They don't call it "cheat-lation" for nothing

Regular readers here are probably most familiar with the so-called "complementary and alternative medicine" therapy known as chelation therapy in the context of its use, or, more specifically, its misuse in "treating" autistic children, a misuse that has resulted in at least one death, a five-year-old autistic boy named Abubakar Tariq Nadama. However, before the profit potential of chelating nonexistent mercury in autistic children was even a gleam in Dr. Roy Kerry's eye, there was another equally dubious use of chelation therapy: to treat atherosclerotic coronary artery and peripheral vascular disease, a "therapy" that is, alas, still very much alive and well today.

While the rationale for chelation therapy for autism was based on the highly dubious belief that it would eliminate mercury from vaccines that supposedly caused autism, the rationale for chelation therapy for vascular disease was based on a contention that on first glance seems not nearly as ridiculous. There is a proper use for chelation therapy, and that is to eliminate heavy metals in the case of acute, documented heavy metal toxicity. However, this is not what we're talking about. However, the original rationale of chelationists did sort of make sense superficially. Basically, because there is often calcium in advanced atherosclerotic plaques, it was speculated, perhaps using chelation therapy to "pull out" the extra calcium would allow soften the "hardening" of the arteries associated with those calcium deposits and decrease the blockage. For a number of reasons that I've explained before, this simplistic view just doesn't hold up to science. For one thing, most atherosclerotic plaques don't contain calcium. That's a very late development in a mature plaque that's been there for a while. It's quite possible to die from an acute blockage of an artery causing a heart attack or a stroke without a bit of detectable calcium being there. Of course, like all "alternative" therapies, as soon as one rationale is pounded down by science, advocates pop up with another one, like an altie version of Whac-A-Mole. For chelation therapy, these rationales, tortured as they may be, included increased parathyroid hormone secretion, decreased free radicals, or, believe it or not, increased production of NO. (Given the affinity one of the regular commenters has for this molecule, I almost shudder to mention this last speculation.)

The story of chelation therapy followed a frequent script in that some case series from four or five decades ago studying it looked promising, but more recent randomized clinical trials in the 1990s showed it to be no more effective than a placebo in the relief of symptoms of angina or claudication. Furthermore, no study has ever shown objective evidence that chelation therapy decreases the volume of obstructing atherosclerotic plaques, an important functional correlate to test its claim that it improves blood flow. Of course, in this parallel universe of altieland, where scientific evidence and well-designed clinical trials showing no efficacy better than a placebo mean nothing compared to testimonials can't stop chelation therapy from rising again and again to feast on the dollars of the credulous. Such a situation can, of course, lead to only one thing. That's right, a multimillion dollar "clinical trial" sponsored by the National Center for Complementary and Alternative Medicine (NCCAM).

Subscribers to Medscape can now read a detailed history of how this boondoggle came to be written by Kimball C. Atwood IV, MD; Elizabeth Woeckner, AB, MA; Robert S. Baratz, MD, DDS, PhD; and Wallace I. Sampson, MD, entitled Why the NIH Trial to Assess Chelation Therapy (TACT) Should Be Abandoned. Those who have a subscription to Medscape should read the entire nine-page article (and, of course, also read this for my peerless prose and scintillating commentary). Those who do not can register for free to have access to the article, and I encourage you to do so. For those who do not wish to register with Medscape, I will try to summarize, along with judicious excerpts, the reasons why this $30 million dollar clinical trial is almost certainly an utter waste of taxpayer money that will resolve nothing in terms of demonstrating or disproving any efficacy from chelation therapy.

The article is truly disturbing.

First, a bit about the study:

The National Institutes of Health (NIH) is sponsoring a $30 million, 5-year, phase 3 Trial to Assess Chelation Therapy (TACT) for coronary artery disease (CAD). It was begun in 2003, but after 3 years only half of the planned 2000 subjects had been recruited. The trial involves the intravenous (IV) administration of the chelating agent disodium ethylene-diamine-tetra-acetic acid (EDTA), for which there was a brief enthusiasm among academics during the 1950s. That enthusiasm ended abruptly in 1963 with the publication of a disconfirming case series. Nevertheless, a tiny but strident group of physicians has continued to administer IV "chelation therapy" in their offices, claiming that it dramatically improves symptoms and prolongs life in 80% to 90% of patients with CAD or peripheral vascular disease (PVD). Chelationists also prescribe high doses of both IV and oral vitamin and mineral "supplements," asserting that these are necessary additions to the regimen. Unless otherwise stated, in this article "chelation" refers to IV infusions of disodium EDTA given with such supplements.

