Why the NIH Trial to Assess Chelation Therapy (TACT) Should Be Abandoned

Kimball C. Atwood IV, MD; Elizabeth Woeckner, AB, MA; Robert S. Baratz, MD, DDS, PhD; Wallace I. Sampson, MD

Disclosures

Medscape J Med. 2008;10(5):115 

In This Article

Discussion

The argument made in the American Heart Journal and in the TACT protocols, that "case series encompass[ing] thousands of patients with successful outcomes[29]" are adequate to justify a large trial of Na2EDTA chelation despite previous, negative RCTs with an aggregate sample size of 275, is not supported by a rigorous appraisal of those case series. The early case series were honest attempts to investigate a method that at first seemed promising according to the understanding of atherosclerosis and the clinical investigations at the time; within a few years it had become clear that the method was not useful. In regard to the later series, there is ample evidence, both in the articles themselves and in other sources, of implausible results and of bias in the extreme. The later series are not credible as case reports; they are better characterized, to quote Alfred Soffer, as the offerings of "pseudoscientific zealots.[9,10,11]"

Thus the few, credible case reports agree with the RCTs: There is no evidence that chelation is a useful treatment for cardiovascular disease. On the contrary, the weight of the evidence from both the case series and the RCTs argues that chelation is ineffective, even if this conclusion has not been proved beyond a shadow of a doubt -- as, logically, it can never be.

Nor has it been shown that "established guidelines" render IV disodium EDTA and megadoses of supplements safe. Responsible trials have reported a small but significant incidence of potentially life-threatening complications and a larger incidence of minor but uncomfortable side effects. There is ample additional evidence -- found predominantly in court opinions and newspapers, not cited by the TACT protocols -- of deaths and serious injuries associated with chelation given by ACAM members. There is laboratory evidence that the "standard" chelation solution may increase oxidative stress. In estimating risk, the NIH might reconsider its confidence in "the clinical experience of the ACAM,[4]" which has continually misrepresented the issue.

What, then, of the hypothetical "small to moderate benefit[29]" that has never been reported? This explanation for the chelation phenomenon -- in essence, that advocates' far-fetched claims are simple exaggerations of modest efficacy -- is unlikely. Far more likely are the classic errors in judgment that have encouraged advocates of every spurious therapeutic claim throughout history, eg, failure to recognize the variable course of symptoms, the post hoc fallacy, errors in diagnosis, confirmation bias, affirmation bias, selection bias, social and cultural biases, demand characteristics, and all of the rest.[319]

In the early years of chelation, "enthusiasts" exaggerated those judgmental errors because the usual primary outcome, a reduction in angina pectoris, was especially sensitive to a "placebo effect.[126,251,252,262]" Later, chelation zealots exaggerated them further, spurred by abundant financial rewards,[58,59] by other chelationists' flawed "studies"( Table 2 ), and by fraud.[44] It is no mere coincidence that chelationists peddle myriad additional treatments, most famously Laetrile, that resemble one another only in being pseudoscientific and lucrative.[7]

Randomized, blind, controlled trials were devised to correct for such judgmental errors. Although RCTs may not be perfect, a few such trials from disparate sources, unanimously showing no advantage for chelation, carry far more weight than chelationists' opinions. In the historical context of chelation promoted as a treatment for atherosclerosis, such "absence of evidence of efficacy" constitutes substantial "evidence of absence of efficacy," contrary to Dr. Lamas' assertion.[29] Underpowered or not, the RCTs and the rest of the "totality of the evidence[5]" -- case series that are either disconfirming or not credible, implausible hypothesized mechanisms, evidence of substantial risks, evidence of pro-oxidant effects, and advocacy arising exclusively from biased, unreliable sources -- refute the claim of equipoise.

These are compelling reasons to limit any current investigations of unapproved uses of Na2EDTA, if they can be justified at all, to laboratory and animal studies -- as stipulated, for example, by paragraph 11 of the Helsinki Declaration:

Medical research involving human subjects must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and on adequate laboratory and, where appropriate, animal experimentation.[176]

What, then, induced the NIH to proceed with the TACT, so shortly after the NHLBI scientific review panel had overwhelmingly rejected a proposal for a similar study?[169] The evidence suggests that the NIH solicited the trial only after extraordinary pressure from a powerful congressman and from the ACAM lobby.[41,42,168,171,173] Those applying the pressure must have been content to redirect it to the nascent NCCAM, because they knew that this NIH Center had been established exactly for that purpose: to provide a diversion for legislators who imagined that they and a few of their constituents were better than real scientists at distinguishing between the plausible and the implausible.[172]

