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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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Dummy Medicine, Dummy Doctors, and a Dummy Degree, Part 2.2: Harvard Medical School and the Curious Case of Ted Kaptchuk, OMD (cont. again)

“Strong Medicine”: Ted Kaptchuk and the Powerful Placebo

At the beginning of the first edition of The Web that has no Weaver, published in 1983, author Ted Kaptchuk portended his eventual academic interest in the placebo:

A story is told in China about a peasant who had worked as a maintenance man in a newly established Western missionary hospital. When he retired to his remote home village, he took with him some hypodermic needles and lots of antibiotics. He put up a shingle, and whenever someone came to him with a fever, he injected the patient with the wonder drugs. A remarkable percentage of these people got well, despite the fact that this practitioner of Western medicine knew next to nothing about what he was doing. In the West today, much of what passes for Chinese medicine is not very different from the so-called Western medicine practiced by this Chinese peasant. Out of a complex medical system, only the bare essentials of acupuncture technique have reached the West. Patients often get well from such treatment because acupuncture, like Western antibiotics, is strong medicine.

Other than to wonder if Kaptchuk had watched too many cowboy ‘n’ Native American movies as a kid, when I first read that passage I barely blinked. Although the Chinese peasant may have occasionally treated someone infected with a bacterium susceptible to his antibiotic, most people will get well no matter what you do, because most illnesses are self-limited. Most people feel better even sooner if they think that someone with special expertise is taking care of them. If you want to call those phenomena the “placebo effect,” in the colloquial sense of the term, fine. That, I supposed, was what Kaptchuk meant by “strong medicine.”

Turns out I was mistaken. Let’s briefly follow Kaptchuk’s career path after 1983. In the 2000 edition of The Web, he wrote:

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Posted in: Acupuncture, Basic Science, Book & movie reviews, Chiropractic, Clinical Trials, Homeopathy, Medical Academia, Science and Medicine

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Of SBM and EBM Redux. Part IV: More Cochrane and a little Bayes

NB: This is a partial posting; I was up all night ‘on-call’ and too tired to continue. I’ll post the rest of the essay later…

Review

This is the fourth and final part of a series-within-a-series* inspired by statistician Steve Simon. Professor Simon had challenged the view, held by several bloggers here at SBM, that Evidence-Based Medicine (EBM) has been mostly inadequate to the task of reaching definitive conclusions about highly implausible medical claims. In Part I, I reiterated a fundamental problem with EBM, reflected in its Levels of Evidence scheme, that although it correctly recognizes basic science and other pre-clinical evidence as insufficient bases for introducing novel treatments into practice, it fails to acknowledge that they are necessary bases. I explained the difference between “plausibility” and “knowing the mechanism.”

I showed, with several examples, that in the EBM lexicon the word “evidence” refers almost exclusively to the results of clinical trials: thus, when faced with equivocal or no clinical trials of some highly implausible claim, EBM practitioners typically declare that there is “not enough evidence” to either accept or reject the claim, and call for more trials—although in many cases there is abundant evidence, other than clinical trials, that conclusively refutes the claim. I rejected Prof. Simon’s assertion that we at SBM want to “give (EBM) a new label,” making the point that we only want it to live up to its current label by considering all the evidence. I doubted Prof. Simon’s contention that “people within EBM (are) working both formally and informally to replace the rigid hierarchy with something that places each research study in context.”

In Part II I responded to the widely held assertion, also held by Prof. Simon, that there is “societal value in testing (highly implausible) therapies that are in wide use.” I made it clear that I don’t oppose simple tests of basic claims, such as the Emily Rosa experiment, but I noted that EBM reviewers, including those employed by the Cochrane Collaboration, typically ignore such tests. I wrote that I oppose large efficacy trials and public funding of such trials. I argued that the popularity gambit has resulted in human subjects being exposed to dangerous and unethical trials, and I quoted language from ethics treatises specifically contradicting the assertion that popularity justifies such trials. Finally, I showed that the alleged popularity of most “CAM” methods—as irrelevant as it may be to the question of human studies ethics—has been greatly exaggerated.

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Posted in: Clinical Trials, Energy Medicine, Faith Healing & Spirituality, Medical Academia, Medical Ethics, Science and Medicine

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Of SBM and EBM Redux. Part III: Parapsychology is the Role Model for “CAM” Research

This is the third post in this series*; please see Part II for a review. Part II offered several arguments against the assertion that it is a good idea to perform efficacy trials of medical claims that have been refuted by basic science or by other, pre-trial evidence. This post will add to those arguments, continuing to identify the inadequacies of the tools of Evidence-Based Medicine (EBM) as applied to such claims.