In response to chelationists' claims, between 1990 and 2001 academics conducted a series of randomized controlled trials (RCTs), studying a total of nearly 300 subjects. They found no evidence that chelation is superior to placebo for the treatment of CAD or PVD. Chelationists repudiated each of these studies.

For any other "conventional" medical therapy, the same number and quality of randomized studies showing a lack of efficacy would be its death knell, more than enough to shut down most further investigations. Certainly, no "conventional" therapy would win a $30 million grant from the NIH to be studied based on such data. Indeed, if chelation therapy were a "big pharma" treatment, chances are very good that the pharmaceutical company making the drug would have already cut its losses--at least, if it had to pay for the clinical trial. Once again, in the brave new world of "integrative medicine" and NCCAM, neither biological plausibility, lack of preclinical evidence, nor good evidence from clinical trials that a therapy is no better than placebo lops off enough limbs of the hypothesis that a chelation therapy improves symptoms and outcomes in coronary artery and peripheral vascular disease to deter true believers from forging onward, just like the Black Knight in Monty Python and the Holy Grail tried to do. They always find a way to discount the studies. They even find a way to use a drug that is familiar to readers here:

The primary substance used in the trial is the IV chelating agent disodium EDTA (edetate disodium; edathamil disodium; Na2EDTA [Endrate]). A potent chelator of cations, especially calcium, it is FDA-approved only for rapid, emergency treatments of hypercalcemia or digitalis toxicity, and for those indications it has long been obsolete. Na2EDTA is specifically contraindicated for "generalized arteriosclerosis." Its labeling includes a "black box" warning: "The use of this drug in any particular patient is recommended only when the severity of the clinical condition justifies the aggressive measures associated with this type of therapy." Several deaths have been associated with unapproved uses of the drug by ACAM members.

Yes, it's the same drug that Dr. Roy Kerry.

But how did such a crappy study ever come to be, much less be funded by the NIH to the tune of $30 million? The answer, not surprisingly, involves one of the foremost promoters of quackery in the federal government, Representative Dan Burton (R-IN).

In March 1999, ACAM presidents L. Terry Chappell and Ted Rozema shilled for chelation at a hearing of the House Committee on Government Reform, chaired by a powerful "health freedom" ally and veteran of the Laetrile wars, Rep. Dan Burton (R-IN). NHLBI Director Claude Lenfant, whom Burton had summoned, was present. Burton criticized the NHLBI for "never funding any research into chelation therapy"; he criticized the National Library of Medicine for not listing the Journal of Advancement in Medicine on MEDLINE; he criticized the FTC for "launch[ing] an attack on the free flow of information from a non-profit professional medical association."

Burton scolded Director Lenfant for his institute's "bias" against chelation and other "alternative" methods and declared that he, Burton, would personally bring the purportedly large number of applications for chelation research "right to your office and lay them on your desk." Dr. Lenfant replied that there had been only 1 proposal to the NHLBI for a clinical study of chelation in the previous 30 years.

Initially, the NIH resisted, concluding that there was an insufficient scientific basis to justify such as study and that it was too expensive. However, Burton is powerful and responsible for a whole lot of woo being funded by the federal government, not to mention promotion of Ron Paul-style "health freedom" legislation. Eventually he prevailed, and TACT was born. Not only that, but the trial was to be run by ACAM a group dedicated to "alternative" therapies, particularly chelation therapy, an offspring of which is the American Association for Health Freedom, as described:

On April 30, 2001, the NCCAM and the NHLBI jointly issued a Request for Applications (RFA) for a $30 million, "multi-site, randomized, double-blinded, placebo-controlled trial investigating the efficacy and safety of EDTA (ethylene diamine tetra-acetic acid) chelation therapy in individuals suffering from Coronary Artery Disease." The ACAM's influence was explicit: "It is expected that the trial will investigate the EDTA Chelation treatment protocol recommended by ACAM." It was also implicit: "Common conventional medical treatments for CAD include percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft (CABG) surgery, procedures that are invasive and costly." There was no mention of statins, aspirin, angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, nitrates, antihypertensives, smoking cessation, diet, exercise, or other common "conventional" medical treatments for CAD.

The RFA cited several articles by Edward McDonagh, the chelationist who had previously admitted in a court of law to having falsified his data.[44] The 2001 and 2003 TACT protocols contain at least 5 more references to studies by McDonagh, including one purporting to show that chelation is not nephrotoxic and another purporting to show that it does not cause bone loss. The protocols misrepresent a large part of the rest of the chelation literature, as we discuss in Parts III and IV.