That "the fix was in" is suggested by the ACAM's intimate involvement in the stated rationale, in the planning (even prior to the Burton Hearing),[4] and in the execution of the trial. It can also be inferred from the choice of the more dangerous disodium salt of EDTA -- otherwise pointless, given Dr. Lamas' rejection of decalcification in favor of the heavy metals hypothesis[4] -- and from the presence of 2 ideologues on key oversight committees: past ACAM President L. Terry Chappell on the "Special Emphasis Committee" that reviewed Dr. Lamas' original protocol,[39] and past ABCMT Chairman Robert Nash on the DSMB.[47] Each of these appointments violated formal NIH policies.[183]

Even so, it seems that it was necessary to fashion a scientific and social case for the trial. Thus the "lack of adequate prior research" and the "widespread use of chelation therapy in lieu of established therapies" made the TACT a "public health imperative.[2]" The results "will provide either a significant positive result or an informative null result,[4]" which will "lead to changes in clinical practice, ultimately benefitting patients.[29]"

Such a case could only be justified by misrepresenting the science and the tiny subculture in which chelation thrives. TACT literature includes numerous examples of factual errors, language distortions, and failures to cite "relevant sources of information.[176]" Some examples seem purposeful, eg, the misleading descriptions of case series on pp. 7-8 of the 2003 protocol,[5] or the erroneous portrayal of an article that reported pro-oxidant effects of iron in the presence of EDTA.[4,312] Others seem merely lazy: the duplications and other errors in Table 2 that appear to have been copied from another source, or the recurrent citations, in both TACT protocols and in a 2006 editorial by Dr. Lamas in the British Journal of Cardiology,[49] of a 1982 article[320] as the source of a statement that could not have been made until at least 1993. The BJC editorial contains more inaccuracies.

In his 2000 editorial in the American Heart Journal, Dr. Lamas inflated the number of patients who receive chelation in a year by a factor of at least 20.[29] Later the NCCAM and the TACT protocols offered a reduced estimate, but not plainly so: Rather than report the number of patients, they reported the number of "visits," only mentioning elsewhere that each patient typically makes at least 30 visits in the first year.[2,3,4,5] In the recent British Journal of Cardiology editorial, Dr. Lamas offered yet another estimate, 3-4 times the likely reality, on the basis of a survey that had warned that its chelation estimate did "not meet [the] standard of reliability or precision[321]" -- a point that Dr. Lamas failed to mention. Intentional or not, such obscurities have nurtured the myth of "widespread use," a chief rationale for the TACT.

Against all prior experience, Dr. Lamas initially declared that a large chelation trial would "lead to changes in clinical practice.[29]" Later the TACT protocols retreated from that position, but not so much that a naive reader might have suspected the truth: "a...result upon which rational clinical decision-making and health policy can be based[4]" [emphasis added]. By the time he wrote his American Heart Journal editorial, Dr. Lamas should have known enough to predict that no amount of scientific evidence would be likely to change chelationists' claims. The NHLBI Scientific Review Committee[169] had correctly made that observation just prior to the publications of the PATCH reports,[27,28] even though the committee lacked Dr. Lamas' advantage of having spent more than a year collaborating with chelationists and, ostensibly, researching chelation literature.[4]

TACT literature has repeatedly conflated Na2EDTA and the safer CaEDTA, as typified by the false assertion that "EDTA...is approved by the U.S. Food and Drug Administration (FDA) for use in treating lead poisoning and toxicity from other heavy metals.[2]" More misrepresentations include the citations of several articles by a chelationist who had previously admitted under oath to having falsified his data[44]; failure to cite 2 substudies of the Danish RCT, one reporting evidence of bone loss[23] and the other demonstrating discrepancies between outcomes reported by academic researchers and those reported by chelationists[24]; the unexplained absence, in the 2003 protocol, of the "markers of oxidative stress" TACT substudy that had been stipulated by the RFA and included in the 2001 protocol[1,4]; and the failure to cite several biochemistry articles that reported pro-oxidant effects of EDTA and vitamin C.

