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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 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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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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