Prof. Simon Replies

Prior to the posting of Part II, statistician Steve Simon, whose views had been the impetus for this series, posted another article on his blog, responding to Part I of this series. He agreed with some of what both Dr. Gorski and I had written:

The blog post by Dr. Atwood points out a critical distinction between “biologically implausible” and “no known mechanism of action” and I must concede this point. There are certain therapies in CAM that take the claim of biological plausibility to an extreme. It’s not as if those therapies are just implausible. It is that those therapies must posit a mechanism that “would necessarily violate scientific principles that rest on far more solid ground than any number of equivocal, bias-and-error-prone clinical trials could hope to overturn.” Examples of such therapies are homeopathy, energy medicine, chiropractic subluxations, craniosacral rhythms, and coffee enemas.

The Science Based Medicine site would argue that randomized trials for these therapies are never justified. And it bothers Dr. Atwood when a systematic review from the Cochrane Collaboration states that no conclusions can be drawn about homeopathy as a treatment for asthma because of a lack of evidence from well conducted clinical trials. There’s plenty of evidence from basic physics and chemistry that can allow you to draw strong conclusions about whether homeopathy is an effective treatment for asthma. So the Cochrane Collaboration is ignoring this evidence, and worse still, is implicitly (and sometimes explicitly) calling for more research in this area.

On the other hand:

There are a host of issues worth discussing here, but let me limit myself for now to one very basic issue. Is any research justified for a therapy like homeopathy when basic physics and chemistry will provide more than enough evidence by itself to suggest that such research is futile(?) Worse still, the randomized trial is subject to numerous biases that can lead to erroneous conclusions.

I disagree for a variety of reasons.

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Posted in: Acupuncture, Clinical Trials, Energy Medicine, Faith Healing & Spirituality, Herbs & Supplements, Homeopathy, Medical Academia, Medical Ethics, Science and Medicine

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Of SBM and EBM Redux. Part II: Is it a Good Idea to test Highly Implausible Health Claims?

Review

This is the second post in a series* prompted by an essay by statistician Stephen Simon, who argued that Evidence-Based Medicine (EBM) is not lacking in the ways that we at Science-Based Medicine have argued. David Gorski responded here, and Prof. Simon responded to Dr. Gorski here. Between that response and the comments following Dr. Gorski’s post it became clear to me that a new round of discussion would be worth the effort.

Part I of this series provided ample evidence for EBM’s “scientific blind spot”: the EBM Levels of Evidence scheme and EBM’s most conspicuous exponents consistently fail to consider all of the evidence relevant to efficacy claims, choosing instead to rely almost exclusively on randomized, controlled trials (RCTs). The several quoted Cochrane abstracts, regarding homeopathy and Laetrile, suggest that in the EBM lexicon, “evidence” and “RCTs” are almost synonymous. Yet basic science or preliminary clinical studies provide evidence sufficient to refute some health claims (e.g., homeopathy and Laetrile), particularly those emanating from the social movement known by the euphemism “CAM.”

It’s remarkable to consider just how unremarkable that last sentence ought to be. EBM’s founders understood the proper role of the rigorous clinical trial: to be the final arbiter of any claim that had already demonstrated promise by all other criteria—basic science, animal studies, legitimate case series, small controlled trials, “expert opinion,” whatever (but not inexpert opinion). EBM’s founders knew that such pieces of evidence, promising though they may be, are insufficient because they “routinely lead to false positive conclusions about efficacy.” They must have assumed, even if they felt no need to articulate it, that claims lacking such promise were not part of the discussion. Nevertheless, the obvious point was somehow lost in the subsequent formalization of EBM methods, and seems to have been entirely forgotten just when it ought to have resurfaced: during the conception of the Center for Evidence-Based Medicine’s Introduction to Evidence-Based Complementary Medicine.

Thus, in 2000, the American Heart Journal (AHJ) could publish an unchallenged editorial arguing that Na2EDTA chelation “therapy” could not be ruled out as efficacious for atherosclerotic cardiovascular disease because it hadn’t yet been subjected to any large RCTs—never mind that there had been several small ones, and abundant additional evidence from basic science, case studies, and legal documents, all demonstrating that the treatment is both useless and dangerous. The well-powered RCT had somehow been transformed, for practical purposes, from the final arbiter of efficacy to the only arbiter. If preliminary evidence was no longer to have practical consequences, why bother with it at all? This was surely an example of what Prof. Simon calls “Poorly Implemented Evidence Based Medicine,” but one that was also implemented by the very EBM experts who ought to have recognized the fallacy.

There will be more evidence for these assertions as we proceed, but the main thrust of Part II is to begin to respond to this statement from Prof. Simon: “There is some societal value in testing therapies that are in wide use, even though there is no scientifically valid reason to believe that those therapies work.”

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Posted in: Chiropractic, Clinical Trials, Energy Medicine, Health Fraud, History, Homeopathy, Medical Academia, Medical Ethics, Naturopathy, Politics and Regulation, Science and Medicine

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