In August 2002, the NCCAM announced the TACT award, naming Dr. Lamas as PI. Director Straus, citing "the widespread use of chelation therapy in lieu of established therapies [and] the lack of adequate prior research to verify its safety and effectiveness...," declared that "The public health imperative to undertake a definitive study of chelation therapy is clear."

What drives me crazy about this study is that it violates the usual order of development of a therapy. Come to think of it, that's what drives me crazy about most clinical trials of "CAM" studies. There's no preclinical data to support a trial. No clinical trial of a pharmaceutical company's product would never, ever--ever--be allowed to bypass the preclinical stage, yet that happens with many "CAM" studies. The usual order of investigations of a proposed treatment is as follows: (1) in vitro studies (cell culture, etc.); (2) animal studies; (3) phase I clinical trials in humans; (4) phase II trials; (5) phase III trials. Steps 1 and 2 are known as the "preclinical" phase; everything after is the clinical trial phase. After the step of in vitro studies, each subsequent step is contingent upon the previous one's having demonstrated safety--at the very least. Furthermore, before therapies can progress from preclinical to clinical, there should be evidence of efficacy in animal trials, and before large phase III studies are done, phase II studies should demonstrate efficacy against the disease against which the new therapy is being tested. True, one can sometimes justify bypassing, for instance, phase II trials in the case of a phase I trial that shows compelling evidence of efficacy, given that phase I trials aren't designed to show efficacy, but it's really, really hard to imagine a situation in which it is justifiable to bypass preclinical studies. Yet TACT (and most "CAM" studies) flip this sequence upside down and dispense with the preclinical evidence that provides evidence for scientific plausibility and activity in a non-human vertebrate animal. As noted by Atwood et al, this sequence is also considered part and parcel of practicing ethical human subjects experimentation and is stipulated in full or part by pertinent treatises, including the Helsinki Declaration, the US Code of Federal Regulations, and the NCCAM's own policies.

Not surprisingly, the design of this trial was highly suspect. Not only was the protocol itself scientifically implausible, a mix of disodium EDTA and a bunch of supplements, as well as procaine and heparin added for unclear reasons. it is placebo-controlled, but the protocol stipulates that the chelation solution must be mixed on site, allowing ample opportunity for investigators to break blinding, either purposely or even inadvertently. Another questionable aspect of the trial is that it specifies so many endpoints to be measured and subgroup analyses to be done that, unless the statistics are rigorous, one or more are likely to turn up positive just by chance alone. Worse still, many of the sites at which this trial will be carried out are clinics where chelationists practice their woo. Indeed, Dr. RW did a little tour of these sites in 2006, and many of them are clinics of serious woo (1, 2, 3, 4, 5, 6). After reading Dr. RW and Atwood et al, I can only conclude that the reason for such an incompetent design is because the investigators are incompetent (arguably true) or ideologues (definitely true for several of them at least), or both. (Guess which option I take; that's right, the last.) In any case, the way this study is currently designed, it's clear that it will not be adequately powered to evaluate many of its endpoints and it's likely to produce false positives. Even if the study is completely negative, chelationists will simply ignore it, as CAM advocates nearly always do when reality conflicts with woo.

Worse, it turns out that this trial was dubious from the very start not just from a scientific standpoint but from an ethical standpoint as well. Not only is it testing a drug that has an unfavorable risk-benefit profile, one that's only indicated for very specific and uncommon clinical situations, instead of the safer calcium salt of EDTA, but a strong argument is made in this article that the risk/benefit ratio was misrepresented on the consent form, calling into question the very ethical basis of this trial. In essence, it is argued that the "positive" case series are presented to patients (and were presented to the Institutional Review Board) in a far more favorable light than the science and clinical trials would demand. The case series included as support were invariably done by advocates and poorly designed. Worse, some investigators are using dubious tactics to advertise for patients:

As previously stated, about 70 of 80 identifiable TACT chelation practice Web sites promote chelation. Some reproduce, verbatim, several of the statements that the FTC cited as false in its complaint against the ACAM in 1998. One such site, the Wellness and Longevity Center of Louisiana, is owned by Sangeeta Shah, listed by the ACAM as a member of its Board of Directors, a member of the TACT Liaison Committee, and a member of the ACAM Marketing/Public Relations committee.

Such postings introduce bias into the trial and are contrary to Federal Regulations that prohibit investigators from promoting investigational new drugs; the postings may also constitute "misbranding" of Na2EDTA, for which there is a precedent involving "chelation pioneer" H. Ray Evers. The same co-investigators appear to be selling chelation infusions outside of the context of the TACT, which, if true, is also contrary to Federal Regulations.[224] Such practices call attention to language in the TACT RFA requiring that "all trial sites have routine...audits to monitor for...non-compliance with...regulatory requirements...." We wonder whether TACT auditors have informed the FDA of these apparent violations of regulatory requirements.