Chelationists constitute a tiny, fringe group of practitioners who encourage a tinier fraction of the population to buy chelation and other dubious treatments, and to eschew established therapies. Their history is replete with pseudoscientific and unethical practices; it is also replete with regulatory and criminal investigations and sanctions, some involving TACT co-investigators even since the trial began.[200,201] TACT literature gives not the slightest hint of that sordid history: Only 3 years after the FTC had cited the ACAM for falsely advertising chelation, the prestigious NIH endorsed it as "the world's...most respected organization of physicians who employ chelation therapy.[4,163]" Only a year after the FDA had exposed the GLACM IRB as a ruse to shield quackery from the law, the NIH approved the TACT's description of its members as "prominent experts.[4,140,141]"

The TACT consent form reflects much of this misleading language.[6] It blurs the distinction between the 2 EDTA salts: It neglects to mention that the EDTA used for lead poisoning is typically infused in the hospital with continuous monitoring and nursing care, whereas the EDTA used in the TACT is both inherently more dangerous and is administered in a more dangerous way. The form omits the relevant scientific and social background of chelation. It lacks an honest appraisal of the prior evidence. It omits several reported risks. Its straight-faced reference to "a standard intravenous mixture established by the American College for Advancement in Medicine" suggests, to the unsuspecting subject, a promising investigational treatment endorsed by a professional organization comparable in legitimacy to the American College of Cardiology.

All in all, such misrepresentations have served to submit 2000 unwary subjects and $30 million of public money to an unethical trial of a dubious treatment that, had it been accurately represented and judged by the usual criteria, would certainly have been disqualified again.

Even if the TACT is completed, which it should not be, it is unlikely to reduce the promotion of reckless uses of Na2EDTA. Whatever the outcome, chelationists have already positioned themselves to continue the practice: By virtue of ridding the body of toxic heavy metals, they claim, chelation is useful for more than 70 conditions. Without exception, chelationists have refused to accept previous results that contradict their beliefs.[57,152,153,154,155,156,157,158,159,160,161,162] Their response to the TACT, should it yield definitive, negative results, is unlikely to be different.

The trial, moreover, is unlikely to yield "an informative negative result[49]" even though chelation is almost certainly ineffective for CAD. It is more likely to yield ambiguous results. There are multiple endpoints, including subjective quality-of-life measures, and several subgroup analyses.[4,5] The variety of trial settings increases the likelihood of heterogeneity of procedures and reporting. Promotions of chelation by TACT co-investigators have already introduced unacceptable bias into the trial.[7] There is ample, additional opportunity for mischief, and ample reason to think that several co-investigators are inclined to make it.[7] The statistical analyses will not be Bayesian.[322,323,324]

Thus, merely on the basis of chance and bias, it is likely that some outcome data in some subgroups will differ sufficiently, between those receiving Na2EDTA and those receiving placebo, to reassure chelationists that chelation "works" and to sustain "lingering questions of efficacy[29]" in the minds of apologists. Dr. Lamas himself has made much of 2 or 3 "tantalizing positive secondary outcomes[29]" of a previous trial in which only 15 subjects received Na2EDTA, and in which the remaining 30 secondary outcomes and all 7 primary outcomes were unequivocally negative.[25] The all-but-inevitable "tantalizing positive secondary outcomes" of the TACT would likely lead to years of additional, unnecessary trials or, at the very least, unremitting peddling of chelation by practitioners armed with fresh fodder in their perpetual battle against rational standards of care.

The NIH has hired nearly 100 unqualified co-investigators to care for nearly 2000 unsuspecting subjects.[7] In announcing the TACT, the late NCCAM Director Stephen Straus tacitly acknowledged that such soon-to-be co-investigators had been pushing chelation "in lieu of established treatments.[2]" The TACT consent form warns subjects to "continue to use proven standard medicines for heart attack patients,[6]" but the Declaration of Helsinki expects better:

Medical research involving human subjects should be conducted only by scientifically qualified persons and under the supervision of a clinically competent medical person. The responsibility for the human subject must always rest with a medically qualified person and never rest on the subject of the research, even though the subject has given consent.[176]

It is the obligation of investigators to provide reasonable predictions of efficacy and assurances of safety, on the basis of all "relevant sources of information,[176]" prior to exposing human subjects to a phase 3 trial. The TACT investigators did not do that.

Most medical journals now subscribe to the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, established by the International Committee of Medical Journal Editors.[325,326] Because the Uniform Requirements include honoring the Helsinki Declaration, it appears that any report emanating from the TACT could not be published in one of the subscribing journals.

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