In 2006, TACT chelationist Co-Investigator Rajiv Chandra advertised for subjects in a semiannual report of the Parrish Medical Center in Titusville, Florida:

If you participate in this study, you will receive 28 months of treatment, and be asked to participate in up to 32 months of follow-up. You will not be charged for participating in this exciting study and will receive the study drug and vitamin and mineral supplements.

Is Dr. Chandra giving the "study drug" to all of his TACT subjects, contrary to protocol, or is he merely making that promise as a recruitment ploy?

Either way, it's highly unethical, as is the consent form for the trial, which, as Atwood et al put it:

...fails to state that a plausible scientific rationale for the treatment is lacking. It fails to state that no body of basic science or animal studies supports the treatment. It does not state that formal phase 1 studies -- the standard means by which the safety of a drug is investigated -- have not been done. It does not state that the only controlled clinical studies so far -- totaling 285 patients -- have found no evidence for efficacy. It does not state that conducting a phase 3 study of a method with that background is highly irregular and is contrary to formal language in human studies treatises, in US Federal Code, and in the NCCAM's own literature.

The consent form does not state that the preponderance of current opinion within the field of cardiovascular disease is that chelation is an ineffective treatment for CAD. The AHA, for example, has written: "According to qualified scientists who are familiar with research in heart disease, there's only a very small chance that chelation therapy will work.[232]" The AHA, furthermore, would support a human trial only if a preliminary study were to demonstrate that EDTA could safely and effectively "dissolve" atherosclerotic plaques.[232]

There's so much more wrong with the consent form, including that even the case studies touted chelationists as evidence of its efficacy for cardiovascular disease are not particularly compelling when looked at with a critical eye, as Atwood et al describe in excruciating detail for virtually every major case series done since the 1950s. It was also shown that there were far more deaths in these trials than is commonly admitted by chelationists and how many of these studies were poorly designed and done without any controls. There's also the risk of renal failure, which tends to be underestimated.

Reading this masterful (and long--I mean longer than Orac long) article, I became more and more incensed. How on earth, in this era of flat NIH budgets, that, when adjusted for inflation, are actually declining, could such an unethical trial testing a scientifically implausible and dubious hypothesis have been funded to the tune of $30 million? Atwood et al have an idea:

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? The evidence suggests that the NIH solicited the trial only after extraordinary pressure from a powerful congressman and from the ACAM lobby. 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.

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), 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 -- 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, and past ABCMT Chairman Robert Nash on the DSMB. Each of these appointments violated formal NIH policies.

A more blatant example of what happens when pseudoscience is promoted by powerful legislators and finds its way into the NIH you'd be hard pressed to find. Worse, as I mentioned before, for the reasons described above TACT is unlikely to produce a concrete result that would at least let those of us of a science- and evidence-based mindset point to its results as strong evidence that chelation therapy doesn't work for vascular disease. For one thing, it's being run by chelationists, all of whom make lots and lots of money administering chelation ($100 to $150 a dose, usually for 30 to 40 doses) and all of whom thus have a strong financial incentive to produce a positive result. Indeed, the double standard of CAM advocates amazes me. If big pharma ran a trial this inept, this unethical, and this riddled with blatant conflicts of interest, you can bet that CAM advocates would be screaming to high heaven about it--and rightly so. I'd be screaming about it too. This trial, on the other hand, is just hunky dory because it's done for an "alternative" therapy, upon which it bestows an undeserved patina of scientific credibility.

As I go to my office and lab this morning, to try to do high quality scientific research based on good science designed to improve our understanding of cancer and hopefully lead to more effective therapies, it galls me to no end to see the equivalent of 15-20 R01 grants going to fund this woo. Worse, it's TACT is not the only example of an unethical and scientifically worthless trial being funded not because the science is compelling but because powerful lobbies and legislators who are true believers in woo applied pressure to the NIH to do them. Indeed, if you want another example, albeit not nearly as damaging to the Treasury, read Dr. Atwood's account of the trial of Nicholas Gonzalez's pancreatic cancer protocol^{1, 2, 3, 4, 5, 6}, which subjected patients to a highly onerous and difficult to follow protocol of supplements and enemas while denying them effective palliative care, was funded based on lobbying and not compelling science or data, and whose results have never been published (and likely never will be published). But what galls me more is that thousands of patients are being subjected to unnecessary risk with minimal chance of receiving a commensurate benefit (or any benefit at all). It goes against everything the Common Rule is designed to prevent, but, it seems, human subjects protections are optional in clinical trials of "alternative" medicine.